Current Medicinal Chemistry - Volume 26, Issue 19, 2019

Mitochondria are cytoplasmic double-membraned organelles that are involved in a myriad of key cellular regulatory processes. The loss of mitochondrial function is related to the pathogenesis of several human diseases. Over the last decades, an increasing number of studies have shown that dietary polyphenols can regulate mitochondrial redox status, and in some cases, prevent or delay disease progression. This paper aims to review the role of four dietary polyphenols – resveratrol, curcumin, epigallocatechin-3-gallate nd quercetin – in molecular pathways regulated by mitochondria and their potential impact on human health. Cumulative evidence showed that the aforementioned polyphenols improve mitochondrial functions in different in vitro and in vivo experiments. The mechanisms underlying the polyphenols’ beneficial effects include, among others, the attenuation of oxidative stress, the regulation of mitochondrial metabolism and biogenesis and the modulation of cell-death signaling cascades, among other mitochondrial-independent effects. The understanding of the chemicalbiological interactions of dietary polyphenols, namely with mitochondria, may have a huge impact on the treatment of mitochondrial dysfunction-related disorders.

Cholecystokinin (CCK) is an important neuro-intestinal peptide hormone produced by the enteroendocrine I-cells in the upper part of small intestine. Protein- and fat-enriched food plays an important role in triggering CCK secretion from the intestine. Carbohydrates stimulate only small amounts of CCK release. The CCK-1 receptor (CCK-1R) is largely localized in the gallbladder, sphincter of Oddi, pancreas, small intestine, gastric mucosa, and pyloric sphincter, where it is responsible for CCK to regulate multiple digestive processes including gallbladder contraction, pancreatic secretion, small intestinal transit, and gastric emptying. Accumulated evidence clearly demonstrates that CCK regulates gallbladder and small intestinal motility through CCK-1R signaling cascade and the effect of CCK-1R on small intestinal transit is a physiological response for regulating intestinal cholesterol absorption. Disruption of the Cck or the Cck-1r gene in mice significantly increases the formation of cholesterol gallstones by disrupting gallbladder emptying and biliary cholesterol metabolism, as well as promoting intestinal absorption of cholesterol. Abnormalities in gallbladder motility function in response to exogenously administered CCK are found primarily in patients with cholesterol gallstones. Patients with pigment gallstones display an intermediate degree of gallbladder motility defect without gallbladder inflammation and enlarged fasting gallbladder. Dysfunctional gallbladder contractility has been found under several conditions such as pregnancy, obesity, diabetes, celiac disease, and total parenteral nutrition although gallstones are not observed. The gallbladder-specific CCK-1R-selective agonist may lead to an efficacious novel way for preventing gallstone formation by promoting gallbladder emptying, particularly for pregnant women and subjects with dysfunctional gallbladder motility function such as celiac patients, as well as patients with total parenteral nutrition.

Background: Functional foods are designed to have physiological benefits and reduce the risk of chronic disease beyond basic nutritional functions. Conditions related to overnutrition such as Metabolic Syndrome and Type 2 diabetes are increasingly serious concerns in Western societies. Several nutrient classes are considered to protect against these conditions and this review focuses on the latest clinical and preclinical evidence supporting their efficacy and the molecular mechanisms by which they act. Methods: The review searched the literature for information and data on the following functional food components and their protective effects against Metabolic Syndrome and Type 2 Diabetes: Dietary fiber; Medium-chain triglycerides and Ketone esters; ω3 Polyunsaturated fatty acids and Antioxidants. Results: Data from a hundred and four studies were reviewed and summarized. They indicate that dietary fiber results in the production of beneficial short chain fatty acids via intestinal microbiota, as well as increasing intestinal secretion of incretins and satiety peptides. Medium chain triglycerides and ketone esters promote thermogenesis, inhibit lipolysis and reduce inflammation. They also decrease endogenous synthesis of triglycerides and fatty acids. ω3-PUFA’s act to soften inflammation through an increase in adiponectin secretion. Antioxidants are involved in the protection of insulin sensitivity by PTP1B suppression and SIRT1 activation. Conclusion: Functional foods have actions that complement and/or potentiate other lifestyle interventions for reversing Metabolic Syndrome and Type 2 Diabetes. Functional foods contribute to reduced food intake by promoting satiety, less weight gain via metabolic uncoupling and improved insulin sensitivity via several distinct mechanisms.

