BITS Faculty Publications
Permanent URI for this communityhttp://localhost:4000/handle/123456789/1867
Browse
72 results
Search Results
Item Esculetin and phloretin combination mitigates acute kidney injury-diabetes comorbidity via regulating mitophagy and inflammation: a dual-pronged approach(Wiley, 2025-03) Jadhav, Hemant R.; Gaikwad, Anil BhanudasInduction of PINK1/Parkin-mediated mitophagy and reducing inflammation via targeting the TLR4/NF-κB axis simultaneously could be a promising therapy for the complex pathophysiology of AKI-diabetes comorbidity. Earlier, esculetin by mitophagy activation and phloretin by inhibiting inflammation have shown promising renoprotection. Therefore, we aimed to evaluate the synergistic renoprotective ability of esculetin and phloretin combination against AKI-diabetes comorbidity. AKI-diabetes comorbidity was mimicked in vivo by bilateral ischemia/reperfusion injury (IRI) in diabetic rats and in vitro by sodium azide-induced hypoxia/reperfusion injury (HRI) under hyperglycemic conditions. The cells were pretreated with esculetin (50 μM) and phloretin (50 μM) for 24 h. Similarly, the diabetic AKI rats received esculetin (50 mg/kg/day, p.o.) and phloretin (50 mg/kg/day, p.o.) pretreatment for 4 days and 1 h before surgery. Further, the obtained samples were utilized for different experiments. Esculetin and phloretin in diabetic AKI rats preserved kidney function and prevented kidney injury, indicated by reduced plasma creatinine, blood urea nitrogen, and kidney injury molecule 1. Esculetin improved mitophagy, indicated by increased mitophagosome formation, increased PINK1, Parkin, LC3B, and decreased p62 expression. Similarly, phloretin suppressed the diabetic AKI-related increased expression of inflammatory mediators including NF-κB, TLR4, TNF-α, and MCP-1. Moreover, combination therapy showed a more pronounced effect via synergistically improving mitophagy, maintaining ΔΨm, preventing mitochondrial dysfunction, reducing inflammation, and apoptosis. Esculetin and phloretin combination ameliorated AKI-diabetes comorbidity more effectively than their monotherapies. Esculetin upregulated the PINK1/Parkin-mediated mitophagy, and phloretin reduced inflammation by inhibiting the TLR4/NF-κB axis, thereby synergistically preventing kidney dysfunction.Item Corrigendum to: Design and development of chromene-3-carboxylate derivatives as antidiabetic agents: Exploring the antidiabetic potential via dual inhibition of angiotensin II type 1 receptor and neprilysin enzyme(Elsevier, 2025-10) Gaikwad, Anil Bhanudas; Jadhav, Hemant R.Diabetes mellitus, particularly type II diabetes mellitus, is a metabolic condition that has a substantial impact on the health of individuals. The implication of diabetes with increased risk of cardiovascular diseases (CVD) and, consequently, myocardial infarction is well established. However, developing new antidiabetic drugs with an established efficacy on cardiovascular health is an underdeveloped area of research. To address this, in the present study, a new series of chromene-3-carboxylate derivatives (1B1–1B22) as dual inhibitors of Angiotensin II Type 1 Receptor (AT1R) and Neprilysin (NEP), which are recognized targets in diabetes with CVD, is reported. The compounds were rationally designed and synthesized, considering the pharmacophoric features of these two targets. The evaluation was performed via glucose uptake, α-amylase, AT1R, and NEP inhibition assay. The derivatives were found to increase glucose uptake and inhibit all three targets, of which compound 1B15 was the most active. The most active compound, 1B15, reduced the oxidative stress and restored the mitochondrial membrane potential. The biological findings were further corroborated by in silico studies, which included molecular modelling and dynamics. It was deduced that 1B15 remains unionized in acidic to weak basic pH and may be passively absorbed. Further, the molecule was found to undergo hydroxylation as a means of Phase I metabolism and glucuronic conjugation in Phase II. The wet lab experiments on 1B15 further validated the insilico absorption and metabolism prediction. The compounds, particularly 1B15, could be explored further as a lead for its utility as an antidiabetic with profound implications on cardiovascular health.Item A novel combination of exogenous klotho combined with telmisartan ameliorated diabetic cardiomyopathy via an antifibrotic mechanism(Wiley, 2025-09) Jadhav, Hemant R.; Gaikwad, Anil BhanudasDiabetic cardiomyopathy (DCM) is a progressive heart disorder associated with diabetes mellitus, leading to structural and functional cardiac abnormalities. The mechanisms responsible include renin-angiotensin-aldosterone (RAAS) activation, inflammation, apoptosis, and metabolic disturbances. Despite well-established epidemiological links, treatments for DCM are elusive. This study evaluated the efficacy of a novel combination of recombinant Klotho (KL) and the angiotensin receptor blocker telmisartan (TEL) in treating DCM, as well as investigating potential mechanisms involved. DCM was induced with a single dose of streptozotocin (55 mg/kg, i.p.), followed by a 4-week induction period. For treatment, rats were assigned to five groups: Normal control (NC), Diabetic control (DC), DC + KL (0.01 mg/kg, S.C.), DC + TEL (10 mg/kg, p.o.), and KL + TEL combination. Plasma biochemistry assessed cardiac damage (LDH, CK-MB) and stress markers (ANP, BNP). Electrocardiogram (ECG) measured