Bio
Recieved his PhD in molecular biology from Shoolini University, India. He is trying to understand the implications of oxidative stress and circadian rhythms in IC/BPS and Nocturia repectively.
Stanford Advisors
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Amy Dobberfuhl, Postdoctoral Faculty Sponsor
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Amy Dobberfuhl, Postdoctoral Research Mentor
Contact
https://orcid.org/0000-0001-6494-720XProjects
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Role of Oxidative stress/ROS in IC/BPS, Stanford University
The pathogenesis leading to the onset of IC/BPS and relapsing flares associated with this condition are unclear. Oxidative damage and free radicals may be implicated in the development of IC/BPS as Pathways shown to be involved in the IC/BPS, like JNK and ion channels like TRPs are regulated by ROS. ROS provide as cell signaling molecules in normal biologic processes, and are thus present during metabolic, and physiologic processes. Oxidative stress occurs when there is an imbalance between oxidants and antioxidants, which can lead to IC/BPS. We are trying to understand the role of ROS in the development of IC/BPS via analysing the different molecular pathways and ion channels. The major focus is on JNKs and TRPs.
Location
california
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Circadian dysregulation and Nocturia
Circadian dysregulation and the effects of aging, for example, the development of oxidative stress and mitochondrial dysfunction, may play a role in nocturia voiding symptoms. We are trying to understand the link between Circadian dysregulation and Nocturia by analyzing the expression levels of different circadian genes in patients suffering from Nocturia. Our main focus is on peroxiredoxins and aquaporins. Peroxiredoxins are conserved biomarkers for Circadian rhythms and oxidative stress whereas Aquaporin 3 channels, present in urothelial cells, are involved in the transportation of water, urea and some ions.
Location
California
All Publications
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Mechanisms of oxidative stress in interstitial cystitis/bladder pain syndrome.
Nature reviews. Urology
2024
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by bladder and/or pelvic pain, increased urinary urgency and frequency and nocturia. The pathophysiology of IC/BPS is poorly understood, and theories include chronic inflammation, autoimmune dysregulation, bacterial cystitis, urothelial dysfunction, deficiency of the glycosaminoglycan (GAG) barrier and urine cytotoxicity. Multiple treatment options exist, including behavioural interventions, oral medications, intravesical instillations and procedures such as hydrodistension; however, many clinical trials fail, and patients experience an unsatisfactory treatment response, likely owing to IC/BPS phenotype heterogeneity and the use of non-targeted interventions. Oxidative stress is implicated in the pathogenesis of IC/BPS as reactive oxygen species impair bladder function via their involvement in multiple molecular mechanisms. Kinase signalling pathways, nociceptive receptors, mast-cell activation, urothelial dysregulation and circadian rhythm disturbance have all been linked to reactive oxygen species and IC/BPS. However, further research is necessary to fully uncover the role of oxidative stress in the pathways driving IC/BPS pathogenesis. The development of new models in which these pathways can be manipulated will aid this research and enable further investigation of promising therapeutic targets.
View details for DOI 10.1038/s41585-023-00850-y
View details for PubMedID 38326514
View details for PubMedCentralID 3513327
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The Potential Role of Persister Cells in Urinary Tract Infections.
Current urology reports
2023
Abstract
This review explores the role of persister cells in urinary tract infections (UTIs). UTIs are one of the most common bacterial infections, affecting millions of people worldwide. Persister cells are a subpopulation of bacteria with dormant metabolic activity which allows survival in the presence of antibiotics.This review summarizes recent research on the pathogenesis of persister cell formation in UTIs, the impact of persister cells on the effectiveness of antibiotics, the challenges they pose for treatment, and the need for new strategies to target these cells. Furthermore, this review examines the current state of research on the identification and characterization of persister cells in UTIs, as well as the future directions for investigations in this field. This review highlights the importance of understanding the role of persister cells in UTIs and the potential impact of targeting these cells in the development of new treatments.
View details for DOI 10.1007/s11934-023-01182-5
View details for PubMedID 37907771
View details for PubMedCentralID 6396617
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Pathophysiologic Insights into the Transition from Asymptomatic Bacteriuria to Urinary Tract Infection.
Current urology reports
2023
Abstract
Asymptomatic bacteriuria (ASB) can be found in the general population but it is more common in catheterized patients. Some patients develop urinary tract infections (UTI) and others stay asymptomatic throughout time. The scientific community lacks a pathophysiologic explanation of why asymptomatic bacteriuria stays asymptomatic most of the time, and why and how it sometimes transitions to UTI. In an attempt to bridge this gap in knowledge, a summary of the current literature is conducted on the pathophysiologic differences between ASB and UTI, beyond their clinical differences.ASB and UTI cannot be differentiated just by their phylogroup or number of virulence factors. The difference may be in their metabolism gene expression. The literature lacks a pathophysiological explanation of the transition from ASB to UTI, and recent discoveries suggest that metabolic gene expression may hold the key.
