Department of Pharmacy

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Acyl-coa synthetase long-chain isoenzymes in kidney diseases: mechanistic insights and therapeutic implications
(Wiley, 2024-08) Gaikwad, Anil Bhanudas
Long-chain acyl-CoA synthetases (ACSLs) are pivotal enzymes in fatty acid metabolism, essential for maintaining cellular homeostasis and energy production. Recent research has uncovered their significant involvement in the pathophysiology of various kidney diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), diabetic kidney disease (DKD), and renal cell carcinoma (RCC). While ACSL1, ACSL3, ACSL4, and ACSL5 have been extensively studied for their roles in processes such as ferroptosis, lipid peroxidation, renal fibrosis, epithelial-mesenchymal transition, and tumor progression, the role of ACSL6 in kidney diseases remain largely unexplored. Notably, these isoenzymes exhibit distinct functions in different kidney diseases. Therefore, to provide a comprehensive understanding of their involvement, this review highlights the molecular pathways influenced by ACSLs and their roles in modulating cell death, inflammation, and fibrosis during kidney disease progression. By examining these mechanisms in detail, this review underscores the potential of ACSLs as biomarkers and therapeutic targets, advocating for further research to elucidate the precise roles of individual ACSL isoenzymes in kidney disease progression. Understanding these mechanisms opens new avenues for developing targeted interventions and improving therapeutic outcomes for patients with kidney diseases.
Advanced non-invasive diagnostic techniques for visualization and estimation of kidney fibrosis
(Elsevier, 2021-08) Gaikwad, Anil Bhanudas
Kidney fibrosis is marked by excessive extracellular matrix deposition during disease progression. Unfortunately, existing kidney function parameters do not predict the extent of kidney fibrosis. Moreover, the traditional histology methods for the assessment of kidney fibrosis require liquid and imaging biomarkers as well as needle-based biopsies, which are invasive and often associated with kidney injury. The repetitive analyses required to monitor the disease progression are therefore difficult. Hence, there is an unmet medical need for non-invasive and informative diagnostic approaches to monitor kidney fibrosis during the progression of chronic kidney disease. Here, we summarize the modern advances in diagnostic imaging techniques that have shown promise for non-invasive estimation of kidney fibrosis in pre-clinical and clinical studies.
Advances in CRISPR-Cas systems for kidney diseases
(Elsevier, 2025) Gaikwad, Anil Bhanudas
Recent advances in CRISPR-Cas systems have revolutionised the study and treatment of kidney diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), diabetic kidney disease (DKD), lupus nephritis (LN), and polycystic kidney disease (PKD). CRISPR-Cas technology offers precise and versatile tools for genetic modification in monogenic kidney disorders such as PKD and Alport syndrome. Recent advances in CRISPR technology have also shown promise in addressing other kidney diseases like AKI, CKD, and DKD. CRISPR-Cas holds promise to edit genetic mutations underlying these conditions, potentially leading to more effective and long-lasting treatments. Furthermore, the adaptability of CRISPR-Cas systems allows for developing tailored therapeutic strategies that specifically target the genetic and molecular mechanisms contributing to different kidney diseases. Beyond DNA modifications, CRISPR-Cas technologies also enable editing noncoding RNA, such as lncRNAs and miRNAs, in kidney diseases. Despite these advancements, significant challenges persist, including delivery efficiency to specific kidney cells and potential off-target effects. However, the rapid progress in CRISPR-Cas technology suggests a transformative impact on the future management of kidney diseases, offering the potential for enhanced patient outcomes through personalised and precise therapeutic approaches. This chapter highlights the recent advancement of CRISPR-Cas systems and their potential applications in various kidney diseases.
