Chronic liver disease (CLD) is a growing health concern which accounts for two million deaths per year. Obesity, alcohol overconsumption, and progressive cholestasis are commonly characterized by ...persistent low-grade inflammation and advancing fibrosis, which form the basis for development of end-stage liver disease complications, including hepatocellular carcinoma. CLD pathophysiology extends to the intestinal tract and is characterized by intestinal dysbiosis, bile acid dysregulation, and gut barrier disruption. In addition, macrophages are key players in CLD progression and intestinal barrier breakdown. Emerging studies are unveiling macrophage heterogeneity and driving factors of their plasticity in health and disease. To date, in-depth investigation of how gut-liver axis disruption impacts the hepatic and intestinal macrophage pool in CLD pathogenesis is scarce. In this review, we give an overview of the role of intestinal and hepatic macrophages in homeostasis and gut-liver axis disruption in progressive stages of CLD.
Due to the usually late diagnosis and lack of effective therapies, hepatocellular carcinoma (HCC), which poses a growing global health problem, is characterized by a poor prognosis. Angiogenesis ...plays an important role in HCC progression, and vascular endothelial growth factor (VEGF) and angiopoietins (Angs) are key drivers of HCC angiogenesis. VEGF-targeting strategies already represent an important component of today's systemic treatment landscape of HCC, whereas targeting the Ang/Tie2 signaling pathway may harbor future potential in this context due to reported beneficial anticancer effects when targeting this pathway. In addition, a better understanding of the relation between Angs and HCC angiogenesis and progression may reveal their potential as predictive factors for post-treatment disease progression and prognosis. In this review, we give a comprehensive overview of the complex role of Ang/Tie2 signaling in HCC, pinpointing its potential value as biomarker and target for HCC treatments, aiding HCC diagnosis and therapy.
Introduction: Irisin is a novel hormone originally identified for its role as a regulator of peripheral metabolism and recently found to protect synapses and rescue memory in mouse models of ...Alzheimer's disease (AD). However, whether and how cerebrospinal fluid (CSF) irisin varies in relation to canonical AD biomarkers and cognition in humans remains unknown.
Methods: We determined CSF levels of irisin and brain‐derived neurotrophic factor (BDNF) and examined their correlations with CSF amyloid beta (Aβ)42, total tau, and Mini‐Mental State Exam (MMSE) scores in a cohort comprising AD patients (n = 14) and non‐demented controls (NDC; n = 25).
Results: CSF irisin correlated positively with BDNF, Aβ42, and MMSE scores, but not with CSF total tau.
Discussion: Results indicate that CSF irisin and BDNF are directly correlated with Aβ pathology and cognition in AD.
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death globally. HCC is a complex multistep disease and usually emerges in the ...setting of chronic liver diseases. The molecular pathogenesis of HCC varies according to the etiology, mainly caused by chronic hepatitis B and C virus infections, chronic alcohol consumption, aflatoxin-contaminated food, and non-alcoholic fatty liver disease associated with metabolic syndrome or diabetes mellitus. The establishment of HCC models has become essential for both basic and translational research to improve our understanding of the pathophysiology and unravel new molecular drivers of this disease. The ideal model should recapitulate key events observed during hepatocarcinogenesis and HCC progression in view of establishing effective diagnostic and therapeutic strategies to be translated into clinical practice. Despite considerable efforts currently devoted to liver cancer research, only a few anti-HCC drugs are available, and patient prognosis and survival are still poor. The present paper provides a state-of-the-art overview of in vivo and in vitro models used for translational modeling of HCC with a specific focus on their key molecular hallmarks.
