Prevalence and clinical impact of sarcopenia in liver transplant recipients: A meta-analysis.

BACKGROUND: The prevalence of sarcopenia in patients undergoing liver transplantation (LT) remains to be determined partly because of different diagnostic criteria. Sarcopenia has recently been recognized as a new prognostic factor for predicting outcomes in LT candidates. AIM: To estimate the prevalence of sarcopenia and evaluate its clinical effect on LT candidates. METHODS: This systematic search was conducted in PubMed, Web of Science, Embase, and Cochrane Library for original English-language articles that investigated the prevalence and influence of sarcopenia in patients undergoing LT from database inception to November 30, 2022. Cohort studies of the definition of sarcopenia that estimate sarcopenia prevalence and evaluate its effect on clinical outcomes and the risk of mortality were included. RESULTS: Twenty-five studies involving 7760 patients undergoing LT were included. The pooled prevalence of sarcopenia in patients undergoing LT was 40.7% [95% confidence intervals (95%CI): 32.1-49.6]. The 1-, 3-, and 5-year cumulative probabilities of post-LT survival in patients with preoperative sarcopenia were all lower than those without sarcopenia (P < 0.05). Sarcopenia was associated with an increased risk of post-LT mortality in patients undergoing LT (adjusted hazard ratio: 1.58; 95%CI: 1.21-2.07). Patients with preoperative sarcopenia had a longer intensive care unit stay, a high risk ratio of sepsis, and serious post-LT complications than those without sarcopenia. CONCLUSION: Sarcopenia is prevalent in a substantial proportion of patients undergoing LT and is strongly and independently associated with higher a risk of mortality risk.

LONP1 ameliorates liver injury and improves gluconeogenesis dysfunction in acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe liver disease with complex pathogenesis. Clinical hypoglycemia is common in patients with ACLF and often predicts a worse prognosis. Accumulating evidence suggests that glucose metabolic disturbance, especially gluconeogenesis dysfunction, plays a critical role in the disease progression of ACLF. Lon protease-1 (LONP1) is a novel mediator of energy and glucose metabolism. However, whether gluconeogenesis is a potential mechanism through which LONP1 modulates ACLF remains unknown. METHODS: In this study, we collected liver tissues from ACLF patients, established an ACLF mouse model with carbon tetrachloride (CCl 4 ), lipopolysaccharide (LPS), and D-galactose (D-gal), and constructed an in vitro hypoxia and hyperammonemia-triggered hepatocyte injury model. LONP1 overexpression and knockdown adenovirus were used to assess the protective effect of LONP1 on liver injury and gluconeogenesis regulation. Liver histopathology, biochemical index, mitochondrial morphology, cell viability and apoptosis, and the expression and activity of key gluconeogenic enzymes were detected to explore the underlying protective mechanisms of LONP1 in ACLF. RESULTS: We found that LONP1 and the expressions of gluconeogenic enzymes were downregulated in clinical ACLF liver tissues. Furthermore, LONP1 overexpression remarkably attenuated liver injury, which was characterized by improved liver histopathological lesions and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in ACLF mice. Moreover, mitochondrial morphology was improved upon overexpression of LONP1. Meanwhile, the expression and activity of the key gluconeogenic enzymes were restored by LONP1 overexpression. Similarly, the hepatoprotective effect was also observed in the hepatocyte injury model, as evidenced by improved cell viability, reduced cell apoptosis, and improved gluconeogenesis level and activity, while LONP1 knockdown worsened liver injury and gluconeogenesis disorders. CONCLUSION: We demonstrated that gluconeogenesis dysfunction exists in ACLF, and LONP1 could ameliorate liver injury and improve gluconeogenic dysfunction, which would provide a promising therapeutic target for patients with ACLF.

Application of Global Leadership Initiative on Malnutrition criteria in patients with liver cirrhosis.

