Biology subjects

Bravo, G. M.

Publications and source records attributed to Bravo, G. M..

3 recordsLinked to original sources

bioRxiv2025

Exercise Conditioning Enhances Insulin Sensitivity with Metabolic and Glycemic Control Driven by Hepatic Silencing of HMGB1 in Type 2 Diabetic Mice

Type 2 Diabetes (T2D) is characterized by chronic insulin resistance and inflammation. Exercise induces hyperglycemia control in T2D more than pharmacologic therapies alone. High Mobility Group Box 1 (HMGB1) is a ubiquitous nuclear factor for T2D progression. We hypothesize that hepatic silencing of HMGB1 in T2D and exercise will increase insulin sensitivity and shift metabolic routes, decrease liver damage and improve metabolic health in T2D mice. MethodsLiver HMGB1 KO (HMGB1{Delta}) was induced with AAV8-TBG in HMGB1 flox mice (AAV8-EGFP was used as wildtype controls). T2D mice were induced with a low-dose STZ and a high-fat diet. T2D mice ran for four weeks (1hr daily). Dual Energy X-Ray Absorptiometry (DEXA), A1C, glycemia, HMGB1, metabolomics and metabolic cage analysis were performed pre- and post-exercise. RT-PCR, immunoblotting and immunohistochemistry for glucose metabolism markers were performed in tissue samples. ResultsT2D HMGB1{Delta} mice show 20% less hyperglycemia compared to controls with a strong correlation between reduced HMGB1 levels and lower A1C following exercise. Additionally, fat percentage, liver damage, and glycogen storage were significantly reduced. These findings highlight the high potential effect of exercise potentiated has via HMGB1 governed mechanisms and highlights HMGB1 as a therapeutic target for managing hyperglycemia in T2D. ARTICLE HIGHLIGHTSHMGB1 hepatic silencing in Type 2 Diabetic mice is a promising therapeutic target for enhancing Insulin sensitivity. Combination of hepatic HMGB1 silencing and exercise potentiates the metabolic benefits and liver protection in Type 2 Diabetic mice. Shift in metabolic routes and carbohydrate metabolism due to regulation of hepatic HMGB1 expression makes HMGB1 an ideal target for pharmacologic intervention. However, our study also underscores the value of exercise as the primary focus of diabetic glucose control aided by enhanced therapeutic targeting of HMGB1 for chronic inflammation and hyperglycemia.

molecular biology↗

bioRxiv2025

Targeting CRM1-HMGB1 Nuclear Translocation in Type 2 Diabetes-Driven Metabolic Dysfunction Associated Steatotic Liver Disease

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) prevalent in Type-2 Diabetes (T2D) and contributes to progression of Non-Alcoholic Steatohepatitis (NASH). Acetyl-High Mobility Group Box 1 (HMGB1,) a proinflammatory isoform of HMGB1, is released as a DAMP in T2D associated hepatic inflammatory condition. Chromosomal Maintenance 1 (CRM1), a nuclear transporter protein, maintains the nuclear-cytoplasm translocation of hepatic HMGB1 in T2D. We hypothesize that inhibition of CRM1/HMGB1 nuclear shuttling is a therapeutic target for MASLD in T2D. Methods: We performed immunohistochemical analysis of acetyl-HMGB1 and CRM1 in human liver biopsies from control, T2D, and T2D-NASH (n:4 per group). H&E staining to evaluate inflammation and disease stratification. In vitro, studies involved targeted inhibition of CRM1 using Leptomycin-B and HMGB1 with Glycyrrhizin in T2D Huh7 human hepatocytes. Results: T2D subjects with NASH exhibit an increase in acetyl-HMGB1 nuclear and cytoplasmic translocation compared to DM and controls. Acetyl-HMGB1 increased 2-fold in the nucleus and 4-fold in the cytoplasm; CRM1 increased 6-fold in the nucleus and 8-fold in the cytoplasm of T2D/NASH subjects compared to controls. Targeted inhibition of CRM1 and HMGB1 prevented acetyl-HMGB1 hepatocyte release with the most prominent effect in T2D-NASH conditions. Conclusions: Hepatic CRM1/HMGB1 inhibition could be a potential therapeutic target for T2D-driven MASLD.

pathology↗

bioRxiv2024

High-Intensive Interval Training Decreases Circulating HMGB1 in Insulin Resistant Patients; Plasma Lipidomics Identifies Associated Cardiometabolic Benefits

Background: Exercise is a fundamental primary standard of care for cardiometabolic health. Body Weight (BW) High-Intensity Interval Training (HIIT) is an effective strategy for reducing cardiometabolic markers in individuals with insulin resistance and Type-2 diabetes (T2D). High-mobility group box 1 (HMGB1), a ubiquitous nuclear factor, plays an ample role beyond an alarmin in T2D development and progression. Our group has described this novel role previously, showing the beneficial effect of whole body HMGB1 silencing in decreasing hyperglycemia in diabetic mice. In the present study we tested the hypothesis that BW-HIIT as an effective exercise training modality will decrease cardiometabolic risk with a concomitant decrease in circulating HMGB1 more prominently in insulin resistant individuals compared to non-insulin resistant individuals contrasting to what we can evidence in a preclinical murine model of insulin resistance; Methods: Human and mouse pre- and post-exercise serum/plasma samples were analyzed for Lipidomics as well as Metabolic and Cytokine Multiplex assays. Standard of care, as well as cardiometabolic parameters, was also performed in human subjects; Results: insulin resistant individuals had the most positive effect, primarily with a decrease in the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). as an index of insulin resistance as well as decreased HMGB1 post-exercise. Lipidomic analysis illustrated the highly beneficial effect of exercise training using a modified HIIT program, showing an enhanced panel of circulating lipids post-exercise exclusively in insulin resistant individuals. Plasma multiplex revealed significant translational heterogeneity in our studies with distinct metabolic hormone responses to exercise conditioning with a decrease in inflammatory markers in insulin resistant individuals; Conclusions: The current study demonstrated that 6-week BW-HIIT training improves cardiometabolic, anti-inflammatory markers, metabolic hormones, and insulin sensitivity in humans, strongly associated with decreased circulating HMGB1. Overall, these experiments reinforce the potential of HMGB1 as a marker of changes in insulin resistance and the positive effect of exercise training on insulin resistance possibly preventing the development of T2D and associated complications.

molecular biology↗