Dhananjay Kumar

Louisiana State University Health Sciences Center Shreveport

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Shiv Kumar Sarin

Institute of Liver and Biliary Sciences

Chhagan Bihari

Institute of Liver and Biliary Sciences

Nidhi Nautiyal

Institute of Liver and Biliary Sciences

Rakhi Maiwall

Institute of Liver and Biliary Sciences

Deepanshu Maheshwari

Institute of Liver and Biliary Sciences

Arif Yurdagul

Louisiana State University Health Sciences Center Shreveport

Sheetalnath Rooge

Institute of Liver and Biliary Sciences

Anupam Kumar

Vanderbilt University Medical Center

Smriti Shubham

Institute of Liver and Biliary Sciences

Guresh Kumar

Institute of Liver and Biliary Sciences

Cooperative Institutions

European Foundation for the Study of Chronic Liver Failure

213

Canon (Japan)

213

Institute of Liver and Biliary Sciences

Inserm

Assistance Publique – Hôpitaux de Paris

Louisiana State University Health Sciences Center Shreveport

All India Institute of Medical Sciences

Louisiana State University Health Sciences Center New Orleans

Université Paris Cité

Chinese Academy of Sciences

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Establishment of a Murine Model of Acute-on-Chronic Liver Failure with Multi-organ Dysfunction

Research Square (Research Square) (2021)

Nidhi Nautiyal Deepanshu Maheshwari Dhananjay Kumar Rekha Kumari Suchi Gupta

Abstract Background and Aims: Acute-on-chronic liver failure (ACLF) is a distinct clinical entity with high probability of organ failure and mortality. Experimental models of ACLF are needed to understand the pathophysiology and natural course of the disease.Methodology and Results: To mimic the syndrome of ACLF, chronic liver disease was induced by intra-peritoneal administration of carbon tetrachloride (CCl 4 ) for 10 weeks, followed by acute injury with acetaminophen (APAP) and lipopolysaccharide (LPS) administration. Blood, ascitic fluid and organs were collected to study cell death, regeneration and fibrosis. APAP/LPS induced second insult to the CCL 4 animals showed progressive and significant increase in bilirubin (p < 0.05), prothrombin time (P < 0.0001) and blood ammonia (p < 0.001) post-acute injury similar to human ACLF. Ascites was noticed by day 11 (median serum-ascites albumin gradient, SAAG ((1.2(1.1–1.3) g/dL) suggestive of portal hypertension. At 24 hours post-APAP/LPS infusion, the liver tissue showed increased hepatocyte ballooning and endothelial cell TUNEL positivity. This was followed by progressive hepatocyte necrosis from perivascular region at day 7 to lobular region by day 11 acute injury. They also showed regression in fibrous septa (p < 0.005) in comparison to cirrhosis. A progressive loss of hepatic regeneration (proliferating cell nuclear antigen; p < 0.005) was also seen following APAP/LPS injury. These animals also showed a significant increase in serum creatinine (p < 0.05) levels and renal tubular injury by day 11 which was not present in cirrhotic animals.Conclusion: The CCL4/APAP/LPS (CALPS) model of ACLF mimics the clinical, biochemical and histological features of ACLF with demonstrable progressive hepatocyte necrosis, liver failure, impaired regeneration, development of portal hypertension and organ dysfunction in an animal with chronic liver disease.

Liver disease

10.21203/rs.3.rs-438031/v1

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SAT-557-YI Loss of fibronectin contribute to poor maturation of monocyte to resolving macrophages in acute and chronic liver injury

Journal of Hepatology (2024)

Sandeep Kumar Dhananjay Kumar Deepanshu Maheshwari Sunidhi Diwakar Nidhi Nautiyal

Monocyte

10.1016/s0168-8278(24)01197-8

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The interplay between nonalcoholic fatty liver disease and atherosclerotic cardiovascular disease

Frontiers in Cardiovascular Medicine (2023)

