Browsing by Author "Majumder, Syamantak"

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14K prolactin derived 14-mer antiangiogenic peptide targets bradykinin-/nitric oxide-cGMP-dependent angiogenesis
(FEBS Press, 2024-09) Majumder, Syamantak
Over the past few decades, VEGF-targeted antiangiogenic therapy for cancers has gained increasing attention. Nevertheless, there are still several limitations such as the potential resistance mechanisms arising in cancer cells against these therapies and their potential adverse effects. These limitations highlight the need for novel anti-angiogenesis molecules and better understanding of the mechanisms of tumor angiogenesis. In the present study, we investigated the antiangiogenic properties of a novel 14-mer antiangiogenic peptide (14-MAP) derived from N-terminal 14 kDa buffalo prolactin and characterized its mode of action. 14-MAP at the picomolar concentration inhibited VEGF- and bradykinin (an autacoid peptide expressed in vascular tissues in pathophysiology, BK)-stimulated endothelial nitric oxide (eNO) production, cell migration, and proliferation in endothelial cells and vessel development in the chick embryo. Although this peptide inhibited both VEGF- and BK-dependent angiogenic processes, its action was more pronounced in the latter. Moreover, the interference of 14-MAP with the eNO synthase (eNOS)-cyclic GMP pathway was also identified. A combination of a low dose of Avastin, a widely used drug targeting VEGF-dependent angiogenesis, and 14-MAP significantly reduced tumor size in an in vivo model of human colon cancer. Taken together, our results suggest that 14-MAP, a BK- and eNOS-dependent antiangiogenic peptide, might be useful for overcoming the limitation of VEGF-targeted antiangiogenic therapy in cancer patients. However, further studies will be required to further characterize its mode of action and therapeutic potential.
Activated pericyte attenuates endothelial functions: nitric oxide – cGMP rescues activated pericyte-associated endothelial dysfunctions
(CSP, 2007-11-23) Majumder, Syamantak
Hepatic stellate cells are liver-specific pericytes and exist in close proximity with endothelial cells. The activation of liver pericytes is intrinsic to liver pathogenesis, and leads to endothelial dysfunction, including the low bioavailability of nitric oxide (NO). However, the role of nitric oxide in pericyte–endothelium cross-talk has not yet been elucidated. This work examines the cellular mechanism of action of NO in pericyte-mediated endothelial dysfunction. We used in vitro coculture and conditioned medium systems to study the effects of activated liver pericytes on endothelial function, and an egg yolk vascular bed model was used to study the effects of activated pericytes on angiogenesis. This study also demonstrates that activated pericytes attenuate the migration, proliferation, permeability, and NO production of endothelial cells. Our results demonstrate that activated pericytes restrict angiogenesis in egg yolk vascular bed models, and NO supplementation recovers 70% of the inhibition. Our results also demonstrate that supplementation with NO, sildenafil citrate (phosphodiesterase inhibitor), and 8-bromo-cGMP (cGMP analog) partially recovers activated-pericyte-mediated endothelium dysfunction. We conclude that NO–cGMP alleviates activated-pericyte-associated endothelial dysfunction, including angiogenesis, in a cGMP-dependent
Angular difference in human coronary artery governs endothelial cell structure and function
(Springer, 2022-10) Majumder, Syamantak; Kuncharam, Bhanu Vardhan Reddy
Blood vessel branch points exhibiting oscillatory/turbulent flow and lower wall shear stress (WSS) are the primary sites of atherosclerosis development. Vascular endothelial functions are essentially dependent on these tangible biomechanical forces including WSS. Herein, we explored the influence of blood vessel bifurcation angles on hemodynamic alterations and associated changes in endothelial function. We generated computer-aided design of a branched human coronary artery followed by 3D printing such designs with different bifurcation angles. Through computational fluid dynamics analysis, we observed that a larger branching angle generated more complex turbulent/oscillatory hemodynamics to impart minimum WSS at branching points. Through the detection of biochemical markers, we recorded significant alteration in eNOS, ICAM1, and monocyte attachment in EC grown in microchannel having 60o vessel branching angle which correlated with the lower WSS. The present study highlights the importance of blood vessel branching angle as one of the crucial determining factors in governing atherogenic-endothelial dysfunction.
