| |
| | | | |
Photo by Giammarco Boscaro on Unsplash
Scroll for a plethora of ebooks related to historical research methods and theories. For full citations, click on the Word document at the bottom of the page.
The historical evolution and research trends of life cycle assessment, graphical abstract.
Total Downloads
Total Views and Downloads
People have relied on plant-based remedies for centuries, as botanicals play a crucial role in traditional medicine. Ancient civilizations across the globe, including China, India, and the Americas, turned to plants for their curative properties. These cultures had faith in the therapeutic potential of plants to address various health concerns, from digestive system issues to skin problems. In our time, researchers are trying to understand the potential of these plants to gain a deeper understanding of their advantages. Some contemporary medications even stem from plant extracts with a long history of use. Yet, ensuring the safety and effectiveness of these natural treatments presents challenges. Scientists need to create standard usage methods and guarantee high-quality products. We should learn from both historical and current practices when it comes to plant-based medicine. By merging age-old wisdom with cutting-edge research, we can discover innovative ways to harness plants for health benefits while honoring ancient healing customs. Scientists face a tough task when they study plants used in old-fashioned healing. They need to prove these plants work and are safe, but they also want to respect age-old wisdom. Researchers have started running careful tests to check if these plants do what traditional healers say they do. They're trying to find out what makes these plants tick how they work in the body, and how much people should take. For this to work traditional healers, scientists, and rule-makers need to team up. By mixing old knowledge with new science tricks, we can get a full picture of how plants might help keep us healthy. New ways to look at chemicals and genes have made it easier to spot and understand the good stuff in plants. This helps create plant extracts that always have the same amount of the helpful ingredients. Looking ahead, we need clear rules about growing, picking, and preparing healing plants to keep them good quality and make sure we don't run out. We also need to teach doctors and regular folks about these plant medicines - how they can help and how to use them. This way, we can fit these old remedies into our modern health care in a smart way. This Research Topic aims to explore the multifaceted role of botanicals in traditional medicine, encompassing both historical perspectives and modern scientific advancements. Contributors are encouraged to investigate themes such as the pharmacological properties of specific botanicals, their traditional uses across different cultures, and the integration of botanical medicine into contemporary healthcare practices. Manuscripts may include original research articles focusing on clinical trials, laboratory studies elucidating the biochemical mechanisms of botanicals, ethnobotanical surveys documenting traditional knowledge, and reviews synthesizing current understanding and future directions in botanical medicine. We welcome manuscripts that address challenges in quality control, sustainability, and regulatory considerations in the cultivation and utilization of medicinal plants. The goal is to foster a comprehensive dialogue that bridges traditional wisdom with evidence-based medicine, promoting informed decisions in healthcare and advancing the global understanding of botanicals' therapeutic potential.
Keywords : • Botanicals • Traditional medicine • Pharmacological properties • Ethnobotany • Integrative healthcare
Important Note : All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.
Topic coordinators, submission deadlines.
Manuscript Summary | |
Manuscript |
Manuscripts can be submitted to this Research Topic via the following journals:
No records found
total views article views downloads topic views
Top referring sites, about frontiers research topics.
With their unique mixes of varied contributions from Original Research to Review Articles, Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author.
Future Journal of Pharmaceutical Sciences volume 10 , Article number: 129 ( 2024 ) Cite this article
172 Accesses
Metrics details
Cancer is a persistent global health challenge, demanding continuous exploration of innovative therapeutic strategies. Hydroxytyrosol (HT), derived from olive oil, has garnered attention for its potent antioxidant and anti-inflammatory properties, revitalizing interest due to recent breakthroughs in comprehending its intricate anticancer mechanisms.
This review conducts a detailed analysis of hydroxytyrosol’s molecular mechanisms in cancer. Delve into the complex pathways and processes underlying its anticancer properties, including its impact on critical cellular events such as inhibiting cancer cell growth, proliferation, metastasis, and apoptosis. We meticulously evaluate HT efficacy and safety through scrutiny of preclinical and clinical studies. Additionally, we explore the potential synergistic effects of combining HT with conventional cancer therapies to improve treatment outcomes while reducing side effects, offering a comprehensive approach to cancer management.
This review stands as a valuable resource for researchers, clinicians, and policymakers, providing profound insights into HT potent anticancer activity at the molecular level. It underscores the immense potential of natural compounds in the intricate realm of cancer management and highlights the urgent need for further research to translate these discoveries into effective clinical applications. Ultimately, it fosters the development of targeted and personalized therapeutic approaches, reigniting hope in the ongoing battle against cancer and enhancing the quality of life for those afflicted by this relentless disease.
Cancer refers to a set of functional abilities that human cells acquire when they transition from regular developmental stages to abnormal growth states, more especially abilities that are essential for the development of aggressive tumors [ 1 ]. Worldwide, the prevalence of cancer diseases is constantly rising, resulting in millions of fatalities every year. According to the most recent projections, the worldwide cancer burden will rise significantly over the coming decades, rising by 47% by 2040 compared to the year 2020 [ 2 , 3 ]. Globally, about ten million cancer patients died in 2020 and 19 million cancer patients were newly diagnosed which is expected to increase in future [ 3 , 4 ]. In the USA, approximately 2,001,140 new cancer patients and 611,720 cancer deaths are projected to occur in 2024 [ 5 ]. Deaths of cancer patients continued to be decreased by 2021, preventing over 4 million mortality since 1991 due to reductions in smoking, earlier diagnosis of cancers, and enhanced better quality treatment in both the adjuvant and metastatic settings. However, the rates of cancer cases increased in period of 2015–2019 by 0.6–1% every year for pancreas, breast and uterine corpus cancers and by 2–3% every year for kidney, prostate, liver (female) and human papillomavirus-associated oral cancers [ 5 ]. Therefore, finding innovative cancer treatment approaches is crucial to decreasing patient suffering and the cost of the current cost-prohibitive treatments.
More and more scientists worldwide are attempting to find innovative anticancer drugs and develop new effective techniques to treat this terrible disease as a result of numerous flaws in conventional therapeutic formulations. The advancement of science has ushered in the creation of numerous treatments as well as diagnostic techniques that have played a pivotal role in managing and, to some extent, even curing various types of cancer. Approximately 70–95 percent of people in underdeveloped nations still utilize traditional medicines today. The vast majority of currently used chemotherapy medications with clinical approval was derived from numerous natural sources, including microorganisms and terrestrial and aquatic plants [ 6 ]. Natural compounds and their derivatives, with their diverse structures and favorable pharmacological properties, demonstrate remarkable potential for developing chemotherapeutic agents [ 7 ]. As a result of this early accomplishment, numerous research organizations worldwide are committed to isolating novel structural leads from various plant species and evaluating them for possible anticancer actions [ 8 ].
Hydroxytyrosol (HT) is one of these promising substances, being a primary phenolic compound found in virgin olive oil. Oxygen and nitrogen free radicals are scavenged by the potent antioxidant HT. Additionally, in neural hybridoma cells, HT guards DNA from oxidative damage by activating Nrf2, and HT promotes the expression of antioxidant enzyme [ 9 ]. It also displays analgesic and anti-inflammatory properties and inhibits the growth of colon and breast cancer cells by regulating gene expression, resulting in pro-apoptotic effects [ 10 , 11 , 12 , 13 , 14 ].
While the precise mechanism of HT’s impact on cancer cells remains unclear, it may involve reduced Pin1 levels causing cyclin D1 to translocate to the cytoplasm, leading to its degradation. Cyclin D1 plays a vital role in driving the G1/S cell cycle transition, promoting the proliferation of tumor cells [ 15 ]. Pin1 is a peptidyl-prolyl cis/trans isomerase enzyme that plays a crucial role in the regulation of cell cycle progression. Pin1 specifically recognizes and binds to phosphorylated serine or threonine residues preceding proline in its substrate proteins. It has been implicated in the regulation of cyclin D1 stability [ 16 ]. The interaction between Pin1 and cyclin D1 has been shown to influence the subcellular localization of cyclin D1. Reduced levels of peptidyl-prolyl cis–trans isomerase NIMA-interacting 1 (Pin1) can disrupt the normal regulation of cyclin D1, leading to its translocation to the cytoplasm. In the cytoplasm, cyclin D1 is subjected to ubiquitin-mediated degradation, preventing its accumulation and promoting cell cycle arrest [ 17 ].
Furthermore, HT has shown protective properties against breast cancer development, safeguarding DNA in normal breast cells in vitro. Earlier research has shown its antioxidant, hypoglycemic, anti-thrombotic, hypocholesterolemic, anti-inflammatory, and antibacterial properties. Furthermore, hydroxytyrosol has demonstrated its ability to shield human erythrocytes from oxidative damage, promote eye health, modulate the immune system, and reduce the risk of atherosclerosis and coronary heart disease. It is also regarded as a crucial anticancer substance [ 12 , 18 , 19 ]. Many research studies have demonstrated that hydroxytyrosol exhibits both anti-inflammatory and antioxidant characteristics. Furthermore, it hinders the proliferation of various tumor cell lines by stimulating molecular signaling pathways that induce apoptosis and cell cycle arrest [ 20 , 21 ]. The growth of pancreatic cancer cells has also been inhibited by this substance in a dose-dependent manner [ 22 ]. With a focus on plant by-products, we sought to study the most significant and promising studies relating to novel chemical hydroxytyrosol derived from natural products with anticarcinogenic potential.
A systematic literature search was carried out on PubMed, Web of Science, Scopus, Embase, and Google Scholar databases to identify original articles on the biological activities of primary olive oil phenols. The search utilized keywords such as hydroxytyrosol, tyrosol, oleuropein, oleocanthal, oleacein, olive oil phenols, along with terms like antioxidant, anti-inflammatory, cardioprotective, neuroprotective, osteoprotective, anticancer, antidiabetic, antiobesity, antimicrobial, metabolism, and bioavailability. The extensive literature gathered was then manually curated to ensure its relevance to the subject. This curation included both emerging insights and well-established findings. Additionally, literature dated prior to 2010 was included when deemed relevant to the topic.
Hydroxytyrosol is a colorless solid organic compound, chemically represented as (HO) 2 C 6 H 3 CH 2 CH 2 OH, and it belongs to the group of phenolic phytochemicals. It is commonly found in olive fruit and oils, often in the form of esters with the secoiridoid elenolic acid [ 23 , 24 ]. The hydroxytyrosol derivatives are obtained as by-products from olive trees and their leaves during the olive oil manufacturing process [ 25 ]. The synthesis of hydroxytyrosol occurs in single-step reaction from tyrosols. When the conversion of tyrosine into 3,4-dihydroxyphenylalanine (DOPA) happens that could lead to the synthesis of hydroxytyrosol. Hydroxytyrosol is readily soluble in organic solvents, while it exhibits only slight solubility in water, typically around 10 mg/mL, at room temperature [ 26 ]. The partitioning coefficients of hydroxytyrosol in between oil and water phases were found to be 0.010 [ 27 ]. The diverse biological properties of hydroxytyrosol stem from its potent antioxidant and radical-scavenging attributes. Its effectiveness is also influenced by the presence of an ortho-dihydroxy conformation in the aromatic ring, which is akin to catechol [ 28 ]. Moreover, hydroxytyrosol has demonstrated the ability to enhance endothelial function, reduce oxidative stress, provide neuro- and cardio-protection, positively affect lipid and hemostatic profiles, and exhibit anti-inflammatory properties [ 29 ] (Fig. 1 ).
Structure of hydroxytyrosol
Hydroxytyrosol is found in both olive leaves and fruits, which belong to the Oleaceae family. It serves as a significant component of olive leaf extract, olive mill wastewater, and virgin olive oil. Notably, it is regarded as having the highest in vitro antioxidant potential among all the polyphenols in olive oil [ 10 ]. It is stable in its free form and readily get penetrated into tissues [ 30 ]. In olive fruits or olive oil, tyrosol and hydroxytyrosol are considered to be an important dietary phenolic component. They are well known for their scavenging attribute and either can be found in ester form of secoiridoid elenolic acid or in free form [ 27 , 31 ]. Both hydroxytyrosol and tyrosol are natural compounds known for their diverse pharmacological properties. They demonstrate a wide array of effects, including anti-inflammatory, antioxidant, anti-genotoxic, anti-hyperglycemic, anti-depressant, anticancer, neuroprotective, and anti-atherogenic properties, among others (Fig. 2 ). They also prevent keratinocytes apoptosis induced by radiation, mitochondrial dysfunction induced by acrylamide and acrolein-induced deoxyribonucleic acid (DNA) damaged, etc. [ 19 , 31 , 32 , 33 , 34 , 35 , 36 ]. Hydroxytyrosol can be obtained from fat’s main source in Mediterranean diet. The Mediterranean diet, originating in olive-growing regions in the Mediterranean Basin in the 1960s, emphasizes plant-based foods with a primary focus on various fats, predominantly sourced from olive oil. This dietary pattern leads to a significant consumption of mono-unsaturated and polyunsaturated fats while minimizing the intake of saturated fats [ 37 ]. Hydroxytyrosol is the sole polyphenol in the market with an authorized health claim, approved by the European Food Safety Authority [ 37 , 38 ]. The Mediterranean diet primarily comprises fruits, vegetables, and olive oil as its main components. In Mediterranean nations, despite a relatively high fat intake, the prevalence of cardiovascular disease is significantly lower compared to countries like the USA, where fat consumption is also relatively high. The European Commission has established a scientific panel on dietetic products, nutrition, and allergies as a division under the jurisdiction of the European Food Safety Authority. This panel assesses hydroxytyrosol as a novel product, deeming it safe for the public while excluding children under the age of three and pregnant or nursing women. This assessment aligns with the standards set for novel food constituents, as outlined in Article 3(1) of Regulation (EC) 258/97. EFSA has evaluated hydroxytyrosol as safe for human consumption as a new food, establishing a daily limit for potential adverse effects at 50 mg/kg of body weight [ 39 ]. In the USA, a dosage of 5 mg of hydroxytyrosol per serving is considered safe for its inclusion in processed foods [ 40 ]. An accepted daily safe dosage for adults is 800 mg, and this compound contributes significantly to the health benefits associated with extra virgin olive oil [ 41 ]. Bioavailability studies indicate that hydroxytyrosol from olive oil is effectively absorbed after ingestion and demonstrates significant biological effects that are dependent on the dose [ 42 ]. Olives provide natural antioxidants that protect against oxidative stress, a factor linked to diseases such as coronary heart disease, cancer, and neurological disorders.
Ethnopharmacological properties of hydroxytyrosol
Preclinical and clinical studies have indicated that hydroxytyrosol is absorbed in the colon and small intestine, following a dose-dependent pattern [ 43 , 44 ]. Transport through intestinal epithelium occurs via passive bidirectional diffusion. The absorption of hydroxytyrosol depends upon the nature of the vehicle it is carried in. A study found that rats absorbed 99% of hydroxytyrosol in olive oil, compared to 75% in an aqueous solution [ 45 ]. Also, the rate of absorption varies depending on the type of animal. For example, rats absorb at a rate that is different from that of humans since rats lack a gallbladder [ 46 ]. Tissue distribution studies in rats, conducted after intravenous administration of radioactive hydroxytyrosol, showed a short half-life in the blood (1–2 min), with the majority accumulating in the kidneys just 5-min post-injection [ 47 ]. Further, hydroxytyrosol is also widely distributed in different organs including the liver, lungs, skeletal muscle, and heart (Fig. 3 ). It easily crosses the blood–brain barrier and enters the brain. Additionally, it can also be synthesized endogenously from dihydroxyphenylacetic acid by dihydroxyphenylacetic acid reductase, an enzyme present in the brain [ 48 ] . It undergoes initial metabolic processes in enterocytes and subsequently in the liver . These stages are vital as hydroxytyrosol undergoes various transformations and modifications, which are believed to contribute to its therapeutic properties [ 49 ]. Three metabolic pathways have been proposed for hydroxytyrosol: (1) Oxidation, which is carried by enzymes aldehyde dehydrogenase and alcohol dehydrogenase, rendering dihydroxyphenylacetic acid (2) Methylation, which is carried by the enzyme catechol-O-methyltransferase, giving rise to dihydroxyphenylacetic acid, and (3) Methylation-Oxidation, which results to homovanillic acid [ 47 ]. Indeed, the primary metabolites of hydroxytyrosol encompass aldehydes, O-methylated forms, and acids, which are created through the oxidation of glucuronide, sulfates, aliphatic alcohol, as well as N-acetylcysteine and sulfated derivatives [ 44 ]. In rats, it takes around 5 h; in humans, it takes around 4 h for hydroxytyrosol and its metabolites to be discharged from the urine [ 43 ]. Similar to absorption, the elimination of hydroxytyrosol and its metabolites varies depending on the method of administration used for the compound. A study revealed that the elimination of hydroxytyrosol through urine is higher when it is administered as a natural component of olive oil compared to its external administration in low-fat yogurt or refined olive oil [ 46 ]. Absorption and urinary excretion of hydroxytyrosol and its metabolites differ between rats and humans, with both processes being lower in rats compared to humans. Therefore, these findings indicate that rats may not be a suitable model for studying hydroxytyrosol metabolism.