BACKGROUND: The Global Leadership Initiative on Malnutrition (GLIM) criteria were published to build a global consensus on nutritional diagnosis. Reduced muscle mass is a phenotypic criterion with strong evidence to support its inclusion in the GLIM consensus criteria. However, there is no consensus regarding how to accurately measure and define reduced muscle mass in clinical settings. This study aimed to investigate the optimal reference values of skeletal muscle mass index for diagnosing sarcopenia and GLIM-defined malnutrition, as well as the prevalence of GLIM-defined malnutrition in hospitalized cirrhotic patients. METHODS: This retrospective study was conducted on 1002 adult patients with liver cirrhosis between January 1, 2018, and February 28, 2022, at Beijing You-An Hospital, Capital Medical University. Adult patients with a clinical diagnosis of liver cirrhosis and who underwent an abdominal computed tomography (CT) examination during hospitalization were included in the study. These patients were randomly divided into a modeling group (cohort 1, 667 patients) and a validation group (cohort 2, 335 patients). In cohort 1, optimal cut-off values of skeletal muscle index at the third lumbar skeletal muscle index (L3-SMI) were determined using receiver operating characteristic analyses against in-hospital mortality in different gender groups. Next, patients in cohort 2 were screened for nutritional risk using the Nutritional Risk Screening 2002 (NRS-2002), and malnutrition was diagnosed by GLIM criteria. Additionally, the reference values of reduced muscle mass in GLIM criteria were derived from the L3-SMI values from cohort 1. Multivariate logistic regression analysis was used to analyze the association between GLIM-defined malnutrition and clinical outcomes. RESULTS: The optimal cut-off values of L3-SMI were 39.50 cm 2 /m 2 for male patients and 33.06 cm 2 /m 2 for female patients. Based on the cut-off values, 31.63% (68/215) of the male patients and 23.3% (28/120) of the female patients had CT-determined sarcopenia in cohort 2. The prevalence of GLIM-defined malnutrition in cirrhotic patients was 34.3% (115/335) and GLIM-defined malnutrition was an independent risk factor for in-hospital mortality in patients with liver cirrhosis ( Wald = 6.347, P  = 0.012). CONCLUSIONS: This study provided reference values for skeletal muscle mass index and the prevalence of GLIM-defined malnutrition in hospitalized patients with liver cirrhosis. These reference values will contribute to applying the GLIM criteria in cirrhotic patients.

The effects and safety of anticoagulation or antiplatelet therapy following TIPS in cirrhotic patients with portal hypertension: A meta-analysis.

Introduction: Transjugular intrahepatic portosystemic shunt (TIPS) is an effective way to improve portal hypertension, however, the role of anticoagulation or antiplatelet therapy following TIPS remains controversial. We conducted this study to evaluate the efficacy and safety of anticoagulation or antiplatelet therapy following TIPS. Methods: A literature search was conducted on anticoagulation or antiplatelet therapy after TIPS using Pubmed, Web of Science, EMBASE, and Cochrane. The retrieval period was from the earliest accessible date in the database to 31 October 2022. We collected information on the incidence of stent dysfunction, bleeding, hepatic encephalopathy, the new occurrence of portal vein thrombosis, and the survival rate. Stata was analyzed in RevMan. Results: 1. Four studies received anticoagulation or antiplatelet therapy after TIPS without control groups. According to the single-group rate meta-analysis, stent dysfunction occurred at 27% [95% CI (0.19, 0.38)], bleeding occurred at 21% [95% CI (0.14, 0.29)], new portal vein thrombosis occurred at 17% [(95%CI(0.04.0.71)], hepatic encephalopathy occurred at 47% [95%CI (0.34, 0.63)], and death occurred at 31% [95% CI (0.22, 0.42)]. 2. Eight studies, including 1025 patients, compared anticoagulation and antiplatelet therapy after TIPS to TIPS alone. In terms of stent dysfunction, bleeding, and hepatic encephalopathy, there were no significant differences between the two groups. The use of anticoagulation or antiplatelet therapy may result in a significant decrease in the incidence of new portal vein thrombosis and mortality over 1 year. Discussion: Anticoagulant or antiplatelet therapy may not improve the patency rate of TIPS, but may effectively prevent new portal vein thrombosis after TIPS. Following TIPS, the use of anticoagulants or antiplatelet drugs does not lead to an increase in bleeding or death.

Cu-Sn Aerogels for Electrochemical CO2 Reduction with High CO Selectivity.

This work reports the synthesis of CuxSny alloy aerogels for electrochemical CO2 reduction catalysts. An in situ reduction and the subsequent freeze-drying process can successfully give CnxSny aerogels with tuneable Sn contents, and such aerogels are composed of three-dimensional architectures made from inter-connected fine nanoparticles with pores as the channels. Density functional theory (DFT) calculations show that the introduction of Sn in Cu aerogels inhibits H2 evolution reaction (HER) activity, while the accelerated CO desorption on the catalyst surface is found at the same time. The porous structure of aerogel also favors exposing more active sites. Counting these together, with the optimized composition of Cu95Sn5 aerogel, the high selectivity of CO can be achieved with a faradaic efficiency of over 90% in a wide potential range (-0.7 V to -1.0 V vs. RHE).

