A structure-based pharmacophore modelling approach to identify and design new neprilysin (NEP) inhibitors: An in silico-based investigation.

Neutral endopeptidase or neprilysin (NEP) cleaves the natriuretic peptides, bradykinin, endothelin, angiotensin II, amyloid ß protein, substance P, etc., thus modulating their effects on heart, kidney, and other organs. NEP has a proven role in hypertension, heart disease, renal disease, Alzheimer's, diabetes, and some cancers. NEP inhibitor development has been in focus since the US FDA approved a combination therapy of angiotensin II type 1 receptor inhibitor (valsartan) and NEP inhibitor (sacubitril) for use in heart failure. Considering the importance of NEP inhibitors the present work focuses on the designing of a potential lead for NEP inhibition. A structure-based pharmacophore modelling approach was employed to identify NEP inhibitors from the pool of 1140 chemical entities obtained from the ZINC database. Based on the docking score and pivotal interactions, ten molecules were selected and subjected to binding free energy calculations and ADMET predictions. The top two compounds were studied further by molecular dynamics simulations to determine the stability of the ligand-receptor complex. ZINC0000004684268, a phenylalanine derivative, showed affinity and complex stability comparable to sacubitril. However, in silico studies indicated that it may have poor pharmacokinetic parameters. Therefore, the molecule was optimized using bioisosteric replacements, keeping the phenylalanine moiety intact, to obtain five potential lead molecules with an acceptable pharmacokinetic profile. The works thus open up the scope to further corroborate the present in silico findings with the biological analysis.

Molecular insights into P2X signalling cascades in acute kidney injury.

Acute kidney injury (AKI) is a critical health issue with high mortality and morbidity rates in hospitalized individuals. The complex pathophysiology and underlying health conditions further complicate AKI management. Growing evidence suggests the pivotal role of ion channels in AKI progression, through promoting tubular cell death and altering immune cell functions. Among these channels, P2X purinergic receptors emerge as key players in AKI pathophysiology. P2X receptors gated by adenosine triphosphate (ATP), exhibit increased extracellular levels of ATP during AKI episodes. More importantly, certain P2X receptor subtypes upon activation exacerbate the situation by promoting the release of extracellular ATP. While therapeutic investigations have primarily focused on P2X4 and P2X7 subtypes in the context of AKI, while understanding about other subtypes still remains limited. Whilst some P2X antagonists show promising results against different types of kidney diseases, their role in managing AKI remains unexplored. Henceforth, understanding the intricate interplay between P2X receptors and AKI is crucial for developing targeted interventions. This review elucidates the functional alterations of all P2X receptors during normal kidney function and AKI, offering insights into their involvement in AKI. Notably, we have highlighted the current knowledge of P2X receptor antagonists and the possibilities to use them against AKI in the future. Furthermore, the review delves into the pathways influenced by activated P2X receptors during AKI, presenting potential targets for future therapeutic interventions against this critical condition.

Targeting DNA methylation in diabetic kidney disease: A new perspective.

Diabetic kidney disease (DKD) is a leading diabetic complication causing significant mortality among people around the globe. People with poor glycemic control accompanied by hyperinsulinemia, dyslipidemia, hypertension, and obesity develop diabetic complications. These diabetic patients develop epigenetic changes and suffer from diabetic kidney complications even after subsequent glucose control, the phenomenon that is recognized as metabolic memory. DNA methylation is an essential epigenetic modification that contributes to the development and progression of several diabetic complications, including DKD. The aberrant DNA methylation pattern at CpGs sites within several genes, such as mTOR, RPTOR, IRS2, GRK5, SLC27A3, LCAT, and SLC1A5, associated with the accompanying risk factors exacerbate the DKD progression. Although drugs such as azacytidine and decitabine have been approved to target DNA methylation for diseases such as hematological malignancies, none have been approved for the treatment of DKD. More importantly, no DNA hypomethylation-targeting drugs have been approved for any disease conditions. Understanding the alteration in DNA methylation and its association with the disease risk factors is essential to target DKD effectively. This review has discussed the abnormal DNA methylation pattern and the kidney tissue-specific expression of critical genes involved in DKD onset and progression. Moreover, we also discuss the new possible therapeutic approach that can be exploited for treating DNA methylation aberrancy in a site-specific manner against DKD.

