Changes in the ultrasound presentation of hepatocellular carcinoma: a center's three decades of experience.

PURPOSE: Ultrasound (US) surveillance is a cornerstone for early diagnosis of HCC, anyway US presentation has undergone significant changes. With the aim of evaluating the effects of US surveillance program in the real-world clinical practice, we wanted to evaluate US presentation of HCCs over the last 30 years and the differences of HCCs presentation according to etiology. METHODS: 174 patients diagnosed between 1993 and 98 (G1), 96 between 2003 and 08 (G2), 102 between 2013 and 18 (G3), were compared. US patterns were: single, multiple or diffuse nodules. The echo-patterns: iso-, hypo-, hyper-echoic, or mixed. In G1, the HCC diagnosis was mainly histologic; in G2 by EASL 2001 and AASLD 2005, in G3 AASLD 2011, EASL 2012, and AISF 2013 guidelines. RESULTS: HCV was the most frequent etiology, dropping between G1 (81%) and G3 (66%) (P < 0.01), metabolic increased between G1 (5%) and G3 (14%) (P < 0.01). Single HCC was more prevalent in G3 vs G1 (65.6% vs 40%) (P < 0.0001), multiple nodules in G1 (50%) vs G3 (33.3%) (P < 0.02) and diffuse in G1 (16%) vs G2 (2%) and vs G3 (1%) (P < 0.001). The most frequent echo-pattern was hypo-echoic G1 (50%) vs G2 (79%) and G1 vs G3 (65%) (P < 0.01). Iso-echoic pattern was the least frequent (7-12%). Mixed pattern decreased from G1 (28%) to G3 (12%) (P < 0.002). In G3 there were more multiple or diffuse HCCs in metabolic (P < 0.03). CONCLUSION: US presentation became less severe due to surveillance programs. HCV remains the most frequent cause, an increase in metabolic etiology has been shown throughout the decades.

Real life experience on the use of Remdesivir in patients admitted to COVID-19 in two referral Italian hospital: a propensity score matched analysis.

Remdesivir (RDV) was the first Food and Drug Administration (FDA)-approved medication for COVID-19, with discordant data on efficacy in reducing mortality risk and disease progression. In the context of a dynamic and rapidly changing pandemic landscape, the utilization of real-world evidence is of utmost importance. The objective of this study is to evaluate the impact of RDV on patients who have been admitted to two university referral hospitals in Italy due to COVID-19. All patients older than 18 years and hospitalized at two different universities (Bari and Palermo) were enrolled in this study. To minimize the effect of potential confounders, we used propensity score matching with one case (Remdesivir) and one control that never experienced this kind of intervention during hospitalization. Mortality was the primary outcome of our investigation, and it was recorded using death certificates and/or medical records. Severe COVID-19 was defined as admission to the intensive care unit or a qSOFAscore ≥ 2 or CURB65scores ≥ 3. After using propensity score matching, 365 patients taking Remdesivir and 365 controls were included. No significant differences emerged between the two groups in terms of mean age and percentage of females, while patients taking Remdesivir were less frequently active smokers (p < 0.0001). Moreover, the patients taking Remdesivir were less frequently vaccinated against COVID-19. All the other clinical, radiological, and pharmacological parameters were balanced between the two groups. The use of Remdesivir in our cohort was associated with a significantly lower risk of mortality during the follow-up period (HR 0.56; 95% CI 0.37-0.86; p = 0.007). Moreover, RDV was associated with a significantly lower incidence of non-invasive ventilation (OR 0.27; 95% CI 0.20-0.36). Furthermore, in the 365 patients taking Remdesivir, we observed two cases of mild renal failure requiring a reduction in the dosage of Remdesivir and two cases in which the physicians decided to interrupt Remdesivir for bradycardia and for QT elongation. Our study suggests that the use of Remdesivir in hospitalized COVID-19 patients is a safe therapy associated with improved clinical outcomes, including halving of mortality and with a reduction of around 75% of the risk of invasive ventilation. In a constantly changing COVID-19 scenario, ongoing research is necessary to tailor treatment decisions based on the latest scientific evidence and optimize patient outcomes.

Genetic Biomarkers of Sorafenib Response in Patients with Hepatocellular Carcinoma.

