Vascular Effects of SGLT2 Inhibitors: Evidence and Mechanisms.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were initially developed as glucose-lowering agents for type 2 diabetes mellitus (T2DM). However, robust clinical evidence has demonstrated that their therapeutic benefits extend beyond glycemic control. SGLT2i reduce hospitalization for heart failure (HF), slow the progression of chronic kidney disease (CKD), and provide cardiorenal protection even in individuals without diabetes but with cardiovascular disease.

Interleukin-6 Modulates Endoplasmic Reticulum Stress Signaling and Mitochondrial Protein Complexes in the Kidney Following Acute Exhaustive Exercise.

Endoplasmic Reticulum (ER) homeostasis is closely regulated by an adaptive signaling network identified as the unfolded protein response (UPR), which is tightly related to the inflammatory pathway. However, physical exercise increases plasma concentrations of interleukin-6 (IL-6), which exhibits both pro- and anti-inflammatory properties that mediate ER function and mitochondrial metabolism, making its investigation relevant in physiological and pathological contexts. In kidney diseases, the IL-6 levels are effective in predicting mortality risk.

Bidirectional shifts in Pm20d1 expression impact thermogenesis and metabolism.

Background: Peptidase M20 domain containing 1 (PM20D1) is a secreted N-fatty acyl amino synthase and hydrolase that controls tissue and blood levels of N-fatty acyl amino acids. In brown adipocytes, N-fatty acyl amino acids bind to mitochondria and act as uncouplers of mitochondria, independent of UCP1. Interventions aimed at increasing or inhibiting PM20D1 expression considerably impact energy balance and metabolism; however, little is known about naturally occurring variants of the PM20D1/Pm20d1 gene and their impact on phenotype.

The Secretome of Human Deciduous Tooth-Derived Mesenchymal Stem Cells Enhances In Vitro Wound Healing and Modulates Inflammation.

Chronic wounds represent a significant clinical and public health challenge due to impaired tissue repair and high associated morbidity. This study investigates the therapeutic potential of the secretome derived from human mesenchymal stem cells obtained from the pulp of deciduous teeth (hDP-MSCs) in promoting skin wound healing. After confirming the mesenchymal identity and multipotent differentiation potential of hDP-MSCs by using flow cytometry and histological staining, the effects of the secretome on human keratinocyte (HaCaT) cultures were evaluated.

Extracellular Vesicles from Post-COVID-19 Patients Alter Endothelial Function Under Protein Restriction.

The COVID-19 pandemic worsened global food insecurity and malnutrition. Protein restriction increases the risk of poor COVID-19 outcomes and cardiovascular disease. Post-COVID-19 syndrome remains a public health concern, although its underlying mechanisms are not yet fully understood.

Inhibition of glucagon secretion from pancreatic α-cells by the bile acid TUDCA involves a S1PR2-PI3K pathway.

The global prevalence of type 2 diabetes (T2D) continues to rise, and predictions indicate alarming records in coming decades. Although pancreatic β-cell dysfunction and insulin resistance are key factors in the etiology of T2D, the impairment of α-cells has been also implicated. Hyperglucagonemia and altered suppression of glucagon release can be frequently found in individuals with T2D, contributing to hyperglycemia.

Time-restricted feeding combined with exercise improves hepatic and glycaemic metabolism in obese mice: A sex-dependent study.

Erratic feeding patterns, such as those experienced by shift workers, can exacerbate obesity and metabolic-associated fatty liver disease (MAFLD). Both nutritional factors and sexual dimorphism influence the progression of MAFLD. Time-restricted feeding (TRF) has emerged as a promising strategy to mitigate the effects of obesity, supported by evidence of its benefits for metabolic disorders like MAFLD.

HIF-1 attenuates high-fiber diet-mediated proliferation and stemness of colonic epithelium.

The complex interplay between diet, microbiota, and host is exemplified by the effects of dietary fiber on the intestine. Inulin ingestion triggers epithelial changes in the colon that depend on microbiota-derived molecules, including enhanced proliferation, increased mucus production, and elevated antimicrobial peptide secretion. Here we employed a multilayered and multi-omics approach, including dietary interventions, intestinal organoids, and both genetic and pharmacological interventions to investigate the impact of inulin on two aspects of diet-microbiota-host interactions: intestinal hypoxia and hypoxia-inducible factor (HIF)-1 signaling in intestinal epithelial cells (IECs).

