المؤلفون: Juneja, Pinky, Sharma, Aarti, Shasthry, S. M., Kumar, Guresh, Tripathi, Dinesh M., Rajan, V., Rastogi, Archana, Sarin, Shiv K., Kaur, Savneet

المصدر: Frontiers in Physiology; 2023, p1-10, 10p

مصطلحات موضوعية: CIRRHOSIS of the liver, DUODENUM, GENE expression, REFERENCE values, MORTALITY

مستخلص: Dilated and dysfunctional gut lymphatic vessels (LVs) have been reported in experimental cirrhosis. Here, we studied LVs in duodenal (D2)-biopsies of liver cirrhosis patients and investigated the prognostic role of a LV marker, podoplanin (PDPN), in predicting the mortality of patientswith cirrhosis. A prospective, single-center cohort study was performed in liver cirrhosis patients (n = 31) and matched healthy controls (n = 9). D2-biopsies were obtained during endoscopy procedure, immunostained with PDPN, and scored based on 1) intensity and 2) density of positively-stained LVs per high power field. Gut and systemic inflammation were estimated by quantifying duodenal CD3+ intraepithelial lymphocytes (IELs), CD68+ macrophages, and serum TNF-α and IL-6 levels, respectively. Gut permeability and inflammation as assessed by quantifying gene expression of TJP1, OCLN, TNF-α, and IL-6 in D2-biopsies. Gene expression of LV markers, PDPN (8-fold), and LYVE1 (3-fold)was enhanced in D2-biopsies of cirrhosis patients compared to control (p < 0.0001). The mean PDPN score in decompensated cirrhosis patients (6.91 ± 1.26, p < 0.0001) was significantly increased as compared to those with compensated (3.25 ± 1.60). PDPN score positively and significantly correlated with the number of IELs (r = 0.33), serum TNF-α (r = 0.35), and IL-6 (r = 0.48) levels, while inversely correlated with TJP1 expression (r = -0.46, p < 0.05 each). In Cox regression, the PDPN score was a significant and independent 3-month-mortality predictor in patients (HR: 5.61; 1.08-29.109; p = 0.04). The area under the curve for the PDPN score was 84.2, and cutoff value for predicting mortality was =6.5 with 100% sensitivity and 75% specificity. Collectively, dilated LVs with high PDPN expression in D2-biopsies is a characteristic feature of patients with decompensated cirrhosis. PDPNscore correlateswith enhanced gut and systemic inflammation and also associates with 3-month mortality in cirrhosis. [ABSTRACT FROM AUTHOR]

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المؤلفون: Kaur, Savneet, Tripathi, Dinesh M., Yadav, Angeera

المصدر: Frontiers in Physiology; 8/4/2020, Vol. 11, pN.PAG-N.PAG, 7p

مصطلحات موضوعية: COVID-19, ENDOTHELIUM, PATHOLOGY, SARS-CoV-2, SYMPTOMS

مستخلص: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome–related coronavirus-2 (SARS-CoV-2) has affected millions of people globally. Clinically, it presents with mild flu-like symptoms in most cases but can cause respiratory failure in high risk population. With the aim of unearthing newer treatments, scientists all over the globe are striving hard to comprehend the underlying mechanisms of COVID-19. Several studies till date have indicated a dysregulated host immune response as the major cause of COVID-19 induced mortality. In this Perspective, we propose a key role of endothelium, particularly pulmonary endothelium in the pathogenesis of COVID-19. We draw parallels and divergences between COVID-19-induced respiratory distress and bacterial sepsis-induced lung injury and recommend the road ahead with respect to identification of endothelium-based biomarkers and plausible treatments for COVID-19. [ABSTRACT FROM AUTHOR]

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المؤلفون: Tripathi, Dinesh Mani, Hassan, Mohsin, Siddiqui, Hamda, Kaur, Impreet, Rawal, Preety, Bihari, Chaggan, Kaur, Savneet, Sarin, Shiv K.