Phloretin as an add-on therapy to losartan attenuates diabetes-induced AKI in rats: A potential therapeutic approach targeting TLR4-induced inflammation.

AIM: Targeting 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. MAIN METHODS: To mimic diabetic AKI condition, bilateral ischemia-reperfusion injury (BIRI) was done in diabetic male Wistar rats, and sodium azide treatment was given to high glucose NRK52E cells to mimic hypoxia-reperfusion injury. In diabetic rats, phloretin (50 mg/kg/per os (p.o.)) and losartan (10 mg/kg/p.o.) treatment was given for 4 days and 1 h prior to surgery while in NRK52E cells, both drugs (phloretin 50 µM and losartan 10 µM) were given 24 h prior to the hypoxia condition. The in vivo and in vitro samples were further used for different experiments. KEY FINDINGS: Treatment with phloretin and losartan decreased diabetic and AKI biomarkers such as plasma creatinine, blood urea nitrogen (BUN), and kidney injury molecular 1 (KIM1). Moreover, a combination of phloretin and losartan significantly preserved ΔΨm and kidney morphology potentially by inhibiting TLR4-associated inflammation and AT1R-associated mitochondrial dysfunction, thereby oxidative stress. SIGNIFICANCE: Combination therapy of phloretin and losartan was more effective than monotherapies. Both drugs target TLR4/MyD88/NF-κB pathway and reduce inflammation and mitochondrial dysfunction in AKI under diabetic condition.

Metabolic reprogramming: Unveiling the therapeutic potential of targeted therapies against kidney disease.

As a high-metabolic-rate organ, the kidney exhibits metabolic reprogramming (MR) in various disease states. Given the >800 million cases of kidney disease worldwide in 2022, understanding the specific bioenergetic pathways involved and developing targeted interventions are vital needs. The reprogramming of metabolic pathways (glucose metabolism, amino acid metabolism, etc.) has been observed in kidney disease. Therapies targeting these specific pathways have proven to be an efficient approach for retarding kidney disease progression. In this review, we focus on potential pharmacological interventions targeting MR that have advanced through Phase III/IV clinical trials for the management of kidney disease and promising preclinical studies laying the groundwork for future clinical investigations.

Nutraceuticals and network pharmacology approach for acute kidney injury: A review from the drug discovery aspect.

Acute kidney injury (AKI) has become a global health issue, with ∼12 million reports yearly, resulting in a persistent increase in morbidity and mortality rates. AKI pathophysiology is multifactorial involving oxidative stress, mitochondrial dysfunction, epigenetic modifications, inflammation, and eventually, cell death. Hence, therapies able to target multiple pathomechanisms can aid in AKI management. To change the drug discovery framework from "one drug, one target" to "multicomponent, multitarget," network pharmacology is evolving as a next-generation research approach. Researchers have used the network pharmacology approach to predict the role of nutraceuticals against different ailments including AKI. Nutraceuticals (herbal products, isolated nutrients, and dietary supplements) belong to the pioneering category of natural products and have shown protective action against AKI. Nutraceuticals have recently drawn attention because of their ability to provide physiological benefits with less toxic effects. This review emphasizes the nutraceuticals that exhibited renoprotection against AKI and can be used either as monotherapy or adjuvant with conventional therapies to boost their effectiveness and lessen the adverse effects. Additionally, the study sheds light on the application of network pharmacology as a cost-effective and time-saving approach for the therapeutic target prediction of nutraceuticals against AKI.

Concomitant inhibition of TLR-4 and SGLT2 by phloretin and empagliflozin prevents diabetes-associated ischemic acute kidney injury.

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-ß/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.

Receptor-mediated mitophagy: An emerging therapeutic target in acute kidney injury.

