Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy.

BACKGROUND: Active targeting by surface-modified nanoplatforms enables a more precise and elevated accumulation of nanoparticles within the tumor, thereby enhancing drug delivery and efficacy for a successful cancer treatment. However, surface functionalization involves complex procedures that increase costs and timelines, presenting challenges for clinical implementation. Biomimetic nanoparticles (BNPs) have emerged as unique drug delivery platforms that overcome the limitations of actively targeted nanoparticles. Nevertheless, BNPs coated with unmodified cells show reduced functionalities such as specific tumor targeting, decreasing the therapeutic efficacy. Those challenges can be overcome by engineering non-patient-derived cells for BNP coating, but these are complex and cost-effective approaches that hinder their wider clinical application. Here we present an immune-driven strategy to improve nanotherapeutic delivery to tumors. Our unique perspective harnesses T-cell exhaustion and tumor immune evasion to develop a groundbreaking new class of BNPs crafted from exhausted T-cells (NExT) of triple-negative breast cancer (TNBC) patients by specific culture methods without sophisticated engineering. METHODS: NExT were generated by coating PLGA (poly(lactic-co-glycolic acid)) nanoparticles with TNBC-derived T-cells exhausted in vitro by acute activation. Physicochemical characterization of NExT was made by dynamic light scattering, electrophoretic light scattering and transmission electron microscopy, and preservation and orientation of immune checkpoint receptors by flow cytometry. The efficacy of chemotherapy-loaded NExT was assessed in TNBC cell lines in vitro. In vivo toxicity was made in CD1 mice. Biodistribution and therapeutic activity of NExT were determined in cell-line- and autologous patient-derived xenografts in immunodeficient mice. RESULTS: We report a cost-effective approach with a good performance that provides NExT naturally endowed with immune checkpoint receptors (PD1, LAG3, TIM3), augmenting specific tumor targeting by engaging cognate ligands, enhancing the therapeutic efficacy of chemotherapy, and disrupting the PD1/PDL1 axis in an immunotherapy-like way. Autologous patient-derived NExT revealed exceptional intratumor accumulation, heightened chemotherapeutic index and efficiency, and targeted the tumor stroma in a PDL1+ patient-derived xenograft model of triple-negative breast cancer. CONCLUSIONS: These advantages underline the potential of autologous patient-derived NExT to revolutionize tailored adoptive cancer nanotherapy and chemoimmunotherapy, which endorses their widespread clinical application of autologous patient-derived NExT.

Estradiol and Estrone Have Different Biological Functions to Induce NF-κB-Driven Inflammation, EMT and Stemness in ER+ Cancer Cells.

In general, the risk of being diagnosed with cancer increases with age; however, the development of estrogen-receptor-positive (ER+) cancer types in women are more closely related to menopausal status than age. In fact, the general risk factors for cancer development, such as obesity-induced inflammation, show differences in their association with ER+ cancer risk in pre- and postmenopausal women. Here, we tested the role of the principal estrogens in the bloodstream before and after menopause, estradiol (E2) and estrone (E1), respectively, on inflammation, epithelial-to-mesenchymal transition (EMT) and cancer stem cell enrichment in the human ER+ cervical cancer cell line HeLa. Our results demonstrate that E1, contrary to E2, is pro-inflammatory, increases embryonic stem-transcription factors (ES-TFs) expression and induces EMT in ER+ HeLa cells. Moreover, we observed that high intratumoural expression levels of 17ß-Hydroxysteroid dehydrogenase (HSD17B) isoforms involved in E1 synthesis is a poor prognosis factor, while overexpression of E2-synthetizing HSD17B isoforms is associated with a better outcome, for patients diagnosed with ER+ ovarian and uterine corpus carcinomas. This work demonstrates that E1 and E2 have different biological functions in ER+ gynaecologic cancers. These results open a new line of research in the study of ER+ cancer subtypes, highlighting the potential key oncogenic role of E1 and HSD17B E1-synthesizing enzymes in the development and progression of these diseases.

Expression of IMP3 in a retrospective cohort of melanomas with selective lymph node biopsy.