The identification of biomarkers for predicting inter-individual sorafenib response variability could allow hepatocellular carcinoma (HCC) patient stratification. SNPs in angiogenesis- and drug absorption, distribution, metabolism, and excretion (ADME)-related genes were evaluated to identify new potential predictive biomarkers of sorafenib response in HCC patients. Five known SNPs in angiogenesis-related genes, including VEGF-A, VEGF-C, HIF-1a, ANGPT2, and NOS3, were investigated in 34 HCC patients (9 sorafenib responders and 25 non-responders). A subgroup of 23 patients was genotyped for SNPs in ADME genes. A machine learning classifier method was used to discover classification rules for our dataset. We found that only the VEGF-A (rs2010963) C allele and CC genotype were significantly associated with sorafenib response. ADME-related gene analysis identified 10 polymorphic variants in ADH1A (rs6811453), ADH6 (rs10008281), SULT1A2/CCDC101 (rs11401), CYP26A1 (rs7905939), DPYD (rs2297595 and rs1801265), FMO2 (rs2020863), and SLC22A14 (rs149738, rs171248, and rs183574) significantly associated with sorafenib response. We have identified a genetic signature of predictive response that could permit non-responder/responder patient stratification. Angiogenesis- and ADME-related genes correlation was confirmed by cumulative genetic risk score and network and pathway enrichment analysis. Our findings provide a proof of concept that needs further validation in follow-up studies for HCC patient stratification for sorafenib prescription.

Effectiveness of a Food Supplement Based on Glucomannan, D-Chiro-Inositol, Cinnamomum zeylanicum Blume and Inulin in Patients with Metabolic Syndrome.

Metabolic syndrome (MetS) is associated with cardiovascular risk factors, such as insulin resistance, dyslipidaemia, hypertension and abdominal obesity. Given the growing need to investigate food supplements with positive health effects, this study was aimed at testing the benefits of a specific supplement for people with MetS. Fifty-eight subjects with MetS and T2DM or impaired glucose tolerance assuming metformin, were randomly assigned to take a food supplement of glucomannan, D-chiro-inositol, Cinnamomum zeylanicum blume and inulin at a daily fixed dose of 4 g orally for four months. Body weight, waist circumference, plasma lipid profile (total cholesterol, LDL, HDL and triglyc-erides), plasma glycaemic profile and visceral adiposity index (VAI) were measured at baseline and after four months of supplementation. After 16 weeks, in subjects with T2DM or insulin resistance who took the supplement (+ metformin), there was a significant reduction in body weight and BMI (p < 0.0001), serum insulin (p < 0.05) and the HOMA index (p < 0.01), as well as in the lipaemic pattern, with a significant improvement in total serum cholesterol (p < 0.005), triglycerides (p < 0.03) and LDL (p < 0.02). Our study shows that the food supplement tested is a valid and safe alternative therapeutic approach in the management of MetS and all its resulting risk factors, as its efficacy has been demonstrated across anthropometric, glucose, lipid and hepatic parameters.

Anemia as a risk factor for disease progression in patients admitted for COVID-19: data from a large, multicenter cohort study.

In respiratory infections, anemia is both a consequence of acute inflammation and a predictor of poor clinical outcomes. There are few studies investigating the role of anemia in COVID-19, suggesting a potential role in predicting disease severity. In this study, we aimed to assess the association between the presence of anemia at admission and incidence of severe disease and death in patients hospitalized for COVID-19. Data from all adult patients admitted for COVID-19 in University Hospital "P. Giaccone" Palermo, and University Hospital of Bari, Italy, were retrospectively collected from 1st of September 2020 to 31 August 2022. The association between anemia (defined as Hb < 13 g/dl and < 12 g/dl in males and females, respectively), in-hospital mortality and severe COVID-19 was tested using a Cox's regression analysis. Severe COVID-19 forms were defined as admission to intensive or sub-intensive care unit or a qSOFAscore ≥ 2 or CURB65scores ≥ 3. p values were calculated using the Student's t test for continuous variables and the Mantel-Haenszel Chi-square test for categorical ones. The association between anemia and the mortality was made using a Cox's regression analysis, adjusted, in two models, for the potential confounders and using a propensity score. Among the 1562 patients included in the analysis, prevalence of anemia was 45.1% (95% CI 43-48%). Patients with anemia were significantly older (p < 0.0001), reported more co-morbidities, and presented higher baseline levels of procalcitonin, CRP, ferritin and IL-6. Overall, the crude incidence of mortality was about four times higher in patients with anemia compared to those without. After adjusting for 17 potential confounders, the presence of anemia significantly increased the risk of death (HR = 2.68; 95% CI: 1.59-4.52) and of risk of severe COVID-19 (OR = 2.31; 95% CI: 1.65-3.24). The propensity score analysis substantially confirmed these analyses. Our study provides evidence that, in patients hospitalized for COVID-19, anemia is both associated with a more pronounced baseline pro-inflammatory profile and higher incidence of in-hospital mortality and severe disease.

