Publications by authors named "Tirthadipa Pradhan-Sundd"

Sickle cell disease (SCD)-associated chronic hemolysis promotes oxidative stress, inflammation, and thrombosis leading to organ damage, including liver damage. Hemoglobin scavenger receptor CD163 plays a protective role in SCD by scavenging both hemoglobin-haptoglobin complexes and cell-free hemoglobin. A limited number of studies in the past have shown a positive correlation of CD163 expression with poor disease outcomes in patients with SCD.

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Cigarette smoking is associated with a higher risk of ICU admissions among patients with flu. However, the etiological mechanism by which cigarette smoke (CS) exacerbates flu remains poorly understood. Here, we show that a mild dose of influenza A virus promotes a severe lung injury in mice preexposed to CS but not room air for 4 weeks.

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Sickle cell disease (SCD) is a monogenic disorder that affects 100,000 African-Americans and millions of people worldwide. Intra-erythrocytic polymerization of sickle hemoglobin (HbS) promotes erythrocyte sickling, impaired rheology, ischemia and hemolysis, leading to the development of progressive liver injury in SCD. Liver-resident macrophages and monocytes are known to enable the clearance of HbS; however, the role of liver sinusoidal endothelial cells (LSEC) in HbS clearance and liver injury in SCD remains unknown.

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Sickle cell disease (SCD) is an autosomal recessive monogenic disorder caused by a homozygous mutation in the β-globin gene, which leads to erythrocyte sickling, hemolysis, vaso-occlusion, and sterile inflammation. The administration of oral L-glutamine has been shown to reduce the frequency of pain in SCD patients; however, the long-term effect of L-glutamine in SCD remains to be determined. To understand the long-term effect of L-glutamine administration in the liver we used quantitative liver intravital microscopy and biochemical analysis in humanized SCD mice.

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Sickle cell disease (SCD) is an autosomal recessive genetic disorder that affects ∼100,000 Americans and millions of people worldwide. Erythrocyte sickling, vaso-occlusion, sterile inflammation, and hemolysis are the major pathophysiological pathways leading to liver injury in SCD. Although hepatic dysfunction affects up to 10%-40% of patients with SCD, therapeutic approaches to prevent liver injury in SCD are not known, and the molecular mechanisms promoting progressive liver injury in SCD remain poorly understood.

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Acute lung injury, referred to as the acute chest syndrome, is a major cause of morbidity and mortality in patients with sickle cell disease (SCD), which often occurs in the setting of a vaso-occlusive painful crisis. P-selectin antibody therapy reduces hospitalization of patients with SCD by ∼50%, suggesting that an unknown P-selectin-independent mechanism promotes remaining vaso-occlusive events. In patients with SCD, intraerythrocytic polymerization of mutant hemoglobin promotes ischemia-reperfusion injury and hemolysis, which leads to the development of sterile inflammation.

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Article Synopsis
  • Hemophilia A is a genetic bleeding disorder caused by low levels of coagulation factor VIII (FVIII), traditionally treated with IV FVIII treatments.
  • Recent research shows gene therapy using a vector called adeno-associated virus (AAV) can help, but challenges like cellular stress and immune response limit its effectiveness.
  • In a study with FVIII-deficient mice, researchers found that a specific type of liver cell's structural changes hindered gene transfer, indicating that the absence of proper liver cell function affects the success of this therapy.
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Aging is the most significant risk factor for the majority of chronic diseases, including liver disease. The cellular, molecular, and pathophysiological mechanisms that promote age-induced hepatovascular changes are unknown due to our inability to visualize changes in liver pathophysiology in live mice over time. We performed quantitative liver intravital microscopy (qLIM) in live C57BL/6J mice to investigate the impact of aging on the hepatovascular system over a 24-mo period.

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Understanding the kinetics and spatiotemporal interactions of living cells within the tissue environment requires real-time imaging. The introduction of two-photon microscopy has substantially boosted the power of live intravital imaging, making it possible to obtain information of individual cells in near-physiologic conditions within intact tissues nondestructively. Intravital imaging of the liver has proved useful in understanding its 3D structure, function, and dynamic cellular interactions.

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Chromosome rearrangement is one of the hallmarks of human malignancies. Gene fusion is one of the consequences of chromosome rearrangements. In this report, we show that gene fusion between solute carrier family 45 member 2 (SLC45A2) and alpha-methylacyl-coenzyme A racemase (AMACR) occurs in eight different types of human malignancies, with frequencies ranging from 45% to 97%.

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Yes-associated protein 1 (YAP1) regulates cell plasticity during liver injury, regeneration, and cancer, but its role in liver development is unknown. We detect YAP1 activity in biliary cells and in cells at the hepatobiliary bifurcation in single-cell RNA sequencing analysis of developing livers. Deletion of Yap1 in hepatoblasts does not impair Notch-driven SOX9+ ductal plate formation but does prevent the formation of the abutting second layer of SOX9+ ductal cells, blocking the formation of a patent intrahepatic biliary tree.