The influence of diet, age, and obesity on hypothalamic omega-3 fatty acid transporter MFSD2a.

Inflammatory proteins present in the context of obesity influence the general permeability of organic biological barriers, including the blood-brain barrier (BBB). Inflammation alters junction proteins, resulting in increased permeability, and may also influence the response pattern of barrier proteins responsible for intracellular nutrient transport. Focusing on the MFSD2a protein (major facilitator superfamily domain containing 2 A), which is present in the BBB, is an important translocator of omega-3 fatty acid (ω3) from the periphery to the central nervous system (CNS), this study aimed to assess the impact of obesity induced by a high-fat diet (HF) on the MFSD2a modulation in the hypothalamus of mice.

The Critical Role of the Bile Acid Receptor TGR5 in Energy Homeostasis: Insights into Physiology and Therapeutic Potential.

Over the past decades, bile acids have been recognized as important signaling molecules with significant roles in metabolic health and disease. Many of their beneficial effects are mediated through the activation of the Takeda G protein-coupled receptor 5 (TGR5), a G protein-coupled receptor ubiquitously expressed in both humans and animals. Upon activation, TGR5 stimulates adenylate cyclase, leading to increased cyclic adenosine monophosphate (cAMP) levels and subsequent activation of protein kinase A (PKA).

Persistent Changes in Hormones and Growth Factors Involved in Ageing in Patients That Recovered from Severe COVID-19.

Background: The coronavirus disease-19 pandemic affected millions of people and its long-term impact on the health of survivors is under evaluation.

Objectives: In this study, we hypothesized that severe coronavirus disease-19 could promote long-term changes in the blood levels of hormones and growth factors known to be involved in the regulation of ageing.

Methods: We evaluated 49 patients that recovered from severe COVID-19 and compared them with matched controls that were never infected by the virus.

Effects of combined training on quality of life in individuals with overweight-related type 2 diabetes: a pilot study of correlations with metabolic, inflammatory and thermogenic markers.

Background: There is still a lack of information regarding the impact of training on the domains that constitute quality of life (QoL), and the relationship between QoL with hormonal, inflammatory and pro-thermogenic/anti-inflammatory components. Thus, the present work aimed to evaluate the effects of combined training (CT) on the QoL of individuals with overweight-related type 2 diabetes mellitus (T2DM) and to correlate (baseline values and CT-induced delta percentage changes (Δ%)) QoL variables with hormonal, inflammatory, and pro-thermogenic/anti-inflammatory components.

Methods: Middle-aged individuals of both sexes and with overweight-related T2DM were assigned to either the control group (CONT group) or the combined training group (CTG).

Resolvin D2 and Its Effects on the Intestinal Mucosa of Crohn's Disease Patients: A Promising Immune Modulation Therapeutic Target.

Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that severely impacts patients' quality of life. Although current therapies have improved symptom management, they often fail to alter disease progression and are associated with immunosuppressive side effects. This study evaluated the immunomodulatory potential of resolvin D2 (RvD2), a pro-resolving lipid mediator, using a murine model of colitis and the ex vivo treatment of intestinal mucosal biopsies from CD patients, comparing its effects to those of conventional anti-TNFα therapy.

Mechanisms underlying the interplay between autophagy and the inflammasome in age-related diseases: Implications for exercise immunology.

Aging is a multifactorial process characterized by cellular dysfunction and increased susceptibility to age-related diseases. The interplay between autophagy and inflammasome has emerged as a critical factor influencing the aging process. Autophagy, which is responsible for degrading damaged cellular components, declines with age, leading to the accumulation of dysfunctional organelles and misfolded proteins.

A nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss.

The emergence of glucagon-like peptide-1 agonists represents a notable advancement in the pharmacological treatment of obesity, yet complementary approaches are essential. Through phenotypic drug discovery, we developed promising nitroalkene-containing small molecules for obesity-related metabolic dysfunctions. Here, we present SANA, a nitroalkene derivative of salicylate, demonstrating notable efficacy in preclinical models of diet-induced obesity.

Intradermal priming to intravesical Bacillus Calmette-Guérin in non-muscle invasive bladder cancer: A translational research and phase I clinical trial.

Objective: To determine the safety and the role of modulating cytokines and proteases in the immune response to intravesical Bacillus Calmette-Guérin (BCG) when primed with systemic intradermal BCG.

