Department of Pharmacy
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Item Renoprotective effect of esculetin against ischemic acute kidney injury-diabetic comorbidity(Taylor & Francis, 2024-02) Gaikwad, Anil Bhanudas; Jadhav, Hemant R.Mitophagy maintains cellular homeostasis by eliminating damaged mitochondria. Accumulated damaged mitochondria can lead to oxidative stress and cell death. Induction of the PINK1/Parkin-mediated mitophagy is reported to be renoprotective in acute kidney injury (AKI). Esculetin, a naturally available coumarin, has shown protective action against diabetic complications. However, its effect on AKI-diabetes comorbidity has not been explored yet. Therefore, we aimed to investigate the renoprotective effect of esculetin against AKI under diabetic conditions via regulating PINK1/Parkin-mediated mitophagy. For this, type 1 diabetic male Wistar rats were treated with two doses of esculetin (50 and 100 mg/kg/day orally) for five days followed by AKI induction by bilateral ischemic-reperfusion injury (IRI). NRK-52E cells grown in high glucose were exposed to sodium azide (10 mM) for induction of hypoxia/reperfusion injury (HRI) in-vitro. Esculetin (50 µM) treatment for 24 h was given to the cells before HRI. The in-vitro samples were utilized for cell viability and ΔΨm assay, immunoblotting, and immunofluorescence. Rats’ plasma, urine, and kidney samples were collected for biochemical analysis, histopathology, and western blotting. Our results showed a significant decrease in kidney injury-specific markers and increased expression of mitophagy markers (PINK1 and Parkin) with esculetin treatment. Moreover, esculetin prevented the HRI and hyperglycemia-induced decrease in ΔΨm and autophagosome marker. Also, esculetin therapy reduced oxidative stress via increased Nrf2 and Keap1 expression. Esculetin attenuated AKI under diabetic condition by preventing mitochondrial dysfunction via inducing PINK1/Parkin-mediated mitophagy, suggesting its potential as an effective therapy for preventing AKI-diabetes comorbidity.Item Network pharmacology combined with molecular docking and dynamics to assess the synergism of esculetin and phloretin against acute kidney injury-diabetes comorbidity(Springer, 2024-04) Jadhav, Hemant R.; Gaikwad, Anil BhanudasAcute kidney injury (AKI) is a global health concern with high incidence and mortality, where diabetes further worsens the condition. The available treatment options are not uniformly effective against the complex pathogenesis of AKI–diabetes comorbidity. Hence, combination therapies based on the multicomponent, multitarget approach can tackle more than one pathomechanism and can aid in AKI–diabetes comorbidity management. This study aimed to investigate the therapeutic potential of esculetin and phloretin combination against AKI–diabetes comorbidity by network pharmacology followed by validation by molecular docking and dynamics. The curative targets for diabetes, AKI, esculetin, and phloretin were obtained from DisGeNET, GeneCards, SwissTargetPrediction database. Further, the protein–protein interaction of the potential targets of esculetin and phloretin against AKI–diabetes comorbidity was investigated using the STRING database. Gene ontology and pathway enrichment analysis were performed with the help of the DAVID and KEGG databases, followed by network construction and analysis via Cytoscape. Molecular docking and dynamic simulations were performed to validate the targets of esculetin and phloretin against AKI–diabetes comorbidity. We obtained 6341 targets for AKI–diabetes comorbidity. Further, a total of 54 and 44 targets of esculetin and phloretin against AKI–diabetes comorbidity were retrieved. The top 10 targets for esculetin selected based on the degree value were AKR1B1, DAO, ESR1, PLK1, CA3, CA2, CCNE1, PRKN, HDAC2, and MAOA. Similarly, phloretin’s 10 key targets were ACHE, CDK1, MAPK14, APP, CDK5R1, CCNE1, MAOA, MAOB, HDAC6, and PRKN. These targets were enriched in 58 pathways involved in the pathophysiology of AKI–diabetes comorbidity. Further, esculetin and phloretin showed an excellent binding affinity for these critical targets. The findings of this study suggest that