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Aging Cell May 2024ATP citrate lyase (ACLY) inhibitors have the potential of modulating central processes in protein, carbohydrate, and lipid metabolism, which can have relevant...
ATP citrate lyase (ACLY) inhibitors have the potential of modulating central processes in protein, carbohydrate, and lipid metabolism, which can have relevant physiological consequences in aging and age-related diseases. Here, we show that hepatic phospho-active ACLY correlates with overweight and Model for End-stage Liver Disease score in humans. Wild-type mice treated chronically with the ACLY inhibitor potassium hydroxycitrate exhibited delayed early mortality. In AML12 hepatocyte cultures, the ACLY inhibitors potassium hydroxycitrate, SB-204990, and bempedoic acid fostered lipid accumulation, which was also observed in the liver of healthy-fed mice treated with potassium hydroxycitrate. Analysis of soleus tissue indicated that potassium hydroxycitrate produced the modulation of wound healing processes. In vivo, potassium hydroxycitrate modulated locomotor function toward increased wire hang performance and reduced rotarod performance in healthy-fed mice, and improved locomotion in mice exposed to cardiotoxin-induced muscle atrophy. Our findings implicate ACLY and ACLY inhibitors in different aspects of aging and muscle regeneration.
PubMed: 38760909
DOI: 10.1111/acel.14205 -
PloS One 2024Insulin resistance is a common pathophysiology in patients with type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Thus, screening...
Insulin resistance is a common pathophysiology in patients with type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Thus, screening for the risk of insulin resistance is important to prevent disease progression. We evaluated the alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio to predict insulin resistance in the general population, regardless of comorbidities. Datasets from the 2015, 2019, and 2020 Korea National Health and Nutrition Examination Surveys were used, and the following four indices were implemented to indicate insulin resistance: fasting serum glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), and β-cell function. We analyzed the degree of association between the liver enzyme profile and insulin resistance indices using Pearson's correlation coefficient and determined the associations using linear or logistic regression analysis. Accordingly, ALT levels in both sexes were positively and consistently correlated with the four aforementioned insulin resistance indices in stratification analyses based on diabetes, dyslipidemia, alcohol consumption, and obesity status. In multivariate linear regression, when comparing with ALT levels, the ALT/AST ratio exhibited superior predictive performance for fasting serum glucose and HOMA-β in Korean men and improved outcomes for all insulin resistance indices in Korean women. In this analysis that included a large community-based population, the ALT/AST ratio was a more useful predictive marker than the HOMA-IR. Regarding the predicted presence or absence of insulin resistance, the ALT/AST ratio could better predict HOMA-IR than the ALT level alone in Koreans. A simple, precise marker that represents the ALT/AST ratio could be a practical method to screen for insulin resistance in the general population, regardless of diabetes mellitus, alcohol intake, and sex.
Topics: Humans; Insulin Resistance; Male; Female; Republic of Korea; Alanine Transaminase; Middle Aged; Cross-Sectional Studies; Aspartate Aminotransferases; Adult; Blood Glucose; Diabetes Mellitus, Type 2; Nutrition Surveys; Cohort Studies; Aged
PubMed: 38758828
DOI: 10.1371/journal.pone.0303333 -
Transplantation Direct Jun 2024Failure to close the abdominal wall after intestinal transplantation (ITx) or multivisceral Tx remains a surgical challenge. An attractive method is the use of...
BACKGROUND
Failure to close the abdominal wall after intestinal transplantation (ITx) or multivisceral Tx remains a surgical challenge. An attractive method is the use of nonvascularized rectus fascia (NVRF) in which both layers of the donor abdominal rectus fascia are used as an inlay patch without vascular anastomosis. How this graft integrates over time remains unknown. The study aims to provide a multilevel analysis of the neovascularization and integration process of the NVRF.
METHODS
Three NVRF-Tx were performed after ITx. Clinical, radiological, histological, and immunological data were analyzed to get insights into the neovascularization and integration process of the NVRF. Moreover, cryogenic contrast-enhanced microfocus computed tomography (microCT) analysis was used for detailed reconstruction of the vasculature in and around the NVRF (3-dimensional histology).
