Honors & Awards
Excellence In Research Publication, CSIR-Central Drug Research Institute, Lucknow, India (2020)
Senior Research Fellowship, Indian Council of Medical Research, New Delhi, India (2016)
Best Poster presentation award, NIMS University (2010)
Bachelors of Pharmacy, IK Gujral Punjab Technical University, Punjab, India, Pharmacy (2009)
Masters in Pharmacy, NIMS University, Jaipur, India, Pharmacology (2011)
Ph.D, AcSIR, New Delhi, India, Cardiovascular Pharmacology (2020)
Joseph Wu, Postdoctoral Faculty Sponsor
Generation of two induced pluripotent stem cell lines carrying the phospholamban R14del mutation for modeling ARVD/C.
Stem cell research
2022; 63: 102834
The phospholamban (PLN) R14del mutation is associated with arrhythmogenic right ventricular dysplasia (ARVD/C). ARVD/C is a cardiac disease characterized by arrhythmias and structural abnormalities in the right ventricle. Because PLN is a regulator of calcium release, this mutation can have deleterious effects on tissue integrity and contraction. This mutation is a trinucleotide (AGA) deletion that leads to an arginine deletion at position 14 of the PLN structure. Here we show two lines carrying this mutation with typical iPSC morphology, pluripotency, karyotype, ability to differentiate into the three germ layers in vitro, and readily availability for studying pathological mechanisms or ARVD/C.
View details for DOI 10.1016/j.scr.2022.102834
View details for PubMedID 35700631
Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation.
Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana, binds to cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis was an risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells were used to model Δ9-THC-induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference, and genistein attenuated the effects of Δ9-THC. In mice, genistein blocked Δ9-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. Genistein is a CB1 antagonist that attenuates Δ9-THC-induced atherosclerosis.
View details for DOI 10.1016/j.cell.2022.04.005
View details for PubMedID 35489334
Engineered Nanoparticle-Protein Interactions Influence Protein Structural Integrity and Biological Significance.
Nanomaterials (Basel, Switzerland)
2022; 12 (7)
Engineered nanoparticles (ENPs) are artificially synthesized particles with unique physicochemical properties. ENPs are being extensively used in several consumer items, elevating the probability of ENP exposure to biological systems. ENPs interact with various biomolecules like lipids, proteins, nucleic acids, where proteins are most susceptible. The ENP-protein interactions are mostly studied for corona formation and its effect on the bio-reactivity of ENPs, however, an in-depth understanding of subsequent interactive effects on proteins, such as alterations in their structure, conformation, free energy, and folding is still required. The present review focuses on ENP-protein interactions and the subsequent effects on protein structure and function followed by the therapeutic potential of ENPs for protein misfolding diseases.
View details for DOI 10.3390/nano12071214
View details for PubMedID 35407332
View details for PubMedCentralID PMC9002493
Generation of two iPSC lines from hypertrophic cardiomyopathy patients carrying MYBPC3 and PRKAG2 variants.
Stem cell research
2022; 61: 102774
Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder characterized by a thick left ventricular wall and an increased risk of arrhythmias, heart failure, and sudden cardiac death. The MYBPC3 and PRAKG2 are known causal genes for HCM. Here we generated two human-induced pluripotent stem cell lines from two HCM patients carrying two heterozygous mutations in MYBPC3 (c.459delC) and PRKAG2 (c.1703C > T). Both iPSC lines expressed pluripotent markers, had a normal karyotype, and were able to differentiate into three germ layers, making them potentially valuable tools for modeling HCM in vitro and investigating the pathological mechanisms related to these two variants.
View details for DOI 10.1016/j.scr.2022.102774
View details for PubMedID 35413566
Xylocarpus moluccensis Fruit Fraction Rescues Cardiac Hypertrophy by Improving Angiogenesis and Regulating NF-κB-Mediated Inflammation
Xylocarpus moluccensis Fruit Fraction Rescues Cardiac Hypertrophy by Improving Angiogenesis and Regulating NF-κB-Mediated Inflammation
2022; 18 (78): 286-295
View details for DOI 10.4103/pm.pm_79_21
Injectable hydrogel for co-delivery of 5-azacytidine in zein protein nanoparticles with stem cells for cardiac function restoration.
