Non-alcoholic fatty liver disease (NAFLD) is closely associated with gut microbiota and has become the most common chronic liver disease worldwide, but the relationship between specific strains and NAFLD has not been fully elucidated. We aimed to investigate whether Akkermansia muciniphila and Bifidobacterium bifidum could prevent NAFLD, the effects of their action alone or in combination, possible mechanisms, and modulation of the gut microbiota.

Mice were fed with high-fat diets (HFD) for 20 weeks, in which experimental groups were pretreated with quadruple antibiotics and then given the corresponding bacterial solution or PBS. The expression of the glycolipid metabolism indicators, liver, and intestinal farnesol X receptors (FXR), and intestinal mucosal tight junction proteins were detected. We also analyzed the alterations of inflammatory and immune status and the gut microbiota of mice.

Both strains were able to attenuate mass gain (p<0.001), insulin resistance (p<0.001), and liver lipid deposition (p<0.001). They also reduced the levels of the pro-inflammatory factors (p<0.05) and the proportion of Th17 (p<0.001), while elevating the proportion of Treg (p<0.01). Both strains activated hepatic FXR while suppressing intestinal FXR (p<0.05), and elevating tight junction protein expression (p<0.05). We also perceived changes in the gut microbiota and found both strains were able to synergize beneficial microbiota to function.

Administration of A. muciniphila or B. bifidum alone or in combination was protective against HFD-induced NAFLD formation and could be used as alternative treatment strategy for NAFLD after further exploration.

Hepatocellular carcinoma (HCC) is one of the most lethal and widespread cancers in the human race. Despite its fatal attributes, there is only a limited understanding of the factors contributing to its pathogenesis at the cellular and molecular levels. Consequently, unraveling new facets involved in HCC progression is elemental for establishing novel targets and biomarkers for this disease. Over the last few years, emerging evidence signifies the role of RNA-induced silencing complex in mediating gene silencing and contributing to HCC. Recent studies also highlight the importance of human telomerase holoenzyme and its complex accessory proteins in the development of HCC. The current review encompasses the multifaceted roles of RNA-induced silencing complex and telomerase activity as well as their synergistic function in HCC.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the leading causes of hepatic fibrosis and liver-related mortality worldwide, despite efficient hepatitis B and C antiviral therapies that have dramatically lowered the disease load. Although significant efforts have been exerted to understand the molecular basis of disease pathogenesis, there are currently few therapeutic alternatives available for NAFLD-associated fibrosis. Thus, NAFLD prevention is critical before the development of disease-related complications. In this context, there is a tremendous substantial global burden on public health systems to actively search for effective preventive and therapeutic targets for NAFLD. In this review, we highlight the current strategies to prevent progression and poor outcomes of NAFLD and to avoid complications associated with disease fibrosis, notably cirrhosis, portal hypertension, and liver cancer. We discuss different nonpharmacological measures, such as lifestyle modifications (weight loss, exercise, healthy diet) and other pharmacological interventions that could prevent NAFLD.

In 2015, the Chinese Society of Hepatology and the Chinese Society of Gastroenterology published a consensus on primary biliary cholangitis (PBC). In the past years, numerous clinical studies have been published in the field of PBC. To guide the clinical diagnosis and management of PBC patients, the Chinese Society of Hepatology invited a panel of experts to assess the new clinical evidence and formulate the current guidelines.

Both combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and cholangiolocarcinoma are rare primary liver cancers. cHCC-CCA is believed to originate from transformed hepatocellular carcinoma or liver stem/progenitor cells. Cholangiolocarcinoma is characterized by ductular reaction-like anastomosing cords and glands resembling cholangioles or canals containing hepatocellular carcinoma components and adenocarcinoma cells. According to the 2019 revision of the World Health Organization criteria, a subtype with stem cell features as a subclassification of cHCC-CCA was abolished for lack of conclusive evidence of the stem cell origin theory. That led to the classification of cholangiolocarcinoma with hepatocytic differentiation as cHCC-CCA. Consequently, cholangiolocarcinoma without hepatocytic differentiation is classified as a subtype of small-duct cholangiocarcinoma and is assumed to originate from the bile duct. Herein, we report the first case of double primary cHCC-CCA and cholangiolocarcinoma without hepatocytic differentiation in different hepatic segments of a cirrhotic liver. We believe this case supports the validity of the new World Health Organization criteria because the pathological finding of cHCC-CCA in this case shows the transformation of hepatocellular carcinoma to cholangiocarcinoma. Furthermore, this case may demonstrate that immature ductular cell stemness and mature hepatocyte cell stemness in hepatocarcinogenesis can coexist in the same environment. The results provide valuable insights into the mechanisms of growth, differentiation, and regulation of liver cancers.

