Nitish R. Mahapatra

Cystathionine gamma-lyase (CTH), a key enzyme in hydrogen sulfide (H ₂ S) biosynthesis, has been studied extensively in models of oxidative stress. Dysregulated CTH has been reported in cardiovascular disease, ischemia-reperfusion (I/R) injury, aging, and xenobiotic stress, where reactive oxygen species are central to pathology. Despite this, how CTH is regulated at the molecular level under basal, ischemic, and reperfusion conditions is largely unknown. We observed that CTH expression is dysregulated during ischemia and reperfusion in Huh7 hepatic cells, mouse liver, and human liver, and therefore systematically dissected its transcriptional, post-transcriptional, and epigenetic control. Promoter-deletion reporter assays identified the -275/+91 bp region as the core human CTH promoter. This region was predicted to harbour binding sites for Sp1, CREB, and NFY, which were confirmed through overexpression, knockdown or inhibition, and ChIP assays in Huh7 cells. Computational and experimental screening identified miR-150-5p and miR-510-5p as novel post-transcriptional regulators that bind directly to the CTH 3’-UTR. We also examined histone marks (H3K9ac, H3K9me3, H3K4me3, and H3K27me3) at the CTH promoter and found that H3K9ac, H3K4me3, and H3K27me3 correlate with CTH expression across basal, ischemic, and reperfusion conditions. Mechanistically, ischemia reduces Sp1 occupancy at the CTH promoter, raises miR-150-5p and miR-510-5p levels, lowers H3K9ac, collectively suppressing CTH. Reperfusion reverses this with greater Sp1 and CREB binding, lower miR-150-5p and miR-510-5p levels, and reduced H3K27me3, restoring CTH expression. Together, these findings reveal novel roles for Sp1, CREB, NFY, miR-150-5p, miR-510-5p, and histone modifications in the regulation of CTH during basal, ischemia and reperfusion conditions.

Biofilms, dense microbial communities embedded in extracellular polymeric substances, present persistent challenges in medical devices by conferring antibiotic resistance and fostering chronic infections. Conventional antimicrobial or enzymatic approaches often fail due to poor penetration into biofilm matrices. This work introduces a dynamic surface capable of mechanically disrupting biofilms, enabling on‐demand cleaning of biomedical interfaces. Here, we present a dual‐responsive bilayer actuator composed of a solvent‐responsive hydrogel and a photoresponsive elastomer. The system harnesses solvent‐ and light‐induced bidirectional bending for effective detachment of bacterial biofilms. The bilayer undergoes upward curvature upon exposure to solvent and reverses to downward curvature upon irradiation with green light (530 nm), demonstrating repeatable and directional actuation. We evaluate the removal of Escherichia coli and Staphylococcus aureus biofilms across 12, 24, and 48 h growth periods, comparing single and cyclic actuation modes. Quantitative analyses show that upward bending (θ∼ 156°) and downward bending (θ∼ −73.7°) each achieve significant detachment, while cyclic actuation further enhances removal efficiency (>70%), particularly for mature 48 h biofilms. Colony‐forming unit assays validate the reduction in viable bacteria following the actuation. This study demonstrates the potential of dual‐responsive actuators as biocompatible, nonchemical strategies for biofilm removal for next‐generation antifouling medical device surfaces.

Hypercholesterolemia is a leading cause of various cardiovascular diseases (CVDs). 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (Hmgcr) is the rate-limiting enzyme in the cholesterol biosynthesis pathway. Previous studies investigated the regulation of Hmgcr expression under various pathophysiological conditions. However, its expression under hypoxia, an important player in the pathogenesis of CVD, is poorly understood. The present study investigated the hepatic expression of Hmgcr and Hif-1α in Spontaneously hypertensive rats [SHR] and its normotensive control, Wistar Kyoto [WKY] rats. Interestingly, hepatic Hmgcr expression was diminished while Hif-1α expression was elevated in SHR. In cultured rat liver cells, the Hmgcr promoter activity/transcript/protein and intracellular cholesterol levels were diminished after hypoxia treatment. Further, while Hif-1α /Runx3 transcript and protein levels were enhanced, Srebf levels decreased upon hypoxia. Knock-down of Hif-1α abrogated the hypoxia-mediated effect on Hmgcr, intracellular cholesterol levels, and the expression of Srebf and Runx3. Chromatin immunoprecipitation (ChIP) assays showed binding of Hif-1α to both endogenous SHR- and WKY-Hmgcr/Srebf/Runx3 domains with similar promoter occupancies. However, differential binding of Hif-1α to Srebf and Runx3 promoter domains were observed from ChIP assay. While HIF-1α showed a negative correlation with HMGCR/SREBF transcript levels, it correlated positively with RUNX3. Additionally, ChIP assays demonstrated differential binding of Srebf and Runx3 to SHR/WKY-Hmgcr promoter domains upon hypoxic stress. Taken together, this study elucidates the regulatory role of Hif-1α in modulating Hmgcr expression and intracellular cholesterol levels via Srebf and Runx3 under hypoxic stress. These findings provide new mechanistic insights underlying cholesterol homeostasis under hypoxia.