RESULTS
Two men (31- and 51-y-old) and 1 woman (49-y-old) underwent 2 multivisceral Tx and 1 combined liver-ITx, respectively. A CT scan showed contrast enhancement around the fascia graft at 5 days post-Tx. At 6 weeks, newly formed blood vessels were visualized around the graft with Doppler ultrasound. Biopsies at 2 weeks post-Tx revealed inflammation around the NVRF and early fibrosis. At 6 months, classical 2-dimensional histological analysis of a biopsy confirmed integration of the fascia graft with strong fibrotic reaction without signs of rejection. A cryogenic contrast-enhanced microCT scan of the same biopsy revealed the presence of microvasculature, enveloping and penetrating the donor fascia.
CONCLUSIONS
We showed clinical, histological, and microCT evidence of the neovascularization and integration process of the NVRF after Tx.
PubMed: 38757048
DOI: 10.1097/TXD.0000000000001624 -
Heliyon May 2024The progression of liver diseases, from viral hepatitis and fatty liver disease to cirrhosis and hepatocellular carcinoma (HCC), is the most representative series of... (Review)
Review
The progression of liver diseases, from viral hepatitis and fatty liver disease to cirrhosis and hepatocellular carcinoma (HCC), is the most representative series of pathological events in liver diseases. While serotonin (5-HT) primarily regulates brain functions such as psychology, mood, and appetite in the central nervous system (CNS), peripheral 5-HT plays a crucial role in regulating tumor development, glucose and lipid metabolism, immune function and inflammatory response related to liver diseases. These peripheral physiological processes involving 5-HT are the key mechanisms driving the development of these liver diseases. This study presents an overview of the existing literature, focusing on the role of 5-HT in HCC, cirrhosis, fatty liver disease, viral hepatitis, and liver injury. In summary, while 5-HT promotes liver regeneration, it can also contribute to the progression of chronic liver disease. These findings indicate the potential for the development and use of 5-HT-related drugs for the treatment of liver diseases, including HCC and cirrhosis.
PubMed: 38756588
DOI: 10.1016/j.heliyon.2024.e30703 -
Frontiers in Cellular and Infection... 2024Infectious diseases are among the factors that account for a significant proportion of disease-related deaths worldwide. The primary treatment approach to combat... (Review)
Review
Infectious diseases are among the factors that account for a significant proportion of disease-related deaths worldwide. The primary treatment approach to combat microbial infections is the use of antibiotics. However, the widespread use of these drugs over the past two decades has led to the emergence of resistant microbial species, making the control of microbial infections a serious challenge. One of the most important solutions in the field of combating infectious diseases is the regulation of the host's defense system. Toll-like receptors (TLRs) play a crucial role in the first primary defense against pathogens by identifying harmful endogenous molecules released from dying cells and damaged tissues as well as invading microbial agents. Therefore, they play an important role in communicating and regulating innate and adaptive immunity. Of course, excessive activation of TLRs can lead to disruption of immune homeostasis and increase the risk of inflammatory reactions. Targeting TLR signaling pathways has emerged as a new therapeutic approach for infectious diseases based on host-directed therapy (HDT). In recent years, stem cell-derived exosomes have received significant attention as factors regulating the immune system. The regulation effects of exosomes on the immune system are based on the HDT strategy, which is due to their cargoes. In general, the mechanism of action of stem cell-derived exosomes in HDT is by regulating and modulating immunity, promoting tissue regeneration, and reducing host toxicity. One of their most important cargoes is microRNAs, which have been shown to play a significant role in regulating immunity through TLRs. This review investigates the therapeutic properties of stem cell-derived exosomes in combating infections through the interaction between exosomal microRNAs and Toll-like receptors.
Topics: Exosomes; Toll-Like Receptors; Humans; MicroRNAs; Animals; Stem Cells; Signal Transduction; Immunity, Innate; Communicable Diseases; Adaptive Immunity
PubMed: 38756232
DOI: 10.3389/fcimb.2024.1384420 -
Nature Communications May 2024Hepatocytes play important roles in the liver, but in culture, they immediately lose function and dedifferentiate into progenitor-like cells. Although this unique...
