Biology subjects

Joshi, S. K.

Publications and source records attributed to Joshi, S. K..

4 recordsLinked to original sources

bioRxiv2025

Deciphering Cannabidiol Neuroregulatory Role in Addiction Pathways , A Systems Level Comparison with THC via Intrinsic Network Pharmacology

Cannabidiol (CBD), a nonpsychoactive phytocannabinoid from Cannabis sativa, has demonstrated potent neuroprotection in a number of neuropsychiatric disorders. Unlike {Delta}9-tetrahydrocannabinol (THC), which acts to stimulate the brains reward circuitry through CB1 receptor activation, CBD seems to stabilize several neuroregulatory circuits without causing addictive reinforcement. Yet a mechanistic systems-level distinction between these two cannabinoids is relatively unexplored. This research uses an eight-layer Intrinsic Network Pharmacology (INP) system to model and compare the molecular effects of CBD and THC on addiction-related networks, combining computational modeling and network pharmacology. The INP system includes molecular trigger mapping, feedback loop dynamics, redox balance, immune signaling, autophagy repair, therapeutic fit, dynamic simulations, and multi-target synergy overlays. In this model, we replicated the action of CBD on major molecules such as Nrf2, ROS, IL-6, dopamine (DA), D2 receptor, and BDNF. Ordinary differential equation (ODE) models were employed to model time-dependent transitions, whereas Boolean logic models simulated binary molecular switches. Comparative reward pathway diagrams were drawn to represent divergent neuropharmacological cascades triggered by CBD and THC. Our simulations show that CBD triggers redox restoration, inhibits inflammatory cytokines, and induces dopaminergic and synaptic stability. Withdrawal simulation also showed that relapse of the partial system could be triggered if CBD is withdrawn suddenly, substantiating its status as a homeostatic stabilizer and not a suppressive one. Network pharmacology fit scoring exhibited CBDs high concordance with antioxidant and neuroplasticity targets, whereas THC mostly mapped onto reward-amplifying nodes. Though these results are hypothesis-driven and computational, they also offer a useful framework for the experimental validation. This work illustrates the utility of INP-based simulations in deciphering polypharmacological drugs such as CBD and presents a scalable paradigm for assaying future candidates for neurotherapeutic use in the study of addiction.

bioinformatics↗

bioRxiv2023

Natural and age-related variation in circulating human hematopoietic stem cells

Hematopoietic stem and progenitor cells (HSPCs) deliver life-long multi-lineage output. However, with aging, we exhibit certain characteristic blood count changes and accumulation of clonal disorders. Better understanding of inter-individual variation in HSPC behavior is needed to understand these age-related phenomena and the transition from health to chronic and acute hematological malignancies. Here we study 627K single circulating CD34+ HSPCs (cHSPCs) from 148 healthy individuals, along with their clinical information and clonal hematopoiesis (CH) profiles, to characterize population-wide and age-related hematopoietic variability. Individuals with CH were linked with reduced frequencies of lymphocyte progenitors and higher RDW. An age-related decrease in lymphoid progenitors was observed, predominantly in males. Inter-individual transcriptional variation in expression of a Lamin-A signature and stemness gene programs were linked with aging and presence of macrocytic anemia. Based on our model for healthy cHSPC variation we construct the normal reference for cHSPC subtype frequencies. We show how compositional and expression deviations from this normal reference can robustly identify myeloid malignancies and pre-malignant states. Together, our data and methodologies present a novel resource, shedding light on various age-related hematopoietic processes, and a comprehensive normal cHSPC reference, which can serve as a tool for diagnosing and characterizing hematological disorders.

molecular biology↗

bioRxiv2021

A noncanonical FLT3 gatekeeper mutation disrupts gilteritinib binding and confers resistance

The recent FDA approval of the FLT3 inhibitor, gilteritinib, for AML represents a major breakthrough for treatment of FLT3 mutated AML. However, patients only respond to gilteritinib for 6-7 months due to the emergence of drug resistance. Clinical resistance to gilteritinib is often associated with expansion of NRAS mutations, and less commonly via gatekeeper mutations in FLT3, with F691L being the most common. We developed an in vitro model that charts the temporal evolution of resistance to gilteritinib from early microenvironmental-mediated resistance to late intrinsic resistance mutations. Our model system accurately recapitulates the expansion of NRAS mutations and the F691L gatekeeper mutations found in AML patients. As part of this study, we also identified a novel FLT3N701K mutation that also appeared to promote resistance to gilteritinib. Using the Ba/F3 system, we demonstrate that N701K mutations effectively act like a gatekeeper mutation and block gilteritinib from binding to FLT3, thereby promoting resistance. Structural modeling of FLT3 reveals how N701K, and other reported gilteritinib resistance mutations, obstruct the gilteritinib binding pocket on FLT3. Interestingly, FLT3N701K does not block quizartinib binding, suggesting that FLT3N701K mutations are more specific for type 1 FLT3 inhibitors (gilteritinib, midostaurin, and crenolanib). Thus, our data suggests that for the FLT3N701K mutation, switching classes of FLT3 inhibitors may restore clinical response. As the use of gilteritinib expands in the clinic, this information will become critical to define clinical strategies to manage gilteritinib resistance.

cancer biology↗

bioRxiv2020

Computational methods to develop potential neutralizing antibody Fab region against SARS-CoV-2 as therapeutic and diagnostic tool

SARS-CoV-2, a global pandemic originated from Wuhan city of China in the month of December 2019. There is an urgency to identify potential antibodies to neutralize the virus and also as a diagnostic tool candidate. At present palliative treatments using existing antiviral drugs are under trails to treat SARS-CoV-2.Whole Genome sequence of Wuhan market sample of SARS-CoV-2 was obtained from NCBI Gene ID MN908947.3.Spike protein sequence PDB ID 6VSB obtained from RCSB database. Spike protein sequence had shown top V gene match with IGLV1-44*01, IGLV1-47*02 and has VL type chain. Whole Genome sequence had shown top V gene match with IGHV1-38-4*01 and has VH type chain. VD chain had shown link to allele HLA-A0206 80%, HLA-A0217 80%, HLA-A2301 75%, HLA-A0203 75%, HLA-A0202 70% and HLA-A0201 55% of binding levels. Some conserved regions of spike protein had shown strong binding affinity with HLA-A-0*201, HLA-A24, HLA-B-5701 and HLA-B-5703 alpha chains. Synthetic Fab construct BCR type antibody IgG (CR5840) had shown Polyspecific binding activity with spike glycoprotein when compared with available Anti-SARS antibody CR3022.Thus we propose CR5840 Fab constructed antibody as potential neutralizing antibody for SARS-CoV-2. Based on germline analysis we also propose cytotoxic T lymphocyte epitope peptide selective system as effective tool for the development of SARS-CoV-2 vaccine.

immunology↗