Deepanshu Maheshwari

Institute of Liver and Biliary Sciences

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Shiv Kumar Sarin

Institute of Liver and Biliary Sciences

Nidhi Nautiyal

Institute of Liver and Biliary Sciences

Chhagan Bihari

Institute of Liver and Biliary Sciences

Rakhi Maiwall

Institute of Liver and Biliary Sciences

Anupam Kumar

Vanderbilt University Medical Center

Subhrajit Biswas

Amity University

Dhananjay Kumar

Louisiana State University Health Sciences Center Shreveport

Archana Rastogi

Institute of Liver and Biliary Sciences

Anupama Kumari

Institute of Liver and Biliary Sciences

Rekha Kumari

Indira Gandhi Institute of Medical Sciences

Cooperative Institutions

Institute of Liver and Biliary Sciences

All India Institute of Medical Sciences

Asian Institute of Gastroenterology

Cellular Research (United States)

Amity University

University Gastroenterology

Canon (Japan)

Institute of Molecular Medicine

Indian Institute of Technology Delhi

All India Institute of Medical Sciences Bhopal

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

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

Cite

Citations (1)

WED-118 Mitoquinol intervention ameliorates cirrhosis associated hematopoietic imbalance and improves innate immune function

Journal of Hepatology (2024)

Deepanshu Maheshwari Nidhi Nautiyal Sandeep Kumar Manisha Bhardwaj Sunidhi Diwakar

10.1016/s0168-8278(24)00822-5

Cite

Citations (0)

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

Cite

Citations (0)

The Quality of Reporting Raises Questions on the Experimental Validity of Animal Studies Conducted in India and Sri Lanka: Preliminary Analysis of a Systematic Survey

Alternatives to Laboratory Animals (2020)

Vijay Pal Singh Ayushi Jain Shubhra A. Gupta Manudharshy Vijayakumar Kunal Pratap

The quality of animal experiments in terms of appropriate reporting is a concern, particularly with regard to their validity and the recording of the measures taken to reduce various types of bias. A systematic survey of 1371 and 236 publications from India and Sri Lanka, respectively, which were published between 1905 and 2017 and indexed in NCBI-PubMed, Cinhal, MEDLINE and Scopus, was carried out. The level of detail in the descriptions of animals used and the measures taken to reduce bias were analysed in each article. Selected parameters from the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines, such as age, weight, sex, sample size calculation, blinding and randomisation were considered. The findings revealed poor reporting standards in animal experiments carried out in India and Sri Lanka, confirming the limited impact of the ARRIVE guidelines. These findings emphasise the urgent need for improvements in the peer review process, both prior to a study being set up and in the post-study reporting phase, and for more stringent adherence to the ARRIVE guidelines in the reporting of animal experiments.

Blinding

Sri lanka

Reporting bias

10.1177/0261192920923105

Cite

Citations (1)

Early loss of bone marrow hematopoietic stem cells drives regeneration failure in cirrhosis

Research Square (Research Square) (2023)

Nidhi Nautiyal Deepanshu Maheshwari Dhananjay Kumar E Pranshu Rao Dinesh Mani Tripathi

Abstract Liver failure is failure of regeneration. Underlying cause of regeneration failure in cirrhosis is not well-defined. Bone marrow stem cells (BMSC) and their progeny play a central role in tissue repair and regeneration and are defective in patients with chronic liver failure. Whether BM failure is cause or consequence of liver failure in cirrhosis is not known. In this study we aim to decipher the underlying relation between BM failure and regeneration failure in cirrhosis. Using murine model of chronic liver injury we showed that loss of BMSC occurs prior to failure of liver regeneration and onset of non-acute decompensation. We further showed, infusion of healthy-BM in cirrhotic-BM dampens the inflammation, increase glycolysis and induce the repopulation of native LT-HSCs. Restoring LT-HSCs reserve in cirrhotic animals restore liver macrophage number and function, accelerate regression of fibrosis, enhanced liver regeneration and delay the onset of non-acute decompensation. It improved liver clearance of immune complex, dampens neutrophil-mediated inflammation and shifted energy metabolism from glycolysis to OXPHOS. Therefore, early loss of BMSC reserve compromise innate immune function of liver and drive the regeneration failure in cirrhosis. We also provide the proof-of-concept that rejuvenating BM-HSC reserve as putative therapeutic approach to prevent regeneration failure in cirrhosis.