Hepatitis B is a vaccine-preventable liver infection caused by the hepatitis B virus (HBV), and is seen as a serious global health problem. HBV infection induces the expression of type I interferon (IFN), including IFN-α and IFN-β, which have anti-HBV activities, and have been used for HBV treatment. IL2-inducible T-cell kinase (ITK) is a tyrosine kinase, which regulates T-cell differentiation and activation, while its precise effects on type I IFN production during HBV infection remain unknown.

We monitored the ITK expression in peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with acute and chronic HBV infection. We used ITK inhibitor ibrutinib to treat hepatocytes and evaluated the type I IFN expression after HBV infection. We also administrated ibrutinib to mice and evaluated its effect on HBV infection in vivo. We generated ITK, suppressor of cytokine signaling 1 (SOCS1) knockout and ITK/SOCS1 double knockout cells using CRISPR, and monitored the HBV-induced type I IFN production.

ITK and type I IFN were upregulated in patients with acute HBV infection. Inhibition of ITK by ibrutinib suppressed HBV-induced expression of type I IFN mRNA in mice. ITK knockout cells had decreased IRF3 activation but promoted the expression of SOCS1. ITK negatively regulated SOSC1 expression. The down regulation of type I IFN in ITK knockout cells after HBV stimulation was abolished in the absence of SOCS1.

ITK regulated HBV-induced expression of type I IFN mRNA by modulating SOCS1.

Personalized medicine is a relatively new approach that addresses differences between patients based on unique features such as genetic make-up, environment, and physiology. Aptamers are synthetic sequences of single-stranded DNA or RNA with a particular three-dimensional conformation that binds to a target. Aptamer-based biosensors are promising tools to detect disease markers, especially in cancer. Gastric cancer is the third most common cause of cancer-related deaths worldwide and has very high prevalence in Asia. Currently, there is a lack of effective screening tools for the early detection of gastric cancer. Thus, identifying new methods to detect markers of gastric cancer is crucial. In this study, the role of aptamer-based biomarkers in early diagnosis of gastric cancer is reviewed.

Iron homeostasis is a complex process in which iron uptake and use are tightly balanced. Primary Type 1 or HFE hemochromatosis results from homozygous mutations in the gene that encodes human homeostatic iron regulator (known as human factors engineering, HFE) protein, a regulator of hepcidin, and makes up approximately 90% of all hemochromatosis cases. However, four types of hemochromatosis do not involve the HFE gene. They are non-HFE hemochromatosis type 2A (HFE2, encoding HJV), type 2B (HAMP, encoding hepcidin), type 3 (TFR2, encoding transferring receptor-2), and types 4A and B (SLC40A1, encoding ferroportin. Non-HFE hemochromatosis is extremely rare. Pathogenic allele frequencies have been estimated to be 74/100,000 for type 2A, 20/100,000 for type 2B, 30/100,000 for type 3, and 90/100,000 for type 4 hemochromatosis. Current guidelines recommend that the diagnosis be made by ruling out HFE mutations, history, physical examination, laboratory values (ferritin and transferrin saturation), magnetic resonance or other imaging, and liver biopsy if needed. While less common, non-HFE hemochromatosis can cause iron overload as severe as the HFE type. In most cases, treatment involves phlebotomy and is successful if started before irreversible damage occurs. Early diagnosis and treatment are important because it prevents chronic liver disease. This review updates the mutations and their pathogenetic consequences, the clinical picture, diagnostic guidelines, and treatment of hemochromatosis.