Ameliorative effect of AT2R and ACE2 activation on ischemic renal injury associated cardiac and hepatic dysfunction
(Elsevier, 2020-11) Gaikwad, Anil Bhanudas
This study explored the role of the depressor arm of renin-angiotensin system (RAS) on ischemic renal injury (IRI)-associated cardio-hepatic sequalae under non-diabetic (ND) and diabetes mellitus (DM) conditions. Firstly, rats were injected with Streptozotocin (55 mg/kg i.p.) to develop DM. ND and DM rats underwent Bilateral IRI followed by 24 h of reperfusion. Further, ND and DM rats were subjected to AT2R agonist-Compound 21 (C21) (0.3 mg/kg/day, i.p.) or ACE2 activator- Diminazene Aceturate (Dize), (5 mg/kg/day, p.o.) per se or its combination therapy. As results, IRI caused cardio-hepatic injuries via altered oxidant/anti-oxidant levels, elevated inflammatory events, and altered protein expressions of ACE, ACE2, Ang II, Ang-(1–7) and urinary AGT. However, concomitant therapy of AT2R agonist and ACE2 activator exerts a protective effect in IRI-associated cardio-hepatic dysfunction as evidenced by inhibited oxidative stress, downregulated inflammation, and enhanced cardio-hepatic depressor arm of RAS under ND and DM conditions.
Angiotensin II type 2 receptor and angiotensin-converting enzyme 2 mediate ischemic renal injury in diabetic and non-diabetic rats
(Elsevier, 2019-10) Gaikwad, Anil Bhanudas
Depressor arm of the renin-angiotensin system (RAS) exerts reno-protective effects in chronic kidney diseases like diabetic nephropathy. However, same is still elusive under AKI and hyperglycaemia comorbidity. Hence, the present study delineates the role of angiotensin-II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) in AKI under normal and hyperglycaemia condition.
Apelinergic system in acute kidney injury: mechanistic insights and therapeutic potential
(Elsevier, 2024-11) Gaikwad, Anil Bhanudas
Acute kidney injury (AKI) has emerged as a global health crisis, surpassing mortality rates associated with several cancers and heart failure. The lack of effective therapies, coupled with challenges in diagnosis and the high cost of kidney transplantation, underscores the urgent need to explore novel therapeutic targets and strategies for AKI. Understanding the intricate pathophysiology of AKI is paramount in this endeavor. The components of the apelinergic system—namely, apelin and elabela/toddler, along with their receptor—are prominently expressed in various kidney cells and have garnered significant attention in renal research. Recent studies have highlighted the renoprotective role of the apelinergic system in AKI. This system exerts its protective effects by modulating several pathophysiological processes, including reducing endoplasmic reticulum (ER) stress, improving mitochondrial dynamics, inhibiting inflammation and apoptosis, promoting diuresis through vasodilation of renal vasculature, and counteracting the effects of reactive oxygen species (ROS). Despite these advancements, the precise involvement of the apelinergic system in the progression of AKI remains unclear. Furthermore, the therapeutic potential of apelin-13 in AKI is not fully understood. This review aims to elucidate the role of the apelinergic system in AKI and its interactions with key pathomechanisms involved in the progression of AKI. Additionally, we discuss the current clinical status of exogenous apelin-13 therapy, providing insights that will guide future research on apelin against AKI.
AT2 receptor agonist Compound 21: A silver lining for diabetic nephropathy
(Elsevier, 2017-11) Gaikwad, Anil Bhanudas
The currently available therapies for diabetic nephropathy, one of the leading causes of renal failure globally are based on inhibition of renin angiotensin system. However, recently, the focus has shifted towards activation of its protective arm rather than the inhibition of deteriorative axis, using specific agonists. Compound 21 (C21), a novel non-peptide Angiotensin II type 2 receptor (AT2) agonist, recently granted orphan drug status for the treatment of a rare disease, idiopathic pulmonary fibrosis has also shown a potent anti-inflammatory, anti-fibrotic, antioxidant and anti-apoptotic potential in various diseases including heart failure, myocardial infarction, chronic inflammatory diseases, and neurological diseases such as ischemic stroke. A pool of evidences suggest that C21, either alone or in combination with angiotensin receptor blockers could be extremely beneficial in the treatment of diabetic nephropathy, a chronic inflammatory condition sharing its pathogenesis with aforementioned diseases. The review analyses the new therapeutic tool, C21, its mechanisms of action for renoprotection in diabetic nephropathy, and its future perspectives and thereby provides an insight into the potential application of C21 as a novel therapeutic tool in the eradication of diabetic nephropathy.