esculetin and phloretin combination as a multicomponent multitarget therapy has the potential to prevent AKI–diabetes comorbidity.Item A perspective on the development of small molecular neprilysin inhibitors (NEPi) with emphasis on cardiorenal disease(Elsevier, 2024-12) Jadhav, Hemant R.; Gaikwad, Anil BhanudasNeprilysin is a cell surface metallo-endopeptidase, commonly identified as neutral endopeptidase (NEP), that plays a crucial role in the cleavage of peptides, for example, natriuretic peptides, angiotensin II, enkephalins, endothelin, bradykinin, substance P, glucagon-like peptide and amyloid beta. In the case of heart failure, a significant upsurge in NEP activity and expression enhances the degradation of natriuretic peptides. Therefore, NEP inhibitors have gained attention in the field of cardiology. NEP has been studied for over 40 years; however, it has recently gained attention with the US FDA approval of a fixed dose combination of sacubitril (NEP inhibitor) and valsartan (AT-1 inhibitor) for chronic heart failure treatment. The present review elucidates the role of neprilysin in cardiorenal disease, its pathophysiology, and how NEP inhibition benefits. It also summarizes the research advances in NEP inhibitors (NEPi) and their structure-activity relationships. Moreover, the review provides insight into NEPi effectiveness - alone or combined with other cardiorenal protective agents. It is expected to help medicinal chemists synthesize and develop novel NEPi.Item Phloretin as an add-on therapy to losartan attenuates diabetes-induced AKI in rats: A potential therapeutic approach targeting TLR4-induced inflammation(Elsevier, 2023-11) Gaikwad, Anil BhanudasTargeting Toll-like receptor 4 (TLR4) and Angiotensin II type 1 receptor (AT1R) could provide renoprotection during acute kidney injury (AKI) mainly by regulating inflammation, oxidative stress, mitochondrial dysfunction, and apoptosis. Phloretin (TLR4 inhibitor) as an add-on therapy to losartan (AT1R inhibitor) could provide more therapeutic benefits against AKI under diabetic condition. We aimed to study the effect of phloretin as an add-on therapy to losartan against AKI under diabetic condition.Item Diabetes and Cardiorenal Complications: A Clinical Review of Existing Therapies and Novel Combinations, Focusing on SGLT2 Inhibitors(Bentham Science, 2023-11) Gaikwad, Anil BhanudasType 2 diabetes mellitus (T2DM) is a set of metabolic disorders specified by hyperglycemia as a result of abnormalities in insulin secretion or sensitivity. Chronic kidney disease (CKD) and cardiovascular disease (CVD) are the widespread co-morbidities of T2DM and share risk factors for onset and progression. Despite numerous mono- and combination therapies exist, the progression of diabetes complications remains a global health concern. Treatment options for diabetic- CKD and CVD include drugs targeting hyperglycemia, hypertension, albuminuria, hyperlipidemia and the renin-angiotensin aldosterone system (RAAS). The sodium-glucose co-transporter 2 channel (SGLT2) is abundantly present in proximal tubules of the kidney and its capacity to recover glucose and sodium from the glomerular filtrate limits urinary glucose and sodium excretion. SGLT2 inhibitors (SGLT2i) reduce sodium and glucose reabsorption in the proximal and thus increase urinary glucose excretion in T2DM. SGLT2i monotherapy can improve but dual SGLT2/RAAS inhibition or SGLT2i along with other classes of drugs are more effective in protecting the kidneys and the cardiovascular system in patients with and without diabetes. Combinations such as empagliflozin and linagliptin, ertugliflozin and metolazone, dapagliflozin and sacubitril- valsartan and many more show promising results. Here, we have reviewed the ongoing and completed clinical trials, addressed current theories, and discussed necessary future research to explain the possible risks and benefits of using an SGLT2i alone and in combination with existing antidiabetic drugs and drugs acting on the cardiovascular systemItem Ameliorative effect of AT2R and ACE2 activation on ischemic renal injury associated cardiac and hepatic dysfunction(Elsevier, 2020-11) Gaikwad, Anil BhanudasThis 