Alexandra C Finney Sandeep R. Das Dhananjay Kumar M. Peyton McKinney Bishuang Cai

Therapeutic approaches that lower circulating low-density lipoprotein (LDL)-cholesterol significantly reduced the burden of cardiovascular disease over the last decades. However, the persistent rise in the obesity epidemic is beginning to reverse this decline. Alongside obesity, the incidence of nonalcoholic fatty liver disease (NAFLD) has substantially increased in the last three decades. Currently, approximately one third of world population is affected by NAFLD. Notably, the presence of NAFLD and particularly its more severe form, nonalcoholic steatohepatitis (NASH), serves as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), thus, raising interest in the relationship between these two diseases. Importantly, ASCVD is the major cause of death in patients with NASH independent of traditional risk factors. Nevertheless, the pathophysiology linking NAFLD/NASH with ASCVD remains poorly understood. While dyslipidemia is a common risk factor underlying both diseases, therapies that lower circulating LDL-cholesterol are largely ineffective against NASH. While there are no approved pharmacological therapies for NASH, some of the most advanced drug candidates exacerbate atherogenic dyslipidemia, raising concerns regarding their adverse cardiovascular consequences. In this review, we address current gaps in our understanding of the mechanisms linking NAFLD/NASH and ASCVD, explore strategies to simultaneously model these diseases, evaluate emerging biomarkers that may be useful to diagnose the presence of both diseases, and discuss investigational approaches and ongoing clinical trials that potentially target both diseases.

Dyslipidemia

Atherosclerotic cardiovascular disease

Steatohepatitis

10.3389/fcvm.2023.1116861

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Differential responses of genotype × environment interaction on Agronomic interventions affect the yield and quality of essential oil of interspecific basil hybrid of Ocimum basilicum L. × Ocimum kilimandscharicum

Ecological Genetics and Genomics (2024)

Ajay Kumar Nilesh Kumar Sharma Ashish Kumar Dhananjay Kumar A.C. Jnanesha

Biplot

Interaction

10.1016/j.egg.2024.100217

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Discovery of FetuinA and global signalling/remodelling modules driving myofibroblast differentiation during corneal wound healing in patients

Investigative Ophthalmology & Visual Science (2016)

Arkasubhra Ghosh Krishnatej Nishtala Dhananjay Kumar Rohit Shetty

Myofibroblast

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Recombinant Human Keratinocyte Growth Factor Induces Akt Mediated Cell Survival Progression in Emphysematous Mice

Archivos de Bronconeumología (2015)

Jai Prakash Muyal Dhananjay Kumar Sudhir Kotnala Vandana Muyal Amit Tyagi

Pancreatic elastase

Keratinocyte growth factor

10.1016/j.arbr.2015.02.023

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Abstract 2078: Integrin α5β1-mediated Interactions With Fibronectin Enhance Tim3 Expression To Drive Efferocytosis By Macrophages

Arteriosclerosis Thrombosis and Vascular Biology (2024)

Rajan Pandit Peyton Wilhite Dhananjay Kumar Theresea-Anne Governale Brenna H. Pearson