Decompensation

Liver Regeneration

Bone marrow failure

10.21203/rs.3.rs-3250973/v1

Cite

Citations (0)

Soluble factors and suppressive monocytes can predict early development of sepsis in acute‐on‐chronic liver failure

Hepatology Communications (2022)

Pushpa Yadav Nirupama Trehanpati Rakhi Maiwall Rashi Sehgal Ravinder Singh

Patients with acute-on-chronic liver failure (ACLF) have a high probability of developing systemic inflammation and sepsis due to immune dysregulation. Fifty-nine patients with ACLF (12 without and 19 with systemic inflammation, and 28 with sepsis) were serially monitored for clinical and immunological changes at baseline, 6 hours, 24 hours, day 3, and day 7 following hospitalization. Ten healthy controls were also included. At all time points, soluble plasma factors and monocyte functions were studied. Patients with ACLF and systemic inflammation showed higher interleukin (IL)-6, vascular endothelial growth factor-a, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1β than patients with no systemic inflammation. Patients with ACLF with sepsis had raised (p < 0.001) levels of IL-1Ra, IL-18, and triggering receptor expressed on myeloid cells 1 (TREM1) compared to patients with ACLF-systemic inflammation. Five of the 19 (26.3%) patients with systemic inflammation developed sepsis within 48-72 hours with a rapid rise in plasma levels of IL-1Ra (1203-35,000 pg/ml), IL-18 (48-114 pg/ml), and TREM1 (1273-4865 pg/ml). Monocytes of patients with ACLF with systemic inflammation and sepsis showed reduced human leukocyte antigen-DR but increased programmed death ligand 1 (PD-L1) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3) (p < 0.04) expression with increased ETosis by monocytes at baseline and until day 7. Conclusion: High and rising levels of plasma IL-1Ra, IL-18, TREM1 soluble factors, and increased suppressive monocytes (PDL1+ve , TIM3+ve ) at baseline can stratify patients with ACLF at high risk of developing sepsis within 48-72 hours of hospitalization.

Monocyte

10.1002/hep4.1949

Cite

Citations (11)

Nicotinamide riboside (NR) supplementation enhances bacterial elimination and reduces fibrosis in an animal model of cirrhosis

Journal of Clinical and Experimental Hepatology (2024)

Nidhi Nautiyal Deepanshu Maheshwari Shivi Chauhan Manisha Bhardwaj Sunidhi Diwakar

10.1016/j.jceh.2024.101965

Cite

Citations (0)

Circulating extracellular vesicles induce monocyte dysfunction and are associated with sepsis and high mortality in cirrhosis

Liver International (2021)

Sukriti Baweja Chhagan Bihari Preeti Negi Swati Thangariyal Anupama Kumari

Abstract Background Sepsis is common in cirrhosis and is often a result of immune dysregulation. Specific stimuli and pathways of inter‐cellular communications between immune cells in cirrhosis and sepsis are incompletely understood. Immune cell‐derived extracellular vesicles (EV) were studied to understand mechanisms of sepsis in cirrhosis. Methods Immune cell‐derived EV were measured in cirrhosis patients [Child‐Turcotte‐Pugh (Child) score A, n = 15; B n = 16; C n = 43 and Child‐C with sepsis (n = 38)], and healthy controls (HC, n = 11). In vitro and in vivo functional relevance of EV in cirrhosis and associated sepsis was investigated. Results Monocyte, neutrophil and hematopoietic stem cells associated EV progressively increased with higher Child score ( P < .001)and correlated with liver disease severity indices (r 2 > 0.3, P < .001), which further increased in Child C sepsis than without sepsis( P < .001); monocyte EV showing the highest association with disease stage [ P = .013; Odds ratio‐4.14(1.34‐12.42)]. A threshold level of monocyte EV of 53/µl predicted mortality in patients of Child C with sepsis [Odds ratio‐6.2 (2.4‐15.9), AUROC = 0.76, P < .01]. In vitro EV from cirrhotic with sepsis compared without sepsis, induced mobilization arrest in healthy monocytes within 4 hours ( P = .004), reduced basal oxygen consumption rate ( P < .001) and induced pro‐inflammatory genes ( P < .05). The septic‐EV on adoptive transfer to C57/BL6J mice, induced sepsis‐like condition within 24 h with leukocytopenia ( P = .005), intrahepatic inflammation with increased CD11b + cells ( P = .03) and bone marrow hyperplasia ( P < .01). Conclusion Extracellular vesicles induce functional impairment in circulating monocytes and contribute to the development and perpetuation of sepsis. High levels of monocyte EV correlate with mortality and can help early stratification of sicker patients.