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Chronic liver disease is one of the leading causes of death in the United States. Coagulopathy is often a sequela of chronic liver disease, however, the role and regulation of coagulation components in chronic liver injury remain poorly understood. Clinical and experimental evidence indicate that misexpression of the procoagulant factor VIII (FVIII) is associated with chronic liver disease.

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Hepatocytes are highly polarized epithelia. Loss of hepatocyte polarity is associated with various liver diseases, including cholestasis. However, the molecular underpinnings of hepatocyte polarization remain poorly understood.

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Article Synopsis
  • P-selectin inhibition can help reduce episodes where blood flow is blocked in SCD patients, but researchers are still looking into its long-term effects.
  • A study using special mice showed that while chronic lack of P-selectin improves liver blood flow, it doesn’t fully protect the liver from damage due to increased cell aging and lower liver cell reproduction.
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Nanomolar concentrations of drag-reducing polymer (DRP) reduce vaso-occlusion in the liver of sickle cell disease (SCD) mice. The potential for DRP as a rheology-based treatment/therapy for SCD warrants further study.

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Article Synopsis
  • * Acute chest syndrome (ACS) is a severe complication of SCD that contributes significantly to patient mortality and can develop from VOE.
  • * Recent research shows that a P-selectin monoclonal antibody, specifically a fusion molecule called TSGL-Ig, can reduce lung vaso-occlusion in SCD mice, demonstrating its potential to prevent both VOE and ACS in SCD patients.
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Article Synopsis
  • Sickle cell disease (SCD) can lead to hepatic crises, but the exact molecular mechanisms of liver injury in SCD are not well understood, prompting research using humanized mouse models and patient blood samples.* -
  • The study found that SCD mice showed liver issues like sinusoidal ischemia and increased liver size due to activation of NF-κB, which disrupted farnesoid X receptor (FXR) function and impaired bile transport and metabolism, causing bile buildup in the liver.* -
  • By blocking NF-κB activation, researchers were able to restore FXR signaling and reduce liver damage in SCD mice, highlighting a potential target for treatments of liver-related complications in sickle cell disease.*
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Article Synopsis
  • P-selectin–deficient mice with sickle cell disease (SCD) show reduced lung vaso-occlusion.
  • These mice can be used as a model to study the effectiveness of anti-P-selectin treatments.
  • This research could help in understanding potential therapies for various complications associated with SCD.
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Article Synopsis
  • In sickle cell disease, the abnormal polymerization of hemoglobin S leads to hemolysis and blockage of small blood vessels, contributing to complications like acute chest syndrome.
  • Researchers used advanced imaging techniques on SCD mice and blood samples to investigate the role of the immune system in causing lung vasoocclusion and injury.
  • They found that platelet activation linked to an inflammasome response results in the formation of inflammatory molecules and platelet-neutrophil aggregates that hinder blood flow, suggesting new therapeutic targets could help prevent acute chest syndrome.
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Background And Aims: The Wnt/β-catenin signaling pathway has a well-described role in liver pathobiology. Its suppression was recently shown to decrease bile acid (BA) synthesis, thus preventing the development of cholestatic liver injury and fibrosis after bile duct ligation (BDL).

Approach And Results: To generalize these observations, we suppressed β-catenin in Mdr2 knockout (KO) mice, which develop sclerosing cholangitis due to regurgitation of BA from leaky ducts.

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Sickle cell disease (SCD) is characterized by chronic hemolysis and repeated episodes of vascular occlusion leading to progressive organ injury. SCD is characterized by unbalanced, simultaneous pro-oxidant and anti-oxidant processes at the molecular, cellular and tissue levels, with the majority of reactions tipped in favor of pro-oxidant pathways. In this brief review we discuss new findings regarding how oxidized hemin, hemolysis, mitochondrial dysfunction and the innate immune system generate oxidative stress while hemopexin, haptoglobin, heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) may provide protection in human and murine SCD.

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Based on their lobule location, hepatocytes display differential gene expression, including pericentral hepatocytes that surround the central vein, which are marked by Wnt-β-catenin signaling. Activating β-catenin mutations occur in a variety of liver tumors, including hepatocellular carcinoma (HCC), but no specific therapies are available to treat these tumor subsets. Here, we identify a positive relationship between β-catenin activation, its transcriptional target glutamine synthetase (GS), and p-mTOR-S2448, an indicator of mTORC1 activation.

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The term blood-bile barrier (BBlB) refers to the physical structure within a hepatic lobule that compartmentalizes and hence segregates sinusoidal blood from canalicular bile. Thus, this barrier provides physiological protection in the liver, shielding the hepatocytes from bile toxicity and restricting the mixing of blood and bile. BBlB is primarily composed of tight junctions; however, adherens junction, desmosomes, gap junctions, and hepatocyte bile transporters also contribute to the barrier function of the BBlB.

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