Chaitanya A. Kulkarni

University of Rochester Medical Center

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Paul S. Brookes

University of Rochester

Robert J. Kerns

University of Iowa

Alexander S. Milliken

University of Rochester

Sergiy M. Nadtochiy

University of Rochester Medical Center

Brian D. Fink

University of Iowa

Pratik Rajesh Chheda

Janssen (United States)

William I. Sivitz

University of Iowa

Aimin Peng

University of Nebraska Medical Center

Dragony Fu

University of Rochester

Yumi Imai

Fraternal Order of Eagles

Cooperative Institutions

Lupin Pharmaceuticals (India)

University of Iowa

Fraternal Order of Eagles

University of Rochester

Washington University in St. Louis

University of Rochester Medical Center

University of Minnesota Medical Center

University of Iowa Hospitals and Clinics

Iowa City VA Health Care System

Harvard University

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Investigating the effects of structural modification of alkyl triphenylphosphonium compounds on mitochondrial uncoupling and accumulation

Chaitanya A. Kulkarni

10.17077/etd.o00k-inm5

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Small molecule SWELL1-LRRC8 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Susheel K. Gunasekar Litao Xie Pratik Rajesh Chheda Kang Chen David M. Kern

Abstract Type 2 diabetes (T2D) is associated with insulin resistance, impaired insulin secretion from the pancreatic β-cell, and nonalcoholic fatty liver disease (NAFLD). SWELL1 (LRRC8a) ablation impairs adipose and skeletal muscle insulin-pAKT2 signaling, β-cell insulin secretion and glycemic control - suggesting that SWELL1-LRRC8 complex dysfunction contributes to T2D pathogenesis. Here, we show that I Cl,SWELL and SWELL1 protein are reduced in adipose and β-cells in murine and human T2D. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-designed active derivatives (SN-40X) of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1-LRRC8 hexameric complex, restore SWELL1-LRRC8 protein, plasma membrane trafficking, signaling and islet insulin secretion via SWELL1-dependent mechanisms. In vivo , SN-401 and active SN-40X compounds restore glycemic control and prevents NAFLD by improving insulin-sensitivity and insulin secretion in murine T2D. These findings demonstrate that small molecule SWELL1 modulators restore SWELL1-dependent insulin-sensitivity and insulin secretion in T2D and may represent a first-in-class therapeutic approach for T2D and NAFLD.

10.1101/2021.02.28.432901

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A Novel Triphenylphosphonium Carrier to Target Mitochondria without Uncoupling Oxidative Phosphorylation

Journal of Medicinal Chemistry (2021)

Chaitanya A. Kulkarni Brian D. Fink Bettine E. Gibbs Pratik Rajesh Chheda Meng Wu

Mitochondrial dysfunction is an underlying pathology in numerous diseases. Delivery of diagnostic and therapeutic cargo directly into mitochondria is a powerful approach to study and treat these diseases. The triphenylphosphonium (TPP+) moiety is the most widely used mitochondriotropic carrier. However, studies have shown that TPP+ is not inert; TPP+ conjugates uncouple mitochondrial oxidative phosphorylation. To date, all efforts toward addressing this problem have focused on modifying lipophilicity of TPP+-linker-cargo conjugates to alter mitochondrial uptake, albeit with limited success. We show that structural modifications to the TPP+ phenyl rings that decrease electron density on the phosphorus atom can abrogate uncoupling activity as compared to the parent TPP+ moiety and prevent dissipation of mitochondrial membrane potential. These alterations of the TPP+ structure do not negatively affect the delivery of cargo to mitochondria. Results here identify the 4-CF3-phenyl TPP+ moiety as an inert mitochondria-targeting carrier to safely target pharmacophores and probes to mitochondria.