Insulin-like growth factor-II mRNA-binding protein 3 (IMP-3), which is a member of the insulin-like growth factor mRNA-binding protein family, is expressed at high levels in many types of cancer, where it plays an important role in cell proliferation, as well as in the processes of invasion, migration, and metastasis. Its expression has also been demonstrated in malignant melanoma, but not in other benign skin lesions, which has raised the possibility of using it as a predictive and prognosis marker. Its relationship with sentinel lymph node biopsy, however, has not been explored yet. A retrospective study including 120 histological samples of patients diagnosed with malignant cutaneous melanoma in Granada, between 2012 and 2018, was developed. All patients had had a sentinel lymph node biopsy (SLNB) performed at Hospital Universitario San Cecilio. IMP3 immunostaining was simultaneously carried out in the cutaneous lesion. We observed a significant difference regarding the percentage of cells expressing IMP3 (29.73 ± 3.81 for negative SLNB vs 44.86 ± 5.91 for positive SLNB, P = .020). Our endpoint calculated according to the ROC curve of 35% was significant with P = .007. H (P = .013) and AR (P = .016) indexes, created by the percentage of positive tumor cells and the intensity of the IMP3 expression, were also statistically significant. The most optimal cut-off points to predict the positivity of the SLNB were 35 for the percentage of positive tumor cells and 70 for the H score. We found a significant association between the expression of IMP3 and the regional nodal status defined by the SLNB on malignant melanomas in our series.

Modulation by hydroxytyrosol of oxidative stress and antitumor activities of paclitaxel in breast cancer.

PURPOSE: The main objective of this study was to test the therapeutic potential of hydroxytyrosol and its combination with paclitaxel in breast cancer on oxidative stress status. METHODS: Impact on proliferation rates of different chemotherapy administration patterns was assayed in MCF-7 and MDA-MB-231 breast cancer cell lines. Breast tumor-bearing rats were randomly assigned to Control, Hydroxytyrosol, Paclitaxel and Paclitaxel plus hydroxytyrosol groups, for 6 weeks. Tumor volume, cell proliferation and several systemic oxidative stress parameters were measured. Anti-proliferative activity in vitro experiments was correlated with in vivo experiments. RESULTS: Combination group did significantly reduce tumor volume when compared with paclitaxel alone. Additionally, the combination improved the antioxidant status without compromising the antitumor activity of standard chemotherapy. CONCLUSION: These findings reveal for the first time that hydroxytyrosol is an active partner in combined therapies with paclitaxel against breast cancer. Combination with hydroxytyrosol would also ensure a less oxidative impact of chemotherapeutic drugs that could potentially improve patient wellness.

Male breast cancer: correlation between immunohistochemical subtyping and PAM50 intrinsic subtypes, and the subsequent clinical outcomes.

Male breast cancer is a rare disease that is still poorly understood. It is mainly classified by immunohistochemistry as a luminal disease. In this study, we assess for the first time the correlation between molecular subtypes based on a validated six-marker immunohistochemical panel and PAM50 signature in male breast cancer, and the subsequent clinical outcome of these different subtypes. We collected 67 surgical specimens of invasive male breast cancer from four different Spanish pathology laboratories. Immunohistochemical staining for the six-marker panel was performed on tissue microarrays. PAM50 subtypes were determined in a research-use-only nCounter Analysis System. We explored the association of immunohistochemical and PAM50 subtypes. Overall survival and disease-free survival were analyzed in the different subtypes of each classification. The distribution of tumor molecular subtypes according PAM50 was: 60% luminal B, 30% luminal A and 10% human epidermal growth factor receptor 2 (Her2) enriched. Only one Her2-enriched tumor was also positive by immunohistochemistry and was treated with trastuzumab. None of the tumors were basal-like. Using immunohistochemical surrogates, 51% of the tumors were luminal B, 44% luminal A, 4% triple-negative and 1% Her2-positive. The clinicopathological characteristics did not differ significantly between immunohistochemical and PAM50 subtypes. We found a significant worse overall survival in Her2-enriched compared with luminal tumors. Male breast cancer seems to be mainly a genomic luminal disease with a predominance of the luminal B subtype. In addition, we found a proportion of patients with Her2-negative by immunohistochemistry but Her2-enriched profile by PAM50 tumors with a worse outcome compared with luminal subtypes that may benefit from anti-Her2 therapies.

Curcumin and Health.