The three facets of the SARS-CoV-2 pandemic during the first two waves in the northern, central, and southern Italy.

BACKGROUND: There is a scarcity of information in literature regarding the clinical differences and comorbidities of patients affected by Coronavirus disease 2019 (COVID-19), which could clarify the different prevalence of the outcomes (composite and only death) between several Italian regions. OBJECTIVE: This study aimed to assess the heterogeneity of clinical features of patients with COVID-19 upon hospital admission and disease outcomes in the northern, central, and southern Italian regions. METHODS: An observational cohort multicenter retrospective study including 1210 patients who were admitted for COVID-19 in Infectious diseases, Pulmonology, Endocrinology, Geriatrics and Internal Medicine Units in Italian cities stratified between north (263 patients); center (320 patients); and south (627 patients), during the first and second pandemic waves of SARS-CoV-2 (from February 1, 2020 to January 31, 2021). The data, obtained from clinical charts and collected in a single database, comprehended demographic characteristics, comorbidities, hospital and home pharmacological therapies, oxygen therapy, laboratory values, discharge, death and Intensive care Unit (ICU) transfer. Death or ICU transfer were defined as composite outcomes. RESULTS: Male patients were more frequent in the northern Italian region than in the central and southern regions. Diabetes mellitus, arterial hypertension, chronic pulmonary and chronic kidney diseases were the comorbidities more frequent in the southern region; cancer, heart failure, stroke and atrial fibrillation were more frequent in the central region. The prevalence of the composite outcome was recorded more frequently in the southern region. Multivariable analysis showed a direct association between the combined event and age, ischemic cardiac disease, and chronic kidney disease, in addition to the geographical area. CONCLUSIONS: Statistically significant heterogeneity was observed in patients with COVID-19 characteristics at admission and outcomes from northern to southern Italy. The higher frequency of ICU transfer and death in the southern region may depend on the wider hospital admission of frail patients for the availability of more beds since the burden of COVID-19 on the healthcare system was less intense in southern region. In any case, predictive analysis of clinical outcomes should consider that the geographical differences that may reflect clinical differences in patient characteristics, are also related to access to health-care facilities and care modalities. Overall, the present results caution against generalizability of prognostic scores in COVID-19 patients derived from hospital cohorts in different settings.

Can Baseline IL-6 Levels Predict Long COVID in Subjects Hospitalized for SARS-CoV-2 Disease?

The immune response to infection plays a crucial role in the pathogenesis of COVID-19, but several patients develop a wide range of persistent symptoms, which is becoming a major global health and economic burden. However, reliable indicators are not yet available to predict the persistence of symptoms typical of the so-called long COVID. Our study aims to explore an eventual role of IL-6 levels as a marker of long COVID. Altogether, 184 patients admitted to the COVID Medicine Unit of the University Hospital in Palermo, Italy, from the 1st of September 2020, were analyzed. Patients were divided into two groups according to the IL-6 serum levels (normal or elevated), considering the serum IL-6 levels measured during the first four days of hospitalization. In our study, higher serum IL-6 levels were associated with a doubled higher risk of long COVID (OR = 2.05; 95% CI: 1.04-4.50) and, in particular, they were associated with a higher incidence of mobility decline (OR = 2.55; 95% CI: 1.08-9.40) and PTSD (OR = 2.38; 95% CI: 1.06-8.61). The analysis of our case series confirmed the prominent role of IL-6 levels in response to SARS-CoV-2 infection, as predictors not only of COVID-19 disease severity and unfavorable outcomes, but also long COVID development trends.

Phenotypical and Functional Alteration of γδ T Lymphocytes in COVID-19 Patients: Reversal by Statins.