Cadmium attenuates bradykinin-driven nitric oxide production by interplaying with the localization pattern of endothelial nitric oxide synthase
(CSP, 2009-06-17) Majumder, Syamantak
Cadmium, a ubiquitous heavy metal, interferes with endothelial functions and angiogenesis. Bradykinin is a Ca-mobilizing soluble peptide that acts via nitric oxide to promote vasodilation and capillary permeability. The objective of the present study was to explore the Cd implications in bradykinin-dependent endothelial functions. An egg yolk angiogenesis model was employed to evaluate the effect of Cd on bradykinin-induced angiogenesis. The results demonstrate that 100 nmol/L Cd attenuated bradykinin-dependent angiogenesis. The results of the in vitro wound healing and tube formation assays by using EAhy 926, a transformed endothelial cell line, suggest that Cd blocked bradykinin-mediated endothelial migration and tube formation by 38% and 67%, respectively, while nitric oxide supplementation could reverse the effect of Cd on bradykinin-induced endothelial migration by 94%. The detection of nitric oxide by using a DAF-2DA fluorescent probe, Griess assay, and ultrasensitive electrode suggests that Cd blocked bradykinin-induced nitric oxide production. Fluorescence imaging of eNOS-GFP transfected endothelial cells, immunofluroscence, and Western blot studies of Cd and bradykinin-treated cells show that Cd interfered with the localization pattern of eNOS, which possibly attenuates nitric oxide production in part. Additionally, Ca imaging of Cd- and bradykinin-treated cells suggests that Cd blocked bradykinin-dependent Ca influx into the cells, thus partially blocking Ca-dependent nitric oxide production in endothelial cells. The results of this study conclude that Cd blunted the effect of bradykinin by interfering with the Ca-associated NOS activity specifically by impeding subcellular trafficking of eNOS.
Characterization of a pro-angiogenic, novel peptide from Russell's viper (Daboia russelii russelii) venom
(Elsiever, 2014-01) Majumder, Syamantak
Present report shows for the first time on the induction of in vitro angiogenesis by a 3.9 kDa novel peptide (RVVAP) purified from Russell's viper venom. Secondary structure of RVVAP is made up of 36.8% α-helix, 33.3% β pleated sheets and 29.9% turns. Optimum angiogenesis and significant elevation in endothelial migration were observed at 50 ng/ml of RVVAP treatment; above this concentration, progressive decrease in wound healing was noted. RVVAP (1.0 μg/ml) was non-cytotoxic to U87-MG, HeLa and HT-29 cells; however, increasing the RVVAP concentration above 500 ng/ml resulted in induction of chromosomal aberrations and delay in cell cycle kinetics of Chinese hamster ovary cells.
Chick Embryo Partial Ischemia Model: A New Approach to Study Ischemia Ex Vivo
(Plos One, 2010-05-07) Majumder, Syamantak
Ischemia is a pathophysiological condition due to blockade in blood supply to a specific tissue thus damaging the physiological activity of the tissue. Different in vivo models are presently available to study ischemia in heart and other tissues. However, no ex vivo ischemia model has been available to date for routine ischemia research and for faster screening of anti-ischemia drugs. In the present study, we took the opportunity to develop an ex vivo model of partial ischemia using the vascular bed of 4th day incubated chick embryo.
Chloroquine attenuates hypoxia-mediated autophagy to curb thrombosis- an ex vivo and in vivo study
(2024-04) Mukherjee, Sudeshna; Majumder, Syamantak; Chowdhury, Shibasish; Chowdhury, Rajdeep
Hypoxia can trigger the activation of blood platelets, leading to thrombosis. If not addressed clinically, it can cause severe complications and fatal consequences as well. The current treatment regime for thrombosis is often palliative and includes long-term administration of anticoagulants, which has the risk of over-bleeding in injury and other secondary effects as well. This demands a deeper understanding of the process and exploration of an alternative therapeutic avenue. Interestingly, recent studies demonstrate that platelets though atypical and enucleated, possess components of autophagy machinery. This cellular homeostatic process though well-studied in non-platelet cells, is under-explored in platelets.