The prevalence of chronic liver disease in adults exceeds 30% in some countries and there is significant interest in developing tests and treatments to help control disease progression and reduce healthcare burden. Breath is a rich sampling matrix that offers non-invasive solutions suitable for early-stage detection and disease monitoring. Having previously investigated targeted analysis of a single biomarker, here we investigated a multiparametric approach to breath testing that would provide more robust and reliable results for clinical use.

To identify candidate biomarkers we compared 46 breath samples from cirrhosis patients and 42 from controls. Collection and analysis used Breath Biopsy OMNI™, maximizing signal and contrast to background to provide high confidence biomarker detection based upon gas chromatography mass spectrometry (GC-MS). Blank samples were also analyzed to provide detailed information on background volatile organic compounds (VOCs) levels.

A set of 29 breath VOCs differed significantly between cirrhosis and controls. A classification model based on these VOCs had an area under the curve (AUC) of 0.95±0.04 in cross-validated test sets. The seven best performing VOCs were sufficient to maximize classification performance. A subset of 11 VOCs was correlated with blood metrics of liver function (bilirubin, albumin, prothrombin time) and separated patients by cirrhosis severity using principal component analysis.

A set of seven VOCs consisting of previously reported and novel candidates show promise as a panel for liver disease detection and monitoring, showing correlation to disease severity and serum biomarkers at late stage.

Iron overload is a condition involving excessive iron deposit in various organs, the liver being the main target organ for iron deposition and overload which are associated with significant liver morbidity and mortality. Iron overload can be categorized into primary and secondary causes. Primary iron overload, so-called hereditary hemochromatosis, is a well-recognized disease with available standard treatment recommendations. However, secondary iron overload is a more diverse disease with many unclear areas to be explored. Secondary iron overload is more prevalent than primary iron overload and occurs as a consequence of various causes which differ significantly across geographic regions. The main causes of secondary iron overload are iron-loading anemias, and chronic liver disease. The liver-related outcomes, patient outcomes, and treatment recommendations in these patients differ depending on the cause of iron overload. This review summarizes the causes, pathophysiology, liver-related outcomes, disease outcomes, and treatments of secondary iron overload.

Liver transplantation (LT) using ABO-incompatible (ABOi) grafts can extend the donor pool to a certain extent and hence reduce the waiting time for transplantation. However, concerns of the impending prognosis associated with this option, especially for patients with liver failure and higher model for end-stage liver disease (MELD) scores, who tend to be more fragile during the waiting period before LT.

Recipients undergoing LT for acute-on-chronic liver failure or acute liver failure were retrospectively enrolled at four institutions. Overall survival was compared and a Cox regression analysis was performed. Propensity score matching was performed for further comparison. Patients were stratified by MELD score and cold ischemia time (CIT) to determine the subgroups with survival benefits.

Two hundred ten recipients who underwent ABOi LT and 1,829 who underwent ABO compatible (ABOc) LT were enrolled. The 5-year overall survival rate was significantly inferior in the ABOi group compared with the ABOc group after matching (50.6% vs. 75.7%, p<0.05). For patients with MELD scores ≤30, using ABOi grafts achieved a comparable overall survival rate as using ABOc grafts (p>0.05). Comparison of the survival rates revealed no statistically significant difference for patients with MELD scores ≥40 (p>0.05). For patients with MELD scores of 31–39, the overall survival rate was significantly inferior in the ABOi group compared with the ABOc group (p<0.001); however, the rate was increased when the liver graft CIT was<8 h.

For recipients with MELD scores ≤30, ABOi LT had a prognosis comparable to that of ABOc LT and can be regarded as a feasible option. For recipients with MELD scores ≥40, ABOi should be adopted with caution in emergency cases. For recipients with MELD scores of 31–39, the ABOi LT prognosis was worse. However, those patients benefited from receiving ABOi grafts with a CIT of <8 h.