heart parameters, including heart rate (HR), QTc, JT interval, RR interval, and Tpeak–Tend intervals. Histological analysis (H&E, Masson's trichrome, and Picrosirius red) was performed to assess myocardial structure and fibrosis. Lastly, immunohistochemistry analysis was performed to check the expression of transforming growth factor-β1 (TGF-β1), pSMAD 2/3, matrix metalloproteinase 9 (MMP9), and PRKN. KL and TEL combination treatment significantly reduced cardiac damage markers, reduced ECG abnormalities, including QTc, improved HR while suppressing pro-fibrotic signaling, enhancing mitophagy, and decreasing fibroblast proliferation. The involvement of pathways involving TGF-β1, pSMAD-2/3, MMP9, and pFOXO3a conferred protection to the heart in experimental in-vivo settings. These findings suggest that the combination of KL and TEL effectively mitigates key pathological features of DCM, highlighting its potential as a targeted treatment strategy.Item Emerging in diabetic cardiomyopathy: molecular pathways and targets for therapeutic intervention(Wiley, 2025) Jadhav, Hemant R.Amongst various complications presented by diabetes, diabetic cardiomyopathy (DCM) is one of the most prominent and vexing complications. Due to the absence of consensus on prevention and treatment strategies, along with limitations in current therapies, a fresh perspective is essential and a requirement of the time. The succeeding review explores research that provides insights into novel molecular targets that could possibly evolve as breakthroughs in restraining the pathological hallmarks of DCM, such as inhibition of cardiomyocyte fibrosis or modulation of various inflammatory pathways, apoptotic pathways such as PANoptosis, cuproptosis, and ferroptosis, and mitochondrial dysfunction. This review shall also explore various RNA-targeting therapeutic areas that can combat the consecution of DCM. Therapeutic intervention targeting Phosphodiesterase 4D (PDE4D), LGR6 (G-protein-coupled receptor containing leucine-rich repeats 6), Interferon gamma inducible protein 16 (IFI16), Growth differentiation factor 11(GDF11), Transcription factor EB(TFEB), Secreted frizzled-related protein 1 (SFRP1), Fibroblast growth factor -21 (FGF21), Takeda G protein-coupled receptor-5 (TGR5), Nuclear receptor of the subfamily 4 (NR4A3), Enhancer of zeste homolog 2 (EZH2), and RNA-based therapeutics such as piR112710 and TUG1 are reviewed. Moreover, how these molecular targets intersect with DCM pathology, and how they can be further explored in a drug discovery paradigm for DCM management, is discussed.Item Histone demethylase inhibitors: developmental insights and current status(Taylor & Francis, 2025-08) Paul, Atish Tulshiram; Jadhav, Hemant R.The discovery of histone demethylases (HDMs) has greatly advanced our epigenetic understanding, particularly their role in post-translational modifications of histones. HDMs regulate cellular functions, such as X chromosome inactivation, differentiation, cell-based aging, and deoxyribonucleic acid (DNA) damage repair. Although crucial for regulating genetic expression, post-translational modifications have been implicated in developing several diseases. The discovery and development of inhibitors targeting HDMs have emerged as an active and rapidly expanding research field over the last few years. This review attempts to collate the available information on different isoforms of HDMs, substrate selectivity, and involvement in various biological functions. Also, the existing as well as emerging HDM inhibitors, especially inhibitors of histone lysine (K) demethylase 1 (KDM1) and the jumonji-C (JmjC) family demethylases (KDM 2–8), are reported along with analysis on insights for the future development of HDM inhibitors.Item Investigation of antibacterial potential of Natsiatum herpeticum Buch.-Ham. ex Arn. using in silico-in vitro approach(Elsevier, 2024-01) Jadhav, Hemant R.Since ages, natural products have laid the foundation for the development of promising antimicrobials. With the advent of antimicrobial resistance, the search for effective antimicrobials continues as its shortfall will menace the healthcare system. Natsiatum herpeticum remained the least explored plant despite its ethnopharmacological claims. DNA barcoding was performed to identify and ensure quality control of the plant materials used in the experiment. QToF-MS analysis followed by network pharmacology revealed TNF and IRAK4 to be the two gene targets that can be modulated by the compounds present in the extract. Analysis of potential drug-like compounds using molecular docking (against 1KZN, 2VF5, 2W9S, and 4CJN) and MD simulation suggested compound CPD2 to be the most potent molecule against the bacterial targets. Bacteriostatic activity against E. coli was exhibited by the extract (MIC=50 μg/ml) in the microtiter-plate dilution method. Our results suggest that N. herpeticum not only exhibits potential bacteriostatic activity against E. coli but can also modulate host-immune responses via TNF and IRAK4-associated pathways.Item Unveiling the potential of novel indol-3-yl-phenyl allylidene hydrazine carboximidamide derivatives as AChE/BACE 1 dual inhibitors: a combined in silico, synthesis and in vitro study(RSC, 2024-07) Jadhav, Hemant R.Alzheimer's disease (AD) is a complex and debilitating neurological disorder that primarily affects the brain, leading to cognitive decline and memory loss. AD is a chronic and progressive disease that