Common and Unique microRNAs in Multiple Carcinomas Regulate Similar Network of Pathways to Mediate Cancer Progression
(Springer Nature, 2020) Chowdhury, Rajdeep; Chowdhury, Shibasish; Majumder, Syamantak; Majumder, Syamantak
Cancer is a complex disease with a fatal outcome. Early detection of cancer, by monitoring appropriate molecular markers is very important for its therapeutic management. In this regard, the short non-coding RNA molecules, microRNAs (miRNAs) have shown great promise due to their availability in circulating fluids facilitating non-invasive detection of cancer. In this study, an in silico comparative analysis was performed to identify specific signature miRNAs dysregulated across multiple carcinomas and simultaneously identify unique miRNAs for each cancer type as well. The miRNA-seq data of cancer patient was obtained from GDC portal and their differential expressions along with the pathways regulated by both common and unique miRNAs were analyzed. Our studies show twelve miRNAs commonly dysregulated across seven different cancer types. Interestingly, four of those miRNAs (hsa-mir-210, hsa-mir-19a, hsa-mir-7 and hsa-mir-3662) are already reported as circulatory miRNAs (circRNAs); while, the miR-183 cluster along with hsa-mir-93 have been found to be incorporated in exosomes signifying the importance of the identified miRNAs for their use as prospective, non-invasive biomarkers. Further, the target mRNAs and pathways regulated by both common and unique miRNAs were analyzed, which interestingly had significant commonality. This suggests that miRNAs that are commonly de-regulated and specifically altered in multiple cancers might regulate similar pathways to promote cancer. Our data is of significance because we not only identify a set of common and unique miRNAs for multiple cancers but also highlight the pathways regulated by them, which might facilitate the development of future non-invasive biomarkers conducive for early detection of cancers.
A comparative study of NONOate based NO donors: Spermine NONOate is the best suited NO donor for angiogenesis
(Elsiever, 2014-01-30) Majumder, Syamantak
Nitric oxide (NO) is a known modulator of angiogenesis. The NONOate subfamily of NO donors has long been used in experimental and clinical studies to promote angiogenesis. However, no studies have been conducted yet to compare the angiogenesis potential of these NO donors in respect to their pattern of NO release. We hypothesize that having different pattern of NO release, each of the NO donors in NONOate subfamily can promote key stages of angiogenesis in differential manner. To verify our hypothesis, NO donors with half life ranging from seconds to several hours and having very different pattern of NO release were selected to evaluate their efficacy in modulating angiogenesis. Endothelial tube formation using EAhy926 cells was maximally increased by Spermine NONOate (SP) treatment. SP treatment maximally induced both ex vivo and in vivo angiogenesis using egg yolk and cotton plug angiogenesis models respectively. Experiment using chick embryo partial ischemia model revealed SP as the best suited NO donor to recover ischemia driven hampered angiogenesis. The present study elaborated that differential release pattern of NO by different NO donors can modulate angiogenesis differentially and also suggested that SP have a unique pattern of NO release that best fits for angiogenesis.
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.
Dapagliflozin in focal segmental glomerulosclerosis: a combined human-rodent pilot study
(American Physiological Society, 2017-11-15) Majumder, Syamantak
Focal segmental glomerulosclerosis (FSGS) is characterized by proteinuria and renal function decline, leading to chronic kidney disease (CKD) and end-stage renal disease (ESRD; Ref. 15). Approximately 55% of patients with idiopathic FSGS with high-grade proteinuria will proceed to ESRD at 10 yr following diagnosis (40). The FSGS lesion can also develop as the end result of a spectrum of sources of glomerular injury, obesity, and reduced nephron mass. Despite current therapies including renin-angiotensin-aldosterone system (RAAS) inhibitors, antihypertensives, and immunosuppressants, clinical outcomes remain suboptimal.
Developing an Ex Vivo Model of Ischemia Using Early Chick-Embryo: A Model to Study Ischemia Related Angiogenesis
(Springer, 2012-06-19) Majumder, Syamantak
Ischemia created in the animals were long been used as a model to study ischemia mediated effects in vivo. Pathological angiogenesis is the key hallmark of various ischemic diseases where blood vessel formation was compromised due to low blood flow. New blood vessels form in order to compensate the low blood perfusion in the ischemic area. This neovascularization and remodeling of the existent vessels protect from the consequences of ischemia associated diseases like myocardial infarction and stroke. A better understanding of the mechanisms of functional vessel formation is a pre-requisite to improve the treatment of ischemic pathologies. Therefore, the research area warrants an easily accessible model in which vessel formation can be both manipulated and studied. However, a limited number of efforts have been put forward yet to develop an ischemia models where ischemia mediated remodeling of vessels can be studied in real time. In present study, we used 4 day grown chick embryo to ligate right vitelline artery and create partial ischemia in the vascular bed of the embryo. The model has been developed based on the principle that blocking blood flow in the vascular bed will stop the nutrient and oxygen supply to the adjacent vessels and thus creating an ischemia like condition. Additionally, ischemia related changes in angiogenesis can be followed and tracked in real time in the vascular bed of the chick embryo. The present ex vivo model can be utilized in studying ischemia related angiogenesis in specific and hypoxia and/or low oxygen mediated angiogenesis in general.