Background: Fatty liver, or steatosis, is a condition of excess accumulation of lipids, mainly under form of triglycerides (TG), in the liver, and it is the hallmark of non-alcoholic fatty liver disease (NAFLD). NAFLD is the most common liver disorder world-wide and it has frequently been associated with obesity, hyperlipidemia and insulin resistance. Free fatty acids (FA) are the major mediators of hepatic steatosis; patients with NAFLD have elevated levels of circulating FA that correlate with disease severity. Methods: Steatosis is a reversible condition that can be resolved with changed behaviors, or that can progress towards more severe liver damages such as steatohepatitis (NASH), fibrosis and cirrhosis. In NAFLD, FA of exogenous or endogenous origin accumulate in the hepatocytes and trigger liver damages. Excess TG are stored in cytosolic lipid droplets (LDs) that are dynamic organelles acting as hubs for lipid metabolism. Results: In the first part of this review, we briefly reassumed the main classes of FA and their chemical classification as a function of the presence and number of double bonds, their metabolic pathways and effects on human health. Then, we summarized the main genetic and diet-induced animal models of NAFLD, as well as the cellular models of NAFLD. Conclusions: In recent years, both the diet-induced animal models of NAFLD as well as the cellular models of NAFLD have found ever more application to investigate the mechanisms involved in NAFLD, and we referred to their advantages and disadvantages.

Healthful dietary patterns and bioactive compounds supplementation can be adopted as simple and easy intervention to prevent, attenuate or cure clinical disorders, especially when it comes to degenerative and chronic diseases. In the recent years, a growing body of evidence indicates Aquaporins (AQPs), a family of membrane channel proteins widely expressed in the human body, among the targets underlying the beneficial action played by some food nutrients and phytochemical compounds. Here, we provide an overview of what is known regarding the AQP modulation exerted by healthful dietary patterns and plant polyphenols.

The obesity epidemic is spreading worldwide without reversal trend and despite specific policies oriented to dietary habits and lifestyle, which seem to have modest effects. Genetic factors only partly explain the rise, whereas environmental factors seem to play a key role, mainly by gene-environment interactions through epigenetic mechanisms. A number of animal and human studies point to maternal diet, intestinal microbiota and chemicals introduced as contaminants with food, all factors able to increase the risk of obesity. Widely diffused toxics (mainly BPA, phthalates, pesticides) are able to promote obesity in children and adults, mainly by acting on the differentiation pathway linking multipotent stromal stem cell to mature adipocyte, modulating epigenetic factors and influencing a series of mechanisms finally leading to altered dietary habits, increased adipocyte formation and fat storage. Furthermore, the adipose tissue is an important target for several chemicals (mainly POPs) which represent a threat to metabolic health. In conclusion, besides excessive individual energy intake and inadequate lifestyle, other broadly diffused and modifiable factors (mainly ingestion of toxic chemicals with food) seem to have a critical role in the rapid epidemiological growing of obesity, also considering trans-generational transmission of risk and later development of obesity due to exposure during early life. Further studies are needed, to better assess interactions between cumulative effects of toxic food contaminants and modification of diet and lifestyle, and to verify the efficacy of primary prevention strategies acting on all these factors and potentially able to reverse the continuous rising of the obesity epidemic.

Background: Non-alcoholic fatty liver disease (NAFLD) affects millions of individuals on a global scale and currently no gold standard treatment exists. The risk of developing NAFLD is considerably higher with increasing body mass index. Consequently, weight loss should be recommended to all overweight patients with fatty liver. However, lifestyle interventions, irrespective of weight status, may also influence the condition. The aim herein is to present examples of short-term interventions which assess direct effects of dietary-related components on hepatic steatosis. Methods: This review includes studies with short-term dietary-related interventions of up to 16 weeks that evaluate their efficacy in reducing intrahepatic lipid contents (hepatic steatosis). This review primarily focuses on the three main macronutrients: dietary carbohydrates, fats and proteins. Results: High saturated fat intake and high consumption of carbohydrates, particularly from simple sugars such as fructose are reported as risk factors for hepatic steatosis. Overall, shortterm hypocaloric diets have shown beneficial effects in reducing intrahepatic lipid contents. Macronutrient manipulations such as carbohydrate restriction as well as the consumption of unsaturated fatty acids are also reported to have efficacious effects. Conclusion: This review highlights the different dietary interventions that can influence hepatic steatosis in the short term, illustrating both pro and anti-steatotic effects.

