Biology subjects

Dev, S.

Publications and source records attributed to Dev, S..

4 recordsLinked to original sources

bioRxiv2025

Beyond Gatekeeping: Efflux Pumps Remotely Destabilize Cytoplasmic Drug-Target Interactions by Limiting Rebinding.

Bacterial efflux pumps are major contributors to multidrug resistance, classically described as "gatekeepers" that reduce drug entry. Here, we uncover an equally potent post-entry mechanism of efflux pumps, revealing that their function extends deep into intracellular drug-target interactions. Using quantitative live-cell fluorescence imaging, we monitored the activity of major efflux systems in Escherichia coli and Pseudomonas aeruginosa with Hoechst (HCT), a DNA-binding inhibitor. As expected, more HCT entered efflux-deficient cells than efflux-active cells. Unexpectedly, the intracellular HCT in efflux-deficient cells also bound DNA more stably, resulting in higher binding affinity. Statistical-physics-based modeling and experimental testing show that that unlike in dilute in vitro conditions, drug molecules that unbind from their targets in intracellular environments rapidly undergo successive rebinding, prolonging the lifetime of the drug-target complex. However, efflux pumps counteract this effect by suppressing rebinding, thereby kinetically destabilizing drug-target interactions and lowering the binding affinity. This kinetic destabilization acts synergistically with canonical gatekeeping to broaden and amplify drug resistance. Our findings reveal an underappreciated biophysical mechanism of efflux pumps, expanding the classical biochemical view of how efflux pumps confer multidrug resistance.

microbiology↗

bioRxiv2025

Hylocereus polyrhizus peel extract restricts DMBA- Croton oil induced skin carcinogenesis: An integrated in vivo and in silico approach

Hylocereus polyrhizus, locally known as red dragon fruit, is valued for its nutritional benefits including high levels of antioxidants and is gaining popularity as both a food and a medicinal plant. The present study addressed the in vivo and in silico chemopreventive potential of Hylocereus polyrhizus peel extract (HPPE) in DMBA-croton oil induced skin carcinogenic model mice. The mRNA expression level of pro-inflammatory cytokines and inflammatory mediators in tumor mass were estimated by real time-RT-qPCR. In addition, molecular docking and molecular dynamic simulation analyses were conducted on the reported compounds. In the in vivo chemopreventive activity assessment, the peel extract at 500 mg/kg was found effective in reducing total tumor number, yield, burden, incidence, and weight. Total proteins and endogenous antioxidants (GSH, SOD, CAT) levels in liver and skin tissues from mice were significantly (P<0.05) elevated. In addition, the HPPE at 500 mg/kg dose significantly reduced (P<0.05) the gene expression of pro-inflammatory cytokines such as TNF-, IL-1{beta}, IL-6, IL-18, and inflammatory mediators like TGF-{beta}1, COX-2, and NF{kappa}B. In the molecular docking studies, reported compounds including Quercimeritrin, Rutin, and Kaempferol 3-O-{beta}-D-glucopyranoside were identified as the top-performing compounds, with a docking score of - 7.4, -7.1 and -7.0 kcal/mol against TGF-{beta}1 protein. This indicates stronger binding interactions compared to vincristine (-5.3 kcal/mol). In drug-likeness assessment, all compounds demonstrated the most favourable ADMET and pharmacokinetic profile. Furthermore, MDS data showed greater dynamic stability for Kaempferol 3-O-{beta}-D-glucopyranoside and Rutin, while vincristine exhibited higher fluctuations. The results suggest that HPPE may serve as a potential inhibitor of skin carcinogenesis through upregulating endogenous antioxidants as well as suppressing different proinflammatory and inflammatory cytokines. Quercimeritrin, Rutin, and Kaempferol 3-O-{beta}-D-glucopyranoside might be the probable leads responsible for this chemopreventive activity. Highlights{checkmark} Hylocereus polyrhizus peel extract (HPPE) demonstrated notable chemopreventive potential against skin cancer. {checkmark}HPPE significantly increased endogenous antioxidants (GSH, SOD, CAT) in liver and skin tissues, suggesting enhanced cellular defense mechanisms. {checkmark}Gene expression of pro-inflammatory cytokines (TNF-, IL-1{beta}, IL-6, IL-18) and inflammatory mediators (TGF-{beta}1, COX-2, NF{kappa}B) were notably suppressed by HPPE. {checkmark}Quercimeritrin (CID: 5282160) demonstrated strong binding to TGF-{beta}1 with a docking score of -7.4 kcal/mol, outperforming vincristine (-5.3 kcal/mol). {checkmark}Kaempferol 3-O-beta-D-glucopyranoside (CID: 5282102) and rutin (CID: 5280805) showed the best ADMET, pharmacokinetic profiles, and molecular stability, supporting their potential as lead compounds.