Understanding Young Taiwanese Consumers' Acceptance, Sensory Profile, and Drivers of Liking for GABA Oolong Tea Beverages with Cold Infusions.

The sensory qualities of Taiwanese teas are evaluated by the experts from the Tea Research and Extension Station (TRES) at tea competitions held annually. The prices of Taiwanese teas are also influenced by the results of these tea competitions. However, a tea winning an award and having a high sensory quality and price does not mean that it is liked by Taiwanese consumers. The check all that apply method (CATA) is a scientific method of sensory evaluation. It is able to evaluate the sensory characteristics with consumers and is cheap and time-saving. Twelve samples of γ-aminobutyric acid (GABA) Oolong tea made by the Taiwan Tea No. 12 cultivar were selected from the first Taiwanese GABA tea competition in 2020. The aim of this research was to study young Taiwanese consumers' acceptability for GABA Oolong tea infusions, and their opinions towards the sensory qualities of teas through questionnaires composed of CATA questions and hedonic scales. Based on the results, the CATA method identified 21 important descriptive terms for GABA tea that were selected by over 20% of consumers. It was found that the consumers like GABA Oolong teas with 13 specific sensory characteristics, but dislike the ones with another 6 specific sensory characteristics. We conjecture that the different process of tea production will affect consumers' preference for GABA Oolong tea. Overall, GABA Oolong tea has the same delightful sensory characteristics as traditional Taiwanese specialty Oolong teas, and is liked by the young Taiwanese consumers.

PINK1 ameliorates acute-on-chronic liver failure by inhibiting apoptosis through mTORC2/AKT signaling.

Acute-on-chronic liver failure (ACLF) is a lethal syndrome with a remarkable short-term death rate. Even worse, effective internal medicine therapies are currently lacking. Increasing evidence indicates apoptosis plays a critical role in the progression of liver failure. PINK1 has an essential function in maintaining cell survival. However, the role and underlying mechanism of PINK1 in apoptosis in ACLF are incompletely understood. Herein, our team discovered that PINK1 remarkably improved ACLF, featured by a reduction in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and an amelioration in the gross and microscopy histopathology appearance of hepatic tissues. Meanwhile, PINK1 affected cleaved caspase-3 expression via mTORC2/AKT, and this effect was eliminated after further intervention with Rictor or AKT. Overall, these findings indicate that PINK1 participates in the regulation of multiple biological functions, including hepatic cell growth and apoptosis in ACLF via the mTORC2/AKT signaling pathway. The present research offers a solid theory-wise foundation for the clinic applications of PINK1 as a valid target for ACLF treatment to reverse or postpone the development of ACLF.

Nrf2-Mediated Ferroptosis Inhibition Exerts a Protective Effect on Acute-on-Chronic Liver Failure.

Although massive hepatocyte cell death and oxidative stress constitute major events of acute-on-chronic liver failure (ACLF), the relationship of ferroptosis with ACLF has yet to be explored. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of ferroptosis. However, if Nrf2 modulates ACLF through ferroptosis remains unknown. Here, the liver tissues of ACLF patients were collected and murine models of ACLF using carbon tetrachloride, D-galactosamine, and lipopolysaccharide as well as an H2O2-induced hepatocyte injury model were established. Upon ACLF, livers exhibited key features of ferroptosis, including lipid peroxidation (increase in malondialdehyde whereas a decrease in glutathione and nicotinamide adenine dinucleotide phosphate), and increased mRNA expression of prostaglandin-endoperoxide synthase-2 (PTGS2). Ferroptosis inducer RSL-3 treatment aggravated liver damage, while ferroptosis inhibitor Ferrostatin-1 administration alleviated ACLF severity, manifesting with improved liver histopathological lesions and reduced serum ALT and AST. Compared with normal liver tissue, Nrf2 was upregulated in ACLF patients and murine models. Pharmacological activation of Nrf2 (Bardoxolone Methyl) attenuated liver damage, prevented lipid peroxidation, upregulated PTGS2 mRNA expression, and improved ferroptosis-specific mitochondrial morphology in vivo. In contrast, Nrf2 inhibitor ML385 exacerbated lipid peroxidation and liver injury. Collectively, Nrf2 plays a protective role in ACLF progression through repressing ferroptosis, which provides promising therapeutic cues for ACLF.

Current understanding of mesenchymal stem cells in liver diseases.