Gastroesophageal reflux disease is a chronic condition with a high prevalence in western countries. Transient lower esophageal sphincter relaxation episodes and a decreased lower esophageal sphincter pressure are the main mechanisms involved. Currently used drugs are efficient on reflux symptoms, but only as long as they are administered, because they do not modify the reflux barrier. Certain nutrients or foods are generally considered to increase the frequency of gastroesophageal reflux symptoms, therefore physicians recommend changes in diet and some patients avoid bothering foods. This review summarizes current knowledge regarding food and gastroesophageal reflux. For example, fat intake increases the perception of reflux symptoms. Regular coffee and chocolate induce gastroesophageal reflux and increase the lower esophageal exposure to acid. Spicy foods might induce heartburn, but the exact mechanism is not known. Beer and wine induce gastroesophageal reflux, mainly in the first hour after intake. For other foods, like fried food or carbonated beverages data on gastroesophageal reflux is scarce. Similarly, there are few data about the type of diet and gastroesophageal reflux. Mediterranean diet and a very low carbohydrate diet protect against reflux. Regarding diet-related practices, consistent data showed that a “short-meal-to-sleep interval” favors reflux episodes, therefore some authors recommend that dinner should be at least four hours before bedtime. All these recommendations should consider patient’s weight, because several meta-analyses showed a positive association between increased body mass index and gastroesophageal reflux disease.

Irritable bowel syndrome (IBS) is a chronic functional disorder of the gastrointestinal tract and is one of the most frequent gastrointestinal diseases. In IBS multiple pathophysiological mechanisms including alterations in intestinal motility, permeability, nutrient absorption, and intestinal microbiota have been implicated. Foods are commonly reported by patients to be a trigger of symptoms and therefore are likely involved in the generation of symptoms in IBS. Among all possible therapeutic options, a first-line approach to IBS is dietary education and identification of foods potentially responsible for the onset or worsening of symptoms. Dietary approaches include reduction of gas-producing foods (i.e. fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs)), lactose and gluten. Further studies are required to link the ultimate role of diets in different IBS subtypes.

Background: The large increase in epidemiological studies on night shift work is due to the important effects of night shift work on workers’ health and psychophysical wellbeing. The short-term effects—insomnia, difficulties in managing work and private life, lower work performance, and more work and extra-work accidents—are easily studied. However, there are several long-term effects that are difficult to study because of the need for detailed exposure assessment and the long latency periods of these diseases. Objective: The aim was to collect epidemiologic evidence of diseases in night shift workers, describing their biological pathways and a set of dietary guidelines. Methods: This is a review on diet and health effects in night shift workers. Results: Significant increases in the rate ratios and hazard ratios of different diseases were associated with modified eating behaviours and poor eating habits among night shift workers. Night shift work is a risk factor for disruption of the circadian rhythms and for some genetic deregulation because it produces the inversion of the sleep/wake cycle and modifies the alternation between activity and rest. Conclusion: A healthy diet and improved dietary practices, together with other factors, can reduce shift workers’ chronic disease risk. The literature showed the importance of eating behaviour in order to prevent diseases in these workers; therefore, educational programmes are necessary to encourage several important lifestyle changes. The target of our future research will be the role of food components in some dietetic habits for the prevention of disease in night shift workers.

