Department of Pharmacy
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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.