Understanding the interaction between the heart and liver is pivotal for managing patients in whom both organs are affected. Studies have shown that cardio-hepatic interactions are bidirectional and that their identification, assessment, and treatment remain challenging. Congestive hepatopathy is a condition that develops in the setting of long-standing systemic venous congestion. If left untreated, congestive hepatopathy may lead to hepatic fibrosis. Acute cardiogenic liver injury develops as a combination of venous stasis and sudden arterial hypoperfusion due to cardiac, circulatory, or pulmonary failure. The treatment of both conditions should be directed toward optimizing the cardiac substrate. Hyperdynamic syndrome may develop in patients with advanced liver disease and lead to multiorgan failure. Cirrhotic cardiomyopathy or abnormalities in pulmonary vasculature, such as hepatopulmonary syndrome and portopulmonary hypertension may also develop. Each complication has unique treatment challenges and implications for liver transplantation. The presence of atrial fibrillation and atherosclerosis in liver disease brings another layer of complexity, particularly in terms of anticoagulation and statin use. This article provides an overview of cardiac syndromes in liver disease, focusing on current treatment options and future perspectives.

This study focused on the effects of the combination of baicalin (BC) and gardenoside (GD) (7:3) on blood-brain barrier (BBB) permeability, brain tissue water content, and aquaporin-4 (AQP-4) expression in rats with cerebral ischemia-reperfusion (I/R) injury. The previous research conducted by the investigators demonstrated that the combination of BC and GD (7:3) has anti-ischemic properties. Further research was conducted to determine the mechanism underlying the reduction in cerebral edema.

A total of 150 male Sprague-Dawley rats were randomly assigned to the following groups to receive treatment: sham, I/R, allyl chloride (AC), 30 mg/kg BC/GD, and 60 mg/kg BC/GD groups. Then, neurobehavioral scores were assigned to determine the effectiveness of the treatment. Evans blue (EB) was used to trace the BBB. The dry/wet method was used to evaluate the brain water content. Transmission electron microscopy was performed to examine the ultrastructure of the brain tissue. Immunohistochemistry and western blot were performed to detect the presence of AQP-4 in the hippocampus. Reverse transcription polymerase chain reaction (RT-PCR) was used to determine the amount of AQP-4 mRNA.

The BBB permeability, brain water content, and AQP-4 expression were significantly greater in the CA1 area of the hippocampus in the I/R group, when compared to the sham group. Furthermore, the endoplasmic reticulum was dilated, and most of the nerve cells underwent degeneration or necrosis. After the BC/GD treatment, the markers improved in a dose-dependent manner.

BC/GD can inhibit the BBB permeability and cerebral edema by reducing the expression of AQP-4 in the CA1 area of the hippocampus in rats after I/R injury, improving the structure of nerve cells and exerting brain-protective effects.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and a leading cause of cancer-related deaths. Standard treatments, such as surgery, chemotherapy, and radiotherapy, frequently fail to produce positive therapeutic outcomes. Thus, it is essential to identify new treatment modalities with improved survival rates. Extracellular vesicles (EVs) are nanosized lipid bilayer vesicles secreted by cells that mediate intercellular communication. EVs have been used to deliver several non-coding RNAs (ncRNAs), including miRNA, circRNA, and lncRNA. These ncRNAs demonstrate excellent tumor-suppressive effects and serve as new therapeutic candidates for HCC. EVs possess several characteristics, including high biocompatibility, enhanced stability, and limited cytotoxicity, making them promising drug-delivery vehicles. Although these characteristics make them better drug carriers than traditional synthetic delivery vehicles, translating engineered EVs into clinical practice has been challenging. In this review, we summarise the tumor-suppressive roles of ncRNAs, the recent progress of EV-associated ncRNAs in HCC treatment, unique features of EVs relevant to drug delivery, and current challenges in the clinical translation of EVs.

Hepatocellular carcinoma (HCC) is a common and deadly cancer. Accumulating evidence supports modulation of autophagy as a novel approach for determining cancer cell fate. The aim of this study to evaluate the effectiveness of sarmentosin, a natural compound, on HCC in vitro and in vivo and elucidated the underlying mechanisms.