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.Item Epigenetic restoration of endogenous Klotho expression alleviates acute kidney injury-diabetes comorbidity(Elsevier, 2022-01) Gaikwad, Anil BhanudasThe present study aimed at exploring the mechanisms behind Klotho regulation in hyperglycemia augmented AKI. In addition, epigenetic ways to restore the Klotho expression in AKI-diabetes comorbidity have been evaluated.Item Role of dietary modifications in the management of type 2 diabetic complications(Elsevier, 2021-06) Gaikwad, Anil BhanudasDiabetes is a chronic metabolic disorder with a high rate of morbidity and mortality. Insufficient insulin secretion and insulin action are two major causes for the development of diabetes, which is characterized by a persistent increase in blood glucose level. Diet and sedentary life style play pivotal role in development of vascular complications in type 2 diabetes. Dietary modification is associated with a reprogramming of nutrient intake, which are proven to be effective for the management of diabetes and associated complications. Dietary modifications modulate various molecular key players linked with the functions of nutrient signalling, regulation of autophagy, and energy metabolism. It activates silent mating type information regulation 2 homolog1 (SIRT1) and AMP-activated protein kinase (AMPK). AMPK mainly acts as an energy sensor and inhibits autophagy repressor Mammalian target of rapamycin (mTOR) under nutritional deprivation. Under calorie restriction (CR), SIRT1 gets activated directly or indirectly and plays a central role in autophagy via the regulation of protein acetylation. Dietary modification is also effective in controlling inflammation and apoptosis by decreasing the level of pro-inflammatory cytokines like nuclear factor kappa- beta (NF-kβ), tissue growth factor-beta (TGF-β), tissue necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). It also improves glucose homeostasis and insulin secretion through beta cell regeneration. This indicates calorie intake plays a crucial role in the pathogenesis of type 2 diabetes-associated complications.Item Klotho: A possible mechanism of action of SGLT2 inhibitors preventing episodes of acute kidney injury and cardiorenal complications of diabetes(Elsevier, 2021-08) Gaikwad, Anil BhanudasDiabetes and cardiorenal comorbidities are major global health concerns, with high economic burdens and mortality rates. Sodium glucose co-transporter-2 inhibitors (SGLT2is) are novel US Food and Drug Administration (FDA)-approved antihyperglycemics with unexpected protective potential against cardiorenal diseases in patients with or without type 2 diabetes mellitus (T2DM). Despite initial concerns, the incidence of episodes of acute kidney injury (AKI) was significantly lower in patients taking SGLT2i compared with other therapies or placebo. Evolving data suggest a link between SGLT2is and the anti-aging protein Klotho in the amelioration of diabetes and cardiorenal diseases. Here, we consider Klotho and SGLT2is as a novel therapeutic approach for the management of AKI and other cardiorenal complications in patients with or without diabetes.Item Diabetes, diabetic complications, and flavonoids(Elsevier, 2016) Gaikwad, Anil BhanudasDiabetes mellitus is among the most prevalent diseases with which a large population of world is suffering from. Incidence of diabetes is on rise all over the world. Hence management of diabetes and related complications is of prime importance. Finding of new drugs and betterment of current therapeutic regimen is necessary to achieve the target of decreasing the mortalities and morbidities related with the diabetes and its complications. Plants have served as a great source of medicines for variety of diseases and aliments including diabetes and its complications. Various groups of phytochemicals derived from plant are identified and reported to have antidiabetic activity along with having potential to treat complications of it. In this chapter we have discussed flavonoid and its different subclasses in context with their antidiabetic activity along with their potential in management and treatment of diabetic complications.