Current Medicinal Chemistry - Volume 27, Issue 2, 2020

Background: Obesity represents the second preventable mortality cause worldwide, and is very often associated with type 2 Diabetes Mellitus (T2DM). The first line treatment is lifestyle modification to weight-loss, but for those who fail to achieve the goal or have difficulty in maintaining achieved results, pharmacological treatment is needed. Few drugs are available today, because of their side effects. Objective: We aim to review actual pharmacological management of obese patients, highlighting differences between Food and Drug Administration - and European Medicine Agency-approved molecules, and pointing out self-medications readily obtainable and widely distributed. Methods: Papers on obesity, weight loss, pharmacotherapy, self- medication and diet-aid products were selected using Medline. Research articles, systematic reviews, clinical trials and meta-analyses were screened. Results: Anti-obesity drugs with central mechanisms, such as phentermine and lorcaserin, are available in USA, but not in Europe. Phentermine/topiramate and naltrexone/bupropion combinations are now available, even though the former is still under investigation from EMA. Orlistat, with peripheral mechanisms, represents the only drug approved for weight reduction in adolescents. Liraglutide has been approved at higher dose for obesity. Anti-obesity drugs, readily obtainable from the internet, include crude-drug products and supplements for which there is often a lack of compliance to national regulatory standards. Conclusions: Mechanisms of weight loss drugs include the reduction of energy intake or the increase in energy expenditure and sense of satiety as well as the decrease of hunger or the reduction in calories absorption. Few drugs are approved, and differences exist between USA and Europe. Moreover, herbal medicines and supplements often sold on the internet and widely used by obese patients, present a risk of adverse effects.

Chemoprevention is based on the use of non-toxic, pharmacologically active agents to prevent tumor progression. In this regard, natural dietary agents have been described by the most recent literature as promising tools for controlling onset and progression of malignancies. Extensive research has been so far performed to shed light on the effects of natural products on tumor growth and survival, disclosing the most relevant signal transduction pathways targeted by such compounds. Overall, anti-inflammatory, anti-oxidant and cytotoxic effects of dietary agents on tumor cells are supported either by results from epidemiological or animal studies and even by clinical trials. Multiple myeloma is a hematologic malignancy characterized by abnormal proliferation of bone marrow plasma cells and subsequent hypercalcemia, renal dysfunction, anemia, or bone disease, which remains incurable despite novel emerging therapeutic strategies. Notably, increasing evidence supports the capability of dietary natural compounds to antagonize multiple myeloma growth in preclinical models of the disease, underscoring their potential as candidate anti-cancer agents. In this review, we aim at summarizing findings on the anti-tumor activity of dietary natural products, focusing on their molecular mechanisms, which include inhibition of oncogenic signal transduction pathways and/or epigenetic modulating effects, along with their potential clinical applications against multiple myeloma and its related bone disease.

Background: Obesity is now recognized as a worldwide health issue and has reached epidemic proportions, affecting both developed and developing countries. The World Obesity Federation stated that “Obesity is a chronic relapsing disease process”: as a result, obesity has been recognized internationally as a chronic disease. The primary cause of the metabolic syndrome and increase of the cardiovascular risk have been identified in "sick fat", a condition then defined as adiposopathy. Heart attacks, strokes and renal failures are pathologies that have mid-risk factors such as dyslipidemia, hypertension and diabetes, which in turn are caused by obesity, whose primary risk factor is represented by the diet. The aim of the present review is to consider the importance of body composition, together with chronic inflammation and a new gut microbiota data that may turn out to be crucial elements of some target treatment of human obesity. Methods: In this review, we performed research using PubMed database reviewing the evidence in the literature of evidence information regarding the link between obesity and body composition in the development of metabolic disease via inflammation markers and in particular, the new role exerted by gut microbiota. Results: Several papers were evaluated searching for differences in fat mass and disease risk. We also identified the same papers dealing with differences in body composition and metabolic syndrome. Our attention focuses also on a new frontier of gut microbiota composition in the body weight decrease and anti-inflammatory effects. Conclusion: To the saving of lean mass, for the prevention of cardiometabolic diseases, also considering the relationship with obesity, it is necessary to reduce the inflammatory state, acting on the gut-microbiota and on the intestinal permeability. To improve the health of the intestinal flora, we propose a 4P medicine and treatment with probiotics, prebiotics, postbiotics, and polyphenols.

The incidence of obesity and diabetes is increasing rapidly worldwide. Obesity and metabolic syndrome are strictly linked and represent the basis of different cardiovascular risk factors, including hypertension and inflammatory processes predisposing to ischemic heart disease, which represent the most common causes of heart failure. Recent advances in the understanding of ischemia/reperfusion mechanisms of injury and mechanisms of cardioprotection are briefly considered. Resistance to cardioprotection may be correlated with the severity of obesity. The observation that heart failure obese patients have a better clinical condition than lean heart failure patients is known as “obesity paradox”. It seems that obese patients with heart failure are younger, making age the most important confounder in some studies. Critical issues are represented by the "obesity paradox” and heart failure exacerbation by inflammation. For heart failure exacerbation by inflammation, an important role is played by NLRP3 inflammasome, which is emerging as a possible target for heart failure condition. These critical issues in the field of obesity and cardiovascular diseases need more studies to ascertain which metabolic alterations are crucial for alleged beneficial and deleterious effects of obesity.

