Sodium­glucose cotransporter­2 inhibitors in obesity and associated cardiometabolic disorders: where do we stand?

As the tide of obesity and its complications are on the rise, there is an urgent need for new drugs with weight­lowering and beneficial metabolic properties. Obesity­related disorders, such as metabolic syndrome, prediabetes, type 2 diabetes (T2D), cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD) make this need more than mandatory. Sodium­glucose cotransporter­2 (SGLT­2) inhibitors (empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin) are the latest class of agents to receive approval for the treatment of T2D. Not long after their marketing, a wide spectrum of target organ­protective and overall beneficial health effects associated with their use began to unveil. An increasing bulk of evidence indicates that these actions are to a great degree independent of glucose lowering, which has led to the broadening of the indications for SGLT­2 inhibitors outside the frame of antihyperglycemic therapy. Additionally, their unique mode of action including increased renal glucose excretion, and hence net energy loss, could render SGLT­2 inhibitors attractive candidates for the treatment of obesity. Very few reviews in the literature have holistically appraised the therapeutic potential of SGLT­2 inhibitors in obesity and its associated complications. Herein, we summarize the currently available evidence regarding the effects of drugs of this class on body adiposity, together with considerations on their potential use as weight loss agents. Furthermore, we attempt to overview their actions and future perspectives of their use with respect to a range of obesity­related disorders, which include cardiovascular, renal, and ovarian dysfunctions, as well as NAFLD and malignancy.

Therapeutic Potential of GLP-2 Analogs in Gastrointestinal Disorders: Current Knowledge, Nutritional Aspects, and Future Perspectives.

PURPOSE OF REVIEW: Although Glucagon-like peptide (GLP)-1 receptor agonists have been used for almost two decades in the treatment of diabetes mellitus type 2 and, lately, in obesity, recent years have seen an increasing interest in the pharmacological agonism of other proglucagon-derived peptides, including GLP-2. Herein, we aimed to review the available evidence on the effects of GLP-2 agonism from animal and clinical studies. Furthermore, we summarize the current clinical applications of GLP-2 agonists among patients with intestinal failure associated with short bowel syndrome (SBS-IF) as well as potential future expansion of their indications to other intestinal disorders. RECENT FINDINGS: Evidence from preclinical studies has highlighted the cellular trophic and functional beneficial actions of GLP-2 on small intestinal and colonic mucosa. Subsequently, pharmacologic agonism of GLP-2 has gathered interest for the treatment of patients with conditions pertaining to the loss of intestinal anatomical and/or functional integrity to a degree requiring parenteral support, collectively referred to as intestinal failure. GLP-2 analogs positively influence nutrient absorption in animal models and humans, although continued therapy is likely needed for sustained effects. The degradation-resistant GLP-2-analog teduglutide has received approval for the treatment of SBS-IF, in which it may decisively reduce patient dependency on parenteral support and improve quality of life. Another two longer-acting analogs, glepaglutide and apraglutide, are currently undergoing phase III clinical trials. The use of GLP-2 analogs is effective in the management of SBS-IF and may show promise in the treatment of other severe gastrointestinal disorders associated with loss of effective intestinal resorptive surface area.

Obesity, Hypovitaminosis D, and COVID-19: the Bermuda Triangle in Public Health.

PURPOSE OF REVIEW: The COVID-19 pandemic has challenged public health to a significant extent by markedly increasing morbidity and mortality. Evidence suggests that obesity and hypovitaminosis D constitute important risk factors for SARS-CoV-2 infection, severity of disease, and poor outcomes. Due to their high prevalence globally, obesity and hypovitaminosis D are considered pandemics. This review presents current epidemiologic and genetic data linking obesity, hypovitaminosis D, and COVID-19, highlighting the importance of the convergence of three pandemics and their impact on public health. We also briefly summarize potential mechanisms that could explain these links. RECENT FINDINGS: Epidemiologic data have shown that obesity is an independent risk factor for COVID-19, severe disease and death, and genetic evidence has suggested a causal association between obesity-related traits and COVID-19 susceptibility and severity. Additionally, obesity is independently associated with hypovitaminosis D, which is highly prevalent in subjects with obesity. Hypovitaminosis D is independently associated with a higher risk for COVID-19, severity, hospitalization, infectious complications, acute respiratory distress syndrome, and poor outcomes. However, genome-wide association studies have not revealed any causal association between vitamin D levels and the risk for COVID-19, while there is no robust evidence for a beneficial role of vitamin D supplementation in the prevention and treatment of COVID-19. In the context of the ongoing COVID-19 pandemic, the epidemiologic impact of obesity and hypovitaminosis D is emphasized. Efforts to increase public awareness and reinforce preventive and therapeutic measures against obesity and hypovitaminosis D are strongly required.