Beneficial Effects of Nuts From India in Cardiovascular Disorders
(Elsevier, 2020) Gaikwad, Anil Bhanudas
Drugs from nature are in incredible demand in various countries for essential human health services because of their wide therapeutic effects and lesser expenses. Medicinal plants are important source of compounds with potential health benefits. Nuts from different medicinal plants are also important source of bioactive phytochemicals such as proteins, fibers, minerals, tocopherols, phytosterols, and phenols. Scientific investigations have interconnected nut utilization with a declined incidence of coronary illness and hypertension. Interventions demonstrated that nut consumption has a cholesterol-lowering effect. Nuts from medicinal plants beneficially affect numerous factors associated with cardiovascular disorders. This chapter presents detail profile of nuts from India and their health effects specifically in cardiovascular disease conditions.
Biomarkers of Multiple Sclerosis and Their Modulation by Natural Products
(Elsevier, 2017) Gaikwad, Anil Bhanudas
Multiple sclerosis (MS) is one of the leading causes of neurological disabilities and can be explained as a chronic, inflammatory, and autoimmune disease related to the central nervous system. Biomarkers play an important role in defining and understanding the various mechanisms involved in the progression of disease. The success of therapeutic treatment of MS can be measured by evaluating biomarkers, which can serve as a “surrogate end point” of clinical outcomes. Biomarkers of MS can be categorized as immune system biomarkers, blood–brain barrier disruption biomarkers, demyelination biomarkers, oxidative stress and excitotoxicity biomarkers, axonal/neuronal damage biomarkers, and remyelination and repair biomarkers. Studies have shown that natural products can modulate biomarkers of MS and can be used for its treatment. Polyunsaturated fatty acids, vitamins (specifically vitamin D), minerals, and trace elements all have promising effects on biomarkers of MS. Phytochemicals like adenanthin, cannabinoids, curcumin, epigallocatechin gallate, glucoraphanin, sulforaphane, hyperforin, matrine, plumbagin, and quercetin have also shown promise as potential treatments for MS. There is a wide scope for research in the domain of multiple sclerosis biomarkers and their modulation by natural products.
Capsicum: A Natural Pain Modulator
(Elsevier, 2017) Gaikwad, Anil Bhanudas
Pain is not only an obnoxious sensation, but also a complex sensory process essential for survival experienced due to activation nociceptors. Many herbal medicines have been used in the management of pain in various traditional systems. Capsicum, a natural herb has been used counter irritant for treatment of neuralgia, lumbago, and rheumatism since ancient time. Capsicum mainly contains active pungent principles; a chemical group of nonvolatile alkaloid compounds collectively called as capsaicinoids responsible for analgesic activity. It has been reported that analgesic and antiinflammatory of capsicum is due to activation of TRPV1 receptors by its active pungent principle capsaicin. It has been reported capsaicin shows analgesic action in chronic pain, acute pain, neuropathic pain, musculoskeletal pain, osteoarthritic pain, cancer pain, gastric pain associated with mucosal damage, and pruritus.