Moiety

Lipophilicity

Linker

Conjugate

10.1021/acs.jmedchem.0c01671

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Citations (77)

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Chaitanya A. Kulkarni Sergiy M. Nadtochiy Leslie Kennedy Jimmy Zhang Sophea Chhim

ABSTRACT Alkb homolog 7 (ALKBH7) is a mitochondrial α-ketoglutarate dioxygenase required for necrotic cell death in response to DNA alkylating agents, but its physiologic role within tissues remains unclear. Herein, we show that ALKBH7 plays a key role in the regulation of dialdehyde metabolism, which impacts cardiac survival in response to ischemia-reperfusion (IR) injury. Using a multi-omics approach, we do not find evidence that ALKBH7 functions as a prolyl-hydroxylase. However, we do find that mice lacking ALKBH7 exhibit a significant increase in glyoxalase I (GLO-1), a dialdehyde detoxifying enzyme. Consistent with increased dialdehyde production, metabolomics analysis reveals rewiring of metabolic pathways related to the toxic glycolytic by-product methylglyoxal (MGO), as well as accelerated glycolysis and elevated levels of MGO protein adducts, in mice lacking ALKBH7. Consistent with roles for both necrosis and glycative stress in cardiac IR injury, hearts from male but not female Alkbh7 -/- mice are protected against IR, although somewhat unexpectedly this protection does not appear to involve modulation of the mitochondrial permeability transition pore. Highlighting the importance of MGO metabolism for the observed protection, removal of glucose as a metabolic substrate or pharmacologic inhibition of GLO-1 both abrogate cardioprotection in ALKBH7 deficient mice. Integrating these observations, we propose that ALKBH7 plays a role in the regulation of glyoxal metabolism, and that protection against necrosis and IR injury bought on by ALKBH7 deficiency originates from hormetic signaling in response to elevated MGO stress.

Lactoylglutathione lyase

Carbohydrate Metabolism

10.1101/2020.05.04.077297

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Inhibition of aldose reductase and anti-cataract action of trans-anethole isolated from Foeniculum vulgare Mill. fruits

Food Chemistry (2011)

Vandana R. Dongare Chaitanya A. Kulkarni M. S. Kondawar Chandrakant S. Magdum Vivek Haldavnekar

Foeniculum

10.1016/j.foodchem.2011.11.005

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Citations (71)

2D to 3D Floor plan Modeling using Image Processing and Augmented Reality

Pradnya Deshmukh Srushti Kulkarni Denzil Samuel Jayesh Mishra Lata Jaywant Sankpal

This paper introduces a novel technique for transforming 2D floor plans into 3D models by combining image processing and augmented reality. The method involves using a smartphone camera to scan a 2D blueprint, followed by extracting the layout and dimensions of the area using computer vision algorithms. Augmented reality techniques are then applied to generate a 3D model that can be manipulated and navigated in real-time. The effectiveness and efficiency of the approach were evaluated using real-world floor plans, and the results were promising. The method has the potential to revolutionize the way architects and designers produce and present floor plans, providing a more immersive and interactive experience that can improve communication and collaboration among design teams. Clients can also benefit from this approach as it can assist them in comprehending and visualizing their designs. Furthermore, the approach can be used in other domains, such as virtual staging for real estate or in virtual reality training simulations for emergency responders. Overall, this pioneering approach has the potential to significantly impact various industries and can pave the way for future advancements in the field of 3D modeling and augmented reality.

Floor plan

Blueprint

10.1109/reedcon57544.2023.10151165

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Complex effects of pH on ROS from mitochondrial complex II driven complex I reverse electron transport challenge its role in tissue reperfusion injury

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Alexander S. Milliken Chaitanya A. Kulkarni Paul S. Brookes

ABSTRACT Generation of mitochondrial reactive oxygen species (ROS) is an important process in triggering cellular necrosis and tissue infarction during ischemia-reperfusion (IR) injury. Ischemia results in accumulation of the metabolite succinate. Rapid oxidation of this succinate by mitochondrial complex II (Cx-II) during reperfusion reduces the co-enzyme Q (Co-Q) pool, thereby driving electrons backward into complex-I (Cx-I), a process known as reverse electron transport (RET), which is thought to be a major source of ROS. During ischemia, enhanced glycolysis results in an acidic cellular pH at the onset of reperfusion. While the process of RET within Cx-I is known to be enhanced by a high mitochondrial trans-membrane ΔpH, the impact of pH itself on the integrated process of Cx-II to Cx-I RET has not been fully studied. Using isolated mitochondria under conditions which mimic the onset of reperfusion (i.e., high [ADP]). We show that mitochondrial respiration (state 2 and state 3) as well as isolated Cx-II activity are impaired at acidic pH, whereas the overall generation of ROS by Cx-II to Cx-I RET was insensitive to pH. Together these data indicate that the acceleration of Cx-I RET ROS by ΔpH appears to be cancelled out by the impact of pH on the source of electrons, i.e. Cx-II. Implications for the role of Cx-II to Cx-I RET derived ROS in IR injury are discussed.