(1) Background: statins have been considered an attractive class of drugs in the pharmacological setting of COVID-19 due to their pleiotropic properties and their use correlates with decreased mortality in hospitalized COVID-19 patients. Furthermore, it is well known that statins, which block the mevalonate pathway, affect γδ T lymphocyte activation. As γδ T cells participate in the inflammatory process of COVID-19, we have investigated the therapeutical potential of statins as a tool to inhibit γδ T cell pro-inflammatory activities; (2) Methods: we harvested peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild clinical manifestations, COVID-19 recovered patients, and healthy controls. We performed ex vivo flow cytometry analysis to study γδ T cell frequency, phenotype, and exhaustion status. PBMCs were treated with Atorvastatin followed by non-specific and specific stimulation, to evaluate the expression of pro-inflammatory cytokines; (3) Results: COVID-19 patients had a lower frequency of circulating Vδ2+ T lymphocytes but showed a pronounced pro-inflammatory profile, which was inhibited by in vitro treatment with statins; (4) Conclusions: the in vitro capacity of statins to inhibit Vδ2+ T lymphocytes in COVID-19 patients highlights a new potential biological function of these drugs and supports their therapeutical use in these patients.

EVOO's Effects on Incretin Production: Is There a Rationale for a Combination in T2DM Therapy?

Type 2 diabetes mellitus (T2DM) is a serious public health concern as it is one of the most common chronic diseases worldwide due to social and economic developments that have led to unhealthy lifestyles, with a considerable impact both in terms of morbidity and mortality. The management of T2DM, before starting specific therapies, includes cornerstones such as healthy eating, regular exercise and weight loss. Strict adherence to the Mediterranean diet (MedDiet) has been related to an inverse association with the risk of T2DM onset, as well as an improvement in glycaemic control; in particular, thanks to the consumption of extra virgin olive oil (EVOO). Agonists of gut-derived glucagon-like peptide-1 (GLP-1), gastrointestinal hormones able to increase insulin secretion in response to hyperglycaemia (incretins), have been recently introduced in T2DM therapy, quickly entering the international guidelines. Recent studies have linked the action of EVOO in reducing postprandial glycaemia to the increase in GLP-1 and the reduction of its inactivating protease, dipeptidyl peptidase-4 (DPP-4). In this review, we explore observations regarding the pathophysiological basis of the existence of an enhanced effect between the action of EVOO and incretins and, consequently, try to understand whether there is a rationale for their use in combination for T2DM therapy.

The clinical impact of an extra virgin olive oil enriched mediterranean diet on metabolic syndrome: Lights and shadows of a nutraceutical approach.

For years it has been established that the only truly effective treatment of metabolic syndrome (MS) is lifestyle modification to prevent its cardiovascular (e.g., coronary artery disease and atherosclerosis), metabolic (e.g., diabetes mellitus), and hepatic (e.g., steatosis and non-alcoholic steatohepatitis) complications. The focal points of this approach are to increase physical activity and intake of a diet characterized by high quantities of fruits, vegetables, grains, fish, and low-fat dairy products, the so called mediterranean diet (MD); however, the added value of MD is the presence of extra virgin olive oil (EVOO), a healthy food with a high content of monounsaturated fatty acids, especially oleic acid, and variable concentrations (range 50-800 mg/kg) of phenols (oleuropein, ligstroside, and oleocanthal, and their derivatives, phenolic alcohols, such as hydroxytyrosol and tyrosol). Phenolic compounds not only determine EVOO's main organoleptic qualities (oxidative stability, specific flavor, and taste features) but, theoretically, make it a source of antioxidant, anti-inflammatory, insulin-sensitizing, cardioprotective, antiatherogenic, neuroprotective, immunomodulatory, and anticancer activity. Although many studies have been carried out on EVOO's clinical effects and attention toward this dietary approach (healthy and palatable food with strong nutraceutical activity) has become increasingly pressing, there are still many dark sides to be clarified, both in terms of actual clinical efficacy and biochemical and molecular activity. Thus, we reviewed the international literature, trying to show the state of the art about EVOO's clinical properties to treat MS (along with correlated complications) and the future prospective of its nutraceutical use.

