Biology subjects

Varma, U.

Publications and source records attributed to Varma, U..

5 recordsLinked to original sources

bioRxiv2024

Targeted glycophagy ATG8 therapy for diabetic heart disease

Diabetic heart disease is highly prevalent and is associated with the early development of impaired diastolic relaxation. The mechanisms of diabetic heart disease are poorly understood and it is a condition for which there are no targeted therapies. Recently, disrupted glycogen-autophagy (glycophagy) and glycogen accumulation have been identified in the diabetic heart. Glycophagy involves glycogen receptor binding and linking with an ATG8 protein to locate and degrade glycogen within an intracellular phago-lysosome. Here we show that glycogen receptor protein STBD1 (starch-binding-domain-protein-1) is mobilized early in the cardiac glycogen response to metabolic challenge in vivo, and that deficiency of a specific ATG8 family protein, Gabarapl1 ({gamma}-aminobutyric-acid-receptor-associated-protein-like-1) is associated with diastolic dysfunction in diabetes. Gabarapl1 gene delivery treatment remediated cardiomyocyte and cardiac diastolic dysfunction in type 2 diabetic mice and diastolic performance of diabetic human iPSC-derived cardiac organoids. We identify glycophagy dysregulation as a mechanism and potential treatment target for diabetic heart disease.

physiology↗

bioRxiv2024

Methods for detection of cardiac glycogen-autophagy

Glycogen-autophagy ( glycophagy) is a selective autophagy process involved in delivering glycogen to the lysosome for bulk degradation. Glycophagy protein intermediaries include STBD1 as a glycogen tagging receptor, delivering the glycogen cargo into the forming phagosome by partnering with the Atg8 homolog, GABARAPL1. Glycophagy is emerging as a key process of energy metabolism and development of reliable tools for assessment of glycophagy activity is an important priority. Here we show that antibodies raised against the N-terminus of the GABARAPL1 protein (but not the full-length protein) detected a specific endogenous GABARAPL1 immunoblot band at 18kDa. A stable GFP-GABARAPL1 cardiac cell line was used to quantify GABARAPL1 lysosomal flux via measurement of GFP puncta in response to lysosomal inhibition with bafilomycin. Endogenous glycophagy flux was quantified in primary rat ventricular myocytes by the extent of glycogen accumulation with bafilomycin combined with chloroquine treatment (no effect observed with bafilomycin or chloroquine alone). In wild-type isolated mouse hearts, bafilomycin alone and bafilomycin combined with chloroquine (but not chloroquine alone) elicited a significant increase in glycogen content signifying basal glycophagy flux. Collectively, these methodologies provide a comprehensive toolbox for tracking cardiac glycophagy activity to advance research into the role of glycophagy in health and disease.

molecular biology↗

bioRxiv2021

Protective role of the Atg8 1 homologue Gabarapl1 in regulating cardiomyocyte glycophagy in diabetic heart disease

Diabetic heart disease is highly prevalent and characterized by diastolic dysfunction. The mechanisms of diabetic heart disease are poorly understood and no targeted therapies are available. Here we show that the diabetic myocardium (type 1 and type 2) is characterized by marked glycogen elevation and ectopic cellular localization - a paradoxical metabolic pathology given suppressed cardiomyocyte glucose uptake in diabetes. We demonstrate involvement of a glycogen-selective autophagy pathway ( glycophagy) defect in mediating this pathology. Genetically manipulated deficiency of Gabarapl1, an Atg8 autophagy homologue, induces cardiac glycogen accumulation and diastolic dysfunction. Stbd1, the Gabarapl1 cognate autophagosome partner is identified as a unique component of the early glycoproteome response to hyperglycemia in cardiac, but not skeletal muscle. Cardiac-targeted in vivo Gabarapl1 gene delivery normalizes glycogen levels, diastolic function and cardiomyocyte mechanics. These findings reveal that cardiac glycophagy is a key metabolic homeostatic process perturbed in diabetes that can be remediated by Gabarapl1 intervention.

molecular biology↗

bioRxiv2021

Chemical characterization; Antimicrobial and Larvicidal activity of essential oil from Callistemon citrinus (Bottle brush) leaves

Mosquito-borne diseases are prevalent in more than 100 countries across the world. They are the major vectors for transmission of Malaria, dengue, yellow fever, filariasis, schistosomiasis, Japanese encephalitis etc. Many of the formerly employed insecticides in mosquito control have harmful effects on human health and other non-target populations, their non-biodegradable nature, the higher rate of bio-magnification in our ecosystem and increasing insecticide resistance on global scale are raising serious concerns. . Therefore, search for natural, eco-friendly alternatives such as bio-insecticides is imperative. In this study, Larvicidal activity of the essential oil obtained from the leaves of Callistemon citrinus was tested on Dengue vector mosquito Aedes aegypti & Chikungunya vector mosquito Culex sp. Also, the chemical composition of the essential oil was recorded using GC-MS analysis. The anti-microbial activity of the essential oil was checked against a few common bacteria and fungi. Callistemon citrinus comes out to be one of such bio-insecticides with many therapeutic active constituents, showing appreciable anti-microbial activity and 80-100% larvicidal activity.

pharmacology and toxicology↗

bioRxiv2019

Information Theoretic Feature Selection Methods for Single Cell RNA-Sequencing

Single cell RNA-sequencing (scRNA-seq) technologies have generated an expansive amount of new biological information, revealing new cellular populations and hierarchical relationships. A number of technologies complementary to scRNA-seq rely on the selection of a smaller number of marker genes (or features) to accurately differentiate cell types within a complex mixture of cells. In this paper, we benchmark differential expression methods against information-theoretic feature selection methods to evaluate the ability of these algorithms to identify small and efficient sets of genes that are informative about cell types. Unlike differential methods, that are strictly binary and univariate, information-theoretic methods can be used as any combination of binary or multiclass and univariate or multivariate. We show for some datasets, information theoretic methods can reveal genes that are both distinct from those selected by traditional algorithms and that are as informative, if not more, of the class labels. We also present detailed and principled theoretical analyses of these algorithms. All information theoretic methods in this paper are implemented in our PO_SCPLOWICTUREDC_SCPLOWRO_SCPLOWOCKSC_SCPLOW Python package that is compatible with the widely used scanpy package.

bioinformatics↗