Background: The devastating effects of heavy alcohol drinking have been long time recognized. In the last decades, potential benefits of modest red wine drinking were suggested. In European countries in which red wide intake is not negligible (such as France), the association between cholesterol and cardiovascular (CV) risk was less evident, suggesting the action of some protective molecules in red wine or other foods and drinks. Methods: This narrative review is based on the material searched for and obtained via PubMed up to May 2016. The search terms we used were: “red wine, cardiovascular, alcohol” in combination with “polyphenols, heart failure, infarction”. Results: Epidemiological and mechanistic evidence of a J-shaped relationship between red wine intake and CV risk further supported the “French paradox”. Specific components of red wine both in vitro and in animal models were discovered. Polyphenols and especially resveratrol largely contribute to CV prevention mainly through antioxidant properties. They exert beneficial effects on endothelial dysfunction and hypertension, dyslipidemia, metabolic diseases, thus reducing the risk of adverse CV events such as myocardial infarction ischemic stroke and heart failure. Of interest, recent studies pointed out the role of ethanol itself as a potential cardioprotective agent, but a clear epidemiological evidence is still missing. The aim of this narrative review is to update current knowledge on the intracellular mechanism underlying the cardioprotective effects of polyphenols and ethanol. Furthermore, we summarized the results of epidemiological studies, emphasizing their methodological criticisms and the need for randomized clinical trials able to clarify the potential role of red wine consumption in reducing CV risk. Conclusion: Caution in avowing underestimation of the global burden of alcohol-related diseases was particularly used.

Gut microbiota, the largest symbiont community hosted in human organism, is emerging as a pivotal player in the relationship between dietary habits and health. Oral and, especially, intestinal microbes metabolize dietary components, affecting human health by producing harmful or beneficial metabolites, which are involved in the incidence and progression of several intestinal related and non-related diseases. Habitual diet (Western, Agrarian and Mediterranean omnivore diets, vegetarian, vegan and gluten-free diets) drives the composition of the gut microbiota and metabolome. Within the dietary components, polymers (mainly fibers, proteins, fat and polyphenols) that are not hydrolyzed by human enzymes seem to be the main leads of the metabolic pathways of gut microbiota, which in turn directly influence the human metabolome. Specific relationships between diet and microbes, microbes and metabolites, microbes and immune functions and microbes and/or their metabolites and some human diseases are being established. Dietary treatments with fibers are the most effective to benefit the metabolome profile, by improving the synthesis of short chain fatty acids and decreasing the level of molecules, such as p-cresyl sulfate, indoxyl sulfate and trimethylamine N-oxide, involved in disease state. Based on the axis diet-microbiota-health, this review aims at describing the most recent knowledge oriented towards a profitable use of diet to provide benefits to human health, both directly and indirectly, through the activity of gut microbiota.

Background: In the last years, several scientific societies and expert groups focused on the role played by nutritional factors, lifestyle and excess of body fat in interfering with female reproduction and fertility. In many studies a confounding factor is represented by polycystic ovary syndrome (PCOS) which is one of the major causes of infertility where genetic and family history are certainly playing a role, together with lifestyle and nutritional factors. Methods: In an attempt to define "the optimal fertility diet", we consider the role played by Mediterranean lifestyle and some macronutrients (animal and vegetable proteins) on ovulatory disorders and female fertility also considering some new visions derived from randomized trials of lifestyle programs in obese infertile women asking for in vitro fertilization or alternative assisted reproduction technologies. Results: Several reports are in favor of an increased consumption of either proteins or low-glycemic index carbohydrates to improve ovulatory disorders and female fertility. In studies concerning infertile women undergoing assisted reproduction, either structured exercise sessions and dietary intervention programs seem to be effective in improving menstrual cycles and fertility as demonstrated by the increased rate of natural conceptions. Conclusion: The findings of this review confirm the important impact of Mediterranean diet and lifestyle in preserving and improving fertility. However, epigenetic factors are very important in determining fertility rate, but genetic background and ethnicity are also playing crucial roles.

Background: Obesity is a major health problem that has become a global epidemic. Overweight and obesity are commonly associated with the development of several pathologies, such as insulin resistance, cardiovascular diseases, sleep apnea and several types of cancer, which can lead to further morbidity and mortality. An increased abdominal adiposity renders overweight and obese individuals more prone to metabolic and cardiovascular problems. Objective: This Review aims to describe the dietary strategies to deal with excess adiposity given the medical, social and economic consequences of obesity. Methods: One hundred and eighty-five papers were included in the present Review. Results: Excess adiposity leads to several changes in the biology, morphology and function of the adipose tissue, such as adipocyte hypertrophy and hyperplasia, adipose tissue inflammation and fibrosis and an impaired secretion of adipokines, contributing to the onset of obesity- related comorbidities. The first approach for obesity management and prevention is the implementation of a diet combined with physical activity. The present review summarizes the compelling evidence showing body composition changes, impact on cardiometabolism and potential adverse effects of very-low calorie, low- and high-carbohydrate, high-protein or low-fat diets. The use of macronutrients during the preprandial and postprandial state has been also reviewed to better understand the metabolic changes induced by different dietary interventions. Conclusion: Dietary changes should be individualised, tailored to food preferences and allow for flexible approaches to reducing calorie intake in order to increase the motivation and compliance of overweight and obese patients.