Background: Obesity is a major cardiovascular risk factor which dramatically impairs endothelium- dependent vasodilation and leads to hypertension and vascular damage. The impairment of the vasomotor response to extracellular autacoids, e.g., acetylcholine, mainly depends on the reduced Nitric Oxide (NO) bioavailability, which hampers vasorelaxation in large conduit arteries. In addition, obesity may affect Endothelium-Dependent Hyperpolarization (EDH), which drives vasorelaxation in small resistance arteries and arterioles. Of note, endothelial Ca2+ signals drive NO release and trigger EDH. Methods: A structured search of bibliographic databases was carried out to retrieve the most influential, recent articles on the impairment of vasorelaxation in animal models of obesity, including obese Zucker rats, and on the remodeling of the endothelial Ca2+ toolkit under conditions that mimic obesity. Furthermore, we searched for articles discussing how dietary manipulation could be exploited to rescue Ca2+-dependent vasodilation. Results: We found evidence that the endothelial Ca2+ could be severely affected by obese vessels. This rearrangement could contribute to endothelial damage and is likely to be involved in the disruption of vasorelaxant mechanisms. However, several Ca2+-permeable channels, including Vanilloid Transient Receptor Potential (TRPV) 1, 3 and 4 could be stimulated by several food components to stimulate vasorelaxation in obese individuals. Conclusion: The endothelial Ca2+ toolkit could be targeted to reduce vascular damage and rescue endothelium- dependent vasodilation in obese vessels. This hypothesis remains, however, to be probed on truly obese endothelial cells.

The number of obese patients undergoing cardiac and noncardiac surgery is rapidly increasing because they are more prone to concomitant diseases, such as diabetes, thrombosis, sleep-disordered breathing, cardiovascular and cerebrovascular disorders. Even if guidelines are already available to manage anesthesia and surgery of obese patients, the assessment of the perioperative morbidity and mortality from heart and brain disorders in morbidly obese surgical patients will be challenging in the next years. The present review will recapitulate the new mechanisms underlying the Heart-brain Axis (HBA) vulnerability during the perioperative period in healthy and morbidly obese patients. Finally, we will describe the nutrigenomics approach, an emerging noninvasive dietary tool, to maintain a healthy body weight and to minimize the HBA propensity to injury in obese individuals undergoing all types of surgery by personalized intake of plant compounds that may regulate the switch from health to disease in an epigenetic manner. Our review provides current insights into the mechanisms underlying HBA response in obese surgical patients and how they are modulated by epigenetically active food constituents.

MicroRNAs (miRNAs) are a group of small endogenous non-coding RNAs involved in many cancers and various cellular processes such as cellular growth, DNA methylation, apoptosis, and differentiation. 13q14.3 chromosomal region contains miR-15 and miR-16 and deletion of this region is a commonly reported aberration in Chronic Lymphoblastic Leukemia (CLL), suggesting miRNAs involvement in CLL pathogenesis. MicroRNAs are known as oncogenes and tumor suppressors in CLL which may also serve as markers of onset and progression of the disease. The most prevalent form of leukemia diagnosed in adults in the western world, chronic lymphocytic leukemia, accounts for one-third of all leukemias. CLL is characterized by the presence of B Cell Malignant Clones in secondary lymphoid tissues, peripheral blood and bone marrow. The precise etiology of CLL is remained to be known, however, a number of Chromosomal Abnormalities such as deletions of 13q14.3, 11q and 17p and trisomy 12 have been detected. In this review, we offer our prospect on how miRNAs are involved in the CLL pathogenesis and disease progression. Further understanding of the underlying mechanisms and regulation of CLL pathogenesis has underscored the need for further research regarding their role in this disease.

p97, also known as valosin-containing protein or CDC48, is a member of the AAA+ protein family that is highly conserved in eukaryotes. It binds to various cofactors in the body to perform its protein-unfolding function and participates in DNA repair, degradation of subcellular membrane proteins, and protein quality control pathways, among other processes. Its malfunction can lead to many diseases, such as inclusion body myopathy, associated with Paget’s disease of bone and/or frontotemporal dementia, amyotrophic lateral sclerosis disease, and others. In recent years, many small-molecule inhibitors have been deployed against p97, including bis (diethyldithiocarbamate)- copper and CB-5083, which entered the first phase of clinical tests but failed. One bottleneck in the design of p97 drugs is that its molecular mechanism remains unclear. This paper summarizes recent studies on the molecular mechanisms of p97, which may lead to insight into how the next generation of small molecules targeting p97 can be designed.

Background: The Low-Density Lipoprotein (LDL) Receptor (LDL-R) is a transmembrane protein playing a crucial role in effective lipid homeostasis. Various therapeutic agents have been used in the management of dyslipidemias, however, the outcome of therapeutic target is debated. Objective: The aim of this review is to summarize and fully understand the current concept regarding LDL-R and its molecular properties, metabolic pathway, factors affecting LDL-R activity and all available pharmacological interventions. Additionally, non-lipid related properties of LDL-R are also referred. Methods: Literature from the PubMed database was extracted to identify papers between 1984 to 2017 regarding LDL-R and therapeutic agents on dyslipidemia management. Results: We analyzed basic data regarding agents associated with LDL-R (Sterol Regulating Element-Binding Proteins - SREBPs, Protein ARH, IDOL, Thyroid Hormones, Haematologic Disorders, Protein convertase subtilisin kexintype 9 - PCSK-9, ApoC-III) as well as non-lipid related properties of LDL-R, while all relevant (common and novel) pharmacological interventions (statins, fibrates, cholesterol absorption inhibitors, bile acid sequestrants and PCSK- 9) are also referred. Conclusion: LDL-R and its molecular properties are involved in lipid homeostasis, so potentially sets the therapeutic goals in cardiovascular patients, which is usually debated. Further research is needed in order to fully understand its properties, as well as to find the potential pharmacological interventions that could be beneficial in cholesterol homeostasis and various morbidities in order to reach the most appropriate therapeutic goal.