Biology subjects

Pennathur, S.

Publications and source records attributed to Pennathur, S..

8 recordsLinked to original sources

bioRxiv2026

Sotagliflozin Reprograms Hepatic Lipid Metabolism and Attenuates Atherosclerosis Beyond Empagliflozin in CKM Mice

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce cardiovascular mortality and chronic kidney disease (CKD) progression in cardiovascular-kidney-metabolic (CKM) syndrome, but this benefit derives primarily from reductions in heart failure and cardiovascular mortality rather than in atherothrombotic events. Sotagliflozin, which inhibits both intestinal SGLT1 and renal SGLT2, is the only drug in this class shown to lower rates of myocardial infarction and stroke in CKD. However, its mechanism remains unclear, and its effectiveness in non-diabetic CKD has not been studied. We hypothesized that dual SGLT1/2 inhibition reprograms systemic substrate utilization toward fatty acid oxidation, which may partially account for this protective effect. Methods: CKD was induced in male low-density lipoprotein receptor-deficient mice by 5/6 nephrectomy. Sham and CKD mice received a high-fat diet and drinking water containing sotagliflozin, empagliflozin, or vehicle for 16 weeks, at doses that produced equivalent fractional excretion of glucose. We quantified atherosclerosis en face and in the aortic sinus. Indirect calorimetry, echocardiography, hepatic RNA sequencing, plasma acylcarnitine profiling, and in vivo deuterium labeling of palmitate were performed. Results: At matched levels of glucosuria and plasma total cholesterol, sotagliflozin decreased body mass, atherosclerosis burden, triglycerides, and TNF- more than empagliflozin, and raised postprandial total GLP-1 approximately 3-fold, while both drugs similarly improved albuminuria and diastolic function. Sotagliflozin increased energy expenditure independent of body mass and lowered respiratory exchange ratio despite compensatory hyperphagia. Sotagliflozin reduced hepatic lipogenic genes and de novo lipogenic flux, while increasing {beta}-oxidation and ketogenesis; empagliflozin only activated the oxidative pathway. Conclusions: In experimental CKM syndrome, dual SGLT1/2 inhibition reduces atherosclerosis and metabolic syndrome more effectively than selective SGLT2 inhibition and is associated with reprogramming of hepatic lipid metabolism. These results suggest that sotagliflozin could be an attractive candidate for mitigating atherosclerotic risk in non-diabetic CKD.

pharmacology and toxicology↗

bioRxiv2025

Dapagliflozin mitigates hypoxia-induced metabolic stress, kidney tubular cell death and fibrosis

Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) slow progression of kidney disease but therapeutic mechanisms remain elusive. Here we report the beneficial effect of dapagliflozin on hypoxia-mediated kidney tubular epithelial cell injury, a contributing factor to kidney disease progression, using a human pluripotent stem cell (hPSC)-derived hypoxic kidney organoid model. Hypoxic organoids showed increased expression of Hypoxia Inducible Factor (HIF)-associated transcriptional targets, decreased tricarboxylic acid (TCA) cycle metabolites and mitochondrial {beta}-oxidation protein expression, and activated unfolded protein response. A transcriptional signature derived from hypoxic organoids 1) identified a subgroup of individuals whose kidney disease subsequently progressed, and 2) correlated with worse tubular injury. Dapagliflozin enhanced mitochondrial stress response resulting in reversed hypoxia-induced tubular epithelial cell apoptosis, reactive oxygen species (ROS) accumulation, and organoid fibrosis. These results indicate that dapagliflozin may contribute to improved kidney disease outcomes by attenuating hypoxia-induced metabolic stress-mediated tubular epithelial cell injury.

cell biology↗

bioRxiv2025

Accelerated osteocytic citrate production in chronic kidney disease is associated with protection of the kidney

