Browsing by Author "Soni"

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Dual blockade of TLR-4 and mu-opioid receptor by very low-dose naltrexone prevents respiratory depression via modulating redox homeostasis and airway inflammation in chronic obstructive pulmonary disease
(Elsevier Inc., 2025) Soni; Vandana Yadav; Vinita Pandey; Atul Kumar Srivastava; Pratikkumar Gaglani; Subhashini
Chronic Obstructive Pulmonary Disease (COPD), is characterized by poorly irreversible airflow obstruction and abnormal inflammatory response in lungs. It represents an innate and adaptive immune response to long term exposure to noxious particles and gases, particularly cigarette smoke (CS). The current pharmacological treatment of COPD is symptomatic and mainly based on the use of bronchodilators reducing the lung function progression. The present study explores a comprehensive exploration into the therapeutic potential of Naltrexone (NTX), an FDA-approved non-peptide opioid antagonist, in managing COPD pathogenesis. NTX exhibits distinct responses across varying dosages where it implies a dose pharmacological profile, with dose-dependent targets yielding diverse effects. The study aims to uncover its efficacy in experimental mice model of COPD by observing redox homeostasis, inflammatory responses, and apoptosis encompassing variable doses. Our findings reveal promising outcomes, particularly with VLDN (100 μg/kgbw and 50 μg/kgbw), where a significant reduction in ROS, NO and positive impacts on TOS and TAS, was observed which indicates its potential as an oxidative stress modulator. Furthermore, VLDN modulated the antioxidant enzymatic activity thereby reducing the apoptotic phenomenon via caspase-3. VLDN significantly reduced the inflammatory response by inhibiting the inflammatory mediators (histamine, LDH and CRP) and suppressing cytokine production (TNF-α, IFN-γ and IL-6). The study also delved into intricate pathway where mechanistically VLDN exerted anti-inflammatory effect by inhibiting the activation of NF-kB/MAPK signalling via TLR4. These findings collectively highlight VLDN multifaceted impact in mitigating oxidative stress, inflammation influencing apoptosis in COPD management, offering valuable insights for future therapeutic strategies. © 2025
Inhibiting SIRT-2 by AK-7 restrains airway inflammation and oxidative damage promoting lung resurgence through NF-kB and MAP kinase signaling pathway
(Frontiers Media SA, 2024) Vandana Yadav; Vinita Pandey; Pratikkumar Gaglani; Atul Srivastava; Soni; Subhashini
Introduction: Chronic obstructive pulmonary disease (COPD) is a major global cause of mortality with limited effective treatments. Sirtuins (SIRT) are histone deacetylases that are involved in the regulation of redox and inflammatory homeostasis. Hence, the present study aims to investigate the role of SIRT-2 in modulating inflammation in a murine model of COPD. Methods: COPD in mice was established by cigarette smoke (CS) exposure for 60 days, and AK-7 was used as the specific SIRT-2 inhibitor. AK-7 (100 µg/kg and 200 µg/kg body weight) was administered intranasally 1 h before CS exposure. Molecular docking was performed to analyze the binding affinity of different inflammatory proteins with AK-7. Results: Immune cell analysis showed a significantly increased number of macrophages (F4/80), neutrophils (Gr-1), and lymphocytes (CD4+, CD8+, and CD19+) in the COPD, group and their population was declined by AK-7 administration. Total reactive oxygen species, total inducible nitric oxide synthase, inflammatory mediators such as neutrophil elastase, C-reactive protein, histamine, and cytokines as IL4, IL-6, IL-17, and TNF-α were elevated in COPD and declined in the AK-7 group. However, IL-10 showed reverse results representing anti-inflammatory potency. AK-7 administration by inhibiting SIRT-2 decreased the expression of p-NF-κB, p-P38, p-Erk, and p-JNK and increased the expression of Nrf-2. Furthermore, AK-7 also declined the lung injury by inhibiting inflammation, parenchymal destruction, emphysema, collagen, club cells, and Kohn pores. AK-7 also showed good binding affinity with inflammatory proteins. Discussion: The current study reveals that SIRT-2 inhibition mitigates COPD severity and enhances pulmonary therapeutic interventions, suggesting AK-7 as a potential therapeutic molecule for COPD medication development. Copyright © 2024 Yadav, Pandey, Gaglani, Srivastava, Soni and Subhashini.