Absorption and disposition of hydroxytyrosol in humans
Pharmacokinetics primarily involves the kinetic study of a compound’s absorption, distribution, metabolism, and excretion in biofluids, tissues, and organs over a specific time period [ 50 ]. Understanding the pharmacokinetics of hydroxytyrosol is essential for optimizing its therapeutic potential and ensuring its safe and effective use. While there is limited research specifically focusing on the pharmacokinetics of hydroxytyrosol, some reports have shed light on its absorption and metabolism. When hydroxytyrosol is orally administered, whether with olive or an aqueous supplement, it is absorbed through the intestine and undergoes rapid metabolism involving both phase-I and phase-II metabolic reactions. Hydroxytyrosol metabolites were undetectable in fasting state plasma but quickly cleared during the postprandial phase and excreted in urine. The maximum concentration (Cmax) is reached within 30 min, and clearance occurs within 2–4 h [ 51 ]. In a preclinical study, hydroxytyrosol was found absent in the brains and cerebrospinal fluid of normal animals but crossed the blood–brain barrier in mice experiencing chronic unpredictable mild stress (CUMS). This suggests that hydroxytyrosol’s beneficial effects primarily target the hippocampus, as it is distributed there due to BBB impairments in stressed mice after oral administration [ 52 ]. Metabolism of hydroxytyrosol primarily occurs in the liver. Studies using in vitro models have identified several metabolic pathways for hydroxytyrosol including glucuronidation and sulfation. These conjugation reactions facilitate the excretion of hydroxytyrosol from the body. The unchanged hydroxytyrosol (free form) is almost undetectable in urine and plasma samples by oral route than intraperitoneal. Food matrix significantly affects the absorption and metabolism of hydroxytyrosol, with extra virgin olive oil recognized as the most effective matrix for improving its bioavailability [ 51 ]. Hydroxytyrosol primarily metabolizes into HVA, DOPAC, and HT-3-S, and these metabolites can be detected in plasma samples from food supplements shortly after ingestion. Among these, DOPAC and HVA reach their peak plasma concentrations approximately 30 min after ingestion. Notably, DOPAC exhibits lower concentrations and faster elimination compared to HVA, largely due to its enzymatic conversion into HVA through the action of catechol methyltransferase enzyme [ 41 , 53 ]. The pharmacokinetics of hydroxytyrosol are subject to influence by several factors, including the administered dose, co-administration with food, and individual variations in metabolism. Finding from the literature regarding pharmacokinetics concluded that hydroxytyrosol showed rapid absorption, hepatic metabolism, and elimination through conjugation reactions. Further research is required to obtain a comprehensive understanding of the complete pharmacokinetic profile of hydroxytyrosol, with a particular focus on its distribution and excretion pathways. Nonetheless, the existing research provides valuable insights into the absorption and metabolism of hydroxytyrosol, which contribute to its potential therapeutic applications.
Hydroxytyrosol demonstrates a multifaceted approach in targeting cellular components relevant to cancer development and progression. Research has demonstrated hydroxytyrosol’s ability to interact with multiple critical molecular targets, making it a good candidate for cancer therapy [ 54 , 55 , 56 ].
Hydroxytyrosol notably focuses on regulating oxidative stress within cells. Hydroxytyrosol, as a strong antioxidant, counters reactive oxygen species (ROS) known to stimulate cancer growth and harm cellular components. By mitigating oxidative stress, hydroxytyrosol helps maintain cellular homeostasis and reduces the risk of cancer initiation (Fig. 4 ) [ 57 ].
Hydroxytyrosol targeting oxidative stress, inflammation, PI3K/Akt/mTOR and MAPK pathways in cancer cells
Hydroxytyrosol also plays a crucial role in modulating inflammatory pathways. Chronic inflammation significantly contributes to the promotion of cancer development and metastasis [ 58 ]. Hydroxytyrosol’s anti-inflammatory properties help suppress pro-inflammatory signaling molecules, thereby curbing cancer-promoting processes and reducing the tumor microenvironment’s pro-tumorigenic effects [ 59 , 60 , 61 ]. Hydroxytyrosol has also shown promise in regulating cell cycle progression. It can induce cell cycle arrest, halting uncontrolled cell proliferation, a hallmark of cancer cells. Its impact on the cell cycle inhibits cancer cell growth and promotes their elimination through apoptosis [ 22 , 59 , 60 , 62 ]. Furthermore, hydroxytyrosol has been found to target specific signaling pathways crucial for cancer survival and invasion. It can modulate various kinases, such as PI3K/AKT and MAPK (Fig. 4 ), which play key roles in cancer cell survival and metastasis [ 62 , 63 ]. By interfering with these pathways, hydroxytyrosol hinders cancer cell growth and motility. In summary, the diverse capabilities of hydroxytyrosol in targeting various cellular components relevant to cancer progression highlight its potential as a promising anticancer agent. Its ability to regulate oxidative stress, inflammation, cell cycle progression, and signaling pathways makes it an intriguing candidate for further research and potential incorporation into cancer treatment strategies.
Zrelli et al. reported that hydroxytyrosol (HT) showed anticancer potential and induced apoptosis in vascular smooth muscle cells (VSMCs) via enhanced nitric oxide production, and reduced Akt phosphorylation levels [ 64 ]. Zubair et al., 2017 exhibited a study that evaluated the anticancer potential of hydroxytyrosol against prostate cancer (LNCaP and C4-2) cells, whereas non-toxic effects against normal cells. The treatment of hydroxytyrosol in prostate cancer significantly induced apoptosis, and that can also inhibit androgen receptor expression [ 22 ]. Calahora et al. (2020) found that hydroxytyrosol, a primary bioactive compound in olive oil, significantly reduces the growth of the breast cancer cell line MCF-7. This effect is likely attained by modulating HIF-1α protein expression, potentially by reducing oxidative stress and inhibiting the PI3K/Akt/mTOR pathway (Fig. 4 ) [ 65 ]. Costantini et al., 2020, reported that hydroxytyrosol primary component of olive oil showed anticancer potential toward human melanoma cell (A375, HT-144 and M74) lines through upregulation of ROS level and induction of apoptosis via increases p53 and γH2AX expression decreases AKT expression [ 66 ].
Jadid et al. (2021) explored the use of nano-encapsulated hydroxytyrosol and curcumin, both individually and in combination, and found that these formulations significantly reduced the proliferation of the pancreatic cancer cell line PANC-1. This effect was achieved by modulating the expression levels of key proteins including BCL-2, BAX, and Cas-9 [ 67 ]. Antonio et al., 2021 found that hydroxytyrosol showed cytotoxic potential against PC-3 and 22Rv1 treated cells but less cytotoxicity toward non-cancerous cells (RWPE-1 cells). Hydrotyrosol exhibited its anticancer potential toward these cell lines by modulating the phospho-AKT/AKT expression levels [ 68 ]. In 2022, Aghaei and colleagues discovered that hydroxytyrosol induced apoptosis in breast cancer cells (MDA-MB-231 and MCF-7) by upregulating pro-apoptotic genes (BAX and CASP3) and downregulating the anti-apoptotic BCL2 gene [ 69 ].
Apoptosis, essential for tissue balance, eliminates damaged cells. Dysregulation in cancer underscores its significance. Inducing apoptosis is a promising cancer therapy approach [ 70 ]. Hydroxytyrosol has been shown to activate caspases which are key enzymes involved in the apoptotic process. Caspase activation cleaves targets, instigating cancer cell apoptosis [ 71 ]. It modulates Bcl-2 proteins, central to apoptosis control. Hydroxytyrosol reduces the levels of the anti-apoptotic protein Bcl-2 while increasing the expression of the pro-apoptotic protein Bax, thereby promoting apoptosis in cancer cells [ 72 ]. Hydroxytyrosol disrupts cancer cell mitochondrial function, releasing pro-apoptotic factors like cytochrome C, activating c-Jun and c-Fos pathways, ultimately inducing apoptosis [ 73 ]. Hydroxytyrosol enhances apoptosis in breast cancer cells by increasing caspase-3 activity, inducing DNA fragmentation, and promoting mitochondrial membrane depolarization. Additionally, it upregulates the pro-apoptotic Bax and downregulates the anti-apoptotic Bcl-2, resulting in the release of cytochrome C and activation of the intrinsic apoptotic pathway [ 74 ]. In prostate cancer, hydroxytyrosol induces apoptosis through various mechanisms. It activates caspase-3 and caspase-9, triggers PARP cleavage, inhibits Akt/STAT3 phosphorylation, and retains NF-kB in the cytoplasm of prostate cancer cells [ 22 ]. Furthermore, hydroxytyrosol treatment activates critical signaling pathways, including MAPK, Akt, JAK/STAT, NF-κB, and TGF-β, which are instrumental in inducing apoptosis. [ 75 , 76 ]. In colon cancer, hydroxytyrosol reduces cell viability and enhances caspase-3 activity, promoting apoptotic cell death [ 71 , 77 ]. Additionally, hydroxytyrosol treatment upregulated pro-apoptotic proteins like p53 and Bax, while downregulating anti-apoptotic proteins like Bcl-2 [ 49 , 63 ]. These findings define that hydroxytyrosol induces apoptosis in colon cancer cells by regulating apoptotic protein expression. Hydroxytyrosol’s apoptotic effects have also been observed in other cancer types, such as liver cancer and leukemia. Hydroxytyrosol induces apoptosis in liver cancer cells via the mitochondrial pathway, with increased Bax expression and reduced Bcl-2 levels [ 78 ]. Hydroxytyrosol treatment induced apoptosis in leukemia cells by activating caspase-3 and caspase-8 while simultaneously inhibiting the NF-κB signaling pathway [ 63 ]. Hydroxytyrosol has been documented to provoke G1 phase arrest in cancer cells, a state often linked with the reduction in levels of cyclin D1, cyclin-dependent kinase 4 (CDK4), and CDK6, which play pivotal roles in regulating the G1-S transition [ 71 ]. Hydroxytyrosol has been shown to induce G2/M phase cell cycle arrest in cancer cells by downregulating cyclin B1 and CDK1, which are essential for the G2-M transition [ 61 ]. Numerous studies have delved into the cell cycle arrest mechanisms induced by hydroxytyrosol in various cancer types. A fundamental anticancer mechanism of hydroxytyrosol centers around cell cycle regulation, particularly in breast cancer. This is achieved by inducing G1 phase cell cycle arrest, involving the increase in cyclin-dependent kinase inhibitors, like p21 and p27, and the reduction in cyclins D1 and E. These actions collectively impede cell cycle progression, resulting in cell cycle arrest [ 79 ]. In colon cancer cells, hydroxytyrosol can induce G2/M phase cell cycle arrest by inhibiting cyclin-dependent kinases, specifically CDK1, and promoting the degradation of cyclin B1, both of which play crucial roles in regulating the G2/M transition [ 71 ]. Hydroxytyrosol induces G1 phase cell cycle arrest in prostate cancer cells through the modulation of key cell cycle regulators, including cyclin D1 and p21 [ 22 , 80 ].
Angiogenesis, essential in numerous cancers, involves the formation of new blood vessels and plays a significant role in tumor growth and metastasis. Blocking angiogenesis can impede tumor progression by restricting the blood supply to tumors [ 81 ]. Angiogenesis, the formation of new blood vessels from existing ones, plays a vital role in embryogenesis, wound healing, and tumor growth. This process is controlled by a delicate balance between pro-angiogenic factors (vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor) and anti-angiogenic factors (Thrombospondin and Angiostatin). Angiogenesis, primarily regulated by VEGF and its receptor VEGFR-2, is pivotal in various diseases, including cancer, diabetic retinopathy, rheumatoid arthritis, and cardiovascular disorders. Especially in case of cancer, tumors require a blood supply to grow beyond a certain size, and they can induce angiogenesis to recruit new blood vessels and provide nutrients for their survival and expansion which is explained by a number of studies [ 42 , 82 ]. Hydroxytyrosol has been shown to possess the capability to suppress the expression of vascular endothelial growth factor (VEGF), a crucial regulator of angiogenesis. By inhibiting VEGF expression, hydroxytyrosol can interfere with the development of new blood vessels, which are vital for tumor growth and metastasis [ 15 ]. Moreover, research has demonstrated that hydroxytyrosol can inhibit the proliferation of endothelial cells, a pivotal factor in the formation of new blood vessels. This anti-proliferative effect can further contribute to the suppression of angiogenesis [ 19 ]. According to studies by Li & Kroetz, (2018); Touyz et al., (2018) and Wu et al., (2008), Blocking VEGF receptor-2 binding with drugs like bevacizumab, sorafenib, and sunitinib inhibits angiogenesis. Yet, these drugs may cause side effects, such as hypertension [ 83 , 84 , 85 ]. Several natural products (Table 1 ) like epigallocatechin-3-gallate (EGCG), procyanidin oligomers, resveratrol, quercetin, caffeic acid phenethyl ester, urolithins, and ellagitannin show anti-angiogenic and anti-VEGF effect without causing hypertension like side effects. Besides these compounds, hydroxytyrosol (in fermented beverages & Olive oil) and Indole acetic acids (in wine) show VEGFR-2 inhibitory effect without causing adverse hypertensive effects, proving their advantage over synthetic drugs. Fortes et al. (2012) found that hydroxytyrosol inhibits endothelial cell apoptosis, alters cell cycle distribution, and impedes cell proliferation, migration, and differentiation into “capillary-like” tubes. Additionally, it inhibits MMP-9, cyclooxygenase 2, and VEGFR-2 phosphorylation, demonstrating its anti-angiogenic properties [ 86 ]. In a study by Lamy et al. (2014), it was noted that hydroxytyrosol inhibits angiogenesis by targeting specific phosphorylation sites (Tyr951, Tyr1059, Tyr1175, and Tyr1214) on vascular endothelial growth factors (VEGFR-2), leading to the inhibition of endothelial cell (EC) signaling and subsequent EC proliferation inhibition. All these studies suggested the hydroxytyrosol and its derivatives have potential anti-angiogenic properties and can be used in the prevention and therapy of cancer (Fig. 4 ) (Bernini et al., 2015). In breast cancer, hydroxytyrosol inhibits angiogenesis by reducing VEGF receptor expression and blocking the PI3K/AKT signaling pathway [ 65 ]. In an in vitro study on colorectal cancer, hydroxytyrosol inhibited angiogenesis by reducing VEGF expression, suppressing matrix metalloproteinase (MMP) activity, which is involved in angiogenesis and tumor invasion, and inhibiting the activation of the PI3K/AKT/mTOR signaling pathway [ 29 , 87 ]. Metastasis is the process by which cancer cells disseminate from the primary tumor to distant organs through the bloodstream or lymphatic system. When cancer cells metastasize, they invade nearby tissues and enter the circulatory or lymphatic systems, allowing them to travel to distant organs or tissues. Metastasis, a fundamental characteristic of malignant tumors and a primary contributor to cancer-related mortality, entails the dissemination of cancer cells to various organs through the bloodstream or lymphatic system. Hydroxytyrosol has been demonstrated to inhibit MMPs, enzymes crucial for the degradation of the extracellular matrix, potentially impeding metastatic processes [ 88 ]. Hydroxytyrosol can hinder the invasion and metastasis of cancer cells by inhibiting matrix metalloproteinases (MMPs). [ 80 , 89 ]. Hydroxytyrosol has been found to inhibit epithelial-mesenchymal transition (EMT), a fundamental stage in cancer metastasis. By preventing cancer cells from acquiring a more invasive and migratory phenotype through EMT, hydroxytyrosol can hinder metastatic spread [ 90 ]. Aghaei et al. in 2022, the anti-proliferative effects of hydroxytyrosol were demonstrated on both MDA-MB-231 and MCF-7 cancer cells, along with an increase in apoptotic activity. It also downregulates the anti-apoptotic ( BCL2 ) gene and upregulates the pro-apoptotic ( BAX and CASP3 ) genes. In a study by León-González et al. (2021) on prostate cancer cell lines (RWPE-1, LNCaP, 22Rv1, and PC-3), hydroxytyrosol and its derivatives demonstrated anti-proliferative effects. This included reduced cell migration in RWPE-1 and PC-3, as well as decreased prostatosphere size and colony formation in 22Rv1. In colorectal cancer cells, Hormozi et al. (2020) demonstrated that hydroxytyrosol induces apoptosis by upregulating the CASP3 gene expression and growing the BAX:BCL2 ratio. Furthermore, hydroxytyrosol enhances antioxidant enzyme activity and reduces LS180 cell proliferation by modifying the antioxidant-defense system in cancer cells. Méndez-Líter et al. (2019) documented the reduction in viability in the breast cancer cell line MCF-7 due to the impact of hydroxytyrosol. Hydroxytyrosol significantly reduced EGFR expression, leading to decreased cell proliferation in human colon cancer cells, and it also reduced tumor growth, along with EGFR expression levels, in HT-29 xenografts (Terzuoli et al., 2016). Hydroxytyrosol inhibits the migration and invasion of breast cancer cells by modulating crucial metastasis-related pathways, such as epithelial-mesenchymal transition (EMT) and matrix metalloproteinase (MMP) activation. The effects of hydroxytyrosol observed in both in vitro and in vivo studies underscore its potential as a promising anti-metastatic agent for breast cancer [ 89 , 91 , 92 ]. Li et al. 2014, the proliferation of human gallbladder cancer cell lines and human cholangiocarcinoma (CCA) was inhibited by hydroxytyrosol. Hydroxytyrosol disrupts (E2)-induced molecular mechanisms, leading to the inhibition of breast cancer cell proliferation (Fu et al., 2010). Some crucial proteins that are involved in the control of these processes were altered in expression by hydroxytyrosol. Additionally, hydroxytyrosol leads to reduced DNA synthesis, suppresses the cell cycle, lowers the levels of CDK-6, and increases cyclin D3 expression. All these factors induce apoptosis in HL 60 cells [ 93 ]. These studies collectively offer a comprehensive summary outlining the anti-angiogenic and anti-metastatic activities of hydroxytyrosol (Fig. 5 ).