Change in histone H3 phosphorylation, MAP kinase p38, SIR 2 and p53 expression by resveratrol in preventing streptozotocin induced type I diabetic nephropathy
(Taylor & Francis, 2009-07) Gaikwad, Anil Bhanudas
Resveratrol has been reported to have a wide variety of biological effects. However, little is known regarding its role on phosphorylation of histone H3, MAP kinase p38, SIR2 and p53 in type I diabetic nephropathy (DN). Hence, the present study was undertaken to examine changes in the above said parameters by resveratrol treatment. Male Sprague-Dawley rats were rendered diabetic using a single dose of streptozotocin (55 mg/kg, i.p.). DN was assessed by measurements of blood urea nitrogen and creatinine levels. Phosphorylation of histone H3, SIR2, p53 and MAP kinase p38 expression were examined by western blotting. This study reports that treatment of resveratrol prevents the decrease in the expression of SIR2 in diabetic kidney. It also prevents increase in p38, p53 expression and dephosphorylation of histone H3 in diabetic kidney. This is the first report which suggests that protection against development of diabetic nephropathy by resveratrol treatment involves change in phosphorylation of histone H3, expression of Sir-2, p53 and p38 in diabetic kidney
Change in post-translational modifications of histone H3, heat-shock protein-27 and MAP kinase p38 expression by curcumin in streptozotocin-induced type I diabetic nephropathy
(Wiley, 2009-01) Gaikwad, Anil Bhanudas
Curcumin has been used to treat cancer, diabetes and other pathologies. However, little is known regarding its role in altering post-translational modifications of histone H3. A recent report suggests that acute hyperglycaemia induces a global down-regulation of gene expression in human tissues and epigenetic regulation of gene expression could be a novel mechanism underlying the pathological processes of hyperglycaemia. The present study was undertaken to examine changes in histone modification by curcumin treatment which prevents development of type I diabetic nephropathy.
Combination of aspirin with telmisartan suppresses the augmented TGFβ/smad signaling during the development of streptozotocin-induced type I diabetic nephropathy
(Elsevier, 2010-04) Gaikwad, Anil Bhanudas
Diabetic nephropathy (DN) is the most common indication for the development of end stage renal diseases. Inflammation is increasingly seen as the core process in the development of diabetes. Inflammatory markers e.g. NFκB (p65 levels), TNFα, COX-2 and TGFβ–smad signaling are the key elements in the development of DN. Renin–angiotensin system suppressors like telmisartan have been used to treat DN, but they are not able to prevent completely because of development of resistance against them. Anti-inflammatory agents like, aspirin acts through both COX dependent and COX independent pathways. Hence, we thought that combining aspirin with telmisartan will be better therapeutic option in preventing the progression of nephropathy in diabetes. In the present study we studied the effect of this combination on inflammatory markers [COX-2, NFκB (p65 levels), TNFα], TGFβ–smad expression in preventing the progression of streptozotocin-induced type I diabetic nephropathy. Treatment of aspirin significantly prevented the progression of nephropathy and inhibited the augmented COX-2, NFκB (p65 levels), TNFα, and TGFβ–smad expression. Combination of aspirin with telmisartan resulted in a further decrease in the development of nephropathy and inflammatory markers in comparison to aspirin alone treatment. This is the first report which shows that aspirin in combination with telmisartan is more proficient in the treatment of diabetic nephropathy than any single drug therapy and involves the change in expression of inflammatory markers and TGFβ–smad signaling.
Compound 21 and Telmisartan combination mitigates type 2 diabetic nephropathy through amelioration of caspase mediated apoptosis
(Elsevier, 2017-06) Gaikwad, Anil Bhanudas
The current study aimed to understand the role of novel, highly selective, orally active, non-peptide Angiotensin II type 2 receptor (AT2R) agonist, Compound 21 and its potential additive effect with Telmisartan on apoptosis and underlying posttranslational modifications in a non-genetic murine model for type 2 diabetic nephropathy (T2DN). An experimental model for T2DN was developed by administering low dose Streptozotocin in high fat diet fed male Wistar rats, followed by their treatment with Telmisartan, C21 or their combination. Our results demonstrated that C21 and Telmisartan combination attenuated metabolic and renal dysfunction, renal morphological and micro-architectural aberrations and hemodynamic disturbances in type 2 diabetic rats. The anti-apoptotic and anti-inflammatory effects of Telmisartan were significantly accentuated by C21 indicated by expression of apoptotic markers (Parp1, Caspase 8, Caspase 7, cleaved PARP and cleaved Caspase 3) and NF-κB mediated inflammatory molecules like interleukin 6, tumour necrosis factor alpha; monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1. C21 was found to improve Telmisartan mediated reversal of histone H3 acetylation at lysine 14 and 27 and expression of histone acetyl transferase, p300/CBP-associated factor also known to regulate NF-κB activity and DNA damage response. C21 in combination with Telmisartan markedly mitigates caspase mediated apoptosis and NF-κB signalling in T2D kidney, which could be partially attributed to its influence on PCAF mediated histone H3 acetylation. Hence further research should be done to develop this combination to treat T2DN.