Nowadays, there are some molecules that have shown over the years a high capacity to act against relevant pathologies such as cardiovascular disease, neurodegenerative disorders or cancer. This article provides a brief review about the origin, bioavailability and new research on curcumin and synthetized derivatives. It examines the beneficial effects on health, delving into aspects such as cancer, cardiovascular effects, metabolic syndrome, antioxidant capacity, anti-inflammatory properties, and neurological, liver and respiratory disorders. Thanks to all these activities, curcumin is positioned as an interesting nutraceutical. This is the reason why it has been subjected to several modifications in its structure and administration form that have permitted an increase in bioavailability and effectiveness against different diseases, decreasing the mortality and morbidity associated to these pathologies.

Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively. The dysfunction of genes involved in the cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a direct abrogation of hypoxia inducible factor (HIF) degradation, resulting in a pseudo-hypoxic state implicated in PCC/PGL development. Recently, somatic post-zygotic mutations in EPAS1 (HIF2A) have been found in patients with multiple PGLs and congenital erythrocytosis. We assessed 41 PCCs/PGLs for mutations in EPAS1 and herein describe the clinical, molecular and genetic characteristics of the 7 patients found to carry somatic EPAS1 mutations; 4 presented with multiple PGLs (3 of them also had congenital erythrocytosis), whereas 3 were single sporadic PCC/PGL cases. Gene expression analysis of EPAS1-mutated tumors revealed similar mRNA EPAS1 levels to those found in SDH-gene- and VHL-mutated cases and a significant up-regulation of two hypoxia-induced genes (PCSK6 and GNA14). Interestingly, single nucleotide polymorphism array analysis revealed an exclusive gain of chromosome 2p in three EPAS1-mutated tumors. Furthermore, multiplex-PCR screening for small rearrangements detected a specific EPAS1 gain in another EPAS1-mutated tumor and in three non-EPAS1-mutated cases. The finding that EPAS1 is involved in the sporadic presentation of the disease not only increases the percentage of PCCs/PGLs with known driver mutations, but also highlights the relevance of studying other hypoxia-related genes in apparently sporadic tumors. Finally, the detection of a specific copy number alteration affecting chromosome 2p in EPAS1-mutated tumors may guide the genetic diagnosis of patients with this disease.

Sunflower Oil but Not Fish Oil Resembles Positive Effects of Virgin Olive Oil on Aged Pancreas after Life-Long Coenzyme Q Addition.

An adequate pancreatic structure is necessary for optimal organ function. Structural changes are critical in the development of age-related pancreatic disorders. In this context, it has been reported that different pancreatic compartments from rats were affected according to the fat composition consumed. Since there is a close relationship between mitochondria, oxidative stress and aging, an experimental approach has been developed to gain more insight into this process in the pancreas. A low dosage of coenzyme Q was administered life-long in rats in order to try to prevent pancreatic aging-related alterations associated to some dietary fat sources. According to that, three groups of rats were fed normocaloric diets containing Coenzyme Q (CoQ) for two years, where virgin olive, sunflower, or fish oil was included as unique fat source. Pancreatic samples for microscopy and blood samples were collected at the moment of euthanasia. The main finding is that CoQ supplementation gives different results according to fat used in diet. When sunflower oil was the main fat in the diet, CoQ supplementation seems to improve endocrine pancreas structure and in particular ß-cell mass resembling positive effects of virgin olive oil. Conversely, CoQ intake does not seem to improve the structural alterations of exocrine compartment previously observed in fish oil fed rats. Therefore CoQ may improve pancreatic alterations associated to the chronic intake of some dietary fat sources.

Impact of diet on breast cancer risk: a review of experimental and observational studies.

Breast cancer, which presents the highest global incidence of all female cancers, is caused by the interaction of genetic and environmental factors. Among the latter, diet has attracted considerable attention, as it is a modifiable risk factor and thus offers an opportunity to design preventive strategies. Nevertheless, only alcohol consumption has been unequivocally related to increased breast cancer risk. Despite the failure of observational studies in human populations to clearly define the nature of the relationship between specific nutrient exposures and breast cancer risk, in vivo and in vitro studies strongly suggest its existence. Moreover, studies at the molecular level have identified the putative action mechanism by which the nutritional constituents of specific foodstuffs may exert protective or enhancing effects with respect to breast cancer risk. The inadequate experimental design of some observational studies, or the occurrence of measurement errors and/or recall bias during data collection, or insufficient follow-up and subject characterization, may underlie these controversies. By improving the methods used to study the relationship between diet and breast cancer risk, and by applying new technologies linked to novel approaches such as "nutrigenomics," it might be possible to derive effective recommendations for breast cancer prevention and thus improve anti-cancer treatment.

