High Mobility Group Box 1 (HMGB1) is a highly conserved non-histone chromatin-associated protein across species, primarily recognized for its regulatory impact on vital cellular processes, like autophagy, cell survival, and apoptosis. HMGB1 exhibits dual functionality based on its localization: both as a non-histone protein in the nucleus and as an inducer of inflammatory cytokines upon extracellular release. Pathophysiological insights reveal that HMGB1 plays a significant role in the onset and progression of a vast array of diseases, viz., atherosclerosis, kidney damage, cancer, and neurodegeneration. However, a clear mechanistic understanding of HMGB1 release, translocation, and associated signaling cascades in mediating such physiological dysfunctions remains obscure. This review presents a detailed outline of HMGB1 structure–function relationship and its regulatory role in disease onset and progression from a signaling perspective. This review also presents an insight into the status of HMGB1 druggability, potential limitations in understanding HMGB1 pathophysiology, and future perspective of studies that can be undertaken to address the existing scientific gap. Based on existing paradigm of various studies, HMGB1 is a critical regulator of inflammatory cascades and drives the onset and progression of a broad spectrum of dysfunctions. Studies focusing on HMGB1 druggability have enabled the development of biologics with potential clinical benefits. However, deeper understanding of post-translational modifications, redox states, translocation mechanisms, and mitochondrial interactions can potentially enable the development of better courses of therapy against HMGB1-mediated physiological dysfunctions.

Cardiovascular diseases (CVDs) are the leading cause of premature morbidity and mortality globally. The identification of novel risk factors contributing to CVD onset and progression has enabled an improved understanding of CVD pathophysiology. In addition to the conventional risk factors like high blood pressure, diabetes, obesity and smoking, the role of gut microbiome and intestinal microbe-derived metabolites in maintaining cardiovascular health has gained recent attention in the field of CVD pathophysiology. The human gastrointestinal tract caters to a highly diverse spectrum of microbes recognized as the gut microbiota, which are central to several physiologically significant cascades such as metabolism, nutrient absorption, and energy balance. The manipulation of the gut microbial subtleties potentially contributes to CVD, inflammation, neurodegeneration, obesity, and diabetic onset. The existing paradigm of studies suggests that the disruption of the gut microbial dynamics contributes towards CVD incidence. However, the exact mechanistic understanding of such a correlation from a signaling perspective remains elusive. This review has focused upon an in-depth characterization of gut microbial metabolites and their role in varied pathophysiological conditions, and highlights the potential molecular and signaling mechanisms governing the gut microbial metabolites in CVDs. In addition, it summarizes the existing courses of therapy in modulating the gut microbiome and its metabolites, limitations and scientific gaps in our current understanding, as well as future directions of studies involving the modulation of the gut microbiome and its metabolites, which can be undertaken to develop CVD-associated treatment options. Clarity in the understanding of the molecular interaction(s) and associations governing the gut microbiome and CVD shall potentially enable the development of novel druggable targets to ameliorate CVD in the years to come.

Cardiometabolic risk and associated dysfunctions contribute largely to the recent rise in mortality globally. Advancements in multi-omics in recent years promise a better understanding of potential biomarkers that enable an early diagnosis of cardiometabolic dysfunction. However, the molecular mechanisms driving the onset and progression of cardiometabolic disorders remain poorly understood. Adipokines are adipocyte-specific cytokines that are central to deleterious cardiometabolic alterations. They exhibit both pro-inflammatory and anti-inflammatory effects, complicating their association with cardiometabolic disturbances. Thus, understanding the cardiometabolic association of adipokines from a molecular and signaling perspective assumes great importance. This review presents a comprehensive outline of the most prominent adipokines exhibiting pro-inflammatory and/or anti-inflammatory functions in cardiometabolic dysfunction. The review also presents an insight into the pathophysiological implications of such adipokines in different cardiometabolic dysfunction conditions, the status of adipokine druggability, and future studies that can be undertaken to address the existing scientific gap. A clear understanding of the functional and mechanistic role of adipokines can potentially improve our understanding of cardiovascular disease pathophysiology and enhance our current therapeutic regimen in the years to come.

Background: Recent studies have shown that Nlrp3 inflammasome activation is importantly involved in podocyte dysfunction induced by nicotine. The present study was designed to test whether acid sphingomyelinase (Asm) and ceramide signaling play a role in mediating nicotine-induced Nlrp3 inflammasome activation and subsequent podocyte damage. Methods and Results: Nicotine treatment significantly increased the Asm expression and ceramide production compared to control cells. However, prior treatment with amitriptyline, an Asm inhibitor significantly attenuated the nicotine-induced Asm expression and ceramide production. Confocal microscopic and biochemical analyses showed that nicotine treatment increased the colocalization of NLRP3 with Asc, Nlrp3 vs. caspase-1, IL-1β production, caspase-1 activity, and desmin expression in podocytes compared to control cells. Pretreatment with amitriptyline abolished the nicotine-induced colocalization of NLRP3 with Asc, Nlrp3 with caspase-1, IL-1β production, caspase-1 activity and desmin expression. Immunofluorescence analyses showed that nicotine treatment significantly decreased the podocin expression compared to control cells. However, prior treatment with amitriptyline attenuated the nicotine-induced podocin reduction. In addition, nicotine treatment significantly increased the cell permeability, O₂ production, and apoptosis compared to control cells. However, prior treatment with amitriptyline significantly attenuated the nicotine-induced cell permeability, O₂ production and apoptosis in podocytes. Conclusions: Asm is one of the important mediators of nicotine-induced inflammasome activation and podocyte injury. Asm may be a therapeutic target for the treatment or prevention of glomerulosclerosis associated with smoking.