Mitochondrial ROS

10.1101/2020.08.31.275438

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Discovery of Halogenated Benzothiadiazine Derivatives with Anticancer Activity

Bader Huwaimel Myla Bhakta Chaitanya A. Kulkarni Alexander S. Milliken Feifei Wang

<div> <div> <div> <p>Mitochondrial respiratory complex II (CII), also known as succinate dehydrogenase, plays a critical role in mitochondrial metabolism. Known but low potency CII inhibitors are selectively cytotoxic to cancer cells including the benzothiadiazine-based anti-hypoglycemic diazoxide. Herein, we study the structure-activity relationship of benzothiadiazine derivatives for CII inhibition for the first time. A number of more potent derivatives were identified. Cytotoxicity evaluation of the novel derivatives resulted in the identification of compounds with greater anticancer effect than the parent; two benzothiadiazine derivative classes (24a-d and 30a, 30c, 30d) that possess activity to reduce the cell viability of 22Rv1 prostate cancer cells and five novel 7-fluorobenzothiadiazine derivatives which possessed significant cytotoxicity in a cellular model of triple negative breast cancer. No correlation between cytotoxicity and CII inhibition was found, indicating an as yet undefined mechanism of action of this scaffold. </p> </div> </div> </div>

Benzothiadiazines

10.26434/chemrxiv.12350912

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Immediate Effectiveness of Chest Proprioceptive Neuromuscular Facilitation (PNF) Technique on Hemodynamic Status in COVID-19 Patients: An Original Research

Cureus (2022)

Pallavi Bhakaney Rashmi R Walke Chaitanya A. Kulkarni Vishnu Vardhan

Introduction COVID-19 is an infectious illness that first appeared in Wuhan, China in December 2019, and subsequently spread over the entire world. Those who were affected suffered from fever, cough, weakness, and breathlessness, along with the probability of developing pneumonia which sometimes leads to respiratory failure. The older population with co-morbidities was at higher risk. Methods In this experimental study, 59 subjects with COVID-19 were included according to pre-decided inclusion and exclusion criteria. Pre-vitals before the treatment were noted such as heart rate, respiratory rate, and oxygen saturation (SPO2), and then the chest proprioceptive neuromuscular facilitation (PNF) technique was given as a treatment regime, and its immediate effect was calculated. Post-vitals were noted immediately after the treatment session. The statistical analysis was made using the student's paired t-test. Results We found a mean difference of 9.45±5.27 in heart rate before and after the intervention provided which is suggestive of a statistically significant increase within normal limits. Also, the mean value of respiratory rate immediately after the intervention was shown as 22.91 and pre-intervention was 19.18 with a mean difference of 2.93±3.95, showing a statistically significant increase in respiratory rate. Additionally, the mean value of SPO2 immediately after the intervention was shown as 92.76 and pre-intervention was 94.64 and had a mean difference of 1.88±1.67 suggestive of high improvement in oxygen saturation immediately after the intervention. Conclusion The present study concludes from the available statistical analysis that chest PNF techniques such as intercostal stretch and anterior basal stretch lift have an immediate impact on improvement in oxygen saturation in COVID-19 patients and can be incorporated as an inpatient treatment regime in the rehabilitation protocol.

Respiratory Rate

Facilitation

Oxygen Saturation

10.7759/cureus.29477

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Citations (2)

Many Routes from Glycolysis to Histone PTMs. Nature “Matters Arising” response to: Zhang et al. Metabolic regulation of gene expression by histone lactylation. (2019) Nature. 574(7779), 575-580.

Chaitanya A. Kulkarni Paul S. Brookes

Multiple histone post-translational modifications (PTMs) originate from small molecule metabolites (e.g. acetyl-lysine from acetyl-CoA) 1. As such, we read with interest the recent Nature paper from Zhang et al. 2 reporting discovery of lysine lactylation as a novel histone mark originating from the metabolite lactate. However, several concerns arise regarding the identity and source of this novel PTM.

Zhàng

10.31219/osf.io/sba8j

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Citations (5)