Methods: Phase 1 and mechanistic longitudinal, prospective, single-blind randomized study (NCT04806178). Twenty-one non-muscle invasive urothelial bladder cancer patients undergoing intravesical adjuvant BCG after transurethral resection of bladder tumor (TURBT) in a teaching hospital between September 2021 and April 2023 were randomized to 0.

Fenofibrate treatment during lactation prevents liver and adipose tissue associated metabolic dysfunction in a rat model of childhood obesity.

Childhood obesity and associated comorbidities in adulthood are of great concern worldwide. Evidence highlights the importance of lactation in later disease development. In this sense, obese children are at great risk of developing adult obesity, insulin resistance, type 2 diabetes, and cardiovascular disease at adulthood.

Towards a consensus atlas of human and mouse adipose tissue at single-cell resolution.

Adipose tissue (AT) is a complex connective tissue with a high relative proportion of adipocytes, which are specialized cells with the ability to store lipids in large droplets. AT is found in multiple discrete depots throughout the body, where it serves as the primary repository for excess calories. In addition, AT has an important role in functions as diverse as insulation, immunity and regulation of metabolic homeostasis.

NAD replenishment restores mitochondrial function and thermogenesis in the brown adipose tissue of mice with obesity.

Brown adipose tissue (BAT) is a highly specialized thermogenic tissue and plays a critical role in controlling energy expenditure and metabolic homeostasis. BAT dysfunction is associated with body weight gain and metabolic disorders in mice models. Here, we investigated the influence of the NAD-biosynthesis pathway in the control of BAT metabolism and function.

Obesity-Induced Metabolic Priming Exacerbates SARS-CoV-2 Inflammation.

Despite the early recognition that individuals living with obesity are more prone to develop adverse outcomes during COVID-19, the mechanisms underlying these conditions are still unclear. During obesity, an accumulation of free fatty acids (FFAs) in the circulation promotes low-grade inflammation. Here, we show that FFAs induce epigenetic reprogramming of monocytes, exacerbating their inflammatory profile after SARS-CoV-2 infection, a mechanism named metabolic-primed immunity.

Excessive exercise elicits poly (ADP-ribose) Polymerase-1 activation and global protein PARylation driving muscle dysfunction and performance impairment.

Excessive exercise combined with inadequate recovery time may trigger fatigue, performance impairment, and ultimately the overtraining syndrome. The intramyocellular mechanisms involved in the overtraining syndrome remain only partially known. Here, we combined multi-omics analyses from isogenic BXD mouse strains with a mouse model of overtraining and excessive exercise protocol in mice and humans to evaluate the molecular mechanism involved in the performance impairment induced by excessive exercise.

Intranasal pramlintide matches intraperitoneal effects on food intake and gastric emptying in mice.

Purpose: Pramlintide is an amylin analog developed as a complementary treatment for diabetes. However, it requires several subcutaneous injections, reducing patients' adherence. Since the intranasal route might be an alternative for drug administration, we evaluated whether intranasal pramlintide treatment exerts comparable actions with intraperitoneal administration.

Notch1 Signalling Is Downregulated by Aerobic Exercise, Leading to Improvement of Hepatic Metabolism in Obese Mice.

Background And Aims: Notch1 protein plays a significant role in hepatic metabolism, as evidenced by its correlation with insulin resistance in the livers of obese individuals, making it an intriguing research target. Therefore, this study aims to investigate the impact of aerobic exercise on Notch1 pathways in the hepatic tissue of obese mice and its role in controlling hepatic metabolism.

Methods: Therefore, we conducted a cross-sectional study utilising liver biopsies from lean and obese humans, as well as an intervention study involving mice subjected to a high-fat diet.

Central FGF19 signaling enhances energy homeostasis and adipose tissue thermogenesis through sympathetic activation in obese mice.

Fibroblast growth factor 19 (FGF19) signaling in the brain is associated with body weight loss, reduced food intake, and improved glycemic control in obese mice through unclear mechanisms. Here, we investigated the effects of central FGF19 administration on peripheral tissues, focusing on adipose tissue and its contributions to body weight loss. Using single-cell RNA sequencing of the adult murine hypothalamus, we found that FGF19 has the potential to target multiple cell populations, including astrocytes-tanycytes, microglia, neurons, and oligodendrocytes.