Major signaling pathways targeted by hydroxytyrosol in angiogenesis and metastasis processes
Fernández-Prior et al., 2021 found that the anti-inflammatory potential of hydroxytyrosol was investigated using the THP-1 cell line. Their analysis of pro-inflammatory cytokines, together with TNF-α, IL-6, and IL-1β, showed the reduction in the gene expression of these cytokines. This indicates the potential of hydroxytyrosol in treating diseases with inflammatory origins. Downregulation of cytokines (IL1, TNF, Cox2 and iNOs) expression was observed to be reduced as a result of hydroxytyrosol treatment and mice on olive oil diet show a significant reduction in cox2 and inducible nitric oxide synthase (iNOs) and its antioxidant activity exhibits the anti-inflammatory activity of hydroxytyrosol [ 59 , 94 , 95 ]. NF-κB, a crucial factor in inflammation, activates the transcription of various cytokine genes. Consequently, inhibiting NF-κB has been acknowledged as a strategy to control inflammatory cytokine. Hydroxytyrosol has been shown to inhibit the activation of both p53 and NF-κB in cells [ 94 , 96 ]. Yonezawa et al. (2018, 2019) documented that hydroxytyrosol inhibits the lipopolysaccharide-mediated stimulation of inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), and interleukin-1 expression, leading to reduction in nitric oxide and prostaglandin E2 production [ 97 , 98 ]. This underscores the anti-inflammatory activity of hydroxytyrosol. In the combination of hydroxytyrosol with pectin/alginate was found effective against TNBS-induced colitis, providing further evidence of the anti-inflammatory properties of hydroxytyrosol [ 99 ].
Hydroxytyrosol exhibited a dose-dependent reduction in SA-β-galactosidase activity in UVA-exposed human dermal fibroblasts (HDFs). Furthermore, it dose-dependently decreased the elevated expression of MMP-1 and MMP-3 induced by UVA exposure. Jeon & Choi (2018) noted that hydroxytyrosol reduced SA-β-galactosidase activity and inhibited the MMP-1 and MMP-3 expression. Moreover, hydroxytyrosol reduced the expression of genes associated with IL-1, IL-6, and IL-8 in UVA-exposed human dermal fibroblasts (HDFs) [ 100 ]. Fuccelli et al. (2018) illustrated that hydroxytyrosol treatment effectively reduced TNF-α production in plasma following intraperitoneal injection of lipopolysaccharide (LPS), indicating its anti-inflammatory potential [ 61 ]. FF-HT exhibited robust anti-inflammatory effects in vivo, resulting in a 16% reduction in plasma TNF levels and a 25% reduction in CRP levels when compared to the model group [ 101 ]. In TNF-activated human umbilical vein endothelial cells (hECs), Echeverría et al. (2017) found that hydroxytyrosol reduced the protein levels of phosphorylated inhibitor of κBα kinase (IKKαβ), inhibitor of κBα (IκBα), and p65, essential components of the NF-κB pathway. The suppression of NF-κB signaling highlights the involvement of NF-κB inactivation in the anti-inflammatory action of hydroxytyrosol [ 102 ]. Tutino et al. (2012) investigated the mechanisms through which hydroxytyrosol (HT) prevents oxidative stress and inflammation in human hepatoma cells while also inhibiting cancer cell proliferation [ 103 ]. Richard et al. (2011) reported that hydroxytyrosol reduced the secretion of cytokines (IL-1α, IL-1β, IL-6, IL-12, TNF-α) and chemokines (CXCL10/IP-10, CCL2/MCP-1), highlighting its anti-inflammatory action [ 104 ]. In vitro, hydroxytyrosol (HTyr) inhibits pro-tumorigenic inflammatory reactions that are brought on by the activation of monocytes and macrophages (in vitro). For example, the anti-inflammatory effectiveness of hydroxytyrosol (HTyr) may be notably attributed to its ability to suppress the NF-κB signaling pathways [ 105 ]. Prolonged oxidative stress and inflammation can lead to the onset of autoimmune and chronic diseases. Several of the studies mentioned above have highlighted hydroxytyrosol’s potential in inhibiting diseases like type II diabetes, rheumatoid arthritis, and inflammatory bowel disease through interactions with their respective receptors [ 106 , 107 ].
Hydroxytyrosol (C 8 H 10 O 3 ) is reported as a phenolic phytochemical compound isolated from olive ( Olea europaea ) leaves and oils. Hydroxytyrosol (HT) from Olea europaea exhibits antibacterial activity against both Gram-positive and Gram-negative bacteria among the isolated phenolic compounds [ 112 ]. In literature, many of the bacteria such as Staphylococcus aureus , Pseudomonas aeruginosa , Salmonella Typhimurium , Listeria monocytogenes , Escherichia coli , Klebsiella pneumoniae , Streptococcus pneumonia , Campylobacter spp. and Acinetobacter baumannii are responsible for causing different types of infections in human population [ 113 ]. Since ages, medicinal plants are used for the isolation of phytochemical compounds showing profound activities against pathogenic bacteria. Currently, HT is a desirable molecule among all the phenolic components of olives having profound applications in medical, nutraceutical, pharmaceuticals and food industries [ 114 ]. Numerous studies in the literature have explored the antimicrobial and antibacterial potential of hydroxytyrosol (HT) from olive leaves, as summarized in Table 2 . These studies offer valuable insights into HT’s potential as a natural antimicrobial agent. In addition to this, phenolic extracts of olive leaves showed potent activity against infections related to respiratory and gastro-intestinal tract [ 115 ].
HT exhibits potent antibacterial activity against a range of bacteria, including Staphylococcus aureus, Salmonella Typhimurium, Escherichia coli, Salmonella enterica, Shigella sonnei, Bacillus cereus, Listeria monocytogenes, Pseudomonas aeruginosa, Clostridium perfringens, and Yersinia sp [ 116 , 117 ]. In 2019, Nazzaro et al. reported significant bacterial growth inhibition at very low concentrations in the polyphenolic extract obtained from three Olea europaea varieties: Ruvea, Ravece, and Ogliara [ 118 ]. Similarly, Rocha-Pimienta et al., (2020) reported significant antimicrobial activity of HT against Gram-negative E. coli and Gram-positive Listeria innocua [ 115 ]. Though, the action mechanism of HT and other phenolic compound is yet now clear but, Martillanes et al. [ 119 ] proposed that the antibacterial effects of phenolic compounds might be due to genetic material modifications, interactions with cell membranes, and the disruption of enzymatic systems. Silvan et al. [ 120 ] reported antibacterial activity in leaf extracts E1 and E2 of Olea europaea against Helicobacter pylori causing chronic gastritis in human population. Characterization of extracts E1 and E2 via HPLC-PAD-MS revealed that E1 is primarily composed of hydroxytyrosol (HT) and its glucosides, while E2 contains hydrophilic compounds like oleuropein (OLE).
In Silvan et al. [ 121 ] reported significant antibacterial activity in Olea europaea leaf extract E1, which comprises hydroxytyrosol and hydroxytyrosol glucosides. These compounds exhibited activity against antibiotic-resistant strains of Campylobacter jejuni and Campylobacter coli . Yuan et al. [ 122 ] reported the antibacterial activity of HT, OL, 3,4-dihydroxybenzoic acid, and caffeic acid against Klebsiella pneumoniae , indicating its possible use as an important pharmaceutical compound. Pannucci et al. [ 123 ] reported antioxidant and antimicrobial activity of HT enriched extract from oil mill wastewater against two olive tree pathogens viz . Agrobacterium tumefaciens and Pseudomonas savastanoi pv. Savastanoi . The chemical characterization of the extract identified hydroxytyrosol as the main component, demonstrating significant antimicrobial activity. Shan et al. [ 124 ] found that hydroxytyrosol exhibits anti-inflammatory and anti-apoptotic activity against pulmonary injury induced by Mycoplasma gallisepticum (MG) in chickens. This effect is achieved by reducing damage and inhibiting the activation of the NF-κB/NLRP3/IL-1β signaling pathway.
Hence, hydroxytyrosol can be seen as an important pharmacological compound having antibacterial activity against an array of different human pathogens.
In addition, it possesses antioxidative, anti-inflammatory, anti-atherogenic, anti-thrombotic, and anticancer properties [ 125 ]. The exact antibacterial mechanism of hydroxytyrosol is not fully understood, but some studies in the literature propose that HT may induce protein denaturation, alter cell membrane permeability, or downregulate genes responsible for cell proliferation [ 126 , 127 ]. Table 2 provides information on the target organisms and mechanisms of action of hydroxytyrosol and its derivatives.
The therapeutically active and anticancer activities of hydroxytyrosol have been linked to its concentrations. Hydroxytyrosol has been reported to exhibit diverse therapeutic activities in isolation, but its primary health-promoting properties often result from synergistic effects when combined with other compounds. It is a component found in virgin olive oil and has previously shown a beneficial role in breast epithelial cell cancer. However, it does not exhibit significant anticancer properties in highly invasive stages of breast cancer cells. [ 132 , 133 ]. Treatment of highly metastatic human breast tumor cells with a combination of hydroxytyrosol and squalene inhibits cell proliferation, promotes apoptosis, and induces DNA damage in breast cancer cells [ 14 ]. Based on the studies mentioned above, there is a belief that a synergistic action may occur between hydroxytyrosol and other phenolic molecules found in olive oil or natural compounds like tyrosol, lycopene, oleuropein, and tea polyphenols. These interactions between various compounds could contribute to the observed therapeutic effects and health benefits associated with olive oil consumption [ 134 ]. Tyrosol is a common constituent of olive oil present as conjugated or free forms and showed several pharmacological functions. Furthermore, a synergistic interaction was observed when tyrosol and hydroxytyrosol were combined to inhibit tumor proliferation and reduce EGFR expression in HT-29 tumor cells. This suggests that the combined action of these compounds may have a more pronounced effect on cancer cell behavior than when used individually. This discovery highlights an intriguing mechanism of action for hydroxytyrosol and indicates that combining it with chemotherapy could be a promising approach for treating colon and rectal cancer [ 15 ]. Toteda and colleagues reported a synergistic effect of hydroxytyrosol in combination with doxorubicin for the treatment of leukemic K562 cells. The combination of hydroxytyrosol and doxorubicin results in a substantial reduction in cell viability, primarily through an increase in the apoptosis process and the induction of double-strand DNA breaks in K562 leukemia cells which suggests a potential synergistic effect of these compounds in combating leukemia [ 135 ]. Furthermore, a study has indicated that hydroxytyrosol demonstrates synergistic antioxidant activity when combined with other phenolic compounds like quercetin and resveratrol which suggests that the collective use of these antioxidants may enhance their effectiveness in combating oxidative stress and promoting overall health [ 136 ].
Nanotechnology holds significant promise in advancing cancer treatment, representing a cutting-edge frontier at the intersection of various disciplines. In vitro diagnosis and drug administration have recently attracted a lot of attention in the field of nanotechnology [ 137 ]. This technology is being created to win the battle against cancer. Drug resistance can now be reversed by active or passive mechanisms owing to studies focusing on nano-based medications [ 138 ]. Nanotechnology-based medications have effectively reduced side effects, enhanced treatment efficacy, and mitigated drug resistance. A wide range of nanoparticles (NPs) has been developed and extensively researched, including polymer-based nanoparticles, nanovesicles, and metal nanoparticles which exhibited potential in overcoming cancer’s resistance to chemotherapy [ 139 , 140 ]. Targeted therapy, photothermal therapy, nanomaterial-based chemotherapy, and sonodynamic therapy are now employed to treat cancer [ 141 , 142 ]. Nanomedicine involves the use of nanoparticles and nanoscale materials for medical purposes, such as drug delivery, diagnostic imaging, and targeted therapy. When hydroxytyrosol is incorporated into nanomedicine formulations, it can enhance the therapeutic effects and improve the bioavailability of the compound.
It includes active as well as passive targeting. Nanoparticles achieve active targeting via ligand-receptor interactions, employing molecules such as siRNAs, proteins, vitamins, amino acids, monoclonal antibodies, and peptides on the surfaces of cancer cells. Nanoparticles’ ligand-mediated targets in cancer cells contribute to their ability to discriminate between tumor cells and healthy ones [ 143 ]. As a result of this interaction, NPs can release the medicine at the target spot by receptor-mediated endocytosis. Passive targeting leverages the increased permeability and retention (EPR) effect, causing nanoparticles (NPs) to accumulate around cancer cells due to their restricted lymphatic circulation. This facilitates the delivery of medication to the intended site using nanocarriers. Since NPs are made of small particles, they are more permeable to cells than larger particles like conventional medications, which the immune system is likely to remove from the cell. A permeability advantage allows NPs to produce an EPR effect [ 144 ].
Many studies focus on the preparation and characterization of poly(lactide-co-glycolide) (PLGA) NPs loaded with hydroxytyrosol. Researchers investigated the stability and bioactivities of the hydroxytyrosol-loaded nanoparticles as follows.
Guan et al. [ 145 ] found that mPEG-PLGA co-loaded with syringopicroside and HT exhibited sustained release of drug, prominent liver distribution, and provided protection against hepatic injury in Sprague–Dawley rats. Jadid et al. [ 67 ] demonstrated that nano-encapsulated hydroxytyrosol (HT) and curcumin (Cur) within poly lactide-co-glycolide-co-polyacrylic acid (PLGA-co-PAA), individually and in combination (HT-Cur), exhibited substantial anti-proliferative, anti-migratory, and apoptosis-inducing effects on pancreatic cancer (PCNA-1) cells. These effects were achieved by modulating migration-related genes (MMP2 and MMP9) and apoptosis-related genes (BAX and Caspase-9).