Dietary antioxidants and lifespan: Relevance of environmental conditions, diet, and genotype of experimental models.

The rise of life expectancy in current societies is not accompanied, to date, by a similar increase in healthspan, which represents a great socio-economic problem. It has been suggested that aging can be manipulated and then, the onset of all age-associated chronic disorders can be delayed because these pathologies share age as primary underlying risk factor. One of the most extended ideas is that aging is consequence of the accumulation of molecular damage. According to the oxidative damage theory, antioxidants should slow down aging, extending lifespan and healthspan. The present review analyzes studies evaluating the effect of dietary antioxidants on lifespan of different aging models and discusses the evidence on favor of their antioxidant activity as anti-aging mechanisms. Moreover, possible causes for differences between the reported results are evaluated.

Male breast cancer: immunohistochemical subtypes and clinical outcome characterization.

AIM: The aim of this study was to assess the molecular subtype profiles of male breast cancer (MBC) and subsequent clinical outcome using a validated 6-marker immunohistochemical panel. METHODS: A total of 43 cases of MBC were examined retrospectively using a semiquantitative immunohistochemical analysis of estrogen receptor (ER), progesterone receptor (PR), Ki-67, human epidermal growth factor receptor 2 (Her2), epidermal growth factor receptor and cytokeratin 5/6. Patients were classified into the following categories: luminal A, luminal B, Her2-positive or basal-like subtypes. RESULTS: The median age of patients was 63 years (r: 32-89). The predominant histology was invasive ductal carcinoma (91%). Only 1 patient had advanced breast cancer at diagnosis. Ninety-three percent were ER-positive and 84% were PR-positive. Two patients had tumors that were ER- and PR-negative. The distribution of tumor molecular subtypes was 19 (44%) luminal A, 22 (51%) luminal B and 2 (5%) basal-like. The Her2-positive tumor subtype was not identified. The clinicopathological characteristics did not differ significantly between tumor subtypes A and B. There were no significant differences in 6-year disease-free survival (74 vs. 82%, p = 0.77) or overall survival (74 vs. 82%, p = 0.69) between luminal A and luminal B subtypes, respectively. CONCLUSION: The most common subtypes in our cohort of MBC were luminal B followed by luminal A, and no differences were found between both tumor subtypes in terms of clinicopathologic characteristics and patient outcome.

Differences reported in the lifespan and aging of male Wistar rats maintained on diets containing fat with different fatty acid profiles (virgin olive, sunflower or fish oils) are not reflected by histopathological lesions found at death in central nervous and endocrine systems.

The present study was designed to examine if dietary fat sources that have shown differences in lifespan and if some aging-related aspects can modulate the range of histopathologic changes in central nervous and endocrine systems that occur during the lifespan of Wistar rats. Moreover, it was attempted to gain insight into the relationship between longevity and the development of the different pathological changes, as well as possible interaction with diet. In order to achieve this, male Wistar rats were randomly assigned to three experimental groups fed semisynthetic and isoenergetic diets from weaning until death with different dietary fat sources, namely virgin olive, sunflower, or fish oil. An individual follow-up until death of each animal was performed. Incidence, severity, and burden of specific or group (i.e., neoplastic or non-neoplastic proliferative and non-proliferative) of lesions was calculated along with individual's disease and individual organ lesion burden. Most of the histopathological lesions found have been described in previous studies. Neoplasms, and in particular pituitary adenomas followed by brain tumors, were the most prevalent lesions found in the rats and the main cause of death involving both systems. Incidence of brain lesions was associated with age-at-death. Assayed dietary fats did not present differential effects on pathological changes occurring in endocrine and central nervous systems throughout rat lifespan.

Hypoxia-Inducible Factor-1 Alpha Expression Is Predictive of Pathological Complete Response in Patients with Breast Cancer Receiving Neoadjuvant Chemotherapy.