Liver diseases caused by various factors have become a significant threat to public health worldwide. Liver transplantation has been considered as the only effective treatment for end-stage liver diseases; however, it is limited by the shortage of donor organs, postoperative complications, long-term immunosuppression, and high cost of treatment. Thus, it is not available for all patients. Recently, mesenchymal stem cells (MSCs) transplantation has been extensively explored for repairing hepatic injury in various liver diseases. MSCs are multipotent adult progenitor cells originated from the embryonic mesoderm, and can be found in mesenchymal tissues including the bone marrow, umbilical cord blood, adipose tissue, liver, lung, and others. Although the precise mechanisms of MSC transplantation remain mysterious, MSCs have been demonstrated to be able to prevent the progression of liver injury and improve liver function. MSCs can self-renew by dividing, migrating to injury sites and differentiating into multiple cell types including hepatocytes. Additionally, MSCs have immune-modulatory properties and release paracrine soluble factors. Indeed, the safety and effectiveness of MSC therapy for liver diseases have been demonstrated in animals. However, pre-clinical and clinical trials are largely required to confirm its safety and efficacy before large scale clinical application. In this review, we will explore the molecular mechanisms underlying therapeutic effects of MSCs on liver diseases. We also summarize clinical advances in MSC-based therapies.

Ferroptosis in liver disease: new insights into disease mechanisms.

Characterized by excessive iron accumulation and lipid peroxidation, ferroptosis is a novel form of iron-dependent cell death, which is morphologically, genetically, and biochemically distinct from other well-known cell death. In recent years, ferroptosis has been quickly gaining attention in the field of liver diseases, as the liver is predisposed to oxidative injury and generally, excessive iron accumulation is a primary characteristic of most major liver diseases. In the current review, we first delineate three cellular defense mechanisms against ferroptosis (GPx4 in the mitochondria and cytosol, FSP1 on plasma membrane, and DHODH in mitochondria), along with four canonical modulators of ferroptosis (system Xc-, nuclear factor erythroid 2-related factor 2, p53, and GTP cyclohydrolase-1). Next, we review recent progress of ferroptosis studies delineating molecular mechanisms underlying the pathophysiology of several common liver diseases including ischemia/reperfusion-related injury (IRI), nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hemochromatosis (HH), drug-induced liver injury (DILI), and hepatocellular carcinoma (HCC). Furthermore, we also highlight both challenges and promises that emerged from recent studies that should be addressed and pursued in future investigations before ferroptosis regulation could be adopted as an effective therapeutic target in clinical practice.

The Study of Correlation Between Serum Vitamin D3 Concentrations and HBV DNA Levels and Immune Response in Chronic Hepatitis Patients.

Chronic hepatitis B (CHB) is a common chronic disease. Previous studies have shown a link between 25-hydroxyvitamin D3 (vitamin D3) concentration and liver disease. Hepatitis B virus (HBV) infection has been attributed to the inappropriate functioning of cell-mediated immunity. However, the effects of vitamin D3, immune cell, and HBeAg status on HBV viral load in CHB patients are still unclear. We investigated the relationship between the serum concentration of vitamin D3, percentage of immune cells in peripheral blood, and the HBV viral load of CHB patients. Sixty CHB patients were recruited, and their blood samples were collected and analyzed. Vitamin D level was measured using a chemiluminescence assay. A level of 30 ng/mL or above was defined as a vitamin D3 sufficiency. We assigned vitamin D3 status as either normal (≥30 ng/mL), insufficient (20-30 ng/mL), or deficient (<20 ng/mL). T-lymphocyte and B-lymphocyte surface markers in peripheral blood were detected using flow cytometry. The factors associated with HBV viral load were analyzed using univariate and multivariate-adjusted models. The mean serum vitamin D3 concentration in the subjects was 20.9±5.6 ng/mL. Up to 88.3% of the patients were either deficient in or had insufficient vitamin D3. The gender, BMI, hepatitis B surface antigen levels, and ALT levels were significantly related to serum vitamin D3 levels. Serum vitamin D3 concentration, HBe status, HBs levels, ALT, and AST levels showed a statistically significant correlation with the HBV DNA levels. Serum vitamin D3 concentrations and hepatitis B surface antigen levels were strongly correlated with HBV DNA levels. Vitamin D3 levels were significantly associated with CD19 numbers (ß:-6.2, 95% CI: -10.5). In multivariate analysis, vitamin D3 levels in the deficient and insufficient groups, and the CD8, HBeAg, and WBC counts were significantly associated with HBV DNA levels. In the immune tolerance phase of HBeAg-negative chronic HBV infection, vitamin D3 may be a modulator of immune function via CD8, CD19, and HBV DNA.