Connexin proteins can form hexameric hemichannels and gap junctions that mediate paracrine and direct intercellular communication, respectively. Gap junction activity is crucial for the maintenance ...of hepatic homeostasis, while connexin hemichannels become particularly active in liver disease, such as hepatitis, fibrosis, cholestasis or even hepatocellular carcinoma. Channels consisting of connexin-like proteins named pannexins have been directly linked to liver inflammation and cell death. The goal of the present study was to characterize the expression and subcellular localization of connexins and pannexins in liver of patients suffering from various chronic and neoplastic liver diseases. Specifically, real-time quantitative reverse transcription polymerase chain reaction, immunoblotting and immunohistochemistry analyses were performed on human liver biopsies. It was found that pannexin1 and pannexin2 gene expression are correlated to a certain degree, as is pannexin1 protein expression with connexin32 and connexin43 protein expression. Furthermore, this study is the first to detect pannexin3 in human patient liver biopsies
via
both immunoblot and immunohistochemistry.
The liver is the largest solid organ in the body, yet it remains incompletely characterized. Here we present a spatial proteogenomic atlas of the healthy and obese human and murine liver combining ...single-cell CITE-seq, single-nuclei sequencing, spatial transcriptomics, and spatial proteomics. By integrating these multi-omic datasets, we provide validated strategies to reliably discriminate and localize all hepatic cells, including a population of lipid-associated macrophages (LAMs) at the bile ducts. We then align this atlas across seven species, revealing the conserved program of bona fide Kupffer cells and LAMs. We also uncover the respective spatially resolved cellular niches of these macrophages and the microenvironmental circuits driving their unique transcriptomic identities. We demonstrate that LAMs are induced by local lipid exposure, leading to their induction in steatotic regions of the murine and human liver, while Kupffer cell development crucially depends on their cross-talk with hepatic stellate cells via the evolutionarily conserved ALK1-BMP9/10 axis.
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•Spatial proteogenomic single-cell atlas of healthy and obese murine and human liver•Validated flow cytometry and microscopy panels for all hepatic cells•LAMs are differentially located in the lean and obese liver•Evolutionary conserved BMP9/10-ALK1 axis is essential for KC development
By combining single-cell and -nucleus sequencing with spatial mapping of RNA and proteins, this vast spatial proteogenomic atlas of healthy and obese human and mouse livers presents methods to identify and localize all hepatic cells and provides insights into hepatic myeloid cells, including identification of reliable surface markers for isolation and localization of hepatic macrophages, characterization of lipid-associated macrophages in both healthy and steatotic livers, determination of a key regulatory axis of Kupffer cell development, and identification of a conserved core gene expression signature of Kupffer cells across 7 species, including chickens and zebrafish.
An hemodialysis population in Central Brazil was screened by polymerase
chain reaction (PCR) and serological methods to assess the prevalence
of hepatitis C virus (HCV) infection and to investigate ...associated risk
factors. All hemodialysis patients (n=428) were interviewed in eight
dialysis units in Goiânia city. Blood samples were collected and
serum samples screened for anti-HCV antibodies by an enzyme-linked
immunosorbent assay (ELISA). Positive samples were retested for
confirmation with a line immunoassay (LIA). All samples were also
tested for HCV RNA by the PCR. An overall prevalence of 46.7% (CI 95%:
42-51.5) was found, ranging from 20.7% (CI 95%: 8.8-38.1) to 90.4% (CI
95%: 79.9-96.4) depending on the dialysis unit. Of the 428 patients,
185 were found to be seropositive by ELISA, and 167 were confirmed
positive by LIA, resulting in an anti-HCV prevalence of 39%. A total of
131 patients were HCV RNA-positive. HCV viremia was present in 63.5% of
the anti-HCV-positive patients and in 10.3% of the anti-HCV-negative
patients. Univariate analysis of risk factors showed that the number of
previous blood transfusions, transfusion of blood before mandatory
screening for anti-HCV, length of time on hemodialysis, and treatment
in multiple units were associated with HCV positivity. However,
multivariate analysis revealed that blood transfusion before screening
for anti-HCV and length of time on hemodialysis were significantly
associated with HCV infection in this population. These data suggest
that nosocomial transmission may play a role in the spread of HCV in
the dialysis units studied. In addition to anti-HCV screening, HCV RNA
detection is necessary for the diagnosis of HCV infection in
hemodialysis patients.
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