المصدر: Frontiers in Physiology; 6/11/2020, Vol. 11, p1-13, 13p

مصطلحات موضوعية: PROGENITOR cells, LIVER cells, PORTAL hypertension, ENDOTHELIAL cells, NEOVASCULARIZATION

مستخلص: Background: Circulating cirrhotic endothelial progenitor cells (EPC) interact with both liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC) and promote angiogenesis in vitro. This study evaluated the effect of cirrhotic and control EPCs on hepatic angiogenesis, microcirculation, and fibrosis in vivo in rat models of cirrhosis. Methodology: Animal models of cirrhosis were prepared by bile duct ligation (BDL). Circulating EPCs isolated from healthy human and cirrhotic blood were characterized by flow cytometry, cultured and administered through the tail vein in BDL rats after 2 weeks of ligation. The cells were given thrice a week for 2 weeks. The untreated group of BDL rats received only saline. Fibrosis was evaluated by Masson's trichrome staining. Dedifferentiated LSECs were identified by the expression of CD31, and activated HSCs were marked as alpha-SMA-positive cells and were studied by immunohistochemistry and western blotting in saline-, healthy EPC-, and cirrhotic EPC-treated rats. In vivo , hepatic and systemic hemodynamic parameters were evaluated. Liver functions were evaluated. Results: In comparison to controls, BDL rats revealed an increase of fibrosis and angiogenesis. Among the treated rats, cirrhotic EPC-treated rats had increased fibrosis grade as compared to healthy EPC-treated and saline-treated rats. There was an increase of both fibrosis and angiogenesis markers, alpha-SMA and CD31 in cirrhotic EPC-treated rats as compared to healthy EPC-treated and saline-treated rats in immunohistochemistry and western blot studies. Cirrhotic EPC-treated BDL rats had high portal pressure and portal blood flow with significantly elevated hepatic vascular resistance in comparison with healthy EPC- and saline-treated BDL animals, without significant differences in mean arterial pressure. Cirrhotic EPC-treated BDL rats also showed a substantial increase in the hepatic expression of angiogenic receptors, VEGFR2 and CXCR4 in comparison with saline-treated rats. Conclusion: The study suggests that transplantation of cirrhotic EPCs enhances LSEC differentiation and angiogenesis, activates HSCs and worsens fibrosis, thus resulting in hepatic hemodynamic derangements in BDL-induced cirrhosis. [ABSTRACT FROM AUTHOR]

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المؤلفون: Rawal, Preety, Siddiqui, Hamda, Hassan, Mohsin, Choudhary, Manish Chandra, Tripathi, Dinesh M., Nain, Vikrant, Trehanpati, Nirupama, Kaur, Savneet

المصدر: Frontiers in Oncology; 4/24/2019, pN.PAG-N.PAG, 9p

مصطلحات موضوعية: LIVER cancer, HEPATITIS B virus, GENE expression, FLOW cytometry, CHEMOTAXIS