Acute kidney injury (AKI) is a global health concern associated with high morbidity and mortality. AKI etiology is linked to mitochondrial dysfunction along with oxidative stress and inflammation. The defective mitochondria are removed via mitophagy for maintaining cellular integrity. The main regulatory mechanisms of mitophagy in response to different stressors are Phosphatase and tensin homolog-induced kinase 1 (PINK1)/Parkin and receptor-mediated. Receptors like B-cell lymphoma 2/adenovirus E1B-interacting protein (BNIP3), BNIP3L, prohibitin2, tacrolimus (FK506)-binding protein8 (FKBP8), autophagy-beclin1-regulator1 (AMBRA1) and SMAD-ubiquitination regulatory factor1 (SMURF1), etc. participate in receptor-mediated mitophagy. In recent studies, receptor-mediated mitophagy showed protective effects in AKI. This review summarizes the evidence related to mitophagy in AKI and outlines the significance of receptor-mediated mitophagy modulation as a possible therapeutic approach in AKI.

Renal ischemia/reperfusion injury: An insight on in vitro and in vivo models.

Optimal tissue oxygenation is essential for its normal function. Suboptimal oxygenation or ischemia contributes to increased mortalities during various pathological conditions such as stroke, acute kidney injury (AKI), cardiac failure. Despite the rapid progression of renal tissue injury, the mechanism underlying renal ischemia/reperfusion injury (IRI) remains highly unclear. Experimental in vitro and in vivo models epitomizing the fundamental process is critical to the research of the pathogenesis of IRI and the development of plausible therapeutics. In this review, we describe the in vitro and in vivo models of IRI, ranges from proximal tubular cell lines to surgery-based animal models like clamping of both renal pedicles (bilateral IRI), clamping of one renal pedicle (unilateral IRI), clamping of one/or both renal arteries/or vein, or unilateral IRI with contralateral nephrectomy (uIRIx). Also, advanced technologies like three-dimensional kidney organoids, kidney-on-a-chip are explained. This review provides thoughtful information for establishing reliable and pertinent models for studying IRI-associated acute renal pathologies.

'PARP'ing fibrosis: repurposing poly (ADP ribose) polymerase (PARP) inhibitors.

Fibrosis is a wound-healing process that results in tissue scarring and organ dysfunction. Several novel mechanisms of fibrogenesis have been discovered recently. In this review, we focus on the role of poly-ADP ribose polymerase (PARP) in major organ fibrosis, such as lungs, heart, liver, and kidneys. PARP is a dynamic enzyme that modulates different cellular proteins by the addition of PAR groups and mediates an array of cellular events in both normal physiological and pathophysiological states. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) recently approved several PARP inhibitors, such as olaparib, niraparib, talazoparib, and rucaparib, for the treatment of ovarian and germline BRCA-mutant breast cancers. Consequently, repurposing these drugs could provide an opportunity to counter organ fibrosis.

Simultaneous inhibition of neprilysin and activation of ACE2 prevented diabetic cardiomyopathy.

BACKGROUND: Neprilysin inhibitors (NEPi) are assisting the renin-angiotensin system (RAS) inhibitors in halting diabetic cardiomyopathy (DCM). Away from conventional tactic, a recent report revealed the renoprotective potential of NEPi and angiotensin-converting enzyme (ACE2) activator combination therapy against diabetic nephropathy. However, this combination so far not evaluated against DCM, thus the present investigation aiming the same. METHODS: Streptozotocin-induced (55 mg/kg, ip) type 1 diabetic (T1D) male Wistar rats were treated with either monotherapy of thiorphan (0.1 mg/kg/day, po) or diminazene aceturate (5 mg/kg/day, po), or their combination therapy, for four weeks. After hemodynamic measurements, all the rats' heart and plasma were collected for biochemistry, ELISA, histopathology, and immunoblotting. RESULTS: Metabolic perturbations and failing cardiac functions associated with diabetes were markedly attenuated by combination therapy. Besides, unfavourable alterations in RAS and natriuretic peptides system (NPS) were corrected by combination therapy. Interestingly, combination therapy significantly increased plasma and heart cGMP levels compared to T1D and monotherapy receiving rats. Moreover, rats receiving combination therapy exhibited significant inhibition of activated NF-κB, TGF-ß and apoptotic signalling, and a notable reduction in cardiac fibrosis when compared to T1D rats. Expressions of posttranslational histone modifications markers; H3K4Me2 and its methyltransferases (SET7/9 and RBBP5) were significantly enhanced in T1D hearts, which were significantly reduced by combination therapy. CONCLUSIONS: The NEPi and ACE2 activator combination therapy effectively prevented DCM by normalising RAS and NPS activities, increasing cGMP, inhibiting inflammatory, pro-fibrotic and apoptotic signalling, and reversing H3K4Me2 and its methyl transferases expressions.