Saini et al. [ 146 ] discovered that nano-capsulated hydroxytyrosol reduced colorectal cancer (HT-29) cell growth by modifying the expression of CDKN1A, CDKN1B, and CCND1 genes. Safi et al. [ 147 ] discovered that the employment of PLGA-co-PAA nano-encapsulated hydroxytyrosol in breast cancer (MCF-7) cells resulted in anti-proliferative effects. This was achieved by arresting the cell cycle through the upregulation of P21 and P27 expression, while concurrently downregulating Cyclin D1 expression. Zygouri et al. [ 148 ] utilized carbon nanotubes as biocompatible carriers for hydroxytyrosol. Their study revealed cytotoxic effects on NIH/3T3 and Tg/Tg cell lines, leading to cell cycle arrest and the generation of ROS.
To study the effect of hydroxytyrosol Fernández-Prior et al. [ 149 ] in THP-1 derived monocytes, treatment of different concentrations (10–100 ppm) were given. A very high cellular viability (100%) was recorded elucidating HT had no negative effects on the integrity of the cells in this cellular model. HT also showed high viability in living human cells without any inhibition effect. Hence, hydroxytyrosol (HT) has potential applications in the treatment of various diseases. Haloui et al. [ 12 ] reported no toxicity associated symptoms like convulsion, diarrhea, locomotor ataxia and mortality after doses (different concentrations) of hydroxytyrosol given to mice concluded that it does not cause any toxicological effect. D’Angelo et al. [ 47 ] found that orally administered hydroxytyrosol in rats did not result in significant adverse effects, after assessing its molecular pharmacokinetics and toxicity. While studying the anti-inflammatory effect of dietary hydroxytyrosol supplement, Voltes et al. [ 110 ] did not notice any symptoms of toxic effect of the hydroxytyrosol. Non-toxic and chemopreventive effects of hydroxytyrosol (HT) have been documented in various healthy and normal cell cultures [ 150 ]. There were not any signs of toxicity such as grip strength, locomotory activity, food consumption, or loss of body weight, observed in treated rats [ 151 ].
Much of the evidence supporting the anticancer properties of hydroxytyrosol comes from in vitro and animal studies. While these findings are encouraging, the translation to clinical applications in humans which is not straightforward. More clinical trials are needed to establish the safety and efficacy of hydroxytyrosol in cancer prevention or treatment. Moreover, the variability in the composition of natural sources of hydroxytyrosol, such as olive oil, can make it challenging to achieve standardized doses. Standardization is crucial for ensuring consistent and reproducible results in both research and potential clinical applications. The potential synergistic or antagonistic effects of these compounds with hydroxytyrosol need further investigation. The complexity of natural products makes it challenging to isolate the specific contribution of hydroxytyrosol alone. The precise molecular mechanisms by which hydroxytyrosol exerts its anticancer effects are not fully understood. More research is needed to elucidate the signaling pathways and targets involved. Future studies and clinical trials will help address these issues and provide a clearer understanding of its potential therapeutic role.
Hydroxytyrosol as an anticancer agent exhibits several strengths in elucidating its potential therapeutic benefits. It effectively synthesizes existing research, highlighting hydroxytyrosol’s promising anticancer properties, such as its antioxidant and anti-inflammatory effects, along with its ability to induce apoptosis and inhibit tumor cell proliferation. Moreover, the review likely discusses the mechanisms underlying hydroxytyrosol’s action, shedding light on its molecular targets and signaling pathways involved in cancer inhibition. However, this review study might encounter limitations stemming from the heterogeneity of research methodologies, dosages, and cancer types studied, which could affect the generalizability of findings. Additionally, the scarcity of human clinical trials and long-term studies could impede the translation of hydroxytyrosol’s potential into clinical practice, highlighting the need for further investigation to validate its efficacy and safety profile. Nonetheless, despite these challenges, the review provides valuable insights into hydroxytyrosol’s anticancer properties, serving as a foundation for future research and clinical trials in this promising field.
The review underscores hydroxytyrosol as an exciting and innovative frontier in cancer research, as recent findings unveil its robust anticancer effects and elucidate the associated molecular mechanisms. Hydroxytyrosol has demonstrated its ability to impede cancer cell proliferation, trigger apoptosis, and suppress metastasis, rendering it a compelling candidate for cancer therapy. Furthermore, its antioxidant and anti-inflammatory properties have proven crucial in mitigating oxidative stress and fostering a less pro-tumorigenic tumor microenvironment. The review emphasizes the importance of recent discoveries in unveiling hydroxytyrosol’s unique mechanisms of action, which are critical for its potential integration into personalized cancer treatment approaches. By targeting various cellular components crucial to cancer development, hydroxytyrosol shows potential in augmenting the effectiveness of current cancer treatments and overcoming drug resistance. Future research should focus on further elucidating the precise molecular interactions and signaling pathways involved in hydroxytyrosol’s anticancer effects, opening up avenues for developing targeted therapies and innovative treatment combinations. Exploring its potential in different cancer types and addressing potential drug interactions are crucial considerations for its successful translation to clinical applications.
All data generated or analyzed during this study are included in the published article.
Adenosine 5’-triphosphate
Bcl-2-associated X protein
Cyclin-Dependent Kinase Inhibitor 1A
Maximum concentration
Cyclooxygenase 2
Deoxyribonucleic Acid
Endothelial cell
Epigallocatechin-3-gallate
Human dermal fibroblasts
High-Performance Liquid Chromatography with Photodiode Array Detection and Mass Spectrometry
Human umbilical vein endothelial cells
Interleukins
Inducible nitric oxide synthase
Lipopolysaccharide
Mycoplasma gallisepticum
Matrix metalloproteinase
Nuclear Factor-Kappa B
Nanoparticles
Peptidyl-prolyl cis–trans isomerase NIMA-interacting 1
Poly(lactide-co-glycolide)
Polylactide-co-glycolide-co-polyacrylic acid
Part per million
Reactive oxygen species
Tamm-Horsfall Protein 1
Hanahan D (2022) Hallmarks of cancer: new dimensions. Cancer Discov 12:31–46. https://doi.org/10.1158/2159-8290.CD-21-1059
Article CAS PubMed Google Scholar
Tuli HS, Sak K, Garg VK, Kumar A, Adhikary S, Kaur G, Parashar NC, Parashar G, Mukherjee TK, Sharma U, Jain A, Mohapatra RK, Dhama K, Kumar M, Singh T (2022) Ampelopsin targets in cellular processes of cancer: Recent trends and advances. Toxicol Rep. https://doi.org/10.1016/j.toxrep.2022.07.013
Article PubMed PubMed Central Google Scholar
Singh D, Vignat J, Lorenzoni V, Eslahi M, Ginsburg O, Lauby-Secretan B, Arbyn M, Basu P, Bray F, Vaccarella S (2023) Global estimates of incidence and mortality of cervical cancer in 2020: a baseline analysis of the WHO Global Cervical Cancer Elimination Initiative. Lancet Glob Health. https://doi.org/10.1016/S2214-109X(22)00501-0
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71:209–249. https://doi.org/10.3322/caac.21660
Siegel RL, Giaquinto AN, Jemal A (2024) Cancer statistics, 2024. CA Cancer J Clin. https://doi.org/10.3322/caac.21820
Article PubMed Google Scholar
Laurindo LF, de Maio MC, Minniti G, de Góes Corrêa N, Barbalho SM, Quesada K, Guiguer EL, Sloan KP, Detregiachi CRP, Araújo AC, de Alvares GR (2023) Effects of medicinal plants and phytochemicals in Nrf2 pathways during inflammatory bowel diseases and related colorectal cancer: a comprehensive review. Metabolites. https://doi.org/10.3390/metabo13020243
Majolo F, de Oliveira Becker LK, Delwing DJ, Marmitt IC, Bustamante-Filho MIG (2019) Medicinal plants and bioactive natural compounds for cancer treatment: Important advances for drug discovery. Phytochem Lett 31:196–207. https://doi.org/10.1016/j.phytol.2019.04.003
Article CAS Google Scholar
Gezici S, Şekeroğlu N (2019) Current perspectives in the application of medicinal plants against cancer: novel therapeutic agents. Anticancer Agents Med Chem. https://doi.org/10.2174/1871520619666181224121004
Rodríguez-Morató J, Xicota L, Fitó M, Farré M, Dierssen M, De La Torre R (2015) Potential role of olive oil phenolic compounds in the prevention of neurodegenerative diseases. Molecules 20:4655–4680. https://doi.org/10.3390/molecules20034655
Article CAS PubMed PubMed Central Google Scholar
Visioli F, Bellomo G, Galli C (1998) Free radical-scavenging properties of olive oil polyphenols. Biochem Biophys Res Commun. https://doi.org/10.1006/bbrc.1998.8735
Deiana M, Aruoma OI, Bianchi MDLP, Spencer JPE, Kaur H, Halliwell B, Aeschbach R, Banni S, Dessi MA, Corongiu FP (1999) Inhibition of peroxynitrite dependent DNA base modification and tyrosine nitration by the extra virgin olive oil-derived antioxidant hydroxytyrosol. Free Radic Biol Med 26:762–769. https://doi.org/10.1016/S0891-5849(98)00231-7
Haloui E, Marzouk B, Marzouk Z, Bouraoui A, Fenina N (2011) Hydroxytyrosol and oleuropein from olive leaves: Potent anti-inflammatory and analgesic activities. J Food Agric Environ 9:128–133
CAS Google Scholar
Escrich E, Moral R, Solanas M (2011) Olive oil, an essential component of the Mediterranean diet, and breast cancer. Public Health Nutr 14:2323–2332. https://doi.org/10.1017/S1368980011002588
Sánchez-Quesada C, Gutiérrez-Santiago F, Rodríguez-García C, Gaforio JJ (2022) Synergistic effect of squalene and hydroxytyrosol on highly invasive MDA-MB-231 breast cancer cells. Nutrients. https://doi.org/10.3390/nu14020255
Terzuoli E, Giachetti A, Ziche M, Donnini S (2016) Hydroxytyrosol, a product from olive oil, reduces colon cancer growth by enhancing epidermal growth factor receptor degradation. Mol Nutr Food Res 60:519–529. https://doi.org/10.1002/mnfr.201500498
Cheng C-W, Tse E (2018) PIN1 in cell cycle control and cancer. Front Pharmacol. https://doi.org/10.3389/fphar.2018.01367
He S, Li L, Jin R, Lu X (2023) Biological function of Pin1 in vivo and its inhibitors for preclinical study: early development, current strategies, and future directions. J Med Chem 66:9251–9277. https://doi.org/10.1021/acs.jmedchem.3c00390
Gordon MH, Paiva-Martins F, Almeida M (2001) Antioxidant activity of hydroxytyrosol acetate compared with that of other olive oil polyphenols. J Agric Food Chem 49:2480–2485. https://doi.org/10.1021/jf000537w
Carluccio MA, Martinelli R, Massaro M, Calabriso N, Scoditti E, Maffia M, Verri T, Gatta V, De Caterina R (2021) Nutrigenomic effect of hydroxytyrosol in vascular endothelial cells: a transcriptomic profile analysis. Nutrients. https://doi.org/10.3390/nu13113990
Bouallagui Z, Han J, Isoda H, Sayadi S (2011) Hydroxytyrosol rich extract from olive leaves modulates cell cycle progression in MCF-7 human breast cancer cells. Food Chem Toxicol 49:179–184. https://doi.org/10.1016/j.fct.2010.10.014
De López Las MC, Hazas C, Piñol A, Macià MJM (2017) Hydroxytyrosol and the colonic metabolites derived from virgin olive oil intake induce cell cycle arrest and apoptosis in colon cancer cells. J Agric Food Chem 65:6467–6476. https://doi.org/10.1021/acs.jafc.6b04933
Zubair H, Bhardwaj A, Ahmad A, Srivastava SK, Khan MA, Patel GK, Singh S, Singh AP (2017) Hydroxytyrosol induces apoptosis and cell cycle arrest and suppresses multiple oncogenic signaling pathways in prostate cancer cells. Nutr Cancer 69:932–942. https://doi.org/10.1080/01635581.2017.1339818
Bendini A, Cerretani L, Carrasco-Pancorbo A, Gómez-Caravaca A, Segura-Carretero A, Fernández-Gutiérrez A, Lercker G (2007) Phenolic molecules in virgin olive oils: a survey of their sensory properties, health effects, antioxidant activity and analytical methods. Overv Last Decade Alessandra Molecules 12:1679–1719. https://doi.org/10.3390/12081679
Gouvinhas I, Machado N, Sobreira C, Domínguez-Perles R, Gomes S, Rosa E, Barros AIRNA (2017) Critical review on the significance of olive phytochemicals in plant physiology and human health. Molecules. https://doi.org/10.3390/molecules22111986
Martínez-Zamora L, Peñalver R, Ros G, Nieto G (2021) Olive tree derivatives and hydroxytyrosol: their potential effects on human health and its use as functional ingredient in meat. Foods. https://doi.org/10.3390/foods10112611
Kalampaliki AD, Giannouli V, Skaltsounis A-L, Kostakis IK, Three-Step A (2019) Gram-scale synthesis of hydroxytyrosol, hydroxytyrosol acetate, and 3,4-dihydroxyphenylglycol. Molecules. https://doi.org/10.3390/molecules24183239
Napolitano A, De Lucia M, Panzella L, d’Ischia M (2010) The Chemistry of Tyrosol and Hydroxytyrosol. In: Olives and Olive Oil in Health and Disease Prevention, Elsevier, pp 1225–1232. https://doi.org/10.1016/B978-0-12-374420-3.00134-0
Sun Y, Zhou D, Shahidi F (2018) Antioxidant properties of tyrosol and hydroxytyrosol saturated fatty acid esters. Food Chem 245:1262–1268. https://doi.org/10.1016/j.foodchem.2017.11.051
Vijakumaran U, Shanmugam J, Heng JW, Azman SS, Yazid MD, Haizum Abdullah NA, Sulaiman N (2023) Effects of hydroxytyrosol in endothelial functioning: a comprehensive review. Molecules. https://doi.org/10.3390/molecules28041861
Bonetti A, Venturini S, Ena A, Faraloni C (2016) Innovative method for recovery and valorization of hydroxytyrosol from olive mill wastewaters. Water Sci Technol 74:73–86. https://doi.org/10.2166/wst.2016.181
St-Laurent-Thibault C, Arseneault M, Longpre F, Ramassamy C (2011) Tyrosol and hydroxytyrosol two main components of olive oil, protect N2a cells against amyloid-β-induced toxicity. Involvement of the NF-κB signaling. Curr Alzheimer Res 8:543–551. https://doi.org/10.2174/156720511796391845
Salucci S, Burattini S, Battistelli M, Buontempo F, Canonico B, Martelli AM, Papa S, Falcieri E (2015) Tyrosol prevents apoptosis in irradiated keratinocytes. J Dermatol Sci 80:61–68. https://doi.org/10.1016/j.jdermsci.2015.07.002
Poudyal H, Lemonakis N, Efentakis P, Gikas E, Halabalaki M, Andreadou I, Skaltsounis L, Brown L (2017) Hydroxytyrosol ameliorates metabolic, cardiovascular and liver changes in a rat model of diet-induced metabolic syndrome: pharmacological and metabolism-based investigation. Pharmacol Res 117:32–45. https://doi.org/10.1016/j.phrs.2016.12.002