Patients with chronic kidney disease (CKD) face elevated fracture incidences, but mechanisms underlying CKD-related bone loss remain unclear. Using the adenine-induced chronic kidney injury (AdKI) murine model, we identified that AdKI induces dysregulated glucose metabolism in bones and kidneys via in vivo and ex vivo metabolic tracing. Ex vivo 13C-metabolic tracing of osteocyte-enriched femora revealed accelerated citrate production from [1,2-13C]-glucose and [U-13C]-glutamine in AdKI mice. These metabolic changes were observed together with increased circulating citrate and Slc13a5 overexpression in bones from AdKI mice. Thus, to explore the role of citrate in AdKI, we utilized mice harboring a loss of function mutation in the citrate importer SLC13A5 (Slc13a5R337*/R337*). Mutant mice displayed elevated osteocytic citrate production, and elevated circulating citrate, without significantly worsened AdKI-related bone loss. Coincident with this, Slc13a5R337*/R337* mutant mice were significantly protected from loss of kidney function with attenuated AdKI-induced nephrolithiasis. We also confirmed that Slc13a5 is highly expressed in cortical bone compared to the kidney, suggesting the effect of the mutation is mediated by SLC13A5s function outside the kidney. Altogether, this study finds that accelerated osteocytic citrate production in CKD is associated with protection of kidney function, and modulation of citrate handling may be a site for therapeutic intervention in CKD.

physiology↗

bioRxiv2024

Rapid prediction of thermodynamically destabilizing tyrosine phosphorylations in cancers

Tyrosine phosphorylations are a prominent characteristic of numerous cancers, necessitating the use of computational tools to comprehensively analyze phosphoproteomes and identify potentially (dys)functional phosphorylations. Here we propose a machine learning-based method to predict the thermodynamic stability change resulting from tyrosine phosphorylation. Our approach, based on prediction of phosphomimetic delta-delta-G from structural features, strongly correlates with experimental mutational scanning cDNA proteolysis data (R = 0.71). We predicted the destabilizing effects of all 384,857 tyrosine residues from the Alphafold2 database. We then applied our approach to a pan-cancer phosphoproteomics dataset, comprising over 600 unique tyrosine phosphorylations across 11 cancer subtypes. We predict destabilizing phosphorylations in both oncogenes and tumor suppressors, where the former likely reflects a generalized relief of auto-inhibition or activating conformational change. We find that the number of circuit topological parallel relations with respect to residues contacting the phosphorylated site is greater for autoinhibited oncogenes than for other proteins (Wilcoxon p = 0.03). Utilizing an extreme gradient-boosting machine learning approach, we obtain an AUC of 0.85 for the prediction of autoinhibited phosphorylation states from circuit topological features. The top destabilized proteins from the pan-cancer data are enriched for chemical and oxidative stress pathways. Among metabolic proteins, highly destabilizing phosphorylations tend to occur in more peripheral proteins with lower network centrality measures (Wilcoxon p = 0.005). We predict 58% of recurrent tyrosine cancer phosphorylations to be destabilizing at the 1 kcal/mol threshold. Our approach can enable rapid screening of destabilizing phosphorylations and phosphomimetic mutations.

systems biology↗

bioRxiv2024

Limitations in mitochondrial programming restrain the differentiation and maturation of human stem cell-derived β cells

Pluripotent stem cell (SC)-derived islets offer hope as a renewable source for {beta} cell replacement for type 1 diabetes (T1D), yet functional and metabolic immaturity may limit their long-term therapeutic potential. Here, we show that limitations in mitochondrial transcriptional programming impede the formation of SC-derived {beta} (SC-{beta}) cells. Utilizing transcriptomic profiling, assessments of chromatin accessibility, mitochondrial phenotyping, and lipidomics analyses, we observed that SC-{beta} cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets that are related to limitations in key mitochondrial transcriptional networks. Surprisingly, we found that reductions in glucose-stimulated mitochondrial respiration in SC-islets were not associated with alterations in mitochondrial mass, structure, or genome integrity. In contrast, SC-islets show limited expression of targets of PPAR, which regulate mitochondrial programming, yet whose functions in {beta} cell differentiation are unknown. Importantly, treatment with WY14643, a potent PPAR agonist, induced expression of mitochondrial targets, improved insulin secretion, and increased the formation of SC-{beta} cells both in vitro and following transplantation. Thus, PPAR-dependent mitochondrial programming promotes the differentiation of SC-{beta} cells and may be a promising target to improve {beta} cell replacement efforts for T1D.