Nutritional Deficiencies Before and After Bariatric Surgery: Prevention and Treatment.

PURPOSE OF REVIEW: Bariatric surgery has the unique ability to drive substantial and sustainable weight loss in people living with obesity. Non-reversibility of these surgical techniques provides lifelong benefits but entails the need for continuous medical follow-up. The purpose of the current paper is to review and summarize current data on nutritional deficiencies in patients before and after bariatric surgery. RECENT FINDINGS: The cornerstone of preventing the emergence of disorders related to nutritional deficiencies is preoperative screening and correct supplementation since they may be exacerbated postoperatively. Following guidelines in conjunction to a lifelong personalized medical approach is of high importance. Bariatric surgery is a well-studied successful and durable means of weight loss that may lead to nutritional deficiencies. There is, thus, a medical need for careful monitoring and treatment of micro- and macronutrient deficiencies by an experienced multidisciplinary team.

A Narrative Review of the Safety of Anti-COVID-19 Nutraceuticals for Patients with Cancer.

Interest in dietary supplements and their efficacy in treating and preventing disease has increased greatly since the outbreak of the COVID-19 pandemic. Due to the risk of severe COVID-19 in patients with cancer, we conducted a narrative review aiming to better understand the data on the safety of the most efficacious "anti-COVID-19" nutraceuticals for patients with cancer. We conducted a PubMed database search aimed at identifying the most effective nutrients for use against COVID-19. For the identified nutraceuticals, we searched PubMed again regarding their safety for patients with cancer. Fifty-four total records (52 independent studies) were retrieved, pertaining to vitamin D, vitamin C, selenium, omega-3 fatty acids, and zinc. Vitamin D results from 23 articles indicated safe use, but two articles indicated potential harm. All 14 articles for vitamin C and five out of six articles for selenium indicated the safety of use (one study for selenium suggested harm with high-dose supplementation). Results for omega-3 fatty acids (seven articles) and zinc (one article), however, were rather mixed regarding safety. We conclude that vitamin D, vitamin C, and selenium supplements are likely safe or even beneficial at typically recommended doses; however, caution is urged with omega-3 fatty acid supplements, and zinc supplements should likely be avoided. More experimental research is needed, and nutraceutical use by patients with cancer should always be under the supervision of a healthcare team.

Saffron for "toning down" COVID-19-related cytokine storm: Hype or hope? A mini-review of current evidence.

AIM: To assess the potential role of saffron in downregulating inflammation and cytokine storm during COVID-19. MAIN FINDINGS: Three main compounds of saffron, i.e., crocetin esters, picrocrocin, and safranal, present strong antioxidant and anti-inflammatory action for several disease states (e.g., Alzheimer's, cancer, and depression) but have also been studied in COVID-19. In particular, based on our comprehensive review of both in vitro and in silico studies, saffron's essential oils and other constituents appear to have both immunomodulatory and anti-asthmatic actions; these actions can be particularly helpful to treat patients with respiratory symptoms due to COVID-19. Moreover, crocin appears to reduce the COVID-19-related cytokine cascade and downregulate angiotensin-converting enzyme 2 (ACE2) gene expression. Last, in silico studies suggest that saffron's astragalin and crocin could have inhibitory actions on SARS-CoV-2 protease and spike protein, respectively. CONCLUSION: Saffron represents a promising substance for toning down cytokine storm during COVID-19, as well as a potential preventive treatment for COVID-19. However, appropriate randomized clinical trials, especially those using biomarkers as surrogates to assess inflammatory status, should be designed in order to assess the clinical efficacy of saffron and allow its use as an adjunct treatment modality, particularly in resource-poor settings where access to drugs may be limited.

Vitamin D and Obesity: Current Evidence and Controversies.