Fabiani R, Fuccelli R, Pieravanti F, de Bartolomeo A, Morozzi G (2009) Production of hydrogen peroxide is responsible for the induction of apoptosis by hydroxytyrosol on HL60 cells. Mol Nutr Food Res. https://doi.org/10.1002/mnfr.200800376
Bu Y, Rho S, Kim J, Kim MY, Lee DH, Kim SY, Choi H, Kim H (2007) Neuroprotective effect of tyrosol on transient focal cerebral ischemia in rats. Neurosci Lett 414:218–221. https://doi.org/10.1016/j.neulet.2006.08.094
Chandramohan R, Pari L, Rathinam A, Sheikh BA (2015) Tyrosol, a phenolic compound, ameliorates hyperglycemia by regulating key enzymes of carbohydrate metabolism in streptozotocin induced diabetic rats. Chem Biol Interact 229:44–54. https://doi.org/10.1016/j.cbi.2015.01.026
Monteiro M, Silva AFR, Resende D, Braga SS, Coimbra MA, Silva AMS, Cardoso SM (2021) Strategies to broaden the applications of olive biophenols oleuropein and hydroxytyrosol in food products. Antioxidants 10:444. https://doi.org/10.3390/antiox10030444
Achmon Y, Fishman A (2014) The antioxidant hydroxytyrosol: biotechnological production challenges and opportunities. Appl Microbiol Biotechnol. https://doi.org/10.1007/s00253-014-6310-6
Turck D, Bresson J, Burlingame B, Dean T, Fairweather-Tait S, Heinonen M, Hirsch-Ernst KI, Mangelsdorf I, McArdle HJ, Naska A, Neuhäuser-Berthold M, Nowicka G, Pentieva K, Sanz Y, Siani A, Sjödin A, Stern M, Tomé D, Vinceti M, Willatts P, Engel K, Marchelli R, Pöting A, Poulsen M, Schlatter J, Turla E, van Loveren H (2017) Safety of hydroxytyrosol as a novel food pursuant to regulation (EC) No 258/97. EFSA J. https://doi.org/10.2903/j.efsa.2017.4728
Fytili C, Nikou T, Tentolouris N, Tseti IK, Dimosthenopoulos C, Sfikakis PP, Simos D, Kokkinos A, Skaltsounis AL, Katsilambros N, Halabalaki M (2022) Effect of long-term hydroxytyrosol administration on body weight, fat mass and urine metabolomics: a randomized double-blind prospective human study. Nutrients. https://doi.org/10.3390/nu14071525
Pastor A, Rodríguez-Morató J, Olesti E, Pujadas M, Pérez-Mañá C, Khymenets O, Fitó M, Covas M-I, Solá R, Motilva M-J, Farré M, de la Torre R (2016) Analysis of free hydroxytyrosol in human plasma following the administration of olive oil. J Chromatogr A 1437:183–190. https://doi.org/10.1016/j.chroma.2016.02.016
Serreli G, Deiana M (2018) Biological relevance of extra virgin olive oil polyphenols metabolites. Antioxidants 7:170. https://doi.org/10.3390/antiox7120170
Granados-Principal S, Quiles JL, Ramirez-Tortosa CL, Sanchez-Rovira P, Ramirez-Tortosa MC (2010) Hydroxytyrosol: from laboratory investigations to future clinical trials. Nutr Rev 68:191–206. https://doi.org/10.1111/j.1753-4887.2010.00278.x
Serreli G, Deiana M (2018) Biological relevance of extra virgin olive oil polyphenols metabolites. Antioxidants (Basel). https://doi.org/10.3390/antiox7120170
Tuck KL, Freeman MP, Hayball PJ, Stretch GL, Stupans I (2001) The in vivo fate of hydroxytyrosol and tyrosol, antioxidant phenolic constituents of olive oil, after intravenous and oral dosing of labeled compounds to rats. J Nutr 131:1993–1996. https://doi.org/10.1093/jn/131.7.1993
Visioli F, Galli C, Grande S, Colonnelli K, Patelli C, Galli G, Caruso D (2003) Hydroxytyrosol excretion differs between rats and humans and depends on the vehicle of administration. J Nutr 133:2612–2615. https://doi.org/10.1093/jn/133.8.2612
D’Angelo S, Manna C, Migliardi V, Mazzoni O, Morrica P, Capasso G, Pontoni G, Galletti P, Zappia V (2001) Pharmacokinetics and metabolism of hydroxytyrosol, a natural antioxidant from olive oil. Drug Metab Dispos 29:1492–1498
PubMed Google Scholar
Xu CL, Sim MK (1995) Reduction of dihydroxyphenylacetic acid by a novel enzyme in the rat brain. Biochem Pharmacol 50:1333–1337. https://doi.org/10.1016/0006-2952(95)02092-6
Arangia A, Marino Y, Impellizzeri D, D’Amico R, Cuzzocrea S, Di Paola R (2023) Hydroxytyrosol and its potential uses on intestinal and gastrointestinal disease. Int J Mol Sci. https://doi.org/10.3390/ijms24043111
Ruiz-Garcia A, Bermejo M, Moss A, Casabo VG (2008) Pharmacokinetics in drug discovery. J Pharm Sci 97:654–690. https://doi.org/10.1002/jps.21009
Bender C, Strassmann S, Golz C (2023) Oral bioavailability and metabolism of hydroxytyrosol from food supplements. Nutrients. https://doi.org/10.3390/nu15020325
Fan L, Peng Y, Li X (2023) Brain regional pharmacokinetics of hydroxytyrosol and its molecular mechanism against depression assessed by multi-omics approaches. Phytomedicine 112:154712. https://doi.org/10.1016/j.phymed.2023.154712
Campesi I, Marino M, Cipolletti M, Romani A, Franconi F (2018) Put “gender glasses” on the effects of phenolic compounds on cardiovascular function and diseases. Eur J Nutr. https://doi.org/10.1007/s00394-018-1695-0
Scoditti E, Carpi S, Massaro M, Pellegrino M, Polini B, Carluccio MA, Wabitsch M, Verri T, Nieri P, De Caterina R (2019) Hydroxytyrosol modulates adipocyte gene and miRNA expression under inflammatory condition. Nutrients. https://doi.org/10.3390/nu11102493
Vilaplana-Pérez C, Auñón D, García-Flores LA, Gil-Izquierdo A (2014) Hydroxytyrosol and potential uses in cardiovascular diseases, cancer, and AIDS. Front Nutr 1:18. https://doi.org/10.3389/fnut.2014.00018
Marković AK, Torić J, Barbarić M, Brala CJ (2019) Hydroxytyrosol, tyrosol and derivatives and their potential effects on human health. Molecules. https://doi.org/10.3390/molecules24102001
Zhao Y-T, Zhang L, Yin H, Shen L, Zheng W, Zhang K, Zeng J, Hu C, Liu Y (2021) Hydroxytyrosol alleviates oxidative stress and neuroinflammation and enhances hippocampal neurotrophic signaling to improve stress-induced depressive behaviors in mice. Food Funct 12:5478–5487. https://doi.org/10.1039/D1FO00210D
Singh N, Baby D, Rajguru JP, Patil PB, Thakkannavar SS, Pujari VB (2019) Inflammation and cancer. Ann Afr Med 18:121–126. https://doi.org/10.4103/aam.aam_56_18
Elmaksoud HAA, Motawea MH, Desoky AA, Elharrif MG, Ibrahimi A (2021) Hydroxytyrosol alleviate intestinal inflammation, oxidative stress and apoptosis resulted in ulcerative colitis. Biomed Pharmacother 142:112073. https://doi.org/10.1016/j.biopha.2021.112073
Velotti F, Bernini R (2023) Hydroxytyrosol interference with inflammaging via modulation of inflammation and autophagy. Nutrients 15:1774. https://doi.org/10.3390/nu15071774
Fuccelli R, Fabiani R, Rosignoli P (2018) Hydroxytyrosol exerts anti-inflammatory and anti-oxidant activities in a mouse model of systemic inflammation. Molecules. https://doi.org/10.3390/molecules23123212
Terzuoli E, Nannelli G, Frosini M, Giachetti A, Ziche M, Donnini S (2017) Inhibition of cell cycle progression by the hydroxytyrosol-cetuximab combination yields enhanced chemotherapeutic efficacy in colon cancer cells. Oncotarget 8:83207–83224. https://doi.org/10.18632/oncotarget.20544
Parra-Perez AM, Pérez-Jiménez A, Gris-Cárdenas I, Bonel-Pérez GC, Carrasco-Díaz LM, Mokhtari K, García-Salguero L, Lupiáñez JA, Rufino-Palomares EE (2022) Involvement of the PI3K/AKT intracellular signaling pathway in the anticancer activity of hydroxytyrosol, a polyphenol from olea europaea, in hematological cells and implication of HSP60 levels in its anti-inflammatory activity. Int J Mol Sci. https://doi.org/10.3390/ijms23137053
Zrelli H, Matsuka M, Araki M, Zarrouk M, Miyazaki H (2011) Hydroxytyrosol induces vascular smooth muscle cells apoptosis through NO production and PP2A activation with subsequent inactivation of Akt. Planta Med 77:1680–1686. https://doi.org/10.1055/s-0030-1271073
Calahorra J, Martínez-Lara E, Granadino-Roldán JM, Martí JM, Cañuelo A, Blanco S, Oliver FJ, Siles E (2020) Crosstalk between hydroxytyrosol, a major olive oil phenol, and HIF-1 in MCF-7 breast cancer cells. Sci Rep. https://doi.org/10.1038/s41598-020-63417-6
Costantini F, Di Sano C, Barbieri G (2020) The hydroxytyrosol induces the death for apoptosis of human melanoma cells. Int J Mol Sci. https://doi.org/10.3390/ijms21218074
Jadid MFS, Shademan B, Chavoshi R, Seyyedsani N, Aghaei E, Taheri E, Goleij P, Hajazimian S, Karamad V, Behroozi J, Sabet MN, Isazadeh A, Baradaran B (2021) Enhanced anticancer potency of hydroxytyrosol and curcumin by <scp>PLGA-PAA nano-encapsulation</scp> on <scp>PANC</scp> -1 pancreatic cancer cell line. Environ Toxicol 36:1043–1051. https://doi.org/10.1002/tox.23103
Antonio JL-G, Prudencio S-M, Juan MJ-V, Herrero-Aguayo V, Antonio JM-H, Enrique G-G, Andrés M, Justo PC, José LE, Gahete MD, Raúl ML (2021) Anticancer activity of hydroxytyrosol and five semisynthetic lipophilic derivatives in prostate cancer cells. Endocr Abstr. https://doi.org/10.1530/endoabs.73.aep397
Article Google Scholar
Aghaei E, Soltanzadeh H, Kohan L, Heiat M (2022) Anti-proliferative effects of hydroxytyrosol against breast cancer cell lines through induction of apoptosis. Gene Cell Tissue. https://doi.org/10.5812/gct-126443
Hsu P-K, Dubeaux G, Takahashi Y, Schroeder JI (2021) Signaling mechanisms in abscisic acid-mediated stomatal closure. Plant J 105:307–321. https://doi.org/10.1111/tpj.15067
de Lopez Las Hazas MC, Piñol C, Macià A, Motilva MJ (2017) Hydroxytyrosol and the colonic metabolites derived from virgin olive oil intake induce cell cycle arrest and apoptosis in colon cancer cells. J Agric Food Chem 65:6467–6476. https://doi.org/10.1021/acs.jafc.6b04933
Hassan ZK, Elamin MH, Omer SA, Daghestani MH, Al-Olayan ES, Elobeid MAR, Virk P (2013) Oleuropein induces apoptosis via the p53 pathway in breast cancer cells. Asian Pacific J Cancer Prevention. https://doi.org/10.7314/APJCP.2013.14.11.6739
Goldsmith CD, Bond DR, Jankowski H, Weidenhofer J, Stathopoulos CE, Roach PD, Scarlett CJ (2018) The olive biophenols oleuropein and hydroxytyrosol selectively reduce proliferation, influence the cell cycle, and induce apoptosis in pancreatic cancer cells. Int J Mol Sci. https://doi.org/10.3390/ijms19071937
Garcia-Guasch M, Medrano M, Costa I, Vela E, Grau M, Escrich E, Moral R (2022) Extra-virgin olive oil and its minor compounds influence apoptosis in experimental mammary tumors and human breast cancer cell lines. Cancers (Basel). https://doi.org/10.3390/cancers14040905
León-González AJ, Sáez-Martínez P, Jiménez-Vacas JM, Herrero-Aguayo V, Montero-Hidalgo AJ, Gómez-Gómez E, Madrona A, Castaño JP, Espartero JL, Gahete MD, Luque RM (2021) Comparative cytotoxic activity of hydroxytyrosol and its semisynthetic lipophilic derivatives in prostate cancer cells. Antioxidants. https://doi.org/10.3390/antiox10091348
Luo C, Li Y, Wang H, Cui Y, Feng Z, Li H, Li Y, Wang Y, Wurtz K, Weber P, Long J, Liu J (2013) Hydroxytyrosol promotes superoxide production and defects in autophagy leading to anti-proliferation and apoptosis on human prostate cancer cells. Curr Cancer Drug Targets. https://doi.org/10.2174/15680096113139990035
Sun L, Luo C, Liu J (2014) Hydroxytyrosol induces apoptosis in human colon cancer cells through ROS generation. Food Funct. https://doi.org/10.1039/c4fo00187g
Zhao B, Ma Y, Xu Z, Wang J, Wang F, Wang D, Pan S, Wu Y, Pan H, Xu D, Liu L, Jiang H (2014) Hydroxytyrosol, a natural molecule from olive oil, suppresses the growth of human hepatocellular carcinoma cells via inactivating AKT and nuclear factor-kappa B pathways. Cancer Lett 347:79–87. https://doi.org/10.1016/j.canlet.2014.01.028
Safi M, Onsori H, Rahmati M (2021) Investigation of the anti-cancer effects of free and PLGA-PAA encapsulated hydroxytyrosol on the MCF-7 breast cancer cell line. Curr Mol Med. https://doi.org/10.2174/1566524020666201231103826
Imran H, Rahman AU, Sohail T, Taqvi SIH, Yaqeen Z (2018) Onosma bracteatum wall: a potent analgesic agent. Bangl J Med Sci 17:36–41. https://doi.org/10.3329/bjms.v17i1.35276
Dudley AC, Griffioen AW (2023) Pathological angiogenesis: mechanisms and therapeutic strategies. Angiogenesis. https://doi.org/10.1007/s10456-023-09876-7
Gallardo-Fernández M, Gonzalez-Ramirez M, Cerezo AB, Troncoso AM, Garcia-Parrilla MC (2022) Hydroxytyrosol in foods: analysis food sources, EU dietary intake, and potential uses. Foods 11:2355. https://doi.org/10.3390/foods11152355
Wu FTH, Stefanini MO, Mac Gabhann F, Popel AS (2009) A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap. PLoS ONE 4:e5108. https://doi.org/10.1371/journal.pone.0005108
Touyz RM, Herrmann SMS, Herrmann J (2018) Vascular toxicities with VEGF inhibitor therapies-focus on hypertension and arterial thrombotic events. J Am Soc Hypertens 12:409–425. https://doi.org/10.1016/j.jash.2018.03.008
Li M, Kroetz DL (2018) Bevacizumab-induced hypertension: clinical presentation and molecular understanding. Pharmacol Ther 182:152–160. https://doi.org/10.1016/j.pharmthera.2017.08.012
Giordano G, Febbraro A, Tomaselli E, Sarnicola ML, Parcesepe P, Parente D, Forte N, Fabozzi A, Remo A, Bonetti A, Manfrin E, Ghasemi S, Ceccarelli M, Cerulo L, Bazzoni F, Pancione M (2015) Cancer-related CD15/FUT4 overexpression decreases benefit to agents targeting EGFR or VEGF acting as a novel RAF-MEK-ERK kinase downstream regulator in metastatic colorectal cancer. J Exp Clin Cancer Res 34:108. https://doi.org/10.1186/s13046-015-0225-7
Abate M, Pisanti S, Caputo M, Citro M, Vecchione C, Martinelli R (2020) 3-hydroxytyrosol promotes angiogenesis in vitro by stimulating endothelial cell migration. Int J Mol Sci. https://doi.org/10.3390/ijms21103657
Gui P, Bivona TG (2022) Evolution of metastasis: new tools and insights. Trends Cancer. https://doi.org/10.1016/j.trecan.2021.11.002
Ramirez-Tortosa C, Sanchez A, Perez-Ramirez C, Quiles JL, Robles-Almazan M, Pulido-Moran M, Sanchez-Rovira P, Ramirez-Tortosa MC (2019) Hydroxytyrosol supplementation modifies plasma levels of tissue inhibitor of metallopeptidase 1 in women with breast cancer. Antioxidants 8:393. https://doi.org/10.3390/antiox8090393
Razali RA, Yazid MD, Saim A, Idrus RBH, Lokanathan Y (2023) Approaches in hydroxytyrosol supplementation on epithelial—mesenchymal transition in TGFβ1-induced human respiratory epithelial cells. Int J Mol Sci. https://doi.org/10.3390/ijms24043974
Granados-Principal S, Choi DS, Brown AMC, Chang J (2013) Abstract 2586: The natural compound hydroxytyrosol inhibits the Wnt/EMT axis and migration of triple-negative breast cancer cells. Cancer Res. https://doi.org/10.1158/1538-7445.am2013-2586
