Mangosteen Extract Shows a Potent Insulin Sensitizing Effect in Obese Female Patients: A Prospective Randomized Controlled Pilot Study.

There is a widely acknowledged association between insulin resistance and obesity/type 2 diabetes (T2DM), and insulin sensitizing treatments have proved effective in preventing diabetes and inducing weight loss. Obesity and T2DM are also associated with increased inflammation. Mangosteen is a tropical tree, whose fruits—known for their antioxidant properties—have been recently suggested having a possible further role in the treatment of obesity and T2DM. The objective of this pilot study has been to evaluate safety and efficacy of treatment with mangosteen extract on insulin resistance, weight management, and inflammatory status in obese female patients with insulin resistance. Twenty-two patients were randomized 1:1 to behavioral therapy alone or behavioral therapy and mangosteen and 20 completed the 26-week study. The mangosteen group reported a significant improvement in insulin sensitivity (homeostatic model assessment-insulin resistance, HOMA-IR −53.22% vs. −15.23%, p = 0.004), and no side effect attributable to treatment was reported. Given the positive preliminary results we report and the excellent safety profile, we suggest a possible supplementary role of mangosteen extracts in the treatment of obesity, insulin resistance, and inflammation

Overweight and obese patients with nickel allergy have a worse metabolic profile compared to weight matched non-allergic individuals

A lack of balance between energy intake and expenditure due to overeating or reduced physical activity does not seem to explain entirely the obesity epidemic we are facing, and further factors are therefore being evaluated. Nickel (Ni) is a ubiquitous heavy metal implied in several health conditions. Regarding this, the European Food Safety Authority has recently released an alert on the possible deleterious effects of dietary Ni on human health given the current levels of Ni dietary intake in some countries. Pre-clinical studies have also suggested its role as an endocrine disruptor and have linked its exposure to energy metabolism and glucose homeostasis dysregulation. Ni allergy is common in the general population, but preliminary data suggest it being even more widespread among overweight patients. OBJECTIVES: The aim of this study has been to evaluate the presence of Ni allergy and its association with the metabolic and endocrine profile in overweight and obese individuals. METHODS: We have evaluated 1128 consecutive overweight and obese outpatients. 784 were suspected of being allergic to Ni and 666 were assessed for it. Presence of Ni allergy and correlation with body mass index (BMI), body composition, metabolic parameters and hormonal levels were evaluated. RESULTS: We report that Ni allergy is more frequent in presence of weight excess and is associated with worse metabolic parameters and impaired Growth Hormone secretion. CONCLUSIONS: We confirm that Ni allergy is more common in obese patients, and we report for the first time its association with worse metabolic parameters and impaired function of the GH-IGF1 axis in human subjects

Predicting Isoform-Selective Carbonic Anhydrase Inhibitors via Machine Learning and Rationalizing Structural Features Important for Selectivity

Carbonic anhydrases (CAs) catalyze the physiological hydration of carbon dioxide and are among the most intensely studied pharmaceutical target enzymes. A hallmark of CA inhibition is the complexation of the catalytic zinc cation in the active site. Human (h) CA isoforms belonging to different families are implicated in a wide range of diseases and of very high interest for therapeutic intervention. Given the conserved catalytic mechanisms and high similarity of many hCA isoforms, a major challenge for CA-based therapy is achieving inhibitor selectivity for hCA isoforms that are associated with specific pathologies over other widely distributed isoforms such as hCA I or hCA II that are of critical relevance for the integrity of many physiological processes. To address this challenge, we have attempted to predict compounds that are selective for isoform hCA IX, which is a tumor-associated protein and implicated in metastasis, over hCA II on the basis of a carefully curated data set of selective and nonselective inhibitors. Machine learning achieved surprisingly high accuracy in predicting hCA IX-selective inhibitors. The results were further investigated, and compound features determining successful predictions were identified. These features were then studied on the basis of X-ray structures of hCA isoform-inhibitor complexes and found to include substructures that explain compound selectivity. Our findings lend credence to selectivity predictions and indicate that the machine learning models derived herein have considerable potential to aid in the identification of new hCA IX-selective compounds