PURPOSE OF REVIEW: Evidence from observational studies suggests that obesity is associated with low vitamin D. As both obesity and hypovitaminosis D present an alarmingly increased prevalence worldwide, there is an intense research interest to clarify all aspects of this association. This review summarizes current evidence from meta-analyses investigating vitamin D status in obesity, including the effects of weight loss and bariatric surgery on vitamin D status and the outcomes of vitamin D supplementation on body weight. We also discuss potential pathophysiologic mechanisms and important controversies. RECENT FINDINGS: Data from meta-analyses consistently support an inverse association of vitamin D levels with body weight. However, the impact of weight loss on improving vitamin D status is small, while studies on the supplementation with vitamin D after bariatric surgery have shown conflicting results regarding vitamin D status. Moreover, interventional studies do not support a beneficial effect of vitamin D supplementation on body weight. These findings warrant a cautious interpretation due to important methodological limitations and confounding factors, such as high heterogeneity of studies, variable methods of determination of vitamin D and definition of deficiency/insufficiency, use of various adiposity measures and definitions of obesity, and inadequate adjustment for confounding variables influencing vitamin D levels. The underlying pathogenetic mechanisms associating low vitamin D in obesity include volumetric dilution, sequestration into adipose tissue, limited sunlight exposure, and decreased vitamin D synthesis in the adipose tissue and liver. Experimental studies have demonstrated that low vitamin D may be implicated in adipose tissue differentiation and growth leading to obesity either by regulation of gene expression or through modulation of parathyroid hormone, calcium, and leptin. Obesity is associated with low vitamin D status but weight loss has little effect on improving this; vitamin D supplementation is also not associated with weight loss. Evidence regarding vitamin D status after bariatric surgery is contradicting. The link between vitamin D and obesity remains controversial due to important limitations and confounding of studies. More research is needed to clarify the complex interplay between vitamin D and adiposity.

The combination of bromelain and curcumin as an immune-boosting nutraceutical in the prevention of severe COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic is still ongoing, while no treatment has been proven effective. COVID-19 pathophysiology involves the activation of three main pathways: the inflammatory, the coagulation and the bradykinin cascades. Here, we highlight for the first time the joint potential therapeutic role of bromelain and curcumin, two well-known nutraceuticals, in the prevention of severe COVID-19. Bromelain (a cysteine protease isolated from the pineapple stem) and curcumin (a natural phenol found in turmeric) exert important immunomodulatory actions interfering in the crucial steps of COVID-19 pathophysiology. Their anti-inflammatory properties include inhibition of transcription factors and subsequent downregulation of proinflammatory mediators. They also present fibrinolytic and anticoagulant properties. Additionally, bromelain inhibits cyclooxygenase and modulates prostaglandins and thromboxane, affecting both inflammation and coagulation, and also hydrolyzes bradykinin. Interestingly, curcumin has been shown in silico studies to prevent entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into cells as well as viral replication, while a recent experimental study has demonstrated that bromelain may also inhibit viral entry into cells. Notably, bromelain substantially increases the absorption of curcumin after oral administration. To the best of our knowledge, this is the first report highlighting the significance of bromelain and, most importantly, the potential preventive value of the synergistic effects of bromelain and curcumin against severe COVID-19.

Could Respiratory Fluoroquinolones, Levofloxacin and Moxifloxacin, Prove to be Beneficial as an Adjunct Treatment in COVID-19?

Since the beginning of the COVID-19 pandemic, researchers have focused on repurposing of existing antibiotics, antivirals and anti-inflammatory drugs to find an effective therapy. Fluoroquinolones are broad spectrum synthetic antimicrobial agents, being chemical derivatives of quinoline, the prodrome of chloroquine. Interestingly, fluoroquinolones may exert antiviral actions against vaccinia virus, papovavirus, CMV, VZV, HSV-1, HSV-2, HCV and HIV. A recent in silico study has shown that the fluoroquinolones, ciprofloxacin and moxifloxacin, may inhibit SARS-CoV-2 replication by exhibiting stronger capacity for binding to its main protease than chloroquine and nelfinavir, a protease inhibitor antiretroviral drug. Remarkably, fluoroquinolones have shown multiple immunomodulatory actions leading to an attenuation of the inflammatory response through the inhibition of pro-inflammatory cytokines. Noteworthy, respiratory fluoroquinolones, levofloxacin and moxifloxacin, constitute fist line therapeutic agents for the management of severe community-acquired pneumonia. They are characterized by advantageous pharmacokinetic properties; higher concentrations in the lungs; and an excellent safety profile comparable to other antibiotics used to treat respiratory infections, such as macrolides and b-lactams. Based on their potential antiviral activity and immunomodulatory properties, the favorable pharmacokinetics and safety profile, we propose the use of respiratory fluoroquinolones as adjuncts in the treatment of SARS-CoV-2 associated pneumonia.

Probiotics, Prebiotics, Synbiotics, Postbiotics, and Obesity: Current Evidence, Controversies, and Perspectives.