To demonstrate the value of hypoxia-inducible factor-1α (HIF-1α) in predicting response in patients with breast cancer receiving standard neoadjuvant chemotherapy (NAC). METHODS: Ninety-five women enrolled in two prospective studies underwent biopsies for the histopathological diagnosis of breast carcinoma before receiving NAC, based on anthracyclines and taxanes. For expression of HIF-1α, EGFR, pAKT and pMAPK, tumor samples were analyzed by immunohistochemistry in tissues microarrays. Standard statistical methods (Pearson chi-square test, Fisher exact test, Kruskal-Wallis test, Mann-Whitney test and Kaplan-Meier method) were used to study the association of HIF-1α with tumor response, survival and other clinicopathologic variables/biomarkers. RESULTS: HIF-1α expression was positive in 35 (39.7%) cases and was significantly associated to complete pathological response (pCR) (p = 0.014). HIF-1α expression was correlated positively with tumor grade (p = 0.015) and Ki-67 expression (p = 0.001) and negativity with progesterone receptors (PR) (p = 0.04) and luminal A phenotype expression (p = 0.005). No correlation was found between HIF-1α expression and EGFR, pAKT and pMAPK. In terms of survival, HIF-1α expression was associated with a significantly shorter disease-free survival (p = 0.013), being identified as an independent prognostic factor in multivariate analysis. CONCLUSIONS: Overexpression of HIF-1α is a predictor of pCR and shorter DFS; it would be valuable to confirm these results in prospective studies.

A Diet Rich in Saturated Fat and Cholesterol Aggravates the Effect of Bacterial Lipopolysaccharide on Alveolar Bone Loss in a Rabbit Model of Periodontal Disease.

Increasing evidence connects periodontitis with a variety of systemic diseases, including metabolic syndrome, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). The proposal of this study was to evaluate the role of diets rich in saturated fat and cholesterol in some aspects of periodontal diseases in a lipopolysaccharide (LPS)-induced model of periodontal disease in rabbits and to assess the influence of a periodontal intervention on hyperlipidemia, atherosclerosis, and NAFLD progression to non-alcoholic steatohepatitis. Male rabbits were maintained on a commercial standard diet or a diet rich in saturated fat (3% lard w/w) and cholesterol (1.3% w/w) (HFD) for 40 days. Half of the rabbits on each diet were treated 2 days per week with intragingival injections of LPS from Porphyromonas gingivalis. Morphometric analyses revealed that LPS induced higher alveolar bone loss (ABL) around the first premolar in animals receiving standard diets, which was exacerbated by the HFD diet. A higher score of acinar inflammation in the liver and higher blood levels of triglycerides and phospholipids were found in HFD-fed rabbits receiving LPS. These results suggest that certain dietary habits can exacerbate some aspects of periodontitis and that bad periodontal health can contribute to dyslipidemia and promote NAFLD progression, but only under certain conditions.

Longevity and Cause of Death in Male Wistar Rats Fed Lifelong Diets Based on Virgin Olive Oil, Sunflower Oil, or Fish Oil.

Extending life by delaying the aging process has been proven to be the most effective way to fight multiple chronic diseases in elderly adults. Evidence suggests that longevity is inversely related to unsaturation of membrane phospholipids. This study investigated how different unsaturated dietary fats affect life span and cause of death in male Wistar rats fed diets based on virgin olive oil (V), sunflower oil (S), or fish oil (F), which were supplemented or not with Coenzyme Q10 (CoQ10). Previous results suggest that individual longevity and survival probability at different ages may be modulated by an appropriate dietary fat treatment. Lifelong feeding with V or F diets would reduce death probability compared to feeding with S diet at certain ages, although the effects of V diet would be maintained for most of life. Furthermore, the addition of lower amounts of CoQ10 reduced mortality associated with S diet, but CoQ10 had no effect on survival when combined with virgin olive oil or fish oil. Supplementation with low doses of CoQ10 failed to increase the maximum life span potential of rats fed a V or F diet. No clear evidence showing that monounsaturated fatty acids, n-3 polyunsaturated fatty acids, or CoQ10 exerted the observed effects by modulating the rate of aging has been found.

Hydroxytyrosol Supplementation Modifies Plasma Levels of Tissue Inhibitor of Metallopeptidase 1 in Women with Breast Cancer.