Catestatin (CST), a 21-amino acids physiological peptide, has emerged as a key modulator of cardiovascular functions due to its anti-hypertensive and cardioprotective properties. However, the ramifications of the most common human variant of CST (viz., Gly364Ser) on cardiovascular pathophysiology remain partially understood. In this study, hypertension was induced in uninephrectomized rats by treatment with deoxycorticosterone-acetate and sodium chloride (DOCA-salt). The DOCA-salt-induced hypertensive (DSHR) animals were then intraperitoneally administered with either CST wild-type (CST-WT) or 364Ser variant (CST-Ser) peptide. CST-Ser was profoundly less effective than CST-WT in rescuing the elevated systolic blood pressure [from ∼211 mmHg to ∼176 mmHg, p < 0.0001 (CST-Ser) versus ∼116 mmHg, p < 0.0001 (CST-WT)] and heart rate [from ∼356 bpm to ∼314 bpm, p = 0.66 (CST-Ser) versus ∼276 bpm, p = 0.02 (CST-WT)]. CST-Ser also showed diminished effects in lowering diastolic blood pressure and mean arterial pressure in the DSHR animals. Furthermore, CST-Ser was inefficient/markedly less potent in rescuing the impaired contractile and diastolic function in DSHR animals [improvements in the contractility index by ∼22 s–1 (CST-Ser), p = 0.15 versus by ∼84 s–1 (CST-WT), p < 0.0001 and decrease in end-diastolic pressure by ∼4 mmHg (CST-Ser), p = 0.015 versus by ∼14 mmHg (CST-WT), p < 0.0001]. Moreover, CST-Ser exerted less potent anti-inflammatory effects on the DSHR hearts than CST-WT. These findings are in concordance with the elevated systolic/diastolic blood pressure observed in Ser variant carriers from various human populations. This study provides compelling evidence for the diminished anti-hypertensive and cardioprotective effects of the CST-Gly364Ser variant.

Chromogranin A (CHGA), a member of the granin family of proteins, has been an attractive therapeutic target and candidate biomarker for several cardiovascular, neurological, and inflammatory disorders. The prominence of CHGA stems from the pleiotropic roles of several bioactive peptides (e.g., catestatin, pancreastatin, vasostatins) generated by its proteolytic cleavage and by their wide anatomical distribution. These peptides are emerging as novel modulators of cardiometabolic diseases that are often linked to high blood cholesterol levels. However, their impact on cholesterol homeostasis is poorly understood. The dynamic nature of cholesterol and its multitudinous roles in almost every aspect of normal body function makes it an integral component of metabolic physiology. A tightly regulated coordination of cholesterol homeostasis is imperative for proper functioning of cellular and metabolic processes. The deregulation of cholesterol levels can result in several pathophysiological states. Although studies till date suggest regulatory roles for CHGA and its derived peptides on cholesterol levels, the mechanisms by which this is achieved still remain unclear. This review aims to aggregate and consolidate the available evidence linking CHGA with cholesterol homeostasis in health and disease. In addition, we also look at common molecular regulatory factors (viz., transcription factors and microRNAs) which could govern the expression of CHGA and genes involved in cholesterol homeostasis under basal and pathological conditions. In order to gain further insights into the pathways mediating cholesterol regulation by CHGA/its derived peptides, a few prospective signaling pathways are explored, which could act as primers for future studies.