Network pharmacology and molecular docking insights into Sirtuin-2 inhibitors (AK-7 and AGK-2): A synergistic strategy for COPD treatment
(Elsevier B.V., 2025) Vandana Yadav; Vinita Pandey; Pratikkumar Gaglani; Atul Kumar Srivastava; Soni; Subhashini
Objective: In the present study network pharmacology analysis of AGK-2 and AK-7 (SIRT-2 inhibitors) were performed to elucidate their mechanism in regulating COPD pathogenesis. Methods: Different database (Swiss Target Prediction, GeneCards and DisGeNet) were used for predicting targets of compound and disease. Drug-Target network was constructed using Cytoscape while functional enrichment and pathway analyses were performed using STRING database. ShinnyGo database was utilized for Annotation, Visualization, and Integrated Discovery, along with Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG). Molecular docking was performed to assess the binding affinities of AGK-2 and AK-7 to key proteins. Results: AK-7 and AGK2 revealed 43 and 41 targets while 3392 targets related to COPD were found. Protein-protein interaction (PPI) network revealed 43 nodes and 133 edges for AK-7 and 41 nodes and 110 edges for AGK-2. Enrichment analysis highlighted distinct involvement of AGK-2 and AK-7 in various aspects of respiratory physiology including molecular signaling and neuronal secretions. AGK-2 revealed to influence pathways as EGFR and Ras/Raf/MAPK, while AK-7 targeted pathways like nitric oxide synthatase and tuberculosis, as well as regulating calcium signaling and neuro-immune interactions associated with COPD. Finally molecular docking revealed that AGK-2 showed good binding affinity with MAPK14 and STAT3. Whereas AK-7 with CASP3 and CXCL8. The findings highlight potency of AGK-2 and AK-7 in modulating inflammation, reactive oxygen species, and neuroimmune interactions, suggesting their efficacy in COPD management through SIRT-2 regulation. Conclusion: The study offers novel insights into the potential of SIRT-2 inhibitors to modulate disease mechanisms at a molecular level. © 2024 Elsevier B.V.
SIRT-2 inhibition by AK-7 orchestrates fibrotic cascades in airways through neuroimmune interaction via TRPA1, TRPM8 and TGF-β signalling
(Elsevier Inc., 2025) Vandana Yadav; Vinita Pandey; Pratikkumar Gaglani; Atul Kumar Srivastava; Soni; Subhashini
Chronic obstructive pulmonary diseases (COPD) is characterized by airflow limitation, chronic inflammation and airway remodeling (AR) in airways and lung parenchyma. AR, a lung response, involves mucus production, airflow issues, and structural changes. It is exacerbated by neurogenic inflammation from activated sensory nerves, highlighting the interplay between neuronal and immune regulation in COPD. Sirtuins play a crucial role in lung remodeling, with SIRT-2 being the least studied. Present study explores how SIRT-2 regulates neurogenic inflammation and fibrosis in experimental BALB/c mice with cigarette smoke-induced COPD. Mice from each group, except the control, were exposed to CS for 60 days and AK-7 (100ug/kg and 200ug/kg) was administered intranasally. The study evaluated lung injury and inflammation marked by increased Cortisol, ACTH, COX-2 and LDH in COPD group with its attenuation by SIRT-2 inhibition. Additionally, CS exposure exhibited neurogenic inflammation represented by activated TPRV1 and TRPM8, elevated neuromediators levels (dopamine, acetylcholine, substance P, serotonin) and their respective receptors which were mitigated by AK-7. CS exposure enhanced fibrosis by targeting the fibrotic cascade, enhancing MMP-9, total collagen, hydroxyproline, and upregulating αSMA, MUC5AC, TGF-β, PKA, GATA-3, FOXO3, and STAT-6. SIRT-2 inhibition effectively reversed all these factors suppressing fibrosis further supported by downregulated SIRT-2 expression and histopathological studies where collagen deposition and mucus production were also attenuated by AK-7. Molecular docking revealed strong binding affinity of certain protein such as COX-2, D5DR and 5HT with AK-7. Overall, targeting SIRT-2 to modulate neuro-immune interplay presents a promising therapeutic approach for addressing AR in COPD. © 2024 Elsevier Inc.