Generalizability of Cardiovascular Safety Trials on SGLT2 Inhibitors to the Real World: Implications for Clinical Practice

Introduction: Following the US Food and Drug Administration (FDA) guidance on the evaluation of novel agents for the treatment of type 2 diabetes mellitus (T2DM), a number of cardiovascular outcomes safety trials (CVOTs) on sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been conducted. These trials show similarities in study design and definition of primary endpoints, but differ in their eligibility criteria. The aim of the present study was to investigate the generalizability of CVOTs on SGLT2i to Italian adults with T2DM; we estimated the proportions of this patient population who would be eligible for enrollment in EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin), DECLARE-TIMI 58 (dapagliflozin), and VERTIS-CV (ertugliflozin) studies. Methods: This observational, cross-sectional study was conducted in 222 Italian diabetes clinics. Data on 455,662 adult patients with T2DM seen during 2016 were analyzed against the published patient eligibility criteria for the four CVOTs. The current use of SGLT2i in potentially eligible patients was assessed. Results: Among the population identified, the proportion of patients meeting major eligibility criteria was 11.7% for EMPA-REG OUTCOME, 29.4% for CANVAS, 55.9% for DECLARE-TIMI 58, and 12.8% for VERTIS-CV. Of the patients eligible for these CVOTs, only a minority (range 4.4-6.8%) was actually prescribed an SGLT2i. Compared with patients in the CVOTs, eligible patients in the real world showed older age and longer diabetes duration, lower BMI and HbA1c levels, lower prevalence of established cardiovascular and cerebrovascular disease, and higher rates of microvascular complications and peripheral arterial disease. Conclusion: The percentage of patients potentially eligible for treatment with SGLT2i varies as a reflection of different eligibility criteria applied in the trials. A large number of patients that could benefit from SGLT2i in terms of not only cardiovascular protection but also renal protection do not receive the treatment

Clinical inertia is the enemy of therapeutic success in the management of diabetes and its complications: A narrative literature review

Diabetes mellitus is a chronic disease characterized by high social, economic and health burden, mostly due to the high incidence and morbidity of diabetes complications. Numerous studies have shown that optimizing metabolic control may reduce the risk of micro and macrovascular complications related to the disease, and the algorithms suggest that an appropriate and timely step of care intensification should be proposed after 3 months from the failure to achieve metabolic goals. Nonetheless, many population studies show that glycemic control in diabetic patients is often inadequate. The phenomenon of clinical inertia in diabetology, defined as the failure to start a therapy or its intensification/de-intensification when appropriate, has been studied for almost 20 years, and it is not limited to diabetes care, but also affects other specialties. In the present manuscript, we have documented the issue of inertia in its complexity, assessing its dimensions, its epidemiological weight, and its burden over the effectiveness of care. Our main goal is the identification of the causes of clinical inertia in diabetology, and the quantification of its social and health-related consequences through the adoption of appropriate indicators, in an effort to advance possible solutions and proposals to fight and possibly overcome clinical inertia, thus improving health outcomes and quality of care

Current evidence to propose different food supplements for weight loss: a comprehensive review

The use of food supplements for weight loss purposes has rapidly gained popularity as the prevalence of obesity increases. Navigating through the vast, often low quality, literature available is challenging, as is providing informed advice to those asking for it. Herein, we provide a comprehensive literature revision focusing on most currently marketed dietary supplements claimed to favor weight loss, classifying them by their purported mechanism of action. We conclude by proposing a combination of supplements most supported by current evidence, that leverages all mechanisms of action possibly leading to a synergistic effect and greater weight loss in the foreseen absence of adverse events. Further studies will be needed to confirm the weight loss and metabolic improvement that may be obtained through the use of the proposed combination

Discovery of monoacylglycerol lipase (MAGL) inhibitors based on a pharmacophore-guided virtual screening study