The etiology of breast cancer can be very different. Most antineoplastic drugs are not selective against tumor cells and also affect normal cells, leading to a wide variety of adverse reactions such as the production of free radicals by altering the redox state of the organisms. Therefore, the objective of this study was to elucidate if hydroxytyrosol (HT) (an antioxidant present in extra virgin olive oil) has a chemomodulatory effect when combined with the chemotherapeutic drugs epirubicin and cyclophosphamide followed by taxanes in breast cancer patients. Changes in plasma levels of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) throughout the chemotherapy treatment were studied. Both molecules are involved in cell proliferation, apoptosis, neoangiogenesis, and metastasis in breast cancer patients. Women with breast cancer were divided into two groups: a group of patients receiving a dietary supplement of HT and a control group of patients receiving placebo. The results showed that the plasma levels of TIMP-1 in the group of patients receiving HT were significantly lower than those levels found in the control group after the epirubicin-cyclophosphamide chemotherapy.

Heart Histopathology and Mitochondrial Ultrastructure in Aged Rats Fed for 24 Months on Different Unsaturated Fats (Virgin Olive Oil, Sunflower Oil or Fish Oil) and Affected by Different Longevity.

Diet plays a decisive role in heart physiology, with lipids having especial importance in pathology prevention and development. This study aimed to investigate how dietary lipids varying in lipid profile (virgin olive oil, sunflower oil or fish oil) affected the heart of rats during aging. Heart histopathology, mitochondrial morphometry, and oxidative status were assessed. Typical histopathological features associated with aging, such as valvular lesions, endomyocardical hyperplasia, or papillary muscle calcification, were found at a low extent in all the experimental groups. The most relevant finding was that inflammation registered by fish oil group was lower compared to the other treatments. At the ultrastructural level, heart mitochondrial area, perimeter, and aspect ratio were higher in fish oil-fed rats than in those fed on sunflower oil. Concerning oxidative stress markers, there were differences only in coenzyme Q levels and catalase activity, lower in sunflower oil-fed animals compared with those fed on fish oil. In summary, dietary intake for a long period on dietary fats with different fatty acids profile led to differences in some aspects associated with the aging process at the heart. Fish oil seems to be the fat most protective of heart during aging.

Oxidative stress status in liver mitochondria and lymphocyte DNA damage of atherosclerotic rabbits supplemented with water soluble coenzyme Q10.

The effects of the administration of water soluble coenzyme Q10 (25 mg/kg per day) over 30 days, after 50 days feeding on a high-fat diet (3% lard + 1.3% cholesterol), were investigated in the plasma and liver mitochondria of rabbits. Results showed that this atherogenic diet enhanced lipid levels both in plasma and liver mitochondria, reduced plasma and mitochondrial concentrations of retinol and coenzyme Q10, led to higher DNA damage in peripheral blood lymphocytes and reactive oxygen species concentration in liver mitochondria. The treatment of animals with coenzyme Q10 reduced (to the healthy group levels) lipid concentration in liver mitochondria with no effect on plasma lipids, increased mitochondrial levels of alpha-tocopherol, restored mitochondrial coenzyme Q10 and improved alpha-tocopherol levels in plasma. Moreover, coenzyme Q10 supplementation reduced mitochondrial reactive oxygen species levels and decreased DNA damage in peripheral blood lymphocytes. The findings suggest that antioxidant therapy with coenzyme Q10 may be used in the treatment of liver pathologies associated to the intake of high-fat, atherogenic, diets.

Hydroxytyrosol: Bioavailability, toxicity, and clinical applications.

Many beneficial properties have been attributed to the Mediterranean diet. Over the years, researchers have attempted to learn which foods and which food components are responsible for good health. One of these components is hydroxytyrosol, an important phenolic compound present in olive oil. Hydroxytyrosol is a molecule of high interest to the pharmaceutical industry due to its anti-inflammatory and antimicrobial qualities its role against cardiovascular diseases and metabolic syndrome and for its neuroprotection, antitumour, and chemo modulation effects. The interest in this molecule has led to wide research on its biological activities, its beneficial effects in humans and how to synthetize new molecules from hydroxytyrosol. This review describes the vast range of information about hydroxytyrosol, focusing on its involvement in biological mechanisms and modulation effects on different pathologies. This review also serves to highlight the role of hydroxytyrosol as a nutraceutical and as a potential therapeutic agent.