Cruz-Lozano M, González-González A, Marchal JA, Muñoz-Muela E, Molina MP, Cara FE, Brown AM, García-Rivas G, Hernández-Brenes C, Lorente JA, Sanchez-Rovira P, Chang JC, Granados-Principal S (2019) Hydroxytyrosol inhibits cancer stem cells and the metastatic capacity of triple-negative breast cancer cell lines by the simultaneous targeting of epithelial-to-mesenchymal transition, Wnt/β-catenin and TGFβ signaling pathways. Eur J Nutr. https://doi.org/10.1007/s00394-018-1864-1
Fabiani R, Fuccelli R, Pieravanti F, de Bartolomeo A, Morozzi G (2009) Production of hydrogen peroxide is responsible for the induction of apoptosis by hydroxytyrosol on HL60 cells. Mol Nutr Food Res 53:887–896. https://doi.org/10.1002/mnfr.200800376
Parkinson L, Cicerale S (2016) The health benefiting mechanisms of virgin olive oil phenolic compounds. Molecules. https://doi.org/10.3390/molecules21121734
Sánchez-Fidalgo S, Cárdeno A, Sánchez-Hidalgo M, Aparicio-Soto M, Villegas I, Rosillo MA, de la Lastra CA (2013) Dietary unsaponifiable fraction from extra virgin olive oil supplementation attenuates acute ulcerative colitis in mice. Eur J Pharm Sci 48:572–581. https://doi.org/10.1016/j.ejps.2012.12.004
Lawrence T, Fong C (2010) The resolution of inflammation: anti-inflammatory roles for NF-kappaB. Int J Biochem Cell Biol 42:519–523. https://doi.org/10.1016/j.biocel.2009.12.016
Yonezawa Y, Miyashita T, Nejishima H, Takeda Y, Imai K, Ogawa H (2018) Anti-inflammatory effects of olive-derived hydroxytyrosol on lipopolysaccharide-induced inflammation in RAW264.7 cells. J Veterin Med Sci 80:1801–1807. https://doi.org/10.1292/jvms.18-0250
Yonezawa Y, Kihara T, Ibi K, Senshu M, Nejishima H, Takeda Y, Imai K, Ogawa H (2019) Olive-derived hydroxytyrosol shows anti-inflammatory effect without gastric damage in rats. Biol Pharm Bull 42:1120–1127. https://doi.org/10.1248/bpb.b18-00979
Voltes A, Bermúdez A, Rodríguez-Gutiérrez G, Reyes ML, Olano C, Fernández-Bolaños J, de la Portilla F (2020) Anti-Inflammatory local effect of hydroxytyrosol combined with pectin-alginate and olive oil on trinitrobenzene sulfonic acid-induced colitis in wistar rats. J Invest Surg 33:8–14
Jeon S, Choi M (2018) Anti-inflammatory and anti-aging effects of hydroxytyrosol on human dermal fibroblasts (HDFs). Biomed Dermatol 2:21. https://doi.org/10.1186/s41702-018-0031-x
Xie Y, Xu Y, Chen Z, Lu W, Li N, Wang Q, Shao L, Li Y, Yang G, Bian X (2017) A new multifunctional hydroxytyrosol-fenofibrate with antidiabetic, antihyperlipidemic, antioxidant and antiinflammatory action. Biomed Pharmacother 95:1749–1758. https://doi.org/10.1016/j.biopha.2017.09.073
Echeverría F, Ortiz M, Valenzuela R, Videla L (2017) Hydroxytyrosol and cytoprotection: a projection for clinical interventions. Int J Mol Sci 18:930. https://doi.org/10.3390/ijms18050930
Tutino V, Caruso MG, Messa C, Perri E, Notarnicola M (2012) Antiproliferative, antioxidant and anti-inflammatory effects of hydroxytyrosol on human hepatoma HepG2 and Hep3B cell lines. Anticancer Res 32:5371–5377
CAS PubMed Google Scholar
Richard N, Arnold S, Hoeller U, Kilpert C, Wertz K, Schwager J (2011) Hydroxytyrosol is the major anti-inflammatory compound in aqueous olive extracts and impairs cytokine and chemokine production in macrophages. Planta Med 77:1890–1897. https://doi.org/10.1055/s-0031-1280022
Bernini R, Merendino N, Romani A, Velotti F (2013) Naturally occurring hydroxytyrosol: synthesis and anticancer potential. Curr Med Chem 20:655–670
Kawaguchi K, Matsumoto T, Kumazawa Y (2011) Effects of antioxidant polyphenols on TNF-alpha-related diseases. Curr Top Med Chem 11:1767–1779
Hu T, He X-W, Jiang J-G, Xu X-L (2014) Hydroxytyrosol and its potential therapeutic effects. J Agric Food Chem 62:1449–1455
Cheng Y, Qu Z, Fu X, Jiang Q, Fei J (2017) Hydroxytyrosol contributes to cell proliferation and inhibits apoptosis in pulsed electromagnetic fields treated human umbilical vein endothelial cells in vitro. Mol Med Rep 16:8826–8832. https://doi.org/10.3892/mmr.2017.7701
Cerezo AB, Labrador M, Gutiérrez A, Hornedo-Ortega R, Troncoso AM, Garcia-Parrilla MC (2019) Anti-VEGF signalling mechanism in HUVECs by melatonin, serotonin, hydroxytyrosol and other bioactive compounds. Nutrients 11:2421. https://doi.org/10.3390/nu11102421
Voltes A, Bermúdez A, Rodríguez-Gutiérrez G, Reyes ML, Olano C, Fernández-Bolaños J, de la Portilla F (2020) Anti-inflammatory local effect of hydroxytyrosol combined with pectin-alginate and olive oil on trinitrobenzene sulfonic acid-induced colitis in wistar rats. J Invest Surg 33:8–14. https://doi.org/10.1080/08941939.2018.1469697
Wu H, Jiang K, Zhang T, Zhao G, Deng G (2017) Hydroxytyrosol exerts an anti-inflammatory effect by suppressing Toll-like receptor 2 and TLR 2 downstream pathways in Staphylococcus aureus-induced mastitis in mice. J Funct Foods 35:595–604. https://doi.org/10.1016/j.jff.2017.06.035
Musa M (2022) Metals and radionuclides uptake by Ottelia alismoides collected from the ex-mining area Iin Kg, Gajah, Perak (Doctoral Dissertation, Faculty of Applied Sciences)
Zapletal K, Machnik G, Okopień B (2022) Review article polyphenols of antibacterial potential-may they help in resolving some present hurdles in medicine? Folia Biol 68:87–96
Utami ND, Nordin A, Katas H, Bt Hj Idrus R, Fauzi MB (2020) Molecular action of hydroxytyrosol in wound healing: an in vitro evidence-based review. Biomolecules. https://doi.org/10.3390/biom10101397
Rocha-Pimienta J, Martín-Vertedor D, Ramírez R, Delgado-Adámez J (2020) Pro-/antioxidant and antibacterial activity of olive leaf extracts according to bioavailability of phenolic compounds. Emir J Food Agric 32:479–487. https://doi.org/10.9755/ejfa.2020.v32.i6.2119
Medina E, de Castro A, Romero C, Brenes M (2006) Comparison of the concentrations of phenolic compounds in olive oils and other plant oils: correlation with antimicrobial activity. J Agric Food Chem 54:4954–4961. https://doi.org/10.1021/jf0602267
Ko KW, Lee BY, Kang HJ (2009) Antioxidant, antimicrobial, and antiproliferative activities of olive (Olea europaea L.) leaf extracts. Food Sci Biotechnol 18:818–821
Nazzaro F, Fratianni F, Cozzolino R, Martignetti A, Malorni L, De Feo V, Cruz AG, d’Acierno A (2019) Antibacterial activity of three extra virgin olive oils of the campania region, southern italy, related to their polyphenol content and composition. Microorganisms. https://doi.org/10.3390/microorganisms7090321
Martillanes S, Rocha-Pimienta J, Cabrera-Bañegil M, Martín-Vertedor D, Delgado-Adámez J (2017) Application of phenolic compounds for food preservation: food additive and active packaging, phenolic compounds - biological activity. INTECH. https://doi.org/10.5772/66885
Silvan JM, Guerrero-Hurtado E, Gutiérrez-Docio A, Alarcón-Cavero T, Prodanov M, Martinez-Rodriguez AJ (2021) Olive-leaf extracts modulate inflammation and oxidative stress associated with human H. pylori infection. Antioxidants (Basel). https://doi.org/10.3390/antiox10122030
Silvan JM, Guerrero-Hurtado E, Gutierrez-Docio A, Prodanov M, Martinez-Rodriguez AJ (2022) Olive leaf as a source of antibacterial compounds active against antibiotic-resistant strains of campylobacter jejuni and campylobacter coli. Antibiotics (Basel). https://doi.org/10.3390/antibiotics12010026
Yuan J-J, Yan H-J, He J, Liu Y-Y (2021) Antibacterial activities of polyphenols from olive leaves against Klebsiella pneumoniae. IOP Conf Ser Earth Environ Sci 680:012060. https://doi.org/10.1088/1755-1315/680/1/012060
Pannucci E, Caracciolo R, Romani A, Cacciola F, Dugo P, Bernini R, Varvaro L, Santi L (2021) An hydroxytyrosol enriched extract from olive mill wastewaters exerts antioxidant activity and antimicrobial activity on Pseudomonas savastanoi pv. savastanoi and Agrobacterium tumefaciens. Nat Prod Res 35:2677–2684. https://doi.org/10.1080/14786419.2019.1662006
Shan C, Xiong Y, Miao F, Liu T, Akhtar RW, Shah SAH, Gao H, Zhu E, Cheng Z (2023) Hydroxytyrosol mitigates Mycoplasma gallisepticum-induced pulmonary injury through downregulation of the NF-κB/NLRP3/IL-1β signaling pathway in chicken. Poult Sci 102:102582. https://doi.org/10.1016/j.psj.2023.102582
Bertelli M, Kiani AK, Paolacci S, Manara E, Kurti D, Dhuli K, Bushati V, Miertus J, Pangallo D, Baglivo M, Beccari T, Michelini S (2020) Hydroxytyrosol: a natural compound with promising pharmacological activities. J Biotechnol 309:29–33. https://doi.org/10.1016/j.jbiotec.2019.12.016
Ghomari O, Sounni F, Massaoudi Y, Ghanam J, Drissi Kaitouni LB, Merzouki M, Benlemlih M (2019) Phenolic profile (HPLC-UV) of olive leaves according to extraction procedure and assessment of antibacterial activity. Biotechnol Rep (Amst) 23:e00347. https://doi.org/10.1016/j.btre.2019.e00347
Reverón I, Plaza-Vinuesa L, Santamaría L, Oliveros JC, de Las Rivas B, Muñoz R, López de Felipe F (2020) Transcriptomic evidence of molecular mechanisms underlying the response of lactobacillus plantarum WCFS1 to hydroxytyrosol. Antioxidants (Basel). https://doi.org/10.3390/antiox9050442
Wei J, Wang S, Pei D, Qu L, Li Y, Chen J, Di D, Gao K (2018) Antibacterial activity of hydroxytyrosol acetate from olive leaves (Olea Europaea L.). Nat Prod Res 32:1967–1970. https://doi.org/10.1080/14786419.2017.1356830
Ghalandari M, Naghmachi M, Oliverio M, Nardi M, Shirazi HRG, Eilami O (2018) Antimicrobial effect of hydroxytyrosol, hydroxytyrosol acetate and hydroxytyrosol oleate on staphylococcus aureus and staphylococcus epidermidis. Electron J General Med. https://doi.org/10.29333/ejgm/85686
Karygianni L, Cecere M, Argyropoulou A, Hellwig E, Skaltsounis AL, Wittmer A, Tchorz JP, Al-Ahmad A (2019) Compounds from Olea europaea and Pistacia lentiscus inhibit oral microbial growth. BMC Complement Altern Med 19:51. https://doi.org/10.1186/s12906-019-2461-4
Popović M, Burčul F, Veršić Bratinčević M, Režić Mužinić N, Skroza D, Frleta Matas R, Nazlić M, Ninčević Runjić T, Jukić Špika M, Bego A, Dunkić V, Vitanović E (2023) In the beginning was the bud: phytochemicals from olive (Olea europaea L.) vegetative buds and their biological properties. Metabolites. https://doi.org/10.3390/metabo13020237
Warleta F, Campos M, Allouche Y, Sánchez-Quesada C, Ruiz-Mora J, Beltrán G, Gaforio JJ (2010) Squalene protects against oxidative DNA damage in MCF10A human mammary epithelial cells but not in MCF7 and MDA-MB-231 human breast cancer cells. Food Chem Toxicol 48:1092–1100. https://doi.org/10.1016/j.fct.2010.01.031
Warleta F, Quesada CS, Campos M, Allouche Y, Beltrán G, Gaforio JJ (2011) Hydroxytyrosol protects against oxidative DNA damage in human breast cells. Nutrients 3:839–857. https://doi.org/10.3390/nu3100839
Hu T, He X-W, Jiang J-G, Xu X-L (2014) Hydroxytyrosol and its potential therapeutic effects. J Agric Food Chem 62:1449–1455. https://doi.org/10.1021/jf405820v
Toteda G, Lupinacci S, Vizza D, Bonofiglio R, Perri E, Bonofiglio M, Lofaro D, La Russa A, Leone F, Gigliotti P, Cifarelli RA, Perri A (2017) High doses of hydroxytyrosol induce apoptosis in papillary and follicular thyroid cancer cells. J Endocrinol Invest 40:153–162. https://doi.org/10.1007/s40618-016-0537-2
Gómez-Caravaca AM, Segura-Carretero A, Fernández-Gutiérrez A, Caboni MF (2011) Simultaneous determination of phenolic compounds and saponins in Quinoa ( Chenopodium quinoa Willd) by a liquid chromatography-diode array detection-electrospray ionization–time-of-flight mass spectrometry methodology. J Agric Food Chem 59:10815–10825. https://doi.org/10.1021/jf202224j
Alle M, Adnan Md (2023) Role of nanotechnology in cancer therapies: recent advances, current issues, and approaches. Adv Smart Nanomater Appl. https://doi.org/10.1016/B978-0-323-99546-7.00022-7
Gogoi P, Kaur G, Singh NK (2022) Nanotechnology for colorectal cancer detection and treatment. World J Gastroenterol. https://doi.org/10.3748/wjg.v28.i46.6497
Jahangirian H, Ghasemian lemraski E, Webster TJ, Rafiee-Moghaddam R, Abdollahi Y (2017) A review of drug delivery systems based on nanotechnology and green chemistry: green nanomedicine. Int J Nanomedicine 12:2957–2978. https://doi.org/10.2147/IJN.S127683
Feng A (2023) Nanotechnology and its role in cancer treatment and diagnosis, highlights in science. Eng Technol 36:1051–1061. https://doi.org/10.54097/hset.v36i.6172
Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R (2021) Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov. https://doi.org/10.1038/s41573-020-0090-8
Mir SA, Hamid L, Bader GN, Shoaib A, Rahamathulla M, Alshahrani MY, Alam P, Shakeel F (2022) Role of nanotechnology in overcoming the multidrug resistance in cancer therapy: a review. Molecules. https://doi.org/10.3390/molecules27196608
Sykes EA, Chen J, Zheng G, Chan WCW (2014) Investigating the impact of nanoparticle size on active and passive tumor targeting efficiency. ACS Nano. https://doi.org/10.1021/nn500299p
Maeda H (2001) The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul. https://doi.org/10.1016/S0065-2571(00)00013-3
Guan Q, Sun S, Li X, Lv S, Xu T, Sun J, Feng W, Zhang L, Li Y (2016) Preparation, in vitro and in vivo evaluation of mPEG-PLGA nanoparticles co-loaded with syringopicroside and hydroxytyrosol. J Mater Sci Mater Med 27:24. https://doi.org/10.1007/s10856-015-5641-x
Sani NS, Onsori H, Akrami S, Rahmati M (2022) A Comparison of the anti-cancer effects of free and PLGA-PAA encapsulated hydroxytyrosol on the HT-29 colorectal cancer cell line. Anticancer Agents Med Chem 22:390–394. https://doi.org/10.2174/1871520621666210308095712
Safi M, Onsori H, Rahmati M (2022) Investigation of the anti-cancer effects of free and PLGA-PAA encapsulated hydroxytyrosol on the MCF-7 breast cancer cell line. Curr Mol Med 22:657–662. https://doi.org/10.2174/1566524020666201231103826
Zygouri P, Athinodorou AM, Spyrou K, Simos YV, Subrati M, Asimakopoulos G, Vasilopoulos KC, Vezyraki P, Peschos D, Tsamis K, Gournis DP (2023) Oxidized-multiwalled carbon nanotubes as non-toxic nanocarriers for hydroxytyrosol delivery in cells. Nanomaterials 13:714. https://doi.org/10.3390/nano13040714
Fernández-Prior Á, Bermúdez-Oria A, Del M, Millán-Linares C, Fernández-Bolaños J, Espejo-Calvo JA, Rodríguez-Gutiérrez G (2021) Anti-inflammatory and antioxidant activity of hydroxytyrosol and 3,4-Dihydroxyphenyglycol purified from table olive effluents. Foods 10:227. https://doi.org/10.3390/foods10020227
Robles-Almazan M, Pulido-Moran M, Moreno-Fernandez J, Ramirez-Tortosa C, Rodriguez-Garcia C, Quiles JL, Ramirez-Tortosa MC (2018) Hydroxytyrosol: bioavailability, toxicity, and clinical applications. Food Res Int 105:654–667. https://doi.org/10.1016/j.foodres.2017.11.053
Auñon-Calles D, Canut L, Visioli F (2013) Toxicological evaluation of pure hydroxytyrosol. Food Chem Toxicol 55:498–504. https://doi.org/10.1016/j.fct.2013.01.030
Download references
Non-Applicable.