PURPOSE OF REVIEW: In this review, we summarize current evidence on gut microbiome and obesity; we discuss the role of probiotics, prebiotics, synbiotics, and postbiotics in obesity prevention and management; and we highlight and analyze main limitations, challenges, and controversies of their use. RECENT FINDINGS: Overall, the majority of animal studies and meta-analyses of human studies examining the use of probiotics and synbiotics in obesity has shown their beneficial effects on weight reduction and other metabolic parameters via their involvement in gut microbiota modulation. Bifidobacterium and Lactobacillus strains are still the most widely used probiotics in functional foods and dietary supplements, but next generation probiotics, such as Faecalibacterium prausnitzii, Akkermansia muciniphila, or Clostridia strains, have demonstrated promising results. On the contrary, meta-analyses of human studies on the use of prebiotics in obesity have yielded contradictory results. In animal studies, postbiotics, mainly short-chain fatty acids, may increase energy expenditure through induction of thermogenesis in brown adipose tissue as well as browning of the white adipose tissue. The main limitations of studies on biotics in obesity include the paucity of human studies; heterogeneity among the studied subgroups regarding age, gender, and lifestyle; and use of different agents with potential therapeutic effects in different formulations, doses, ratio and different pharmacodynamics/pharmacokinetics. In terms of safety, the supplementation with prebiotics, probiotics, and synbiotics has not been associated with serious adverse effects among immune-competent individuals, with the exception of the use of probiotics and synbiotics in immunocompromised patients. Further large-scale Randomized Controlled Trials (RCTs) in humans are required to evaluate the beneficial properties of probiotics, prebiotics, synbiotics, and postbiotics; their ideal dose; the duration of supplementation; and the durability of their beneficial effects as well as their safety profile in the prevention and management of obesity.

How does the joint dermatology-rheumatology clinic benefit both patients and dermatologists?

Psoriasis (Pso) and psoriatic arthritis (PsA) are chronic and debilitating diseases which often develop in the same patient and are linked to a wide range of comorbid conditions. Dermatologists and rheumatologists need to cooperate in combined clinics, especially when they deal with severe, recalcitrant disease, and multiple comorbidities. The clinical and research benefits of this collaboration have been previously described to contribute to a better and more sustainable health care system. To apply a more holistic approach of patients with Pso and PsA, we established the first dual care clinic in Greece, for Pso and PsA patients, based at Attikon General University Hospital. Hereby, we describe the infrastructure and operation of a combined Pso and PsA clinic (PPAC), in the national health care system of Greece, and its impact on the management of Pso and PsA. The PPAC is a single-day joint clinic, held once a week, which consists of three dermatologists and three rheumatologists. We present the results of 185 newly diagnosed patients between December 2018 and January 2019. Mean age of onset of Pso was 34 ± 16 years old and 47 ± 12 years old for PsA. Most patients suffered from severe plaque Pso (144/185, 78%) and asymmetric oligoarticular arthritis (59/185, 32%), for which they were receiving treatment with biologic agents (105/185, 57%). Many required monitoring for hypertension (74/185, 40%), dyslipidemia (69/185, 37%), diabetes (17/185, 9%), and depression (20/185, 11%). Patients reported high levels of care satisfaction (visual analogue scale: 86 ± 11.5), using the PPAC facility, compared to different referrals between specialties. This is the first joint dermatology-rheumatology clinic in Greece, providing comprehensive care in patients with Pso and PsA. Our results support the concept of combined clinics delivering better integrated care for such patients.

Interplay of adipokines and myokines in cancer pathophysiology: Emerging therapeutic implications.

Excess body weight constitutes a worldwide health problem with epidemic proportions impacting on the risk and prognosis of several disease states including malignancies. It is believed that the metabolic changes associated with weight gain, particularly visceral obesity, and physical inactivity could lead to dysfunctional adipose and muscle tissues causing insulin resistance, low-grade chronic inflammation and abnormal secretion of adipokines and myokines. The complex paracrine and endocrine interconnection between adipokines and myokines reflects a yin-yang balance with important implications in processes such as lipolysis control, insulin sensitivity and prevention from obesity-driven chronic low-grade inflammation and cancer promotion through anti-inflammatory adipokines and myokines. Furthermore, the complex pathophysiology of cancer cachexia is based on the interplay between muscle and adipose tissue mediated by free fatty acids, various adipokines and myokines. The purpose of this editorial is to explore the role of the adipose and muscle tissue interplay in carcinogenesis, cancer progression and cachexia, and to examine the mechanisms underpinning their association with malignancy. Understanding of the mechanisms connecting the interplay of adipokines and myokines with cancer pathophysiology is expected to be of importance in the development of therapeutic strategies against cancer cachexia. Advances in the field of translational investigation may lead to tangible benefits to obese and inactive persons who are at increased risk of cancer as well as to cancer patients with cachexia.