Concurrent neprilysin inhibition and renin-angiotensin system modulations prevented diabetic nephropathy.

AIMS: 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. METHODS: We induced diabetes in male Wistar rats by a single dose of streptozotocin (55 mg/kg, i.p.). After four weeks, we treated diabetic rats with thiorphan, telmisartan or diminazene aceturate (Dize) 0.1, 10, 5 mg/kg/day, p.o. alone as monotherapy, or both thiorphan/telmisartan or thiorphan/Dize as combination therapy, for four weeks. Then, plasma and urine biochemistry were performed, and kidneys from all the groups were collected and processed separately for histopathology, ELISA and Western blotting. KEY FINDINGS: Proposed combination therapies attenuated metabolic perturbations, prevented renal functional decline, and normalised adverse alterations in renal ACE, ACE2, Ang-II, Ang-(1-7), neprilysin and cGMP levels in diabetic rats. Histopathological evaluation revealed a significant reduction in glomerular and tubulointerstitial fibrosis by combination therapies. Importantly, combination therapies inhibited inflammatory, profibrotic and apoptotic signalling, way better than respective monotherapies, in preventing DN. CONCLUSION: Renoprotective potential of thiorphan (NEPi)/telmisartan (ARB) and thiorphan/Dize (ACE2 activator) combination therapies against the development of DN is primarily attributed to normalisation of RAS and NPS components and inhibition of pathological signalling related to inflammation, fibrosis, and apoptosis. Hence, we can conclude that NEPi/ARB and NEPi/ACE2 activator combination therapies might be new therapeutic strategies in preventing DN.

Diabetic nephropathy: The regulatory interplay between epigenetics and microRNAs.

Diabetic nephropathy (DN) is still one of the leading causes of end-stage renal disease despite the emergence of different therapies to counter the metabolic, hemodynamic and fibrotic pathways, implicating a prominent role of genetic and epigenetic factors in its progression. Epigenetics is the study of changes in the expression of genes which may be inheritable and does not involve a change in the genome sequence. Thrust areas of epigenetic research are DNA methylation and histone modifications. Noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs) control the expression of genes via post-transcriptional mechanisms. However, the regulation by epigenetic mechanisms and miRNAs are not completely distinct. A number of emerging reports have revealed the interplay between epigenetic machinery and miRNA expression, particularly in cancer. Further research has proved that a feedback loop exists between miRNA expression and epigenetic regulation in disorders including DN. Studies showed that different miRNAs (miR-200, miR-29 etc.) were found to be regulated by epigenetic mechanisms viz. DNA methylation and histone modifications. Conversely, miRNAs (miR-301, miR-449 etc.) themselves modulated levels of DNA methyltranferases (DNMTs) and Histone deacetylases (HDACs), enzymes vital to epigenetic modifications. With already few FDA approved epigenetic -modulating drugs (Vorinostat, Decitabine) in the market and miRNA therapeutic drugs under clinical trial it becomes imperative to analyze the possible interaction between the two classes of drugs in the modulation of a disease process. The purpose of this review is to articulate the interplay between miRNA expression and epigenetic modifications with a particular focus on its impact on the development and progression of DN.

Histone Acetylation Regulates Natriuretic Peptides and Neprilysin Gene Expressions in Diabetic Cardiomyopathy and Nephropathy.