Concomitant inhibition of TLR-4 and SGLT2 by phloretin and empagliflozin prevents diabetes-associated ischemic acute kidney injury
(RSC, 2023-04) Gaikwad, Anil Bhanudas
Toll-like receptor-4 (TLR4) and sodium-glucose co-transporter 2 (SGLT2) signaling is involved in the pathogenesis of diabetes-associated kidney diseases. The purpose of this study was to explore the role and effect of phloretin, a TLR4 inhibitor, as an adjuvant therapy to empagliflozin, an SGLT2 inhibitor, in ischemic acute kidney injury (AKI) under diabetic conditions. To achieve this, firstly we induced type 1 diabetes using streptozotocin (55 mg per kg per intraperitoneally (i.p.)) followed by performing bilateral ischemia-reperfusion kidney injury to induce AKI in male Wistar rats. Treatment with phloretin (50 and 100 mg per kg per orally) and empagliflozin (10 mgper kg per orally) alone or in combination was administered to the diabetic rats for 4 days and 1 h before surgery. Moreover, a hypoxia-reperfusion injury was induced using sodium azide in NRK52E cells under a hyperglycemic environment to mimic the in vivo model. The cells were treated with phloretin (50 μM) and empagliflozin (100 nM) for 24 h. For biochemical analysis, plasma and urine samples were used. The kidney tissues were used to perform immunoblotting, histopathology, and immunohistochemistry. Other experiments like immunofluorescence, cell viability assay, and flow cytometry analysis were performed using the in vitro samples. The study outcomes revealed that compared to monotherapy, combination therapy of phloretin and empagliflozin was significantly effective. Phloretin and empagliflozin target the HMGB1/TLR4/MyD88/IK-β/α/NF-κB pathway to reduce inflammation and apoptosis, in addition to their antihyperglycemic effect. Thus, phloretin, a natural dietary supplement, as an adjuvant therapy to empagliflozin can be helpful to reduce empagliflozin-associated side effects, by reducing its clinical dose and increasing its therapeutic efficacy in AKI-diabetes comorbidity.
Concurrent neprilysin inhibition and renin-angiotensin system modulations prevented diabetic nephropathy
(Elsevier, 2019-03) Gaikwad, Anil Bhanudas
Renin-angiotensin system (RAS) and natriuretic peptides system (NPS) perturbations govern the development of diabetic nephropathy (DN). Hence, in search of a novel therapy against DN, present study targeted both, NPS and RAS simultaneously using a neprilysin inhibitor (NEPi) in combination with either angiotensin receptor blocker (ARB) or angiotensin-converting enzyme 2 (ACE2) activator.
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.