cancer biology↗

bioRxiv2021

Machine learning methods trained on simple models can predict critical transitions in complex natural systems

1. Sudden transitions from one stable state to a contrasting state occur in complex systems ranging from the collapse of ecological populations to climatic change, with much recent work seeking to develop methods to predict these unexpected transitions from signals in time series data. However, previously developed methods vary widely in their reliability, and fail to classify whether an approaching collapse might be catastrophic (and hard to reverse) or non-catastrophic (easier to reverse) with significant implications for how such systems are managed. 2. Here we develop a novel detection method, using simulated outcomes from a range of simple mathematical models with varying nonlinearity to train a deep neural network to detect critical transitions - the Early Warning Signal Network (EWSNet). 3. We demonstrate that this neural network (EWSNet), trained on simulated data with minimal assumptions about the underlying structure of the system, can predict with high reliability observed real-world transitions in ecological and climatological data. Importantly, our model appears to capture latent properties in time series missed by previous warning signals approaches, allowing us to not only detect if a transition is approaching but critically whether the collapse will be catastrophic or non-catastrophic. 4. The EWSNet can flag a critical transition with unprecedented accuracy, overcoming some of the major limitations of traditional methods based on phenomena such as Critical Slowing Down. These novel properties mean EWSNet has the potential to serve as a universal indicator of transitions across a broad spectrum of complex systems, without requiring information on the structure of the system being monitored. Our work highlights the practicality of deep learning for addressing further questions pertaining to ecosystem collapse and have much broader management implications.

ecology↗

bioRxiv2019

Novel strategy for treating neurotropic viral infections using hypolipidemic drug Atorvastatin

Chandipura virus (CHPV) and Japanese Encephalitis Virus (JEV) are known to infect neurons followed by their successful propagation. Increased incidences of central nervous system invasion by the abovementioned viruses have been reported in case of children and elderly thus culminating into severe neurological damage. Literature suggests induction of endoplasmic reticulum (ER)-stress related proteins upon CHPV and JEV infection which help promote viral reproduction. Since earlier studies underscore the pleotropic role of atorvastatin (AT) in neuroprotection against flaviviruses like Hepatitis C and dengue, it was hypothesized that AT might also act as a neuroprotective agent against RNA viruses like CHPV and JEV. AT-mediated antiviral activity was evaluated by assessing survivability of virus-infected mouse pups treated with the drug. Balb C mice were used for in vivo experiments. Neuro2A cell line was used as the model for in vitro experiments. Cells subjected to AT treatment were infected by CHPV and JEV followed by evaluation of ER stress-related and apoptosis-related proteins by immunoblotting technique and immunofluorescence microscopy. Interaction of host protein with viral genome was assessed by RNA-Co-IP. AT treatment exhibited significant anti-viral activity against CHPV and JEV infections via hnRNPC-dependent manner. Viral genome-hnRNPC interaction was found to be abrogated upon AT action. AT was also observed to reduce secretion of proinflammatory cytokines by the neurons in response to viral infection. Moreover, AT treatment was also demonstrated to reduce neuronal death by abrogating virus-induced miR-21 upregulation in hnRNPC-dependent fashion. This study thus suggests probable candidature of AT as antiviral against CHPV and JEV infections.

microbiology↗