Krishna Pal Singh

Lung cancer remains the leading cause of cancer-related mortality worldwide, with significant resistance to conventional therapies, highlighting the urgent need for novel therapeutic strategies. Moringa oleifera (M. oleifera), a medicinal plant rich in diverse bioactive compounds, has shown promising potential for anti-lung carcinoma activity. This study investigates the molecular mechanisms underlying the therapeutic effects of M. oleifera bioactive compounds for their anti-lung cancer activities through an integrated network modeling and molecular docking approach. By constructing comprehensive compound–target–lung cancer pathway networks, we aim to elucidate the multitarget pharmacology of M. oleifera compounds, providing valuable insights into their potential as therapeutic candidates. Computational pipeline was applied to identify 180 phytochemicals from M. oleifera, filtered using Lipinski’s Rule of Five and ADMET properties, resulting in 10 lead compounds followed by their potential biological target proteins in regulating lung cancer progression. We identified 80 targeted proteins involved in lung cancer, with EGFR being the most enriched in pathway enrichment analysis. In the molecular docking analysis, caffeic acid showed the highest binding score (−28.97 kcal/mol) with EGFR forming stable complex during molecular dynamics simulations compared to the known EGFR inhibitor ‘erlotinib’. The overall results suggest that caffeic acid, a key bioactive compound in M. oleifera, is an EGFR-mediated oncogenic signaling inhibitor for lung cancer therapy, warranting further experimental validation to translate these findings into clinical applications.

Objective: Lung cancer remains the leading cause of cancer-related mortality worldwide, with significant resistance to conventional therapies, highlighting the urgent need for novel therapeutic strategies. Moringa oleifera (M. oleifera), a medicinal plant rich in diverse bioactive compounds, has shown promising potential for anti-lung carcinoma activity. This study investigates the molecular mechanisms underlying the therapeutic effects of M. oleifera bioactive compounds through an integrated systems biology and molecular docking approach. By constructing comprehensive compound-target-pathway networks, we aim to elucidate the multitarget pharmacology of M. oleifera compounds, providing valuable insights into their potential as therapeutic candidates. Methods: Bioinformatics tools were used to identify 180 phytochemicals from M. oleifera, filtered using Lipinski’s Rule of Five and ADMET properties, yielding 14 lead compounds. Protein-protein interaction (PPI) analysis identified 89 overlapping lung cancer targets, with EGFR being the most enriched in pathway enrichment analysis. Results: In the analysis, Caffeic acid showed the highest binding affinity (-28.97 kcal/mol) with EGFR through molecular docking and maintained stability during molecular dynamics simulations. This interaction also modulates 12 pathways critical to lung cancer, including MAPK, JAK-STAT, and PI3K/AKT pathways. The overall result suggests that Caffeic acid is an EGFR-mediated oncogenic signalling inhibitor. Conclusion: Caffeic acid is a potential candidate for lung cancer therapy, warranting further experimental validation to translate these findings into clinical applications.

The landscape of clinical management for metastatic melanoma (MM) and other solid tumors has been modernized by the advent of immune checkpoint inhibitors (ICI), including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. While these agents demonstrate efficacy in suppressing tumor growth, they also lead to immune-related adverse events (irAEs), resulting in the exacerbation of autoimmune diseases such as rheumatoid arthritis (RA), ulcerative colitis (UC), and Crohn’s disease (CD). The immune checkpoint inhibitors offer promising advancements in the treatment of melanoma and other cancers, but they also present significant challenges related to irAEs and autoimmune diseases. Ongoing research is crucial to better understand these challenges and develop strategies for mitigating adverse effects while maximizing therapeutic benefits. In this manuscript, we addressed this challenge using network-based approaches by constructing and analyzing the molecular and signaling networks associated with tumor-immune crosstalk. Our analysis revealed that IL6 is the key regulator responsible for irAEs during ICI therapies. Furthermore, we conducted an integrative network and molecular-level analysis, including virtual screening, of drug libraries, such as the Collection of Open Natural Products (COCONUT) and the Zinc15 FDA-approved library, to identify potential IL6 inhibitors. Subsequently, the compound amprenavir was identified as the best molecule that may disrupt essential interactions between IL6 and IL6R, which are responsible for initiating the signaling cascades underlying irAEs in ICI therapies.

The landscape of clinical management for metastatic melanoma (MM) and other solid tumors has been modernized by the advent of immune checkpoint inhibitors (ICI), including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. While these agents demonstrate efficacy in suppressing tumor growth, they also lead to immune-related adverse events (irAEs), resulting in exacerbation of autoimmune diseases such as Rheumatoid arthritis (RA), Ulcerative colitis (UC), and Crohn’s disease (CD). The immune checkpoint inhibitors offer promising advancements in the treatment of melanoma and other cancers, but they also present significant challenges related to irAEs and autoimmune diseases. Ongoing research is crucial to better understand these challenges and develop strategies for mitigating adverse effects while maximizing therapeutic benefits. In this manuscript, we addressed this challenge using network-based approaches by constructing and analyzing molecular and signaling networks associated with tumor-immune cross-talk.. Our analysis revealed that IL6 is the key regulator responsible for irAEs during ICI therapies. Furthermore, we conducted an integrative network and molecular-level analysis, including virtual screening, of drug libraries, such as the Collection of Open Natural Products (COCONUT) and the Zinc15 FDA-approved library, to identify potential IL-6 inhibitors.. Subsequently, the compound amprenavir was identified as the best molecule that may disrupt essential interactions between IL6 and IL6R responsible for initiating signaling cascades underlying irAEs in ICI therapies.