مستخلص: Background: Hepatitis B-X Protein (HBx) encoded in Hepatitis B virus (HBV) is known to play a critical role in development and progression of HBV induced hepatocellular carcinoma (HCC). HBx interacts with and activates various cells in HCC microenvironment to promote tumor initiation, progression and invasion. In this study, we investigated how surrounding stromal cells interact with HBx-infected hepatoma cells by a series of in vitro co-culture studies. Methods: Huh7 hepatoma cells were cultured and transfected with the mammalian expression vector pGFP-HBx. Co-culture assays were performed between HBx-transfected Huh7 cells and conditioned media (CM) from stromal cells [endothelial cell lines (HUVECs) and hepatic stellate cell lines (LX2 cells)]. The effect of these interactions was studied by a series of functional assays like chemotaxis, invasion, and wound healing scratch assays. Also, quantitative real time (RT)-PCRs of the mesenchymal genes was performed in the hepatoma cells with and without the co-cultures. Hep3B cells with an integrated HBV genome were taken as positive controls. Results: HBx-transfected Huh7 cells cultured in presence of CM from HUVECs illustrated enhanced migration and tube formation as compared to HBx-transfected cells cultured alone or co-cultured with LX2 cells. HBx-transfected hepatoma cells incubated with CM from HUVECs also expressed mesenchymal genes including Thy1, CDH2, TGFβR1, VIM, and CD133. ELISAs revealed increased levels of TGF-β in CM from HUVECs. In comparison to unstimulated HBx-transfected Huh7 cells, TGF-β stimulated cells displayed increased invasive properties and mesenchymal gene expression. RT-PCR and flow cytometry analysis further demonstrated that incubation with either CM from HUVECs or TGF-β significantly increased the expression of a stemness marker, CD133 in HBx-infected hepatoma cells. Gene inhibition experiments with CD133 siRNA showed a downregulation of mesenchymal gene expression and properties in TGF-β induced HBx-infected hepatoma cells as compared to that observed in control siRNA treated cells, indicating CD133 as one of the key molecules affecting epithelial to mesenchymal transition (EMT) in HBx-infected cells. Conclusion: The study indicates that secretory factors like TGF-β from neighboring endothelial cells may enhance expression of CD133 and impart an aggressive EMT phenotype to HBx-infected hepatoma cells in HBV induced HCC. [ABSTRACT FROM AUTHOR]

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المؤلفون: Kaur, Savneet, Sehgal, Rashi, Shastry, Saggere M., McCaughan, Geoffrey, McGuire, Helen M., St de Groth, Barbara Fazekas, Sarin, Shiv, Trehanpati, Nirupma, Seth, Devanshi

المصدر: Frontiers in Physiology; 5/22/2018, p1-10, 10p

مصطلحات موضوعية: PROGENITOR cells, LIVER injuries, CIRRHOSIS of the liver, PHENOTYPES, CYTOKINES

مستخلص: Background and Aim: Endothelial progenitor cells (EPCs) have been implicated in liver injury and repair. However, the phenotype and potential of these heterogenous EPCs remain elusive. In particular, their involvement in the pathogenesis of alcoholic liver cirrhosis (ALC) remains unclear. The current study extensively characterized the phenotype and functions of EPCs to understand their role in ALC pathogenesis. Methods: Circulating EPCs were identified as CD34+CD133+CD31+ cells by flow cytometer in ALC patients (n = 7) and healthy controls (HC, n = 7). A comprehensive characterization of circulating EPCs using more than 30 phenotype markers was performed by mass cytometer time of flight (CyTOF) in an independent cohort of age and gender matched ALC patients (n = 4) and controls (n = 5). Ex vivo cultures of circulating EPCs fromALC patients (n=20) and controls (n=18) were also tested for their functions, including colony formation, LDL uptake, lectin binding and cytokine secretion (ELISA). Results: Three distinct populations of circulating EPCs (CD34+CD133+CD31+) were identified, classified on their CD45 expression (negative: CD45-; intermediate: CD45^int; high: CD45^hi). CD45^int and CD45^hi EPCs significantly increased in ALC patients compared to controls (p-val = 0.006). CyTOF data showed that CD45^hi EPCs were distinct from CD45- and CD45^int EPCs, with higher expression of T cell and myeloid markers, including CD3, CD4, HLA-DR, and chemokine receptors, CCR2, CCR5, CCR7, and CX3CR1. Similar to circulating EPCs, percentage of CD45^hiCD34+CD31+ EPCs in ex-vivo cultures from patients, were significantly higher compared to controls (p < 0.05). Cultured EPCs from patients also showed increased LDL uptake, lectin binding and release of TNF-alpha, RANTES, FGF-2, and VEGF. Conclusions: We report the first extensive characterization of circulating human EPCs with distinct EPC subtypes. Increase in CD45^hi EPC subtype in ALC patients with enhanced functions, inflammatory cytokines and angiogenic mediators in patients suggests an inflammatory role for these cells in ALC. [ABSTRACT FROM AUTHOR]

: Copyright of Frontiers in Physiology is the property of Frontiers Media S.A. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)