Hepatocytes play important roles in the liver, but in culture, they immediately lose function and dedifferentiate into progenitor-like cells. Although this unique feature is well-known, the dynamics and mechanisms of hepatocyte dedifferentiation and the differentiation potential of dedifferentiated hepatocytes (dediHeps) require further investigation. Here, we employ a culture system specifically established for hepatic progenitor cells to study hepatocyte dedifferentiation. We found that hepatocytes dedifferentiate with a hybrid epithelial/mesenchymal phenotype, which is required for the induction and maintenance of dediHeps, and exhibit Vimentin-dependent propagation, upon inhibition of the Hippo signaling pathway. The dediHeps re-differentiate into mature hepatocytes by forming aggregates, enabling reconstitution of hepatic tissues in vivo. Moreover, dediHeps have an unexpected differentiation potential into intestinal epithelial cells that can form organoids in three-dimensional culture and reconstitute colonic epithelia after transplantation. This remarkable plasticity will be useful in the study and treatment of intestinal metaplasia and related diseases in the liver.
Topics: Animals; Hepatocytes; Cell Differentiation; Epithelial Cells; Cell Dedifferentiation; Mice; Organoids; Epithelial-Mesenchymal Transition; Intestinal Mucosa; Cells, Cultured; Signal Transduction; Vimentin; Hippo Signaling Pathway; Liver; Mice, Inbred C57BL; Male; Cell Culture Techniques
PubMed: 38750036
DOI: 10.1038/s41467-024-47869-2 -
ELife May 2024Quiescence (G0) maintenance and exit are crucial for tissue homeostasis and regeneration in mammals. Here, we show that methyl-CpG binding protein 2 (Mecp2) expression...
Quiescence (G0) maintenance and exit are crucial for tissue homeostasis and regeneration in mammals. Here, we show that methyl-CpG binding protein 2 (Mecp2) expression is cell cycle-dependent and negatively regulates quiescence exit in cultured cells and in an injury-induced liver regeneration mouse model. Specifically, acute reduction of Mecp2 is required for efficient quiescence exit as deletion of Mecp2 accelerates, while overexpression of Mecp2 delays quiescence exit, and forced expression of Mecp2 after Mecp2 conditional knockout rescues cell cycle reentry. The E3 ligase Nedd4 mediates the ubiquitination and degradation of Mecp2, and thus facilitates quiescence exit. A genome-wide study uncovered the dual role of Mecp2 in preventing quiescence exit by transcriptionally activating metabolic genes while repressing proliferation-associated genes. Particularly disruption of two nuclear receptors, or accelerates quiescence exit, mimicking the Mecp2 depletion phenotype. Our studies unravel a previously unrecognized role for Mecp2 as an essential regulator of quiescence exit and tissue regeneration.
Topics: Animals; Methyl-CpG-Binding Protein 2; Mice; Mice, Knockout; Receptors, Cytoplasmic and Nuclear; Cell Cycle; Liver Regeneration; Gene Expression Regulation
PubMed: 38747706
DOI: 10.7554/eLife.89912 -
BMC Gastroenterology May 2024The liver regeneration is a highly complicated process depending on the close cooperations between the hepatocytes and non-parenchymal cells involving various...
BACKGROUND
The liver regeneration is a highly complicated process depending on the close cooperations between the hepatocytes and non-parenchymal cells involving various inflammatory cells. Here, we explored the role of myeloid-derived suppressor cells (MDSCs) in the processes of liver regeneration and liver fibrosis after liver injury.
METHODS
We established four liver injury models of mice including CCl-induced liver injury model, bile duct ligation (BDL) model, concanavalin A (Con A)-induced hepatitis model, and lipopolysaccharide (LPS)-induced hepatitis model. The intrahepatic levels of MDSCs (CD11bGr-1) after the liver injury were detected by flow cytometry. The effects of MDSCs on liver tissues were analyzed in the transwell co-culture system, in which the MDSCs cytokines including IL-10, VEGF, and TGF-β were measured by ELISA assay and followed by being blocked with specific antibodies.
RESULTS
The intrahepatic infiltrations of MDSCs with surface marker of CD11bGr-1 remarkably increased after the establishment of four liver injury models. The blood served as the primary reservoir for hepatic recruitment of MDSCs during the liver injury, while the bone marrow appeared play a compensated role in increasing the number of MDSCs at the late stage of the inflammation. The recruited MDSCs in injured liver were mainly the M-MDSCs (CD11bLy6GLy6C) featured by high expression levels of cytokines including IL-10, VEGF, and TGF-β. Co-culture of the liver tissues with MDSCs significantly promoted the proliferation of both hepatocytes and hepatic stellate cells (HSCs).
CONCLUSIONS
The dramatically and quickly infiltrated CD11bGr-1 MDSCs in injured liver not only exerted pro-proliferative effects on hepatocytes, but also accounted for the activation of profibrotic HSCs.