Despite significant advances in diagnosing and treating cardiovascular disease, atherosclerosis remains the leading cause of death worldwide. While most atherosclerotic plaques remain asymptomatic, a subset can lead to myocardial infarction, stroke, or sudden death. A plethora of evidence has demonstrated that rupture-prone atheromas contains a large necrotic core owed to defective efferocytosis, the process by which apoptotic cells (ACs) are engulfed and cleared by macrophages. The efficient clearance of apoptotic cells blocks post-apoptotic necrosis and prevents the release of tissue-degrading enzymes, immunogenic epitopes, and proinflammatory mediators. As atherosclerosis advances, substantial remodeling of the extracellular matrix (ECM) occurs whereby transitional ECM proteins, notably fibronectin (FN), deposit into the subendothelial matrix normally dominated by collagen IV and laminins. However, whether macrophage interactions with the ECM alters efferocytosis, inflammation resolution, and atherosclerosis remains unknown. Surprisingly, we discovered that macrophage interactions with FN enhance efferocytosis compared to their interactions with basement membrane proteins. Furthermore, we demonstrate that the primary FN receptor, integrin α5β1, is required for FN-mediated efferocytosis and TIM3 expression, (encoded by Havcr2 ), a known phosphatidylserine receptor that binds to ACs. Moreover, treating mice with established atherosclerosis with the integrin α5β1 antagonistic peptide ATN-161 reduced TIM3 expression in macrophages and expanded necrotic core formation. We also found lesional macrophages from human unstable atheromas displayed significantly lower TIM3 expression compared to macrophages within stable plaques. In a mouse model of atherosclerosis regression, where atherogenic stimuli dissipate, efferocytosis is restored, and FN remains, lesional macrophages showed a substantial increase in TIM3 expression. Thus, while FN is traditionally considered atherogenic in endothelial and smooth muscle cells in the initial stages of atherosclerosis, our data uncovers that macrophage adhesion to FN upregulates TIM3 expression, mediating efferocytosis and promoting features of plaque stability.

efferocytosis

Expression (computer science)

10.1161/atvb.44.suppl_1.2078

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The effect of protein, carbohydrate and fat rich isocaloric meals on postprandial small bowel motility in constipation and diarrhoea predominant IBS patients

Sameer Zar FD Castillo A. Grundy MJ Benson Dhananjay Kumar

Intestinal motility

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Spatially Resolved Metabolites in Stable and Vulnerable Human Atherosclerotic Plaques Identified by Mass Spectrometry Imaging

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Erin H. Seeley Zhipeng Liu Shuai Yuan Chad Stroope Elizabeth D Cockerham

ABSTRACT Impairments in carbohydrate, lipid, and amino acid metabolism drive features of plaque instability. However, where these impairments occur within the atheroma remains largely unknown. Therefore, we sought to characterize the spatial distribution of metabolites within stable and unstable atherosclerosis in both the fibrous cap and necrotic core. Atherosclerotic tissue specimens were scored based on the Stary classification scale and subdivided into stable and unstable atheromas. After performing mass spectrometry imaging (MSI) on these samples, we identified over 850 metabolite-related peaks. Using MetaboScape, METASPACE, and HMDB, we confidently annotated 170 of these metabolites and found over 60 of these were different between stable and unstable atheroma. We then integrated these results with an RNA-sequencing dataset comparing stable and unstable human atherosclerosis. Upon integrating our MSI results with the RNA-seq dataset, we discovered that pathways related to lipid metabolism and long-chain fatty acids were enriched in stable plaques, whereas reactive oxygen species, aromatic amino acid, and tryptophan metabolism were increased in unstable plaques. Acylcarnitines and acylglycines were increased in stable plaques whereas tryptophan metabolites were enriched in unstable plaques. Evaluating spatial differences in stable plaques revealed lactic acid in the necrotic core, whereas pyruvic acid was elevated in the fibrous cap. In unstable plaques, 5-hydroxyindole-acetic acid was enriched in the fibrous cap. Our work herein represents the first step to defining an atlas of metabolic pathways involved in plaque destabilization in human atherosclerosis. We anticipate this will be a valuable resource and open new avenues of research in cardiovascular disease. GRAPHICAL ABSTRACT

Atheroma

Mass spectrometry imaging

10.1101/2022.05.30.494038

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Table of contents

Hepatology (2016)

Karl Langberg Tamar H. Taddei Gregory M. Tiao James Geller Nikolai A. Timchenko

Study> Cover Figure : In this issue, Bihari and coworkers show that progression of cirrhosis is associated with progressive impairment of the hematopoietic stem cell niche in bone marrow (page 1273).This in turn appears to be responsible for the progressive hematological and immune derangements seen in advanced cirrhosis, as well as impaired liver regeneration.

Table (database)

10.1002/hep.28087

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