Not applicable.
Authors and affiliations.
University Center for Research & Development (UCRD), Biotechnology Engineering & Food Technology, Chandigarh University, Gharuan, Mohali, 140413, Punjab, India
Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, Punjab, India
Brahmjot Singh
Kanya Maha Vidyalaya, Jalandhar, 144004, Punjab, India
Department of Botany, School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, 185234, Jammu and Kashmir, India
Palak Bakshi
Advanced Eye Center, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India
Payal Bajaj
Department of Microbiology, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
Manoj Kumar
Institute of Nano Science and Technology, Mohali, Punjab, 140306, India
Sukhvinder Dhiman
Department of Biosciences, University Institute of Biotechnology, Chandigarh University, Mohali, Punjab, 140413, India
Shivam Jasrotia
Department of Chemistry, Chandigarh University, Gharuan, Mohali, 140413, Punjab, India
Parveen Kumar
Government Medical College, Rajouri, Jammu and Kashmir, India
Ranjan Dutta
Sun Yat Sen University, Guangzhou, China
You can also search for this author in PubMed Google Scholar
Conceptualization, investigation, data curation, writing, and original draft preparation were done by AK, BS, KP, PB, PB, PYB, MD, SD, SJ, PK, and RD. Data curation and figure preparation were done by AK,KP, and BS. Writing review, editing, and supervision were done by AK, BS, PK, and MD. The authors have read and approved the final manuscript.
Correspondence to Ajay Kumar .
Ethics approval and consent to participate, consent for publication, competing interests.
The authors declare that they have no competing interests.
Publisher’s note.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .
Reprints and permissions
Cite this article.
Kumar, A., Singh, B., Paul, K. et al. Hydroxytyrosol in cancer research: recent and historical insights on discoveries and mechanisms of action. Futur J Pharm Sci 10 , 129 (2024). https://doi.org/10.1186/s43094-024-00700-7
Download citation
Received : 29 October 2023
Accepted : 06 September 2024
Published : 19 September 2024
DOI : https://doi.org/10.1186/s43094-024-00700-7
Anyone you share the following link with will be able to read this content:
Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative
Increasing globalization and complexity of the tax environment demands in-depth research into tax coverage, tax risks and tax avoidance in multinational companies. This research explains the complex dynamics between these variables with a focus on multinational companies listed on the Indonesia Stock Exchange during 2009–2022. A sample of 714 observations was used to explore the relationship between tax disclosure, tax risk and tax avoidance. Statistical analysis shows that tax disclosure has a negative effect on tax avoidance. This shows that the more transparent a company is in disclosing its tax information, the less the company is involved in tax avoidance. On the other hand, tax risk has a positive effect on tax avoidance, meaning that when a company faces higher tax risk, the company tends to increase its tax avoidance efforts. In particular, this study reveals that tax disclosure also plays a moderating role, weakening the positive influence of tax risk on tax avoidance. Although tax risks can encourage companies to avoid taxes, the level of tax dispersion can reduce this positive impact. The practical relevance of this research provides valuable guidance for tax practitioners, regulators and decision makers in developing more effective tax policies. The results of this research highlight the importance of transparency in reducing tax avoidance practices, while providing insight into how tax risk and tax spread can be managed more efficiently. The academic contribution of this research lies in the development of multinational company taxation literature. By providing a deeper understanding of the relationships between variables, this research provides a foundation for further research in understanding the dynamics of global taxation. In conclusion, this research not only reflects its practical urgency, but also enriches the understanding of multinational corporate taxation in a global context.
This is a preview of subscription content, log in via an institution to check access.
Subscribe and save.
Price includes VAT (Russian Federation)
Instant access to the full article PDF.
Rent this article via DeepDyve
Institutional subscriptions
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Not applicable.
Adams, J. R., Demers, E., and Klassen, K. 2022. Tax aggressive behavior and voluntary tax disclosure: Evidence from corporate sustainability reporting. SSRN Electronic Journal.
Afida, C.N. 2022. Should CbCR go public? A developing country’s perspective of public CbCR. Jurnal Pajak Indonesia 6 (2S): 626–640.
Google Scholar
Aliprandi, G. and Bordes, K. 2023. Tax transparency by multinationals: Trends in country-by-country reports public disclosure. https://shs.hal.science/halshs-04103949 .
Amni, S., R. Fitrios, and A. Silfi. 2023. The influence of thin capitalization, capital intensity, and earnings management on tax avoidance with tax havens country as moderator. International Journal of Science and Business 20 (1): 109–122.
Article Google Scholar
Andersen, T.J. 2020. Managing in dynamic, complex and unpredictable business contexts. Emerald Group Publishing.
Artemenko, D.A., L.A. Aguzarova, F.S. Aguzarova, and E.V. Porollo. 2017. Causes of tax risks and ways to reduce them. European Research Studies Journal 20 (3B): 453–459.
Aslam, A. and Coelho, M. 2021. A firm lower bound: Characteristics and impact of corporate minimum taxation. IMF Working Paper: WP/21/161.
Beer, S., R. De Mooij, and L. Liu. 2018. International corporate tax avoidance: A review of the channels, magnitudes, and blind spots. Journal of Economic Surveys 34 (3): 660–688.
Beuselinck, C., and J. Pierk. 2024. On the dynamics between local and international tax planning in multinational corporations. Review of Accounting Studies 29: 852–888.
Boubaker, S., I. Derouiche, and H. Nguyen. 2022. Voluntary disclosure, tax avoidance and family firms. Journal of Management and Governance 26 (1): 129–158.
Bougie, R. and Sekaran, U. 2020. Research methods for business : A skill building approach, (8th edition - Asia Edition). Hoboken: Wiley.
Bradbury, D., T. Hanappi, and A. Moore. 2018. Estimating the fiscal effects of base erosion and profit shifting: Data availability and analytical issues. Transnational Corporations Journal 25 (2): 91–106.
Bradbury, D., and P. O’Reilly. 2018. Inclusive fiscal reform: Ensuring fairness and transparency in the international tax system. International Tax and Public Finance 25: 1434–1448.
Brown, R.J., B.N. Jorgensen, and P.F. Pope. 2019. The interplay between mandatory country-by-country reporting, geographic segment reporting, and tax havens: Evidence from the European Union. Journal of Accounting and Public Policy 38 (2): 106–129.
Brown, K.B. 2011. Comparative regulation of corporate tax avoidance: An Overview. En a comparative look at regulation of corporate tax avoidance , vol. 12. Dordrecht: Springer.
Bruhne, A.I., and D. Schanz. 2022. Defining and managing corporate tax risk: Perceptions of tax risk experts. Contemporary Accounting Research 39 (4): 2861–2902.
Budiman, N.A., and B. Bandi. 2022. Tax avoidance in Jakarta Islamic index companies. International Journal of Islamic Business Ethics 7 (1): 30–39.
Budiman, N.A., and B. Bandi. 2023. Tax avoidance: How board of directors diversity strategies are applied in facing tax audits? Journal of Corporate Finance, Management, and Banking System 3 (6): 26–37.
Chan, K.H., P.L.L. Mo, and A.Y. Zhou. 2013. Government ownership, corporate governance and tax aggressiveness: Evidence from China. Accounting and Finance 53: 1029–1051.
Chen, S., Y. Huang, N. Li, and T. Shevlin. 2019. How does quasi-indexer ownership affect corporate tax planning? Journal of Accounting and Economics 67: 278–296.
Chen, W. 2021a. Tax risks control and sustainable development: Evidence from China. Meditari Accountancy Research 29 (6): 1381–1400.
Chen, W. 2021b. Too far east is west: Tax risk, tax reform and investment timing. International Journal of Managerial Finance 17 (2): 303–326.
Choi, J., and H. Park. 2022. Tax avoidance, tax risk, and corporate governance: Evidence from Korea. Sustainability 14 (1): 469.
Cuervo-Cazurra, A., M. Dieleman, P. Hirsch, S.B. Rodrigues, and S. Zyglidopoulos. 2021. Multinationals’ misbehavior. Journal of World Business 56 (5): 101244.
Darussalam, D., Septriadi, D., and Kristiaji, B. B. (2022). Transfer Pricing: Ide, Strategi, and Panduan Praktis dalam Perspektif Pajak Internasional (Edisi Kedua). Jakarta: DDTC.
Dewi, A.P.S., and M.D. Ardiyanto. 2020. Pengaruh Penghindaran Pajak and Risiko Pajak terhadap Biaya Utang. Diponegoro Journal of Accounting 9 (3): 1–9.
Di Nino, V., M.M. Habib, and M. Schmitz. 2020. Multinational enterprises, financial centres and their implications for external imbalances: A Euro area perspective. ECB Economic Bulletin 2: 60–83.
Dillon, S. 2017. Tax avoidance, revenue starvation and the age of the multinational corporation. The International Lawyer 50 (2): 275–328.
Drake, K.D., S.J. Lusch, and J. Stekelberg. 2019. Does tax risk affect investor valuation of tax avoidance? Journal of Accounting, Auditing and Finance 34 (1): 151–176.
Dyreng, S. and Hanlon, M. 2021. Tax avoidance and multinational firm behavior. International Tax Policy.
Eisenberg, P. 2018. Does tax transparency tackle tax avoidance?: A stakeholder perspective. International Journal of Advances in Management and Economics 8 (1): 46–59.
Financial Services Authority Circular Letter Number: SE-17/BL/2012 concerning financial report disclosure checklist for all industries in the capital market in Indonesia.
Flagmeier, V. and Müller, J. (2016). Tax loss carryforward disclosure and uncertainty. Arqus-Arbeitskreis Quantitative Steuerlehre.
Fung, S. 2017. The questionable legitimacy of the OECD/G20 BEPS project. Erasmus Law Review 2: 76–88.
Gaaya, S., N. Lakhal, and F. Lakhal. 2017. Does family ownership reduce corporate tax avoidance? The moderating effect of audit quality. Managerial Auditing Journal 32: 731–744.
Gaertner, F. 2014. CEO after-tax compensation incentives and corporate tax avoidance. Contemporary Accounting Research 31: 1077–1102.
Government Regulation Number 55 of 2022 concerning Adjustments to Regulations in the Income Tax Sector.
Guedrib, M., and G. Marouani. 2023. The interactive impact of tax avoidance and tax risk on the firm value: New evidence in the tunisian context. Asian Review of Accounting 31 (2): 203–226.
Guenther, D.A., S.R. Matsunaga, and B.M. Williams. 2017. Is tax avoidance related to firm risk? The Accounting Review 92 (1): 115–136.
Handayani, Y.D., and E.Y. Ibrani. 2023. Reciprocal: Financial reporting aggressiveness-tax reporting aggressiveness and corporate governance. Management Science Research Journal 2 (1): 1–12.
Hanggariksa, M.D., and A.K. Paksi. 2023. Kontribusi Perusahaan Multinasional dalam Menghadapi Pandemi Covid-19 di Indonesia. SOSIOLOGI: Jurnal Ilmiah Kajian Ilmu Sosial and Budaya 25 (1): 1–20.
Hanlon, M., and S. Heitzman. 2010. A review of tax research. Journal of Accounting and Economics 50 (2–3): 127–178.
Hardeck, I., Inger, K.K., Moore, R.D., and Schneider, J. 2023. The impact of tax avoidance and environmental performance on tax disclosure in CSR reports. Journal of the American Taxation Association.
Hardeck, I., K.K. Inger, R.D. Moore, and J. Schneider. 2024. The impact of tax avoidance and environmental performance on tax disclosure in CSR reports. Journal of the American Taxation Association 46 (1): 83–111.
Hariani, A. 2023. Banyak WP Baand Laporkan Rugi, Tapi Bisnis Berkembang. https://www.pajak.com/pajak/banyak-wp-baand-laporkan-rugi-tapi-bisnis-berkembang/ (Accessed 20 September 2023).
Hasseldine, J., and G. Morris. 2013. Corporate social responsibility and tax avoidance: A comment and reflection. Accounting Forum 37 (1): 1–14.
Iqbal, M., D. Savitri, L. Nur, R.D. Andini, and P.R. Silalahi. 2023. Peran Perusahaan Multinasional dalam Meningkatkan Sektor Perekonomian di Indonesia. CEMERLANG: Jurnal Manajemen and Ekonomi Bisnis 3 (1): 64–76.
Jati, A.W., I. Ulum, and C. Utomo. 2019. ax avoidance, corporate governance and Kinerja Keuangan Perusahaan yang Terdaftar dalam Jakarta Islamic Index. Jurnal Reviu Akuntansi and Keuangan 9 (2): 214–225.
Jiang, C. 2023. Tax avoidance of multinational enterprises and its countermeasures. Advances in Economics, Management and Political Sciences 4: 253–259.
Joshi, P. 2020. Does private country-by-country reporting deter tax avoidance and income shifting? Evidence from BEPS action item 13. Journal of Accounting Research 58 (2): 333–381.
Kaal, W. A. (2014). Dynamic regulation of the financial services industry. Legal Studies Research Paper, 13–24.
Kerr, J.N. 2019. Transparency, information shocks, and tax avoidance. Contemporary Accounting Research 36 (2): 1146–1183.
Kessler, J. 2004. Tax avoidance purpose and section 741 of taxes act 1988. British Tax Review 4: 375–409.
Kurniasih, L., Y. Yusri, F. Kamarudin, and A.F.S. Hassan. 2023. The role of country by country reporting on corporate tax avoidance: Does it effective for the tax haven? Cogent Business and Management 10 (1): 1–25.
Law Number 36 of 2008 concerning Income Tax.
Lenz, H. 2020. Aggressive tax avoidance by managers of multinational companies as a violation of their moral duty to obey the law: A Kantian Rationale. Journal of Business Ethics 165: 681–697.
Lin, X., M. Liu, S. So, and D. Yuen. 2019. Corporate social responsibility, firm performance and tax risk. Managerial Auditing Journal 34 (9): 1101–1130.
Lozada, D.C.P. 2023. The effect of tax transparency on consumer and firm behavior: Experimental evidence. Journal of Behavioral and Experimental Economics 104: 101990.
Mangoting, Y., O.Y. Yuliana, J. Effendy, L. Hariono, and V.M. Lians. 2021. The effect of tax risk on tax avoidance. Jurnal Keuangan and Perbankan 25 (3): 570–584.
Martinez, A.L. 2023. Anti-BEPS tax reforms and the WTO: Addressing global tax challenges. SSRN Electronic Journal.
Mason, R. 2020. The transformation of international tax. American Journal of International Law 114 (3): 353–402.
Masri, I., A. Syakhroza, and R. Wardhani. 2019. The role of tax risk management in international tax avoidance practices: Evidence from Indonesia and Malaysia. International Journal of Trade and Global Markets 12 (3–4): 311–322.
Matthews, L.C. and Thakkar, B. 2012. The impact of globalization on cross-cultural communication. InTech.
Mgammal, M.H., and K.N.I.K. Ismail. 2015. Corporate tax disclosure: A review of concepts, theories, constraints, and benefits. Asian Social Science 11 (28): 1–14.
