Biology subjects

BISWAS, A.

Publications and source records attributed to BISWAS, A..

4 recordsLinked to original sources

bioRxiv2026

A Novel MicroRNA-Odorant Receptor Axis Governs Neural Progenitor Cell Proliferation in Zebrafish CNS

Spinal cord injury causes irreversible neurological deficits in mammals; yet zebrafish achieve complete functional recovery through molecular mechanisms that remain poorly defined. In this study we emphasized on a critical miRNA-mediated regulation of Ependymo-radial glial (ERG) cell proliferation in zebrafish spinal cord. Using next-generation sequencing we constructed a spatiotemporal miRNA profile across multiple post-injury time points and identified dre-miR-N1 as a novel injury-responsive miRNA involved in ERG proliferation among several differentially expressed novel miRNAs. Fluorescent in situ hybridization confirmed its robust lesion-site expression and gain-of-function analysis demonstrated that dre-miR-N1 significantly impaired functional recovery. Target prediction and validation unexpectedly identified the odorant receptor gene or42a1 as a high-confidence target and a combinatorial approach of miRNA gain-of-function and or42a1 loss-of-function showed that dre-miR-N1 modulates the proliferative behaviour of or42a1-expressing ERG cells under both homeostatic and injury conditions. These findings uncover a previously unrecognized miRNA-odorant receptor axis governing injury-induced ERG cell expansion establishing a novel molecular framework for endogenous neural regeneration in zebrafish.

neuroscience↗

bioRxiv2024

PDE4 inhibitor Rolipram represses hedgehog signaling via ubiquitin-mediated proteolysis of GLI transcription factors to regress breast cancer

Aberrant activation of the hedgehog signaling pathway positively correlates with progression, invasion and metastasis of several cancers, including breast cancer. Although numerous inhibitors of the Hedgehog signaling pathway are available, several oncogenic mutations of key components of the pathway, including Smoothened (Smo), have limited their capability to be developed as putative anti-cancer drugs. In this study, we have modulated the Hedgehog signaling pathway in breast cancer cell lines and tumor-bearing BALB/c mice, using a specific phosphodiesterase 4 (PDE4) inhibitor rolipram. The results indicated that increased levels of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA), due to the treatment with rolipram on MCF-7 and MDA-MB-231 cells, induced PKA-mediated ubiquitination of Glioma-associated oncogene homolog 2 full length (GLI2FL) and GLI3FL, leading to their transformation to respective repressor forms. This in turn reduced the level of Glioma-associated oncogene homolog 1 (GLI1) transcription factor in a time-dependent manner. We have also shown that elevated level of PKA reduced the level of phosphorylated glycogen synthase kinase 3{beta} (GSK3{beta}), which is known to augment PKA-mediated phosphorylation of GLI2FL and GLI3FL. Rolipram also significantly altered the wound healing capability as well as key markers of wound healing in MCF-7 and MDA-MB-231 cells. Moreover, rolipram caused significant reduction in tumor weight and volume in tumor-bearing mice model. The histological analysis revealed significant reduction in the number of multi-nucleated cells in tumor tissue and substantially reduced levels of cellular infiltration in the lung of rolipram treated tumor-bearing mice. Rolipram also reduced the levels of GLI1 in tumor-bearing mice by enhancing the PKA levels. Therefore, it may be concluded that rolipram can be used as an effective inhibitor of Hedgehog signaling pathway downstream of Smo to control breast cancer progression and metastasis in both hormone-responsive and triple negative breast cancers.

cancer biology↗

bioRxiv2024

Repurposing approved protein kinase inhibitors as potent anti-leishmanials targeting Leishmania MAP kinases

Leishmaniasis is a vast array of chronic diseases caused by the protozoan parasite of the genus Leishmania transmitted by the sandfly belonging to the genus Phlebotomus (Old World) and Lutzomyia (New World). Among the various factors that contribute to the virulence and pathogenesis of the disease, protein kinases play crucial role in modulating the parasites biology in the host system. There are no specific drugs identified to treat the disease specifically. Moreover, resistance against approved anti-leishmanials has made it important to look for a few pre-clinical candidates against visceral leishmaniasis. MAP kinase is one such candidate of protein kinase family that regulates cell proliferation in eukaryotes. In this study, we have identified 23 MAPKs from Leishmania genome and have screened 12 FDA approved protein kinase inhibitors against those MAPKs in search of a potential lead for new drug exploration. Among the inhibitors, sorafenib and imatinib have been identified as potential drug candidates based on multiple criteria including binding affinity, ADME scores, absorption and their ability to cross blood-brain barrier. Furthermore, these drugs showed excellent anti-proliferative effects in Leishmania promastigotes, resulted in change of cell morphology, flagellar length, promoted cell cycle arrest through ROS generation and reduced intra-macrophage parasitic burden. Collectively, these results imply involvement of MAP kinases in infectivity and survival of the parasite and can pave the avenue for repurposing sorafenib and imatinib as anti-leishmanial agents.

bioinformatics↗

bioRxiv2020

Evaluation of modulators of cAMP-response in terms of their impact on cell cycle and mitochondrial activity of Leishmania donovani

With the identification of novel cAMP binding effecter molecules in Trypanosoma, role of cAMP in kinetopalstida parasites gained an intriguing break through. Despite earlier demonstrations of role of cAMP in survival of Leishmania during macrophage infection, there is essential need to specifically clarify involvement of cAMP in various cellular processes in the parasite. In this context, we sought to gain a comprehensive understanding of the effect of cAMPanalogs and cAMP-phosphodiesterase (PDE) inhibitors on proliferation of log phase parasites. Administration of both hydrolysable (8-pCPT-cAMP) and non-hydrolysable analogs (Sp-8-pCPT-cAMPS) of cAMP resulted in significant decrease of Leishmania proliferation. Amongst the various PDE inhibitors, etazolate was found to be potently anti-proliferative. BrdU cell proliferation and K/N/F-enumeration microscopic study revealed that both cAMP analogues and selective PDE inhibitors resulted in significant cell cycle arrest at G1 phase with reduced S-phase population. Furthermore, careful examination of the flagellar motility patterns revealed significantly reduced coordinated forward flagellar movement of the promastigotes with a concomitant decrease in cellular ATP levels. Alongside, 8-pCPT-cAMP and PDE inhibitors etazolate and trequinsin showed marked reduction in mitochondrial membrane potential. Treatment of etazolate at subcytotoxic concentration to infected macrophages significantly reduced parasite burden and administration of etazolate to Leishmania-infected BALB/c mice showed reduced liver and spleen parasite burden. Collectively, these results imply involvement of cAMP in various crucial processes paving the avenue for developing potent anti-leishmanial agent. Author SummaryLeishmania donovani is the causative agent of fatal Visceral Leishmaniasis. The current available medications are toxic, expensive and require long term daily administrations. With an aim to develop improved therapeutic, components of cAMP homeostasis, particularly cAMP-phosphodiesteares, has been targeted for Leishmania and other kinetoplastid pathogens. cAMP plays diverse roles in functional processes involved in cell division, transition into different stages of the life cycle of Leishmania and motility. In this study, the authors found administration of both hydrolysable and non-hydrolysable analogs of cAMP and certain PDE inhibitors resulted in remarkable decrease proliferation with considerable cytopathic impact on promastigotes. The mammalian phosphodiestearse inhibitor etazolate caused significant reduction in parasite load in L. donovani infected macrophages and demonstrated considerable reduction of liver and spleen parasite burden in in vivo mouse infection model. The study suggested that etazolate, with its slightest impact on mammalian host, can be repurposed for developing effective anti-leishmanials.

cell biology↗