Development and evaluation of a simvastatin-loaded biopolymeric scaffold for improved angiogenesis and healing of diabetic wounds
(Elsevier, 2023-09) Roy, Aniruddha; Majumder, Syamantak
In diabetic wounds, lack of angiogenesis limits the supply of oxygen and nutrients at the wound site, resulting in poor healing. A well-known lipid-lowering drug, simvastatin (SIM), exhibited pleiotropic effects in wound healing, including promotion of angiogenesis. However, its clinical application is limited due to its poor physicochemical properties, including low solubility. In this study, a Soluplus and TPGS-based mixed micelle was developed for loading SIM in an in-situ forming chitosan-chondroitin sulfate-based poly-electrolyte complex hydrogel (CH-CS PEC). The hypothesis was that CH-CS PEC would improve overall wound healing due to the favorable viscoelasticity and porosity, whereas SIM would assist neoangiogenesis. SIM-loaded CH-CS PEC exhibited good mechanical stability and viscoelastic properties and demonstrated prolonged release of SIM. The formulation promoted endothelial cell sprouting in an ex-vivo rat aortic ring assay. Applying SIM-loaded CH-CS PEC in a diabetes-induced rat wound model resulted in faster wound closure, increased collagen deposition, and enhanced neovascularization with up-regulation of vascular endothelial growth factor (VEGF) expression. In summary, we have developed a drug-loaded, in-situ forming scaffold that can be directly applied at the wound site and can improve wound healing by promoting angiogenesis and collagen deposition at the wound site. This study demonstrated the combined efficacy of a viscoelastic scaffold and a proangiogenic drug for enhanced wound healing. The easy and simple fabrication method of the drug-loaded scaffold makes it suitable for clinical translation.
The Dipeptidyl Peptidase 4 Substrate CXCL12 Has Opposing Cardiac Effects in Young Mice and Aged Diabetic Mice Mediated by Ca 2+ Flux and Phosphoinositide 3-Kinase γ
(ADA, 2018) Majumder, Syamantak
Blood glucose-lowering therapies can positively or negatively affect heart function in type 2 diabetes, or they can have neutral effects. Dipeptidyl peptidase 4 (DPP-4) inhibitors lower blood glucose by preventing the proteolytic inactivation of glucagon-like peptide 1 (GLP-1). However, GLP-1 is not the only peptide substrate of DPP-4. Here, we investigated the GLP-1-independent cardiac effects of DPP-4 substrates. Pointing to GLP-1 receptor (GLP-1R)-independent actions, DPP-4 inhibition prevented systolic dysfunction equally in pressure-overloaded wild-type and GLP-1R knockout mice. Likewise, DPP-4 inhibition or the DPP-4 substrates substance P or C-X-C motif chemokine ligand 12 (CXCL12) improved contractile recovery after no-flow ischemia in the hearts of otherwise healthy young adult mice. Either DPP-4 inhibition or CXCL12 increased phosphorylation of the Ca2+ regulatory protein phospholamban (PLN), and CXCL12 directly enhanced cardiomyocyte Ca2+ flux. In contrast, hearts of aged obese diabetic mice (which may better mimic the comorbid patient population) had diminished levels of PLN phosphorylation. In this setting, CXCL12 paradoxically impaired cardiac contractility in a phosphoinositide 3-kinase γ-dependent manner. These findings indicate that the cardiac effects of DPP-4 inhibition primarily occur through GLP-1R-independent processes and that ostensibly beneficial DPP-4 substrates can paradoxically worsen heart function in the presence of comorbid diabetes.