SGLT2 Inhibitors as the Most Promising Influencers on the Outcome of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD), the most frequent liver disease in the Western world, is a common hepatic manifestation of metabolic syndrome (MetS). A specific cure has not yet been identified, and its treatment is currently based on risk factor therapy. Given that the initial accumulation of triglycerides in the liver parenchyma, in the presence of inflammatory processes, mitochondrial dysfunction, lipotoxicity, glucotoxicity, and oxidative stress, can evolve into non-alcoholic steatohepatitis (NASH). The main goal is to identify the factors contributing to this evolution because, once established, untreated NASH can progress through fibrosis to cirrhosis and, ultimately, be complicated by hepatocellular carcinoma (HCC). Several drugs have been tested in clinical trials for use as specific therapy for NAFLD; most of them are molecules used to cure type 2 diabetes mellitus (T2DM), which is one of the main risk factors for NAFLD. Among the most studied is pioglitazone, either alone or in combination with vitamin E, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors. Actually, the most promising category seems to be sodium-glucose cotransporter (SGLT2) inhibitors. Their action is carried out by inhibiting glucose reabsorption in the proximal renal tubule, leading to its increased excretion in urine and decreased levels in plasma. Experimental studies in animal models have suggested that SGLT2 inhibitors may have beneficial modulatory effects on NAFLD/NASH, and several trials in patients have proven their beneficial effects on liver enzymes, BMI, blood lipids, blood glucose, and insulin resistance in NAFLD patients, thus creating strong expectations for their possible use in preventing the evolution of liver damage in these patients. We will review the main pathogenetic mechanisms, diagnostic modalities, and recent therapies of NAFLD, with particular attention to the use of SGLT2 inhibitors.

Comorbidities impact and de-prescribing in elderly with HCV-related liver disease: analysis of a prospective cohort.

Management for HCV has undergone a notable change using direct-acting antiviral drugs (DAAs), which are safe and effective even in elderly. Here, we define impact of comorbidities, concomitant medication and drug-drug interactions in elder patients with HCV related disease before starting DAAs regimen. We analyzed data of 814 patients prospectively enrolled at our Unit within the web based model HCV Sicily Network. Out of 814, 590 were treated with DAAs and 414 of them were older than 65 years. We divided those 414 in two groups, one including 215 patients, aged between 65 and 74 years, and another with 199 patients, aged of 75 years and over. Charlson Comorbidity Index (CCI) was assessed for each patient; drug-drug interactions (DDI) and de-prescribing process were carried out appropriately. Within 414 patients included, percentage rates of women treated was higher than males, BMI was lower and cirrhosis was frequently reported in patients older than 75 years. Hypertension, diabetes mellitus, dyslipidemia (p < 0.0001), prostatic pathologies, kidney disease, gastrointestinal disease (p < 0.0001), osteoporosis (p < 0.01) and depression were most common co-morbidities. CCI showed lower scores in the first group as compared with the second one (p < 0.0001). Among drugs, statins were frequently suspended and anti-hypertensive often replaced. DAAs are useful and effective regardless of disease severity, comorbidities, medications and age. De-prescribing allows a stable reduction of number of medications taken with real improvement of quality of life.

The Role of Vitamin Deficiency in Liver Disease: To Supplement or Not Supplement?

Over the past few years, growing interest has been shown for the impact of dietary requirements and nutritional factors on chronic diseases. As a result, nutritional programs have been reinforced by public health policies. The precise role of micronutrients in chronic liver disease is currently receiving particular attention since abnormalities in vitamin levels are often detected. At present, treatment programs are focused on correcting vitamin deficiencies, which are frequently correlated to higher rates of comorbidities with poor outcomes. The literature reviewed here indicates that liver diseases are often related to vitamin disorders, due to both liver impairment and abnormal intake. More specific knowledge about the role of vitamins in liver disease is currently emerging from various results and recent evidence. The most significant benefits in this area may be observed when improved vitamin intake is combined with a pharmacological treatment that may also affect the progression of the liver disease, especially in the case of liver tumors. However, further studies are needed.

Hepatocellular Carcinoma: A Difficult Cancer to Treat.

Hepatocellular carcinoma (HCC) is a very peculiar cancer because it presents several molecular alterations linked to the activation of survival and antiapoptotic signal pathways that are protein in form and not easily targetable by even the newest targeted therapies. In addition, it is almost always a consequence of liver cirrhosis, a serious disease condition in which several drugs are often not tolerated. This is why the study of HCC was such a challenge for Professor Natale D'Alessandro, to whom this work is dedicated, during the latter years of his career. The aim of this review is to summarize studies on different molecules involved in the development, progression, and chemoresistance of HCC, topics on which we have focused our research over the last decade. In particular, we have analyzed the role of inflammatory mediators, such as the cyclooxygenase (COX) enzymes, nuclear factor κB (NF-κB), interleukin 6 (IL-6), as well as other important factors, such as Yin Yang 1 (YY1), in HCC. Moreover, we have reviewed some more recent literature on research aimed at identifying druggable targets in HCC as well as candidate agents for its prevention and treatment.

The NUPR1/p73 axis contributes to sorafenib resistance in hepatocellular carcinoma.