Metabolic syndrome is a frequent metabolic disorder characterized by obesity and insulin resistance seems to be the main pathophysiological alteration. The goal of treating metabolic syndrome is to reduce the risk of coronary heart disease and the development of type 2 diabetes. The lifestyle modification therapy combines specific recommendations on diet alone or combined with other strategies. In this review, we address the following topics: 1) the importance of the high prevalence of metabolic syndrome and obesity, and 2) the role of lifestyle modification focusing on dietary fat intake in the management of MS.

Cholesterol gallstone disease is a major health problem in Westernized countries and depends on a complex interplay between genetic factors, lifestyle and diet, acting on specific pathogenic mechanisms. Overweigh, obesity, dyslipidemia, insulin resistance and altered cholesterol homeostasis have been linked to increased gallstone occurrence, and several studies point to a number of specific nutrients as risk- or protective factors with respect to gallstone formation in humans. There is a rising interest in the identification of common and modifiable dietetic factors that put the patients at risk of gallstones or that are able to prevent gallstone formation and growth. In particular, dietary models characterized by increased energy intake with highly refined sugars and sweet foods, high fructose intake, low fiber contents, high fat, consumption of fast food and low vitamin C intake increase the risk of gallstone formation. On the other hand, high intake of monounsaturated fats and fiber, olive oil and fish (ω-3 fatty acids) consumption, vegetable protein intake, fruit, coffee, moderate alcohol consumption and vitamin C supplementation exert a protective role. The effect of some confounding factors (e.g., physical activity) cannot be ruled out, but general recommendations about the multiple beneficial effects of diet on cholesterol gallstones must be kept in mind, in particular in groups at high risk of gallstone formation.

Cardiovascular diseases (CVD) are the leading cause of mortality worldwide. Diet comprises a mixture of food compounds that has an influence on human health. The relationship between diet and health is extremely complex and strategies to delay or prevent chronic diseases such as CVD are of utmost interest because chronic diseases and more concretely CVD are still the leading cause of death and disability worldwide. In this mini-review, we aimed to summarize the current knowledge about the principal diet components that potentially influence CVD initiation and progression. Current research refers to the Mediterranean dietary pattern, rich in fruits and vegetables, as the most cardioprotective, because of its high concentration of bioactive compounds such as unsaturated fatty acids, polyphenols, fiber, phytosterols, vitamins and minerals, which exert antioxidant, anti-inflammatory and antithrombotic effects contributing to the delay of CVD initiation and progression.

Background: An adequate caloric intake is a major determinant for the health status especially when degenerative conditions become a predominant risk for difficult-to-treat diseases as in aging. Methods: A structured search of literature on the major databases was performed using terms as nutrition, elderly and malnutrition. Results: According to most referenced articles, it appears to be unquestionable that both organic and social risk factors [economic hardship, loneliness, institutionalization] are important as determining causes of protein-caloric malnutrition. Some anthropometric, clinical and laboratory parameters can help to make diagnosis and quantify malnutrition. However, most of them are not cheap or are not simple to perform especially in the setting of General Practice. The application of a simple questionnaire [Mini Nutritional Assessment, MNA] allows to obtain in a fast, easy and non-invasive way a valid assessment of the nutritional status in geriatric patients. The maintenance of the nutritional status is the best measure to counteract the risk of proteincaloric malnutrition and its complications which often sneakily affects elderly population and in particular frail patients. Conclusion: This review, based on updated concepts, examines all the above mentioned points together with some aspects associated with malnutrition as an indicator of disease severity and health costs in the elderly population. Finally, the impact of nutritional intervention and nutrients supplementation on general indices of malnutrition are discussed as a promising strategy.