Dose dependent effects of cadmium on tumor angiogenesis
(Oncotargot, 2017) Majumder, Syamantak
Angiogenesis is crucial for tumor growth and metastasis. Cadmium (Cd) exposure is associated with elevated cancer risk and mortality. Such association is, at least in part, attributable to Cd-induced tumor angiogenesis. Nevertheless, the reported effects of Cd on tumor angiogenesis appear to be either stimulatory or inhibitory, depending on the concentrations. Ultra-low concentrations of Cd (<0.5 μM) inhibit endothelial nitric oxide synthase activation, leading to reduced endothelial nitric oxide production and attenuated tumor angiogenesis. In contrast, low-lose Cd (1-10 μM) up-regulates vascular endothelial growth factor (VEGF)-mediated tumor angiogenesis by exerting sub-apoptotic levels of oxidative stress on both tumor cells and endothelial cells (ECs). The consequent activation of protein kinase B/Akt, nuclear factor-κB, and mitogen-activated protein kinase signaling cascades mediate the increased secretion of VEGF by tumor cells and the up-regulated VEGF receptor-2 expression in ECs. Furthermore, Cd in high concentrations (>10 μM) induces EC apoptosis via the activation of caspase-3, resulting in destruction of tumor vasculature. In this review, we summarize the current knowledge concerning the roles of Cd in tumor angiogenesis, with a focus on molecular mechanisms underlying the dose dependent effects of Cd on various EC phenotypes
Drug Tolerant Cells: An Emerging Target With Unique Transcriptomic Features
(Sage, 2019) Chowdhury, Rajdeep; Majumder, Syamantak; Chowdhury, Shibasish
Long-term outcome of cancer therapy is often severely perturbed by the acquisition of drug resistance. Recent evidence point toward the survival of a subpopulation of tumor cells under acute drug stress that over time can re-populate the tumor. These transiently existing, weakly proliferative, drug-tolerant cells facilitate tumor cell survival until more stable resistance mechanisms are acquired. From a therapeutic perspective, understanding the molecular features of the tolerant cells is critical to attenuation of resistance. In this article, we discuss the transcriptomic features of drug-tolerant osteosarcoma cells that survive a high dose of cisplatin shock. We present the unique transcriptome of the minimally dividing tolerant cells in comparison with the proliferative persisters or resistant cells derived from the tolerant cells. Targeting the tolerant cells can represent an efficient therapeutic strategy impeding tumor recurrence.
Dynamic alterations of H3K4me3 and H3K27me3 at ADAM17 and Jagged-1 gene promoters cause an inflammatory switch of endothelial cells
(Wiley, 2021-09-14) Chowdhury, Shibasish; Majumder, Syamantak; Kuncharam, Bhanu Vardhan Reddy
Histone protein modifications control the inflammatory state of many immune cells. However, how dynamic alteration in histone methylation causes endothelial inflammation and apoptosis is not clearly understood. To examine this, we explored two contrasting histone methylations; an activating histone H3 lysine 4 trimethy- lation (H3K4me3) and a repressive histone H3 lysine 27 trimethylation (H3K27me3) in endothelial cells (EC) undergoing inflammation. Through computeraided reconstruction and 3D printing of the human coronary artery, we developed a unique model where EC were exposed to a pattern of oscillatory/disturbed flow as similar to in vivo conditions. Upon induction of endothelial inflammation, we detected a significant rise in H3K4me3 caused by an increase in the expression of SET1/ COMPASS family of H3K4 methyltransferases, including MLL1, MLL2, and SET1B. In contrast, EC undergoing inflammation exhibited truncated H3K27me3 level engendered by EZH2 cytosolic translocation through threonine 367 phosphorylation and an increase in the expression of histone demethylating enzyme JMJD3 and UTX. Additionally, many SET1/COMPASS family of proteins, including MLL1 (C), MLL2, and WDR5, were associated with either UTX or JMJD3 or both and such association was elevated in EC upon exposure to inflammatory stimuli. Dynamic enrichment of H3K4me3 and loss of H3K27me3 at Notchassociated gene promoters caused ADAM17 and Jagged1 derepression and abrupt Notch activation. Conversely, either reducing H3K4me3 or increasing H3K27me3 in EC undergoing inflammation atte- nuated Notch activation, endothelial inflammation, and apoptosis. Together, these findings indicate that dynamic chromatin modifications may cause an inflammatory and apoptotic switch of EC and that epigenetic reprogramming can potentially im- prove outcomes in endothelial inflammationassociated cardiovascular diseases.