The multikinase inhibitor sorafenib was the first drug approved by the FDA for treating patients with advanced hepatocellular carcinoma (HCC). However, sorafenib resistance remains a major challenge for improving the effectiveness of HCC treatment. Previously, we identified several genes modulated after sorafenib treatment of human HCC cells, including the stress-inducible nuclear protein 1 (NUPR1) gene. Multiple studies have shown that NUPR1 regulates autophagy, apoptosis, and chemoresistance. Here, we demonstrate that treatment of HCC cells with sorafenib resulted in the activation of autophagic flux. NUPR1 knock-down (KD) in HCC cells was associated with increased p62 expression, suggesting an impairment of autophagic flux, and with a significant increase of cell sensitivity to sorafenib. In NUPR1 KD cells, reduced levels of NUPR1 were associated with the increased expression of p73 as well as its downstream transcription targets PUMA, NOXA, and p21. Simultaneous silencing of p73 and NUPR1 in HCC cells resulted in increased resistance to sorafenib, as compared to the single KD of either gene. Conversely, pharmacological activation of p73, via the novel p73 small molecule activator NSC59984, determined synergistic anti-tumor effects in sorafenib-treated HCC cells. The combination of NSC59984 and sorafenib, when compared to either treatment alone, synergistically suppressed tumor growth of HCC cells in vivo. Our data suggest that the activation of the p73 pathway achieved by NUPR1 KD potentiates sorafenib-induced anti-tumor effects in HCC cells. Moreover, combined pharmacological therapy with the p73 activator NSC59984 and sorafenib could represent a novel approach for HCC treatment.

NUPR1 protects liver from lipotoxic injury by improving the endoplasmic reticulum stress response.

Non-alcoholic fatty liver (NAFL) and related syndromes affect one-third of the adult population in industrialized and developing countries. Lifestyle and caloric oversupply are the main causes of such array of disorders, but the molecular mechanisms underlying their etiology remain elusive. Nuclear Protein 1 (NUPR1) expression increases upon cell injury in all organs including liver. Recently, we reported NUPR1 actively participates in the activation of the Unfolded Protein Response (UPR). The UPR typically maintains protein homeostasis, but downstream mediators of the pathway regulate metabolic functions including lipid metabolism. As increases in UPR and NUPR1 in obesity and liver disease have been well documented, the goal of this study was to investigate the roles of NUPR1 in this context. To establish whether NUPR1 is involved in these liver conditions we used patient-derived liver biopsies and in vitro and in vivo NUPR1 loss of functions models. First, we analyzed NUPR1 expression in a cohort of morbidly obese patients (MOPs), with simple fatty liver (NAFL) or more severe steatohepatitis (NASH). Next, we explored the metabolic roles of NUPR1 in wild-type (Nupr1+/+ ) or Nupr1 knockout mice (Nupr1-/- ) fed with a high-fat diet (HFD) for 15 weeks. Immunohistochemical and mRNA analysis revealed NUPR1 expression is inversely correlated to hepatic steatosis progression. Mechanistically, we found NUPR1 participates in the activation of PPAR-α signaling via UPR. As PPAR-α signaling is controlled by UPR, collectively, these findings suggest a novel function for NUPR1 in protecting liver from metabolic distress by controlling lipid homeostasis, possibly through the UPR.

Potential Uses of Olive Oil Secoiridoids for the Prevention and Treatment of Cancer: A Narrative Review of Preclinical Studies.

The Mediterranean diet (MD) is a combination of foods mainly rich in antioxidants and anti-inflammatory nutrients that have been shown to have many health-enhancing effects. Extra-virgin olive oil (EVOO) is an important component of the MD. The importance of EVOO can be attributed to phenolic compounds, represented by phenolic alcohols, hydroxytyrosol, and tyrosol, and to secoiridoids, which include oleocanthal, oleacein, oleuropein, and ligstroside (along with the aglycone and glycosidic derivatives of the latter two). Each secoiridoid has been studied and characterized, and their effects on human health have been documented by several studies. Secoiridoids have antioxidant, anti-inflammatory, and anti-proliferative properties and, therefore, exhibit anti-cancer activity. This review summarizes the most recent findings regarding the pharmacological properties, molecular targets, and action mechanisms of secoiridoids, focusing attention on their preventive and anti-cancer activities. It provides a critical analysis of preclinical, in vitro and in vivo, studies of these natural bioactive compounds used as agents against various human cancers. The prospects for their possible use in human cancer prevention and treatment is also discussed.