Publications by authors named "Janish Kothari"

3 Publications

  • Page 1 of 1

Genetic Polymorphisms Complicate COVID-19 Therapy: Pivotal Role of HO-1 in Cytokine Storm.

Antioxidants (Basel) 2020 Jul 18;9(7). Epub 2020 Jul 18.

Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.

Coronaviruses are very large RNA viruses that originate in animal reservoirs and include severe acute respiratory distress syndrome (SARS) and Middle East respiratory syndrome (MERS) and other inconsequential coronaviruses from human reservoirs like the common cold. SARS-CoV-2, the virus that causes COVID-19 and is believed to originate from bat, quickly spread into a global pandemic. This RNA virus has a special affinity for porphyrins. It invades the cell at the angiotensin converting enzyme-2 (ACE-2) receptor and binds to hemoproteins, resulting in a severe systemic inflammatory response, particularly in high ACE-2 organs like the lungs, heart, and kidney, resulting in systemic disease. The inflammatory response manifested by increased cytokine levels and reactive oxygen species results in inhibition of heme oxygenase (HO-1), with a subsequent loss of cytoprotection. This has been seen in other viral illness like human immunodeficiency virus (HIV), Ebola, and SARS/MERS. There are a number of medications that have been tried with some showing early clinical promise. This illness disproportionately affects patients with obesity, a chronic inflammatory disease with a baseline excess of cytokines. The majority of the medications used in the treatment of COVID-19 are metabolized by cytochrome P450 (CYP) enzymes, primarily CYP2D6. This is further complicated by genetic polymorphisms of CYP2D6, HO-1, ACE, and ACE-2. There is a potential role for HO-1 upregulation to treat/prevent cytokine storm. Current therapy must focus on antivirals and heme oxygenase upregulation. Vaccine development will be the only magic bullet.
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http://dx.doi.org/10.3390/antiox9070636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402116PMC
July 2020

The Effects of Heme Oxygenase Upregulation on Obesity and the Metabolic Syndrome.

Antioxid Redox Signal 2020 05 22;32(14):1061-1070. Epub 2020 Jan 22.

New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York.

Obesity is a chronic condition that is characterized by inflammation and oxidative stress with consequent cardiovascular complications of hypertension, dyslipidemia, and vascular dysfunction. Obesity-induced metabolic syndrome remains an epidemic of global proportions. Gene targeting of the endothelium with a retrovirus using an endothelium-specific promoter vascular endothelium cadherin (VECAD)-HO-1 offers a potential long-term solution to adiposity by targeting the endothelium. This has resulted in improvements of both vascular function and adiposity attenuation. Heme oxygenase plays an ever-increasing role in the understanding of human biology in the complex conditions of obesity and the metabolic syndrome. The heme oxygenase 1 (HO-1) system creates biliverdin/bilirubin, which functions as an antioxidant, and carbon monoxide, which has antiapoptotic properties. Upregulation of HO-1 has been shown to improve adiposity as well as vascular function in both animal and human studies.
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http://dx.doi.org/10.1089/ars.2019.7954DOI Listing
May 2020

Anatomical and electrophysiological changes in striatal TH interneurons after loss of the nigrostriatal dopaminergic pathway.

Brain Struct Funct 2015 Jan 31;220(1):331-49. Epub 2013 Oct 31.

Center for Molecular and Behavioral Neuroscience, Aidekman Research Center, Rutgers University, 197 University Avenue, Newark, NJ, 07102, USA.

Using transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of the tyrosine hydroxylase (TH) promoter, we have previously shown that there are approximately 3,000 striatal EGFP-TH interneurons per hemisphere in mice. Here, we report that striatal TH-EGFP interneurons exhibit a small, transient but significant increase in number after unilateral destruction of the nigrostriatal dopaminergic pathway. The increase in cell number is accompanied by electrophysiological and morphological changes. The intrinsic electrophysiological properties of EGFP-TH interneurons ipsilateral to 6-OHDA lesion were similar to those originally reported in intact mice except for a significant reduction in the duration of a characteristic depolarization induced plateau potential. There was a significant change in the distribution of the four previously described electrophysiologically distinct subtypes of striatal TH interneurons. There was a concomitant increase in the frequency of both spontaneous excitatory and inhibitory post-synaptic currents, while their amplitudes did not change. Nigrostriatal lesions did not affect somatic size or dendritic length or branching, but resulted in an increase in the density of proximal dendritic spines and spine-like appendages in EGFP-TH interneurons. The changes indicate that electrophysiology properties and morphology of striatal EGFP-TH interneurons depend on endogenous levels of dopamine arising from the nigrostriatal pathway. Furthermore, these changes may serve to help compensate for the changes in activity of spiny projection neurons that occur following loss of the nigrostriatal innervation in experimental or in early idiopathic Parkinson's disease by increasing feedforward GABAergic inhibition exerted by these interneurons.
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http://dx.doi.org/10.1007/s00429-013-0658-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007381PMC
January 2015