International journal of pharmaceutics
2021; 603: 120673
Heart failure is major cause of mortality associated with mostly Myocardial infarction (MI). Transplanting mesenchymal stem cells (MSC) have exhibited potential role in myocardial regeneration. Secretion of immune-modulatory cytokines and various growth factors after transplantation plays significant role in remodelling process of MI region. However, low retention, higher shear stress during administration and rejection at host infarct environment hinders therapeutic efficacy. Myocardial regeneration demands for accurate spatio-temporal delivery of MSCs with supportive vascular network that leads to improvement of cardiac function. In this study, injectable alginate based microporous hydrogel has been used to deliver 5-Azacytidine (5-Aza) in zein protein nanoparticle with MSCs for attenuating adverse cardiac remodelling after MI. Zein nanoparticles loaded with 5-Aza were prepared by liquid-liquid dispersion, and it was found that 35% of drug was released in 7 days supported with mathematical modelling. The presence of 5-Aza and zein in developed hydrogel supported in vitro MSC proliferation, migration and angiogenesis. Significant increased expression of cardiac specific markers, GATA4, MEF2C, MLC, SERCA and NKX2.5 was observed in vitro. 5-Aza loaded protein nanoparticle with MSCs encapsulated hydrogels in rat MI model also exhibited substantial improvement of functional cardiac parameters such as cardiac output and ejection fraction. Histopathological analysis showed reduced fibrosis, attenuated infarct expansion and cardiac tissue restoration and angiogenesis. In brief, we developed nanocarrier-hydrogel system a promising strategy for co-delivering 5-Aza as cardiac differentiation cue with MSCs to achieve higher cell retention and enhanced improvement in myocardial regeneration after MI.
View details for DOI 10.1016/j.ijpharm.2021.120673
View details for PubMedID 33964338
Proinflammatory Effect of Endothelial Microparticles Is Mitochondria Mediated and Modulated Through MAPKAPK2 (MAPK-Activated Protein Kinase 2) Leading to Attenuation of Cardiac Hypertrophy.
Arteriosclerosis, thrombosis, and vascular biology
2019; 39 (6): 1100-1112
Objective- This study investigates the functional significance of mitochondria present in endothelial microparticles (EMP) and how MK2 (MAPKAPK2 [MAPK-activated protein kinase 2]) governs EMP production and its physiological effect on cardiac hypertrophy. Approach and Results- Flow cytometric analysis, confocal imaging, oxygen consumption rate measurement through Seahorse were used to confirm the presence of functionally active mitochondria in nontreated EMP (EMP derived from untreated control cells), lipopolysaccharide, and oligomycin treatment increased mitochondrial reactive oxygen species activity in EMP (EMP derived from cells treated with lipopolysaccharide and EMP derived from cells treated with oligomycin, respectively). The dysfunctional mitochondria contained in EMP derived from cells treated with lipopolysaccharide and EMP derived from cells treated with oligomycin induced the expression of proinflammatory mediators in the target endothelial cells leading to the augmented adhesion of human monocytic cell line on EA.hy926 cells. Multiphoton real-time imaging detected the increased adherence of EMP derived from cells treated with oligomycin at the site of carotid artery injury as compared to EMP derived from untreated control cells. MK2 regulates EMP generation during inflammation by reducing E-selectin expression and regulating the cytoskeleton rearrangement through ROCK-2 (Rho-associated coiled-coil containing protein kinase 2) pathway. MK2-deficient EMP reduced the E-selectin and ICAM-1 (intracellular adhesion molecule-1) expression on target endothelial cells leading to reduced monocyte attachment and reduced cardiac hypertrophy in mice. Conclusions- MK2 promotes the proinflammatory effect of EMP mediated through dysfunctional mitochondria. MK2 modulates the inflammatory effect induced during cardiac hypertrophy through EMP.
View details for DOI 10.1161/ATVBAHA.119.312533
View details for PubMedID 31070456
Inhibition of fatty acid synthase is protective in pulmonary hypertension.
British journal of pharmacology
2016; 173 (12): 2030-45
In pulmonary hypertension (PH), similar to cancer, there is altered energy metabolism, apoptosis resistance and cellular proliferation leading to pulmonary vascular remodelling. Proliferating cells exhibit higher rate of de novo fatty acid synthesis to provide lipids for membrane formation and energy production. As inhibition of de novo fatty acid synthesis proved protective in cancer experimentally, therefore, it was hypothesized that modulation of de novo fatty acid synthesis by inhibition of fatty acid synthase (FAS) may prove beneficial for PH.For in vitro studies, human pulmonary artery smooth muscle cells (HPASMCs) were exposed to hypoxia and to induce PH in vivo, rats were treated with monocrotaline (MCT). FAS was inhibited by siRNA (60 nM) and C75 (2 mg·kg(-1) , i.p. once a week for 5 weeks) in in vitro and in vivo studies respectively.Increased expression and activity of FAS were observed in hypoxic HPASMCs and lungs of MCT-treated rats. Inhibition of FAS increased apoptosis and glucose oxidation, but decreased proliferation and markers of autophagy, glycolysis and insulin resistance in hypoxic HPASMCs. It also improved the mitochondrial functions as evident by increased level of ATP and restoration of normal level of ROS and membrane potential of mitochondria. In MCT-treated rats, FAS inhibition decreased right ventricular pressure, hypertrophy, pulmonary vascular remodelling (increased apoptosis and decreased proliferation of cells) and endothelial dysfunction in lungs.Our results demonstrate that FAS activity is modulated in PH, and its inhibition may provide a new therapeutic approach to treat PH.