gradually impairs an individual's ability to function independently, affecting their daily activities and quality of life.1 Worldwide, as of 2023, the current estimate of 50 million people worldwide with dementia is expected to increase to 78 million by 2030 and a staggering 139 million by 2050.2 The disease is characterized by several neuro-pathological features such as reduced levels of acetylcholine (ACh), accumulation of amyloid-β, formation of neurofibrillary tangles made of hyperphosphorylated tau-protein, oxidative stress, and imbalanced biometal levels.3 The current approach to treating neurological disorders involves the use of medication that aims to enhance cognitive functions or alleviate symptoms by targeting the mechanisms of neurotransmitters in the brain using cholinesterase inhibitors (such as donepezil, galantamine, and rivastigmine see Fig. 1) and N-methyl-D-aspartate (NMDA) receptor antagonist i.e. memantine.4,5 Patients with declining cognitive functions who are prescribed cholinesterase inhibitors or similar medications have not shown any significant improvement in preventing the advancement of AD.6 Despite ongoing efforts to develop drugs that modify the course of AD and slow its progression, there are still potential obstacles that may impede success, such as unanticipated toxicity or inadequate effectiveness in human clinical trials.7 The complexity of AD and its multifaceted nature have rendered the existing single-targeted drugs ineffective in producing the desired therapeutic effect. It is widely believed that compounds with the ability to modulate multiple targets are more effective than those that only act on a single target, due to the inadequate results of the one drug one target (ODOT) strategy. Therefore, there is a need for the development of multi-targeted therapies to slow down the progression of the diseaseItem Design, synthesis, in silico, and in vitro evaluation of pyrrol-2-yl-phenyl allylidene hydrazine carboximidamide derivatives as AChE/BACE 1 dual inhibitors(RSC, 2024-08) Jadhav, Hemant R.Alzheimer's disease (AD) manifests as a progressive decline in cognitive function and mental behavior. Targeting two crucial enzymes associated with AD, acetylcholinesterase (AChE) and BACE 1 (Beta-site APP Cleaving Enzyme), in combination, holds promise for therapeutic breakthroughs. In this study, 40 derivatives of pyrrol-2-yl-phenyl allylidene hydrazine carboximidamide were designed based on prior research. These derivatives underwent synthesis and assessment for their inhibitory potential against AChE and BACE 1. ADME predictions indicated favorable physicochemical properties for these compounds. The findings offer novel avenues for exploring the dual inhibition of AChE and BACE 1 as a promising therapeutic strategy for AD.Item Medicinal chemistry-based perspectives on thiophene and its derivatives: exploring structural insights to discover plausible druggable leads(RSC, 2025) Jadhav, Hemant R.Thiophene is a privileged pharmacophore in medicinal chemistry owing to its diversified biological attributes. The thiophene moiety has been ranked 4th in the US FDA drug approval of small drug molecules, with around 7 drug approvals over the last decade. The present review covers USFDA-approved drugs possessing a thiophene ring system. Our analysis reveals that 26 drugs possessing thiophene nuclei have been approved under different pharmacological classes. The review further covers reported thiophene and its substituted analogues with diverse biological activities, including anti-diabetic, anticancer, anti-inflammatory, anticonvulsant, and antioxidant activity. Besides, a section is dedicated to appreciating the implications of structural bioinformatics in drug discovery. Additionally, the manuscript delves into structure–activity relationship studies to explore the chemical groups responsible for eliciting potential therapeutic activities. The review may provide invaluable insights for researchers working with thiophene nuclei in developing novel analogues with greater efficacy and fewer side effects.Item Bioactivity predictions and virtual screening using machine learning predictive model(Taylor & Francis, 2024-01) Jadhav, Hemant R.Recently, there has been significant attention on machine learning algorithms for predictive modeling. Prediction models for enzyme inhibitors are limited, and it is essential to account for chemical biases while developing them. The lack of repeatability in available models and chemical bias issues constrain drug discovery and development. A new prediction model for enzyme inhibitors has been developed, and the model efficacy was checked using Dipeptidyl peptidase 4 (DPP-4) inhibitors. A Python script was prepared and can be provided for personal use upon request. Among various machine learning algorithms, it was found that Random Forest offers the best accuracy. Two models were compared, one with diverse training and test data and the other with a random split. It was concluded that machine learning predictive models based on the Murcko scaffold can address chemical bias concerns. In-silico screening of the Drug Bank database identified two molecules against DPP-4, which are previously proven hit molecules. The approach was further validated through molecular docking studies and molecular dynamics simulations, demonstrating the credibility and relevance of the developed model for future investigations and potential translation into clinical applications.