developmental biology↗

bioRxiv2021

Lipid Alterations in African American Prostate Cancer

African-American (AA) men are more than twice as likely to die of prostate cancer (PCa) than European American (EA) men. Previous in-silico analysis revealed enrichment of altered lipid metabolic pathways in pan-cancer AA tumors. Here, we performed global unbiased lipidomics profiling on 48 matched localized PCa and benign adjacent tissues (30 AA, 24 ancestry-verified, and 18 EA, 8 ancestry verified) and quantified 429 lipids belonging to 15 lipid classes. Significant alterations in long chain polyunsaturated lipids was observed between PCa and benign adjacent tissues, low and high Gleason tumors, as well as associated with early biochemical recurrence, both in the entire cohort, and within AA patients. Altered levels of cholesteryl esters, and phosphatidyl inositols delineated AA and EA PCa, while levels of triglycerides, phosphatidyl glycerol, phosphatidyl choline, phosphatidic acid and cholesteryl esters distinguished AA and EA PCa patients with biochemical recurrence. These first-in-field results implicate lipid alterations as biological factors for prostate cancer disparities.

cancer biology↗

bioRxiv2020

Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology

Intestinal epithelial cell (IEC) damage by T cells contributes to alloimmune, autoimmune and iatrogenic diseases such as graft-versus-host disease (GVHD), inflammatory bowel disease (IBD) and immune checkpoint blockade (ICB) mediated colitis, respectively. Despite significant advances in understanding the aberrant biology of T cells in these diseases, little is known about how the fundamental biological processes of the target IECs influence the disease severity. Here, through analyses of metabolic pathways of IECs, we identified disruption of oxidative phosphorylation without a concomitant change in glycolysis and an increase in succinate levels in several distinct in vivo models of T cell mediated gastrointestinal damage such as GVHD, IBD and ICB mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses identified a critical role for IEC intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations that contributed to the severity of intestinal damage. The critical mechanistic role of IEC intrinsic SDHA was confirmed by complementary chemical and genetic reduction of SDHA and with IEC specific deletion of SDHA. Further in vitro and in vivo mechanistic studies demonstrated that loss of SDHA in IECs was mediated by the perforin-granzyme from the T cells. The loss of SDHA was also validated in human clinical samples. These data identify a critical role for the alteration of the IEC specific mitochondrial complex II component SDHA in the regulation of the severity of T cell mediated intestinal diseases.

immunology↗

bioRxiv2017

DNA-stabilized silver nanoclusters as specific, ratiometric fluorescent dopamine sensors

Neurotransmitters are small molecules that orchestrate complex patterns of brain activity. Unfortunately, there exist few sensors capable of directly detecting individual neurotransmitters. Those sensors that do exist are either unspecific or fail to capture the temporal or spatial dynamics of neurotransmitter release. DNA-stabilized silver nanoclusters (DNA-AgNCs) are a new class of biocompatible, fluorescent nanostructures that have recently been demonstrated to offer promise as biosensors. In this work, we identify two different DNA sequences which form dopamine-sensitive nanoclusters. We demonstrate that each sequence supports two distinct DNA-AgNCs capable of providing specific, ratiometric fluorescent sensing of dopamine concentration in vitro. DNA-Ag nanoclusters therefore offer a novel, low-cost approach to quantification of dopamine, creating the potential for real-time monitoring in vivo.

neuroscience↗