Topics: Animals; Myeloid-Derived Suppressor Cells; Mice; Liver Cirrhosis; Liver Regeneration; CD11b Antigen; Male; Mice, Inbred C57BL; Disease Models, Animal; Liver; Vascular Endothelial Growth Factor A; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Concanavalin A; Ligation; Lipopolysaccharides; Interleukin-10; Transforming Growth Factor beta; Hepatic Stellate Cells; Coculture Techniques; Hepatocytes; Bile Ducts
PubMed: 38745150
DOI: 10.1186/s12876-024-03245-4 -
Scientific Reports May 2024Multiple studies have shown knockdown of chromobox 7 (CBX7) promotes the regenerative capacity of various cells or tissues. We examined the effect of CBX7 on hepatocyte...
Multiple studies have shown knockdown of chromobox 7 (CBX7) promotes the regenerative capacity of various cells or tissues. We examined the effect of CBX7 on hepatocyte proliferation and liver regeneration after 2/3 hepatectomy in a mouse model. For in vitro experiments, NCTC 1469 and BNL CL.2 hepatocytes were co-transfected with siRNA-CBX7-1 (si-CBX7-1), siRNA-CBX7-2 (si-CBX7-2), pcDNA-CBX7, si-BMI1-1, si-BMI1-2, pcDNA-BMI1, or their negative control. For in vivo experiments, mice were injected intraperitoneally with lentivirus-packaged shRNA and shRNA CBX7 before hepatectomy. Our results showed that CBX7 was rapidly induced in the early stage of liver regeneration. CBX7 regulated hepatocyte proliferation, cell cycle, and apoptosis of NCTC 1469 and BNL CL.2 hepatocytes. CBX7 interacted with BMI1 and inhibited BMI1 expression in hepatocytes. Silencing BMI1 aggregated the inhibitory effect of CBX7 overexpression on hepatocyte viability and the promotion of apoptosis. Furthermore, silencing BMI1 enhanced the regulatory effect of CBX7 on Nrf2/ARE signaling in HGF-induced hepatocytes. In vivo, CBX7 silencing enhanced liver/body weight ratio in PH mice. CBX7 silencing promoted the Ki67-positive cell count and decreased the Tunel-positive cell count after hepatectomy, and also increased the expression of nuclear Nrf2, HO-1, and NQO-1. Our results suggest that CBX7 silencing may increase survival following hepatectomy by promoting liver regeneration.
Topics: Animals; Polycomb Repressive Complex 1; NF-E2-Related Factor 2; Signal Transduction; Mice; Cell Proliferation; Hepatocytes; Liver Regeneration; Apoptosis; Hepatectomy; Male; Gene Silencing; Mice, Inbred C57BL; Liver
PubMed: 38744845
DOI: 10.1038/s41598-024-58248-8 -
Stem Cells Translational Medicine May 2024Cholestatic liver disease (CLD) is a severe disease, which can progress to liver cirrhosis, even liver cancer. Hepatic stellate cells (HSCs) activation plays a crucial...
Cholestatic liver disease (CLD) is a severe disease, which can progress to liver cirrhosis, even liver cancer. Hepatic stellate cells (HSCs) activation plays a crucial role in CLD development. Bone mesenchymal stem cells (BMSCs) treatment was demonstrated to be beneficial in liver diseases. However, the therapeutic effect and mechanism of BMSCs on CLD are poorly known. In the present study, we investigated the therapeutic effects and underlying mechanisms of BMSCs transplantation in mouse models of bile duct ligation-induced cholestatic liver fibrosis (CLF). The results revealed that BMSCs significantly improved liver function and reduced the formation of fibrosis after portal vein transplantation. Mechanistically, after coculturing BMSCs and HSCs, we identified that BMSCs alleviated starvation-induced HSCs activation. Further, BMSCs inhibited HSCs activation by decreasing autophagy, and PI3K/AKT/mTOR pathway was involved in the regulation. More importantly, ULK1 is identified as the main autophagy-related gene regulated by BMSCs in HSCs autophagy. Overexpression of ULK1 reversed the suppression of HSCs autophagy by BMSCs. Collectively, our results provide a theoretical basis for BMSCs targeting ULK1 to attenuate HSCs autophagy and activation and suggest that BMSCs or ULK1 may be an alternative therapeutic approach/target for the treatment of CLF.
PubMed: 38736295
DOI: 10.1093/stcltm/szae028