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Biology subjects

Gopalan, J.

Publications and source records attributed to Gopalan, J..

3 recordsLinked to original sources

Insights into the protective mechanisms of N-acetyl cysteine against D-Galactosamine induced acute liver injury in rabbits

Pre-clinical studies in test animals like rodents, rabbits and pigs are extremely important in establishing the efficacy of therapeutic interventions ranging from formulations to medical devices. Diseases like acute liver failure (ALF) are although rare, but most often culminate into a situation where the patient needs an emergency liver transplant. Currently, not many medications are available to manage such patients. Out of the very few available options, N-acetyl cysteine (NAC) is the clinicians drug-of-choice. Administration of NAC has shown improvements in patients survival in the hospitals. Yet the mechanism and its systematic investigation in pre-clinical models like rabbits remains undone. In this report, we establish a drug-induced, controlled-ALF in rabbits using D-galactosamine (D-Gal). We also test the efficacy of NAC in this model system. We support the in-vivo findings with detailed in-vitro assays where we attempt to understand the mechanisms of the prophylactic usage of NAC against D-Gal induced ALF.

pathology↗

A human induced pluripotent stem (hiPS) cell model for the holistic study of epithelial to mesenchymal transitions (EMTs)

The epithelial to mesenchymal transition (EMT) is a widely studied but poorly defined state change due to the variety of ways in which it has been characterized in cells. There is a need for reproducible cell model systems that enable the integration and comparison of different types of measured observations of cells across many distinct cellular contexts. We present human induced pluripotent stem (hiPS) cells as such a model system by demonstrating its utility through a comparative analysis of hiPS cell-EMT in 2D and 3D cell culture geometries. We developed live-imaging-based assays to directly compare examples of changes in cell function (via migration timing), molecular components (via expression of marker proteins), organization (via reorganization of cell junctions), and environment (via dynamics of basement membrane) in the same experimental system. The EMT-related changes we measured occurred earlier in 2D colonies than in 3D lumenoids, likely due to differences in the basement membrane environments associated with 2D vs. 3D initial hiPS cell culture geometries. We have made the 449 60-hour-long 3D time-lapse movies and the associated tools used for analysis and visualization open-source and easily accessible as a resource for future work in this field.

cell biology↗

Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis.

Pathophysiological defects in water homeostasis can lead to renal failure. Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder associated with abnormal cytoskeletal dynamics in the kidney collecting ducts and perturbed calcium and cAMP signaling in the ciliary compartment. We show that collecting ducts in mice lacking the A-Kinase anchoring protein AKAP220 exhibit enhanced development of primary cilia. Mechanistic studies reveal that AKAP220-associated protein phosphatase 1 (PP1) mediates this phenotype by promoting changes in the stability of histone deacetylase 6 (HDAC6) with concomitant defects in actin dynamics. This proceeds through a previously unrecognized adaptor function for PP1 as all ciliogenesis and cytoskeletal phenotypes are recapitulated in mIMCD3 knock-in cells expressing a phosphatase-targeting defective AKAP220-{Delta}PP1 mutant. Pharmacological blocking of local HDAC6 activity alters cilia development and reduces cystogenesis in kidney-on-chip and organoid models of ADPKD. These findings identify the AKAP220-PPI-HDAC6 pathway as a key effector in primary cilia development.

cell biology↗