Dysregulated expression but redundant function of the long non-coding RNA HOTAIR in diabetic kidney disease
(Springer, 2019-08-09) Chowdhury, Shibasish; Majumder, Syamantak
Long non-coding RNAs (lncRNAs) are garnering increasing attention for their putative roles in the pathogenesis of chronic diseases, including diabetic kidney disease (DKD). However, much about in vivo lncRNA functionality in the adult organism remains unclear. To better understand lncRNA regulation and function in DKD, we explored the effects of the modular scaffold lncRNA HOTAIR (HOX antisense intergenic RNA), which approximates chromatin modifying complexes to their target sites on the genome. Methods Experiments were performed in human kidney tissue, in mice with streptozotocin-induced diabetes, the db/db mouse model of type 2 diabetes, podocyte-specific Hotair knockout mice and conditionally immortalised mouse podocytes. Results HOTAIR was observed to be expressed by several kidney cell-types, including glomerular podocytes, in both human and mouse kidneys.However, knockout ofHotair frompodocytes had almost no effect on kidney structure, function or ultrastructure. Glomerular HOTAIR expression was found to be increased in human DKD, in the kidneys of mice with streptozotocin-induced diabetes and in the kidneys of db/db mice. Likewise, exposure of cultured mouse podocytes to high glucose caused upregulation of Hotair expression, which occurred in a p65-dependent manner. Although HOTAIR expression was upregulated in DKD and in high glucose-exposed podocytes, its knockout did not alter the development of kidney damage in diabetic mice. Rather, in a bioinformatic analysis of human kidney tissue, HOTAIR expression closely paralleled the expression of its genic neighbour, HOXC11, which is important to developmental patterning but which has an uncertain role in the adult kidney . Conclusions/interpretation Many lncRNAs have been found to bind to the same chromatin modifying complexes. Thus, there is likely to exist sufficient redundancy in the system that the biological effects of dysregulated lncRNAs in kidney disease may often be inconsequential. The example of the archetypal scaffold lncRNA, HOTAIR, illustrates how lncRNA dysregulation may be a bystander in DKD without necessarily contributing to the pathogenesis of the condition. In the absence of in vivo validation, caution should be taken before ascribing major functional roles to single lncRNAs in the pathogenesis of chronic diseases.
The emerging insight into E3 ligases as the potential therapeutic target for diabetic kidney disease
(Elsevier, 2023-05) Majumder, Syamantak; Gaikwad, Anil Bhanudas
Diabetic kidney disease (DKD) is a major diabetic complication and global health concern, occurring in nearly 30 % to 40 % of people with diabetes. Importantly, several therapeutic strategies are being used against DKD; however, available treatments are not uniformly effective and the continuous rise in the prevalence of DKD demands more potential therapeutic approaches or targets. Epigenetic modifiers are regarded for their potential therapeutic effects against DKD. E3 ligases are such epigenetic modifier that regulates the target gene expression by attaching ubiquitin to the histone protein. In recent years, the E3 ligases came up as a potential therapeutic target as it selectively attaches ubiquitin to the substrate proteins in the ubiquitination cascade and modulates cellular homeostasis. The E3 ligases are also actively involved in DKD by regulating the expression of several proteins involved in the proinflammatory and profibrotic pathways. Burgeoning reports suggest that several E3 ligases such as TRIM18 (tripartite motif 18), Smurf1 (Smad ubiquitination regulatory factor 1), and NEDD4-2 (neural precursor cell-expressed developmentally downregulated gene 4-2) are involved in kidney epithelial–mesenchymal transition, inflammation, and fibrosis by regulating respective signaling pathways. However, the various signaling pathways that are regulated by different E3 ligases in the progression of DKD are poorly understood. In this review, we have discussed E3 ligases as potential therapeutic target for DKD. Moreover, different signaling pathways regulated by E3 ligases in the progression of DKD have also been discussed.
EP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease
(Nature, 2017-06-13) Majumder, Syamantak
The therapeutic targeting of prostanoid subtype receptors may slow the development of chronic kidney disease (CKD) through mechanisms that are distinct from those of upstream COX inhibition. Here, employing multiple experimental models of CKD, we studied the effects of inhibition of the EP4 receptor, one of four receptor subtypes for the prostanoid prostaglandin E2. In streptozotocin-diabetic endothelial nitric oxide synthase knockout mice, EP4 inhibition attenuated the development of albuminuria, whereas the COX inhibitor indomethacin did not. In Type 2 diabetic db/db mice, EP4 inhibition lowered albuminuria to a level comparable with that of the ACE inhibitor captopril. However, unlike captopril, EP4 inhibition had no effect on blood pressure or hyperfiltration although it did attenuate mesangial matrix accumulation. Indicating a glucose-independent mechanism of action, EP4 inhibition also attenuated proteinuria development and glomerular scarring in non-diabetic rats subjected to surgical renal mass ablation. Finally, in vitro, EP4 inhibition prevented transforming growth factor-ß1 induced dedifferentiation of glomerular podocytes. In rodent models of diabetic and non-diabetic CKD, EP4 inhibition attenuated renal injury through mechanisms that were distinct from either broadspectrum COX inhibition or “standard of care” renin angiotensin system blockade. EP4 inhibition may represent a viable repurposing opportunity for the treatment of CKD.