BACKGROUND: Natriuretic peptide system (NPS) alterations are involved in pathogenesis of diabetic cardiomyopathy (DCM) and nephropathy (DN), however its epigenetic regulation is still unclear. Interestingly, histone acetylation epigenetically regulates neprilysin expression in Alzheimer's disease. OBJECTIVES: The present study was aimed at delineating role of histone acetylation in regulation of NPS in DCM and DN. METHODS: Streptozotocin (55 mg/kg, i.p.)-induced diabetic male Wistar rats were used to mimic pathogenesis of DCM and DN. After haemodynamic measurements, all the rat's plasma, heart and kidney were collected for biochemistry, ELISA, protein isolation and western blotting, RT-PCR and chromatin immunoprecipitation (ChIP) assay. RESULTS: Diabetic rats heart and kidney exhibited activation of NF-κB and TGF-ß signalling with increased histone acetyl transferases (PCAF/CBP) expressions and augmented H2AK5Ac, H2BK5Ac, H3K18Ac, and H4K8Ac levels. ChIP assay results showed increased enrichment of H3K18Ac and H2BK5Ac at Nppa, Nppb (Heart) and Mme promoter (Heart/Kidney) in diabetic rats. Enrichment of H2AK5Ac was augmented on Nppa and Mme promoters in diabetic heart, while it remained unchanged on Nppb promoter in heart and Mme promoter in kidney. CONCLUSION: Augmented histone acetylation at promoter regions of NPS gene(s), at least in a part, is responsible for increased expressions of ANP, BNP and NEP in diabetic heart and kidney. Hence, histone acetylation inhibitors can be considered as novel therapeutic targets against DCM and DN.

Telmisartan and thiorphan combination treatment attenuates fibrosis and apoptosis in preventing diabetic cardiomyopathy.

Aims: LCZ696, a first-generation dual angiotensin receptor-neprilysin inhibitor (ARNi), is effective in treating heart failure patients. However, the role of ARNis in treating diabetic cardiomyopathy is poorly understood. This study evaluates the efficacy of a novel combination of telmisartan [angiotensin receptor blocker (ARB)] and thiorphan [neprilysin inhibitor (NEPi)] in ameliorating diabetic cardiomyopathy while, at the same time, exploring the relevant underlying molecular mechanism(s). Methods and results: Diabetes was induced by administration of streptozotocin (55 mg/kg, i.p.) in male Wistar rats. After 4 weeks, diabetic rats were subjected to either thiorphan (0.1 mg/kg/day, p.o.) or telmisartan (10 mg/kg/day, p.o.) monotherapy, or their combination, for a period of 4 weeks. Metabolic and morphometric alterations, failing ventricular functions, and diminished baroreflex indicated development of diabetic cardiac complications. Apart from morphometric alterations, all pathological consequences were prevented by telmisartan and thiorphan combination therapy. Diabetic rats exhibited significant modulation of the natriuretic peptide system, a key haemodynamic regulator; this was normalized by combination therapy. Histopathological studies showed augmented myocardial fibrosis, demonstrated by increased % PSR-positive area, with combination therapy giving the best improvement in these indices. More importantly, the combination of thiorphan and telmisartan was superior in attenuating inflammatory (NF-κB/MCP-1), profibrotic (TGF-ß/Smad7) and apoptotic (PARP/Caspase-3) cascades compared to respective monotherapies when treating rats with diabetic cardiomyopathy. In addition, diabetic heart chromatin was in a state of active transcription, indicated by increased histone acetylation (H2AK5Ac, H2BK5Ac, H3K9Ac, and H4K8Ac) and histone acetyltransferase (PCAF and Ac-CBP) levels. Interestingly, combination treatment was sufficiently potent to normalize these alterations. Conclusion: The protective effect of novel ARB and NEPi combination against diabetic cardiomyopathy can be attributed to inhibition of inflammatory, profibrotic, and apoptotic cascades. Moreover, reversal of histone acetylation assists its protective effect.

Fiend and friend in the renin angiotensin system: An insight on acute kidney injury.