View details for DOI 10.1007/s11934-023-01183-4
View details for PubMedID 37856072
View details for PubMedCentralID 4648343
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Our 11 year experience with percutaneous tibial nerve stimulation (PTNS) in men and women for the treatment of interstitial cystitis / bladder pain syndrome (IC/BPS).
Urology
2023
Abstract
To evaluate the effect of percutaneous tibial nerve stimulation (PTNS) in interstitial cystitis / bladder pain syndrome IC/BPS.Retrospective chart review was completed for patients with at least 10 weekly treatments of PTNS from January 2010 to October 2021. PTNS success was defined as conversion to PTNS maintenance therapy following 12 weeks of PTNS induction therapy. Data were analyzed using GraphPad.Over the 11 year study period, 27 out of 34 patients (mean age 52.9±16.8 years; 25 females, 9 males) completed 12 weeks of PTNS induction therapy, and 48.1% (13/27) successfully converted to PTNS maintenance therapy. Following 12 weeks of PTNS induction therapy, significant improvements were noted in the urgency severity scale (USS range 0-4: 2.9±1.2 before versus 1.1±1.1 after PTNS, p=0.001) and nocturnal urinary frequency (number of voids: 3.3±1.9 before versus 2.2±1.6 after PTNS, p=0.041); and non-significant improvements were noted in daytime void frequency (hours: 1.5±0.7 before versus 2.0±0.9 after PTNS, p=0.090) and the pain domain of the interstitial cystitis symptoms index (ICSI question 4, range 0-4: 2.5±1.4 before versus 1.3±1.8 after PTNS, p=0.082).Our sample size is among the largest sample of PTNS in IC/BPS from a single center. While PTNS achieved non-significant improvements in pain and daytime void frequency, significant improvements were observed in urinary urgency and nocturia. PTNS appears to be a plausible option in the multi-modal approach to managing IC/BPS.
View details for DOI 10.1016/j.urology.2023.08.025
View details for PubMedID 37690542
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PERIPHERAL CIRCADIAN RHYTHMS OF THE BLADDER IN PATIENTS WITH NOCTURIA
WILEY. 2023: S11-S13
View details for Web of Science ID 001043021100009
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Neuroprotective Effects of Fluoxetine on Molecular Markers of Circadian Rhythm, Cognitive Deficits, Oxidative Damage, and Biomarkers of Alzheimer's Disease-Like Pathology Induced under Chronic Constant Light Regime in Wistar Rats
ACS CHEMICAL NEUROSCIENCE
2021; 12 (12): 2233-2246
Abstract
There is mounting evidence of circadian rhythm disruption in Alzheimer's disease (AD); however, the cause-and-effect relationship between them is not understood. Chronic constant light exposure effectively disrupts circadian rhythm in rats. On the basis of previous publications, we hypothesized that chronic constant light exposure might contribute significantly to development of AD-like-phenotype in rats and that fluoxetine (Flx) treatment might protect the brain against it. Adult male rats were exposed to normal light-dark cycles, constant light (LL), constant dark, and LL+Flx (5 mg/kg/day, ZT5) for four months. The expression of molecular markers of circadian rhythm: Per2 transcripts; and protein expression of peroxiredoxin-1 (PRX1) and hyperoxidized peroxiredoxins (PRX-SO2/3) were significantly dysregulated in the suprachiasmatic nuclei (SCN) of LL rats, which was prevented with concomitant fluoxetine administration. The levels of glutamate and γ-aminobutyric acid were dysregulated, and oxidative damage was observed in the SCN and hippocampi of LL rats. Fluoxetine treatment conferred protection against oxidative damage in LL rats. Constant light exposure also impaired rats' performance on Y-maze, Morris maze, and novel object recognition test, which was prevented with fluoxetine administration. A significant elevation in soluble Aβ1-42 levels, which strongly correlated with upregulation of Bace1 and Mgat3 transcripts was observed in the hippocampus of LL rats. Further, the expression of antiaging gene Sirt1 was downregulated, and neuronal damage indicator Prokr2 was upregulated in hippocampus. Fluoxetine rescued Aβ1-42 upregulation and AD-related genes' dysregulation. Our findings show that circadian disruption by exposure to chronic constant light may contribute to progression of AD, which can be prevented with fluoxetine treatment.
View details for DOI 10.1021/acschemneuro.1c00238
View details for Web of Science ID 000664290200016
View details for PubMedID 34029460
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A curious case of cysteines in human peroxiredoxin I.