Immune Dysregulation

Monocyte

10.1111/liv.14875

Cite

Citations (6)

Bioenergetic Failure Drives Functional Exhaustion of Monocytes in Acute-on-Chronic Liver Failure

Frontiers in Immunology (2022)

Deepanshu Maheshwari Dhananjay Kumar Rakesh Kumar Jagdish Nidhi Nautiyal Ashinikumar Hidam

The monocyte-macrophage system is central to the host's innate immune defense and in resolving injury. It is reported to be dysfunctional in acute-on-chronic liver failure (ACLF). The disease-associated alterations in ACLF monocytes are not fully understood. We investigated the mechanism of monocytes' functional exhaustion and the role of umbilical cord mesenchymal stem cells (ucMSCs) in re-energizing monocytes in ACLF.Monocytes were isolated from the peripheral blood of ACLF patients (n = 34) and matched healthy controls (n = 7) and patients with compensated cirrhosis (n = 7); phagocytic function, oxidative burst, and bioenergetics were analyzed. In the ACLF mouse model, ucMSCs were infused intravenously, and animals were sacrificed at 24 h and day 11 to assess changes in monocyte function, liver injury, and regeneration.Patients with ACLF (alcohol 64%) compared with healthy controls and those with compensated cirrhosis had an increased number of peripheral blood monocytes (p < 0.0001) which displayed significant defects in phagocytic (p < 0.0001) and oxidative burst capacity (p < 0.0001). ACLF patients also showed a significant increase in the number of liver macrophages as compared with healthy controls (p < 0.001). Bioenergetic analysis showed markedly reduced oxidative phosphorylation (p < 0.0001) and glycolysis (p < 0.001) in ACLF monocytes. Patients with monocytes having maximum mitochondrial respiration of <37.9 pmol/min [AUC = 0.822, hazard ratio (HR) = 4.5] and baseline glycolysis of ≤42.7 mpH/min (AUC = 0.901, HR = 9.1) showed increased 28-day mortality (p < 0.001). Co-culturing ACLF monocytes with ucMSC showed improved mitochondrial respiration (p < 0.01) and phagocytosis (p < 0.0001). Furthermore, ucMSC therapy increased monocyte energy (p < 0.01) and phagocytosis (p < 0.001), reduced hepatic injury, and enhanced hepatocyte regeneration in ACLF animals.Bioenergetic failure drives the functional exhaustion of monocytes in ACLF. ucMSCs resuscitate monocyte energy and prevent its exhaustion. Restoring monocyte function can ameliorate hepatic injury and promote liver regeneration in the animal model of ACLF.

Bioenergetics

10.3389/fimmu.2022.856587

Cite

Citations (13)

Defects in energy metabolism are associated with functional exhaustion of bone marrow mesenchymal stem cells in cirrhosis.

PubMed (2022)

Dhananjay Kumar Deepanshu Maheshwari Nidhi Nautiyal Smriti Shubham Sheetalnath Rooge

Cellular and functional exhaustion of bone marrow mesenchymal stem cells (BM-MSC) is significantly associated with the loss of HSCs and hepatic osteodystrophy in cirrhosis. The molecular mechanisms underlying the dysfunction of BM-MSCs are not well understood. We investigated the underlying mechanisms of cellular and functional exhaustion of BM-MSCs in cirrhosis.The MSCs were isolated retrospectively from bone marrow of decompensated alcoholic cirrhosis patients {(Trial registration: ClinicalTrials.gov NCT01902511) (n=10; MELD=16.2±2.3; CTP=8.7±2.3)} and age and gender-matched healthy controls (n=8). Global gene expression profile of healthy bone marrow MSCs (hBM-MSCs) and cirrhosis patients BM-MSCs (cBM-MSCs) were done by mRNA sequencing. XFe24-bioanalyzer analyzed the bioenergetic potential of cells. Level of different cytokines and growth factors in BM-plasma and MSCs secretome were analyzed by Luminex-based bead array.Analysis of differentially expressed genes showed significant (P<0.01) up-regulation of genes associated with ubiquitination and catabolism of proteins; TNF signaling, insulin resistance, and down-regulation of genes associated with DNA repair, protein processing, cell cycle, and mitochondrial respiration in cBM-MSCs in comparison to hBM-MSCs. Compared to hBM-MSCs, cBM-MSCs showed a significant defect in glycolysis due to insulin resistance and poor glucose uptake (P=0.002). This led to compromised self-renewal capacity and cellular loss of MSCs in cirrhosis. cBM-MSCs also showed a significant impairment in Oxidative phosphorylation (OXPHOS) due to mitochondrial dysfunction leading to defects in the osteogenic differentiation with early aging and senescence.Compromised energy metabolism due to inflammatory and metabolic stress-induced insulin resistance underlies the cellular and functional exhaustion of BM-MSCs in cirrhosis.

Senescence

Source

Cite

Citations (7)