Besides assisting the maintenance of blood pressure and sodium homeostasis, the renin-angiotensin system (RAS) plays a pivotal role in pathogenesis of acute kidney injury (AKI). The RAS is equipped with two arms i) the pressor arm composed of Angiotensin II (Ang II)/Angiotensin converting enzyme (ACE)/Angiotensin II type 1 receptor (AT1R) also called conventional RAS, and ii) the depressor arm consisting of Angiotensin (1-7) (Ang 1-7)/Angiotensin converting enzyme 2 (ACE2)/MasR known as non-conventional RAS. Activation of conventional RAS triggers oxidative stress, inflammatory, hypertrophic, apoptotic, and pro-fibrotic signaling cascades which promote AKI. The preclinical and clinical studies have reported beneficial as well as deleterious effects of RAS blockage either by angiotensin receptor blocker or ACE inhibitor in AKI. On the contrary, the depressor arm opposes the conventional RAS, has beneficial effects on the kidney but has been less explored in pathogenesis of AKI. This review focuses on significance of RAS in pathogenesis of AKI and provides better understanding of novel and possible therapeutic approaches to combat AKI.

Compound 21 and Telmisartan combination mitigates type 2 diabetic nephropathy through amelioration of caspase mediated apoptosis.

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.

Hidden targets of ubiquitin proteasome system: To prevent diabetic nephropathy.

Diabetic nephropathy (DN) is the major cause of end stage renal failure. Although, several therapeutic targets have emerged to prevent the progression of DN, the number of people with DN still continues to rise worldwide, suggesting an urgent need of novel targets to prevent DN completely. Currently, the role of ubiquitin proteasome system (UPS) has been highlighted in the pathogenesis and progression of various diseases like obesity, insulin resistance, atherosclerosis, cancers, neurodegerative disorders and including secondary complications of diabetes. UPS mainly involves in protein homeostatis through ubiquitination (post translational modification) and proteasomal degradation of various proteins. Ubiquitination, not only involves in proteasomal degradation, but also directs the substrate proteins to participate in multitude of cell signalling pathways. However, very little is known about ubiquitination and UPS in the progression of DN. This review mainly focuses on UPS and its components including E2 conjugating enzymes, E3 ligases and deubiquitinases (DUBs) in the development of DN and thus may help us to find novel therapeutic targets with in UPS to prevent DN completely in future.

Neprilysin inhibitors: A new hope to halt the diabetic cardiovascular and renal complications?

Diabetes is an enormous and ever-growing calamity and a global public health threat of the 21st century. Besides insulin and oral hypoglycaemic drugs, blockage of the renin-angiotensin system (RAS) denotes a key pharmacotherapy for the management of cardiovascular (CVD) and chronic kidney diseases (CKD), which are the leading causes of disability and death among diabetic patients. Neprilysin (NEP) inhibition, auxiliary to RAS blockage increases the bioavailability of natriuretic peptides and benefits the cardio-renal system. Omapatrilat, a dual angiotensin-converting enzyme (ACE) and NEP inhibitor has been reported to show superior anti-hypertensive, anti-atherosclerotic, insulin-sensitizing, cardiovascular and renoprotective effects to ACE inhibitors in experimental animal models for diabetes. In clinical trials on hypertensive subjects Omapatrilat increased the risk of angioedema due to which its further development as anti-hypertensive drug was hampered. This event prompted the development of angiotensin receptor neprilysin inhibitors (ARNi). The first representative of ARNi, LCZ696 (Sacubitril/ Valsartan) halted cardiovascular and renal functional decline and hence protected against CKD and CVD. Recently, LCZ696 was approved by U.S. Food and Drug Administration for the treatment of heart failure. This concise review intends to summarise the currently available reports on NEPi as a therapeutic intervention to treat CVD and CKD associated with diabetes.

Esculetin: A phytochemical endeavor fortifying effect against non-communicable diseases.

Esculetin, a naturally occurring 6,7-dihydroxy derivative of coumarin has shown its potential role in various non-communicable diseases (NCDs) including obesity, diabetes, cardiovascular, renal failure, cancer and neurological disorders. NCDs, responsible for about 70% of the deaths occurring globally are majorly attributed to tobacco or alcohol abuse, sedentary lifestyle, and unhealthy diets. It can be managed by improving access to cost-effective treatment, care and prevention. The beneficial effects of esculetin in NCDs have been ascribed to its antioxidant, anti-proliferative and cytoprotective potential. This review attempts to summarize the beneficial effects shown by the emerging molecule and the underlying mechanisms. This may help us in improving our understanding of the molecule and may encourage the researchers to ponder over further development of esculetin as a potential therapeutic intervention in NCDs.