Redox biology
2020; 37: 101738
Abstract
Peroxiredoxins (Prxs) are antioxidant proteins that are involved in cellular defence against reactive oxygen species and reactive nitrogen species. Humans have six peroxiredoxins, hPrxI-VI, out of which hPrxI and hPrxII belongs to the typical 2-Cys class sharing 90% conservation in their amino acid sequence including catalytic residues required to carry out their peroxidase and chaperone activities. Despite the high conservation between hPrxI and hPrxII, hPrxI behaves differently from hPrxII in its peroxidase and chaperone activity. We recently showed in yeast that in the absence of Tsa1 and Tsa2 (orthologs of hPrx) hPrxI protects the cells against different stressors whereas hPrxII does not. To understand this difference, we expressed catalytic mutants of hPrxI in yeast cells lacking the orthologs of hPrxI/II. We found that the catalytic mutants lacking peroxidase function including hPrxIC52S, hPrxIC173S, hPrxIT49A, hPrxIP45A and hPrxIR128A were not able to grow on media with nitrosative stressor (sodium nitroprusside) and unable to withstand heat stress, but surprisingly they were able to grow on an oxidative stressor (H2O2). Interestingly, we found that hPrxI increases the expression of antioxidant genes, GPX1 and SOD1, and this is also seen in the case of a catalytic mutant, indicating hPrxI can indirectly reduce oxidative stress independently of its own peroxidase function and thus suggesting a novel role of hPrxI in altering the expression of other antioxidant genes. Furthermore, hPrxIC83T was resistant to hyperoxidation and formation of stable high molecular weight oligomers, which is suggestive of impaired chaperone activity. Our results suggest that the catalytic residues of hPrxI are essential to counter the nitrosative stress whereas Cys83 in hPrxI plays a critical role in hyperoxidation of hPrxI.
View details for DOI 10.1016/j.redox.2020.101738
View details for PubMedID 33011678
View details for PubMedCentralID PMC7530344
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Deciphering the in vivo redox behavior of human peroxiredoxins I and II by expressing in budding yeast.
Free radical biology & medicine
2019; 145: 321-329
Abstract
Peroxiredoxins (Prxs), scavenge cellular peroxides by forming recyclable disulfides but under high oxidative stress, hyperoxidation of their active-site Cys residue results in loss of their peroxidase activity. Saccharomyces cerevisiae deficient in human Prx (hPrx) orthologue TSA1 show growth defects under oxidative stress. They can be complemented with hPRXI but not by hPRXII, but it is not clear how the disulfide and hyperoxidation states of the hPrx vary in yeast under oxidative stress. To understand this, we used oxidative-stress sensitive tsa1tsa2Δ yeast strain to express hPRXI or hPRXII. We found that hPrxI in yeast exists as a mixture of disulfide-linked dimer and reduced monomer but becomes hyperoxidized upon elevated oxidative stress as analyzed under denaturing conditions (SDS-PAGE). In contrast, hPrxII was present predominantly as the disulfide in unstressed cells and readily converted to its hyperoxidized, peroxidase-inactive form even with mild oxidative stress. Interestingly, we found that plant extracts containing polyphenol antioxidants provided further protection against the growth defects of the tsa1tsa2Δ strain expressing hPrx and preserved the peroxidase-active forms of the Prxs. The extracts also helped to protect against hyperoxidation of hPrxs in HeLa cells. Based on these findings we can conclude that resistance to oxidative stress of yeast cells expressing individual hPrxs requires the hPrx to be maintained in a redox state that permits redox cycling and peroxidase activity. Peroxidase activity decreases as the hPrx becomes hyperoxidized and the limited protection by hPrxII compared with hPrxI can be explained by its greater sensitivity to hyperoxidation.
View details for DOI 10.1016/j.freeradbiomed.2019.09.034
View details for PubMedID 31580947
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Biological markers for the effects of yoga as a complementary and alternative medicine.
Journal of complementary & integrative medicine
2019; 16 (1)
Abstract
From the last few decades, there are increasing incidences of disorders like premature aging, cardiovascular disease, multiple sclerosis, fibromyalgia, and Alzheimer's disease In addition to medication, researchers have found that yoga, a mind-body therapy, can be used as an alternative medicine. Yoga combines specific physical postures, breathing techniques, relaxation and meditation that improve mental and physical health of the body. The purpose of this review is to collate the research evidences claiming health benefits of performing traditional yogic practices. What are the biological and other reliable indicators to suggest that doing asanas, pranayama, and meditation could reduce or treat wide range of life style disorders are discussed. Importantly, these indicators are otherwise used to assess the severity of disorders. In many of the study it has been shown that yoga improves the redox health of body whose imbalance has been well proven to cause many health complications. The impact of yoga on neurodegenerative diseases have revealed that it reverses memory loss, reduce anxiety, depression and stress, the biological indicators of disease. However, most studies have several limitations and therefore further research into yoga is needed to validate these findings.
View details for DOI 10.1515/jcim-2018-0094
View details for PubMedID 30735481