Cancer cells have a remarkable ability to evade recognition and destruction by the immune system. At the same time, cancer has been associated with chronic inflammation, while certain autoimmune diseases predispose to the development of neoplasia. Although cancer immunotherapy has revolutionized antitumor treatment, immune-related toxicities and adverse events detract from the clinical utility of even the most advanced drugs, especially in patients with both, metastatic cancer and pre-existing autoimmune diseases. Here, the combination of multi-omics, data-driven computational approaches with the application of network concepts enables in-depth analyses of the dynamic links between cancer, autoimmune diseases, and drugs. In this review, we focus on molecular and epigenetic metastasis-related processes within cancer cells and the immune microenvironment. With melanoma as a model, we uncover vulnerabilities for drug development to control cancer progression and immune responses. Thereby, drug repurposing allows taking advantage of existing safety profiles and established pharmacokinetic properties of approved agents. These procedures promise faster access and optimal management for cancer treatment. Together, these approaches provide new disease-based and data-driven opportunities for the prediction and application of targeted and clinically used drugs at the interface of immune-mediated diseases and cancer towards next-generation immunotherapies.

During the last two decades several nanoscale materials were engineered for industrial and medical applications. Among them carbon nanotubes (CNTs) are the most exploited nanomaterials with global production of around 1000 tons/year. Besides several commercial benefits of CNTs, the fiber-like structures and their bio-persistency in lung tissues raise serious concerns about the possible adverse human health effects resembling those of asbestos fibers. In this review, we present a comparative analysis between CNTs and asbestos fibers using the following four parameters: (1) fibrous needle-like shape, (2) bio-persistent nature, (3) high surface to volume ratio and (4) capacity to adsorb toxicants/pollutants on the surface. We also compare mechanisms underlying the toxicity caused by certain diameters and lengths of CNTs and asbestos fibers using downstream pathways associated with altered gene expression data from both asbestos and CNT exposure. Our results suggest that indeed certain types of CNTs are emulating asbestos fiber as far as associated toxicity is concerned.

CCCTC-binding factor (CTCF) plays fundamental roles in transcriptional regulation and chromatin architecture maintenance. CTCF is also a tumour suppressor frequently mutated in cancer, however, the structural and functional impact of mutations have not been examined. We performed molecular and structural characterisation of five cancer-specific CTCF missense zinc finger (ZF) mutations occurring within key intra- and inter-ZF residues. Functional characterisation of CTCF ZF mutations revealed a complete (L309P, R339W, R377H) or intermediate (R339Q) abrogation as well as an enhancement (G420D) of the anti-proliferative effects of CTCF. DNA binding at select sites was disrupted and transcriptional regulatory activities abrogated. Molecular docking and molecular dynamics confirmed that mutations in residues specifically contacting DNA bases or backbone exhibited loss of DNA binding. However, R339Q and G420D were stabilised by the formation of new primary DNA bonds, contributing to gain-of-function. Our data confirm that a spectrum of loss-, change- and gain-of-function impacts on CTCF zinc fingers are observed in cell growth regulation and gene regulatory activities. Hence, diverse cellular phenotypes of mutant CTCF are clearly explained by examining structure–function relationships.

Stability of natural antibodies, peptides and enzymes as molecular recognition elements in chemical and biological sensors has been facing threat due to their lack of stability, complicated ethical issues, time taking processes and signal transduction mechanisms limits. Molecularly imprinted polymers (MIPs) with recent advancements have created synthetic materials that can mimic the function of chemical and biological receptors but with less stability constraints, quick synthesis and with no ethical issues. These polymers can provide high sensitivity and selectivity while maintaining excellent thermal and mechanical stability. In the present study molecularly imprinted polymer matrix has been fabricated for the specific recognition of pesticide Deltamethrin, which is being used widely to control insects in crop management system. The composite membranes have been prepared by using methacrylic acid (MAA) as functional monomer, selected by electrostatic interactions based computational simulation and ethylene glycol dimethacrylate (EGDMA) as cross linker. The garbing of deltamethrin MIP on membrane matrix was confirmed by the UV-VIS spectrophotometer, FTIR and Scanning Electron Microscopy (SEM). The detoxification and separation of Deltamethrin was done using a solid phase extraction (SPE) and a specially designed membrane syringe holder, which could separate and detect the herbicide up to a very sensible limit, 20 µg/ml.