View details for DOI 10.1111/bph.13495
View details for PubMedID 27061087
View details for PubMedCentralID PMC4882492
- Non-carbonyl Curcuma longa [NCCL] protects the heart from myocardial ischemia/reperfusion injury by reducing endothelial microparticle mediated inflammation in rats RSC ADVANCES 2016; 6 (60): 54938-54948
Curcuma oil reduces endothelial cell-mediated inflammation in postmyocardial ischemia/reperfusion in rats.
Journal of cardiovascular pharmacology
2014; 64 (3): 228-36
Endothelial cells initiated inflammation persisting in postmyocardial infarction needs to be controlled and moderated for avoiding fatal complications. Curcuma oil (C.oil, Herbal Medicament), a standardized hexane soluble fraction of Curcuma longa has possessed neuroprotective effect. However, its effect on myocardial ischemia/reperfusion (MI/RP) and endothelial cells remains incompletely defined. Here, using in vivo rat MI/RP injury model and in vitro cellular approaches using EA.hy926 endothelial cells, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and myograph, we provide evidence that with effective regimen and preconditioning of rats with C.oil (250 mg/kg, PO), before and after MI/RP surgery protects rats from MI/RP-induced injury. C.oil treatment reduces left ventricular ischemic area and endothelial cell-induced inflammation, specifically in the ischemic region (*P < 0.0001) and improved endothelial function by reducing the expression of proinflammatory genes and adhesion factors on endothelial cells both in vitro and in vivo. Furthermore, mechanistic studies have revealed that C.oil reduced the expression of adhesion factors like E-selectin (#P = 0.0016) and ICAM-1 ($P = 0.0069) in initiating endothelial cells-induced inflammation. In line to the real-time polymerase chain reaction expression data, C.oil reduced the adhesion of inflammatory cells to endothelial cells as assessed by the interaction of THP-1 monocytes with the endothelial cells using flow-based adhesion and under inflammatory conditions. These studies provide evidence that salutary effect of C.oil on MI/RP could be achieved with pretreatment and posttreatment of rats, C.oil reduced MI/RP-induced injury by reducing the endothelial cell-mediated inflammation, specifically in the ischemic zone of MI/RP rat heart.
View details for DOI 10.1097/FJC.0000000000000110
View details for PubMedID 24853488
Synthetic FXR agonist GW4064 is a modulator of multiple G protein-coupled receptors.
Molecular endocrinology (Baltimore, Md.)
2014; 28 (5): 659-73
The synthetic nuclear bile acid receptor (farnesoid X receptor [FXR]) agonist GW4064 is extensively used as a specific pharmacological tool to illustrate FXR functions. We noticed that GW4064 activated empty luciferase reporters in FXR-deficient HEK-293T cells. We postulated that this activity of GW4064 might be routed through as yet unknown cellular targets and undertook an unbiased exploratory approach to identify these targets. Investigations revealed that GW4064 activated cAMP and nuclear factor for activated T-cell response elements (CRE and NFAT-RE, respectively) present on these empty reporters. Whereas GW4064-induced NFAT-RE activation involved rapid intracellular Ca(2+) accumulation and NFAT nuclear translocation, CRE activation involved soluble adenylyl cyclase-dependent cAMP accumulation and Ca(2+)-calcineurin-dependent nuclear translocation of transducers of regulated CRE-binding protein 2. Use of dominant negative heterotrimeric G-protein minigenes revealed that GW4064 caused activation of Gαi/o and Gq/11 G proteins. Sequential pharmacological inhibitor-based screening and radioligand-binding studies revealed that GW4064 interacted with multiple G protein-coupled receptors. Functional studies demonstrated that GW4064 robustly activated H1 and H4 and inhibited H2 histamine receptor signaling events. We also found that MCF-7 breast cancer cells, reported to undergo GW4064-induced apoptosis in an FXR-dependent manner, did not express FXR, and the GW4064-mediated apoptosis, also apparent in HEK-293T cells, could be blocked by selective histamine receptor regulators. Taken together, our results demonstrate identification of histamine receptors as alternate targets for GW4064, which not only necessitates cautious interpretation of the biological functions attributed to FXR using GW4064 as a pharmacological tool but also provides a basis for the rational designing of new pharmacophores for histamine receptor modulation.
View details for DOI 10.1210/me.2013-1353
View details for PubMedID 24597548
View details for PubMedCentralID PMC5414852