CRISPR/Cas9 based knockout of lncRNA MALAT1 attenuates TGF-β1 induced Smad 2/3 mediated fibrosis during AKI-to-CKD transition
(Elsevier, 2025) Gaikwad, Anil Bhanudas; Majumder, Syamantak
Acute kidney injury (AKI) is a significant clinical issue with potential long-term consequences, as even a single episode can progress to chronic kidney disease (CKD). The AKI-to-CKD transition involves complex pathophysiology, including persistent inflammation, apoptosis, and fibrosis. Long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been recognized as a potential therapeutic target for various kidney diseases, including AKI and CKD. In our previous study, we conducted the transcriptomic analysis of lncRNAs in-vitro and animal models of AKI-to-CKD transition and found several dysregulated lncRNAs such as MALAT1, MEG3, NEAT1, MIAT, and H19 in this transition. Among these, we have selected lncRNA MALAT1 to further validate its role in AKI-to-CKD transition as a therapeutic target via a cluster regularly intercept short palindromic protein (CRISPR) associated protein 9 (Cas9)-mediated knockout approach in NRK52E cells. Guide RNAs (gRNAs) were designed to target MALAT1, and the PX459 turbo green fluorescence protein (GFP) plasmid containing MALAT1 gRNA1&2 was transfected into NRK52E cells using CRISPRMAX. Results demonstrated that MALAT1 knockout significantly reduced MALAT1 expression and attenuated Smad2/3-mediated fibrosis by decreasing pSmad2, pSmad2/3, Smad4, vimentin, fibronectin, collagen-I, and α-SMA expression levels, while increasing Smad7, Smurf2, and E-cadherin levels. These findings suggest that targeting the MALAT1/Smad2/3 pathway could be a potential therapeutic target for mitigating fibrosis to prevent AKI-to-CKD transition.
Crosstalk between kidney and liver in non-alcoholic fatty liver disease: mechanisms and therapeutic approaches
(Taylor & Francis, 2020-03) Gaikwad, Anil Bhanudas
Liver and kidney are vital organs that maintain homeostasis and injury to either of them triggers pathogenic pathways affecting the other. For example, non-alcoholic fatty liver disease (NAFLD) promotes the progression of chronic kidney disease (CKD), vice versa acute kidney injury (AKI) endorses the induction and progression of liver dysfunction. Progress in clinical and basic research suggest a role of excessive fructose intake, insulin resistance, inflammatory cytokines production, activation of the renin–angiotensin system, redox imbalance, and their impact on epigenetic regulation of gene expression in this context. Recent developments in experimental and clinical research have identified several biochemical and molecular pathways for AKI-liver interaction, including altered liver enzymes profile, metabolic acidosis, oxidative stress, activation of inflammatory and regulated cell death pathways. This review focuses on the current preclinical and clinical findings on kidney–liver crosstalk in NAFLD-CKD and AKI-liver dysfunction settings and highlights potential molecular mechanisms and therapeutic targets.
Curcumin as an Adjuvant to Breast Cancer Treatment
(Bentham Science, 2015-06) Gaikwad, Anil Bhanudas
Cancer is the second largest leading cause of death worldwide and breast cancer is the most prevailing cause of mortality among all cases of malignant neoplastic disease in adult females. The incidence rate of breast malignant neoplastic disease is predominantly higher in Western women, when compared to women in Asian nations. The definitive reason for this conflict is even unknown, but dietary factors have been conceived to account for approximately 30% of cancers in Western nations. It has been hypothesized that ethnicity, including use of a variety of spices in the food would be a major reason. Among all spices, turmeric (Curcuma longa) has been proven for its better anticancer potential. In this review different molecular mechanisms including cell cycle arrest; G0/G1 and/or G2/M phase cell cycle arrest by up-regulating Cdk inhibitor, p21/WAF/CIPI and p53, inhibition of transcriptional factors; NFΚB, AP-1, TNFα, IL, STAT-3, and PPAR-γ, downstream gene regulation; c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNFα, interleukins and MMP-9, growth factors; bFGF, EGF, GCSF, IL-8, PDGF, TGFα, TNF, VEGF and cell adhesion molecules; fibronectin, vitronectin, and collagen which are involved in angiogenesis and metastasis, alsothe effectiveness of curcumin, when given in combination with chemotherapeutics like cyclophosphamide, doxorubicin, mitomycin etc. in treating breast cancer have been reviewed.