Monoacylglycerol lipase (MAGL) is an important enzyme of the endocannabinoid system that catalyzes the degradation of the major endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL is associated with pathological conditions such as pain, inflammation and neurodegenerative diseases like Parkinson's and Alzheimer's disease. Furthermore, elevated levels of MAGL have been found in aggressive breast, ovarian and melanoma cancer cells. Due to its different potential therapeutic implications, MAGL is considered as a promising target for drug design and the discovery of novel small-molecule MAGL inhibitors is of great interest in the medicinal chemistry field. In this context, we developed a pharmacophore-based virtual screening protocol combined with molecular docking and molecular dynamics simulations, which showed a final hit rate of 50% validating the reliability of the in silico workflow and led to the identification of two promising and structurally different reversible MAGL inhibitors, VS1 and VS2. These ligands represent a valuable starting point for structure-based hit-optimization studies aimed at identifying new potent MAGL inhibitors

Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide

ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Dysregulated aggrecanase activity of ADAMTS-5 has been directly linked to the etiology of osteoarthritis (OA). For this reason, ADAMTS-5 is a pharmaceutical target for the treatment of OA. ADAMTS-5 shares high structural and functional similarities with ADAMTS-4, which makes the design of selective inhibitors particularly challenging. Here we exploited the ADAMTS-5 binding capacity of β-N-acetyl-d-glucosamine to design a new class of sugar-based arylsulfonamides. Our most promising compound, 4b, is a non-zinc binding ADAMTS-5 inhibitor which showed high selectivity over ADAMTS-4. Docking calculations combined with molecular dynamics simulations demonstrated that 4b is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Furthermore, the interaction between 4b and the ADAMTS-5 Dis domain is mediated by hydrogen bonds between the sugar moiety and two lysine residues (K532 and K533). Targeted mutagenesis of these two residues confirmed their importance both for versicanase activity and inhibitor binding. This positively-charged cluster of ADAMTS-5 represents a previously unknown substrate-binding site (exosite) which is critical for substrate recognition and can therefore be targeted for the development of selective ADAMTS-5 inhibitors

Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide

ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Dysregulated aggrecanase activity of ADAMTS-5 has been directly linked to the etiology of osteoarthritis (OA). For this reason, ADAMTS-5 is a pharmaceutical target for the treatment of OA. ADAMTS-5 shares high structural and functional similarities with ADAMTS-4, which makes the design of selective inhibitors particularly challenging. Here we exploited the ADAMTS-5 binding capacity of β-N-acetyl-d-glucosamine to design a new class of sugar-based arylsulfonamides. Our most promising compound, 4b, is a non-zinc binding ADAMTS-5 inhibitor which showed high selectivity over ADAMTS-4. Docking calculations combined with molecular dynamics simulations demonstrated that 4b is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Furthermore, the interaction between 4b and the ADAMTS-5 Dis domain is mediated by hydrogen bonds between the sugar moiety and two lysine residues (K532 and K533). Targeted mutagenesis of these two residues confirmed their importance both for versicanase activity and inhibitor binding. This positively-charged cluster of ADAMTS-5 represents a previously unknown substrate-binding site (exosite) which is critical for substrate recognition and can therefore be targeted for the development of selective ADAMTS-5 inhibitors

Development of a fluorogenic ADAMTS-7 substrate

The extracellular protease ADAMTS-7 has been identified as a potential therapeutic target in atherosclerosis and associated diseases such as coronary artery disease (CAD). However, ADAMTS-7 inhibitors have not been reported so far. Screening of inhibitors has been hindered by the lack of a suitable peptide substrate and, consequently, a convenient activity assay. Here we describe the first fluorescence resonance energy transfer (FRET) substrate for ADAMTS-7, ATS7FP7. ATS7FP7 was used to measure inhibition constants for the endogenous ADAMTS-7 inhibitor, TIMP-4, as well as two hydroxamate-based zinc chelating inhibitors. These inhibition constants match well with IC50 values obtained with our SDS-PAGE assay that uses the N-terminal fragment of latent TGF-β–binding protein 4 (LTBP4S-A) as a substrate. Our novel fluorogenic substrate ATS7FP7 is suitable for high throughput screening of ADAMTS-7 inhibitors, thus accelerating translational studies aiming at inhibition of ADAMTS-7 as a novel treatment for cardiovascular diseases such as atherosclerosis and CAD