Mgammal, M.H. 2019. The effect of components of tax saving on tax disclosure: A panel data approach in malaysian listed companies. Pacific Accounting Review 31 (4): 574–601.
Mgammal, M.H. 2020. Corporate tax planning and corporate tax disclosure. Meditari Accountancy Research 28 (2): 327–364.
Minister of Finance Regulation Number 213/PMK.03/2016 concerning Types of Documents and/or Additional Information that Must be Kept by Taxpayers Carrying Out Transactions with Parties Who Have Special Relationships, and Procedures for Managing Them.
Moraes, G.S.C., E.M. Nascimento, S.V.N. Soares, and B.F.L. Primola. 2021. Tax avoidance and tax disclosure: A study of Brazilian listed companies. Contextus: Contemporary Journal of Economics and Management 19 (13): 197–216.
Neuman, S.S., T.C. Omer, and A.P. Schmidt. 2020. Assessing tax risk: Practitioner perspectives. Contemporary Accounting Research 37 (3): 1788–1827.
Noonan, C., and V. Plekhanova. 2023. Mandatory binding dispute resolution in the base erosion and profit shifting (BEPS) two pillar solution. International and Comparative Law Quarterly 72 (2): 437–476.
OECD. 2023a. International Collaboration to End Tax Avoidance. https://www.oecd.org/tax/beps/ (Accessed 20 November 2023).
OECD. 2023b. OECD guidelines for multinational enterprises on responsible business conduct. https://doi.org/10.1787/81f92357-en .
Oguttu, A. 2020. Curtailing BEPS through enforcing corporate transparency: The challenges of implementing country-by-country reporting in developing countries and the case for making public country-by-country reporting mandatory. World Tax Journal 12 (4): 799–828.
Parada, L. and Bondi, M. (2023). Response to the UN resolution A/RES/77/244 on promotion of inclusive and effective tax cooperation at the united nations. SSRN Electronic Journal.
Payne, D.M., and C.A. Raiborn. 2018. Aggressive tax avoidance: A conundrum for stakeholder. Journal of Business Ethics 147: 469–487.
Pratama, A., and A.P. Pratiwi. 2022. Tax disclosure in financial statements: The case of Indonesia. International Journal of Applied Economics, Finance and Accounting 14 (1): 50–59.
Purba, A.R. and Siahaan, C. 2021. The effects of globalization on international communication in the world business. https://doi.org/10.2139/ssrn.3962731 .
Purbolakseto, H., B. Tjahjadi, and H. Tjaraka. 2022. Peran ukuran perusahaan memoderasi pengaruh risiko pajak perusahaan terhadap penghindaran pajak. Jurnal Ekonomi Akuntansi and Manajemen 21 (2): 169–186.
Puspitasari, M., and D. Septriadi. 2023. Analysis of the implementation of base erosion and profit shifting (BEPS) inclusive framework on Indonesian tax regulation. Contemporary Accounting Case Studies 2 (2): 364–384.
Qatawneh, A.M., A. Bader, and K.T. Amayreh. 2023. The Impact of tax legislation on public shareholding companies tax disclosure: A comparative study between the Jorandian tax system and the US tax system (State of Illinois). International Journal of Professional Business Review 8 (6): 1–19.
Raiborn, C.A., M.F. Massoud, and D.M. Payne. 2015. Tax avoidance: The GOOD, THE BAD, AND THE FUTUre. Journal of Business and Management 21 (1): 77–94.
Rajput, S.K.O. and Marwat, J. 2019. Tax Avoidance and earning management in Pakistan. Corporate Governance: Disclosure.
Rakhmayani, A., C.Y.D. Ekaristi, and M. Aresteria. 2022. Consequences of tax avoidance. Tax Accounting Applied Journal 1 (1): 18–28.
Ria, R. 2023. Profitability moderation on the effect of tax avoidance on company value. Jurnal Multidisiplin Maandi 3 (5): 1099–1104.
Richardson, G., G. Taylor, and R. Lanis. 2013. Determinants of transfer pricing aggressiveness: Empirical evidence from australian firms. Journal of Contemporary Accounting and Economics 9 (2): 136–150.
Richardson, G., B. Wang, and X. Zhang. 2016. Ownership structure and corporate tax avoidance: Evidence from publicly listed private firms in China. Journal of Contemporary Accounting and Economics 12: 141–158.
Robinson, L.A., and A.P. Schmidt. 2013. Firm and investor responses to uncertain tax benefit disclosure requirements. Journal of the American Taxation Association 35 (2): 85–120.
Rudyanto, A. (2024). Does tax disclosure in global reporting initiative (GRI)-based sustainability reporting mitigate aggressive tax avoidance? Evidence from a developing country. Journal of Global Responsibility.
Salihu, I.A., H.A. Annuar, and S.N.S. Obid. 2015. Foreign investors’ interests and corporate tax avoidance: Evidence from an emerging economy. Journal of Contemporary Accounting and Economics 11: 138–147.
Seegert, N. 2017. Optimal tax policy under uncertainty over tax revenues.
Shen, Y. 2023. Contingency information disclosure and corporate tax avoidance. Frontiers in Business, Economics and Management 7 (2): 112–119.
Spence, M. 1973. Job market signaling. The Quarterly Journal of Economics 87 (3): 355–374.
Sreesing, P. 2018. Taxes and risk-taking behavior: evidence from mergers and acquisitions in the G7 nations. The Journal of Risk Finance 19 (3): 277–294.
Stiglingh, M., A.R. Smit, and A. Smit. 2022. The relationship between tax transparency and tax avoidance. South African Journal of Accounting Research 36 (1): 1–21.
Submitter, G.J., N.D. Mohanadas, A.S.A. Salim, and S. Ramasamy. 2019. A theoretical review on corporate tax avoidance: shareholder approach versus stakeholder approach. Journal of Finance and Banking Review 4 (3): 82–88.
Tang, T.Y. 2020. A review of tax avoidance in China. China Journal of Accounting Research 13 (4): 327–338.
Tanto, V. 2016. The international company and tax avoidance. European Journal of Economics and Business Studies 2 (2): 42–50.
Tax Justice Network. 2023. CORRECTION: Countries are losing 1.7% more to tax havens than we reported. https://taxjustice.net/press/correction-countries-are-losing-1-7-more-to-tax-havens-than-we-reported/ (accessed 25 September 2023).
Taylor, G., and G. Richardson. 2012. International corporate tax avoidance practices: Evidence from australian firms. The International Journal of Accounting 47 (4): 469–496.
Tulus, C. and Yasmine, N. (2020). Dynamic capability as connection of the triangle company, environment and strategy. Social Science Research Network.
Wang, N., and Y. Guan. 2023. Calculus logic function in tax risk avoidance in different stages of enterprises. Applied Mathematics and Nonlinear Sciences 8 (1): 1889–1900.
Wencel, A. 2022. The disclosure of tax risk in the financial reports of public companies. The Theoretical Journal of Accounting 46 (3): 197–215.
Yahya, A., N. Asiah, and R. Nurjanah. 2023. Tax avoidance in relationship on capital intensity, growth opportunities, financial distress and accounting conservatism. Journal of Business Management and Economic Development 1 (2): 154–165.
Download references
The authors are grateful to the Directorate of Research, Technology, and Community Service of the Ministry of Education, Culture, Research, and Technology for funding this research activity.
Authors and affiliations.
Department Accounting, Faculty Economy and Business, Muria Kudus University, Kudus, Indonesia
Nita Andriyani Budiman
Department Accounting, Faculty Economy and Business, Sebelas Maret University, Surakarta, Indonesia
Bandi Bandi, Ari Kuncara Widagdo & Eko Arief Sudaryono
You can also search for this author in PubMed Google Scholar
NAB, BB, AKW and EAS authors agreed on the content of the study. NAB, BB, AKW and EAS collected all the data for analysis. NAB agreed on the methodology. NAB, BB, AKW and EAS completed the analysis based on agreed steps. Results and conclusions are discussed and written together. All authors read and approved the final manuscript.
Correspondence to Nita Andriyani Budiman .
Conflict of interest.
The authors have no conflicts of interest to declare.
This article does not contain any studies with human or animal subjects performed by any of the authors.
Informed consent was obtained from all individual participants included in the study.
Consent for publication, additional information, publisher's note.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Indicator | No. | Disclosure items |
---|---|---|
Permanent difference | 1 | Non deductible expenses |
2 | Impairment of receivables | |
3 | Selling fixed assets | |
4 | Income tax payable | |
5 | Adjustment for changes in tax rates | |
6 | Income subject to final taxation | |
7 | Withholding tax | |
8 | Amortization expense of intangible assets | |
Temporary difference | 9 | Impairment of investments |
10 | Previously unrecognized deferred tax assets | |
11 | Exchange rate difference | |
12 | Non-taxable income | |
13 | Deferred tax expense | |
14 | Adjustment for investments accounted for using the equity method | |
15 | Deferred tax on pension benefit obligations | |
16 | Post-employment benefits | |
17 | Adjustment for errors in prior periods | |
18 | Deferred tax on undistributed earnings of foreign subsidiaries | |
19 | Recognition of deferred tax assets | |
Differences in foreign tax rates | 20 | Parent or subsidiary company operating in different jurisdictions |
Fiscal losses | 21 | Expected tax benefits or tax loss carryforwards |
22 | Tax loss carryforward | |
23 | Unrecognized tax losses | |
24 | tax loss reserve | |
Other | 25 | Incentive tax |
26 | Tax assessment notice or tax bill | |
27 | Tax provision | |
28 | Derivative financial instruments |
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
Reprints and permissions
Budiman, N.A., Bandi, B., Widagdo, A.K. et al. The evolution of tax strategies in multinational companies: a historical perspective. Int J Discl Gov (2024). https://doi.org/10.1057/s41310-024-00265-0
Download citation
Received : 09 August 2024
Accepted : 09 September 2024
Published : 25 September 2024
DOI : https://doi.org/10.1057/s41310-024-00265-0
Anyone you share the following link with will be able to read this content:
Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative
IMAGES
VIDEO
COMMENTS
Historical research is the process of investigating and studying past events, people, and societies using a variety of sources and methods. This type of research aims to reconstruct and interpret the past based on the available evidence.
What is Historical Research? Stephen Petrina May 2020 History— Few methods reduce to cliché as readily as history: "history is bunk," "history shows," "history teaches," "history is our guide," "that's ancient history," etc. This is partially due to different senses of history. Beard (1946) differentiates among three ...
Historical method is the collection of techniques and guidelines that historians use to research and write histories of the past. Secondary sources, primary sources and material evidence such as that derived from archaeology may all be drawn on, and the historian's skill lies in identifying these sources, evaluating their relative authority ...
This step-by-step guide progresses from an introduction to historical resources to information about how to identify a topic, craft a thesis and develop a research paper.
Steps in Historical Research. Historical research involves the following steps: Identify an idea, topic or research question. Conduct a background literature review. Refine the research idea and questions. Determine that historical methods will be the method used. Identify and locate primary and secondary data sources.
When to Use the Historical Research Method? You can use historical research method to: Uncover the unknown fact. Answer questions Identify the association between the past and present. Understand the culture based on past experiences.. Record and evaluate the contributions of individuals, organisations, and institutes.
What do historians do? Historical researchers often use documentary, biographical, oral history, and archival methods, in addition to many of the methods commonly used across the social sciences. Historical research is often concerned with topics related to social change over time and data can take many forms, including photographs and secondary data and documents from a range of official and ...
Overview This guide is an introduction to selected resources available for historical research. It covers both primary sources (such as diaries, letters, newspaper articles, photographs, government documents and first-hand accounts) and secondary materials (such as books and articles written by historians and devoted to the analysis and interpretation of historical events and evidence).
Featuring a wealth of examples that illustrate the methods used by seasoned experts, The Princeton Guide to Historical Research reveals that, however varied the subject matter and sources, historians share basic tools in the quest to understand people and the choices they made.
Tools and techniques for historical research. If you are just starting out in HPS, this will be the first time for many years - perhaps ever - that you have done substantial library or museum based research. The number of general studies may seem overwhelming, yet digging out specific material relevant to your topic may seem like finding ...
Historians use historical research methods to obtain data from primary and secondary sources and, then, assess how the information contributes to understanding a historical period or event. Historical research methods are used with primary and secondary sources. Below is a description of each type of source. What Is a Primary Source?
"Historical method refers to the use of primary historical data to answer a question. Because the nature of the data depends on the question being asked, data may include demographic records, such as birth and death certificates; newspapers articles; letters and diaries; government records; or even architectural drawings.
A wide-ranging critical survey of methods for historical research at all levels Historians have become increasingly sensitive to social and cultural theory since the 1980s, yet the actual methods by which research is carried out in History have been largely taken for granted. Research Methods for History encourages those researching the past to think creatively about the wide range of methods ...
We conduct historical research for a number of reasons: - to avoid the mistakes of the past. - to apply lessons from the past to current problems. - to use the past to make predictions about the present and future. - to understand present practices and policies in light of the past. - to examine trends across time.
Historical research involves looking at the past and what has been recorded, determining its credibility or accuracy and drawing from it for modern conclusions. Learn more about the definitions ...
The use of archival data, oral history, and documentary research - methods covered in this part - traditionally define the historical method. The methods and methodologies associated with historical studies have reflected the changes in the larger field of history.
Research Methods The Shapiro Library subscribes to the SAGE Research Methods database, a resource designed for those who are doing research or who are learning how to do research. Methods and practices covered include writing research questions and literature reviews, choosing research methods, conducting oral histories, and more.
Secondary sources interpret original documents and give you background information about the topic you want to research. Examples of secondary sources are: articles, dictionaries, encyclopedias, textbooks and books that interpret or review research works.
Historians provide insight into the past. By means of books, articles, websites, or presentations, they offer information to colleagues, students, and a wider public. In their work, historians constantly ask questions about the past, and they answer those questions by researching historical literature and sources.
In pursuit of the answers, we will survey a variety of approaches to the past used by historians writing in the last several decades. We will examine how these historians conceive of their object of study, how they use primary sources as a basis for their accounts, how they structure the narrative and analytical discussion of their topic, and ...
Qualitative and Quantitive Research Historians rely on primary and secondary sources when conducting research and writing historical works. They also use qualitative and/or quantitative research methods to support their arguments and conclusions.
Data Analysis in Historical Research Methodology to synthesize a very large amount of data into a meaningful narrative Organize information into categories Locate patterns or themes Develop a coding system Advantages of Historical Research Allows investigation of topics and questions that can be studied in no other way. Study evidence from the ...
GUIDELINES FOR HISTORICAL RESEARCH AND WRITING HOW TO APPROACH RESEARCH AND WRITING A. Fourteen Steps to a good historical research paper. In A Short Guide to Writing About History Richard Marius outlines fourteen steps that every student should follow in writing a historical research paper. 1. Identify your audience.
Research Methods and Theory ebooks. Scroll for a plethora of ebooks related to historical research methods and theories. For full citations, click on the Word document at the bottom of the page. Collaborative Historical Research in the Age of Big Data: ...
SLCA research is still in the development stage, facing challenges such as lack of standardized evaluation methods, scattered research fields, and underestimation of the evaluation at the use stage. Future research will focus on unifying and refining the index system, developing and applying diversified models, and providing reference ...
Scientists need to create standard usage methods and guarantee high-quality products. We should learn from both historical and current practices when it comes to plant-based medicine. By merging age-old wisdom with cutting-edge research, we can discover innovative ways to harness plants for health benefits while honoring ancient healing customs.
Background Cancer is a persistent global health challenge, demanding continuous exploration of innovative therapeutic strategies. Hydroxytyrosol (HT), derived from olive oil, has garnered attention for its potent antioxidant and anti-inflammatory properties, revitalizing interest due to recent breakthroughs in comprehending its intricate anticancer mechanisms. Main Body This review conducts a ...
The FBI released detailed data on over 14 million criminal offenses for 2023 reported to the Uniform Crime Reporting (UCR) Program by participating law enforcement agencies.
Increasing globalization and complexity of the tax environment demands in-depth research into tax coverage, tax risks and tax avoidance in multinational companies. This research explains the complex dynamics between these variables with a focus on multinational companies listed on the Indonesia Stock Exchange during 2009-2022. A sample of 714 observations was used to explore the relationship ...