Cell functions and signaling pathways were analyzed in HepG2 cells using western blotting, real-time PCR, siRNA, transmission electron microscopy and flow cytometry. BALB/c nude mice were injected with HepG2 cells to produce a xenograft tumour nude mouse model for in vivo assessments and their tumors, hearts, lungs and kidneys were isolated.

We found that autophagy was induced by sarmentosin in a concentration- and time-dependent manner in human HCC HepG2 cells by western blot assays and scanning electron microscopy. Sarmentosin-induced autophagy was abolished by the autophagy inhibitors 3-methyladenine, chloroquine, and bafilomycin A1. Sarmentosin activated Nrf2 in HepG2 cells, as shown by increased nuclear translocation and upregulated expression of Nrf2 target genes. Phosphorylation of mTOR was also inhibited by sarmentosin. Sarmentosin stimulated caspase-dependent apoptosis in HepG2 cells, which was impaired by silencing Nrf2 or chloroquine or knocking down ATG7. Finally, sarmentosin effectively repressed HCC growth in xenograft nude mice and activated autophagy and apoptosis in HCC tissues.

This study showed sarmentosin stimulated autophagic and caspase-dependent apoptosis in HCC, which required activation of Nrf2 and inhibition of mTOR. Our research supports Nrf2 as a therapeutic target for HCC and sarmentosin as a promising candidate for HCC chemotherapy.

Liver cirrhosis can lead to liver failure and eventually death. Macrophages are the main contributors to cirrhosis and have a bidirectional role in regulating matrix deposition and degradation. Macrophage-based cell therapy has been developed as an alternative to liver transplantation. However, there is insufficient evidence regarding its safety and efficacy. In this study, we aimed to explore the effect of combining insulin-like growth factor 2 (IGF2) with bone marrow-derived macrophages (BMDMs) to treat mice with liver cirrhosis.

We assessed liver inflammation, fibrosis regression, liver function, and liver regeneration in mice with CCl4-induced cirrhosis and treated with BMDM only or IGF2 + BMDM. We performed in vitro experiments in which activated hepatic stellate cells (HSCs) were co-cultured with macrophages in the presence or absence of IGF2. The polarity of macrophages and the degree of inhibition of HSCs were examined. The effect of IGF2 on macrophages was also verified by the overexpression of IGF2.

Combining IGF2 with BMDM reduced liver inflammation and fibrosis and increased hepatocyte proliferation. Combining IGF2 with BMDM was more effective than using BMDM alone. In vitro experiments demonstrated that IGF2 inhibited HSCs activation by upregulating NR4A2 to promote the anti-inflammatory macrophages phenotype. IGF2 also increased the synthesis of matrix metalloproteinases (MMPs) by macrophages, which may explain why administering IGF2 combined with BMDM was more effective than administering BMDM only.

Our study provides a theoretical basis for the future use of BMDM-based cell therapy to treat liver cirrhosis.

Gastrointestinal stromal tumors are the most common mesenchymal tumors of the gastrointestinal tract. They originate from the interstitial cells of Cajal and are usually found in extrahepatic gastrointestinal sites. However, a small subset are derived from the liver and are known as primary hepatic gastrointestinal stromal tumors (PHGIST). They have a poor prognosis and are historically difficult to diagnose. Our objective was to review and update the latest evidence-based knowledge concerning PHGIST, with a focus on epidemiology, etiology, pathophysiology, clinical presentation, histopathology, and treatment. These tumors are usually found incidentally, occur sporadically, and are associated with mutations of KIT and PDGFRA genes. PHGIST is a diagnosis of exclusion, as it has the same molecular, immunochemistry and histological appearance as gastrointestinal stromal tumors (GIST). Thus, imaging, such as positron emission tomography-computed tomography (PET-CT) must be used to rule out metastatic GIST before a diagnosis can be made. However, with mutation analysis and pharmacological advances, tyrosine kinase inhibitors are typically pursued with or without surgical intervention. Other potential treatments include transcatheter arterial chemoembolization and tumor ablation. However, these are typically considered palliative options. As there are only a limited number of publications regarding PHGIST, data concerning morbidity and mortality are not yet available. Immunohistopathology can help develop screening guidelines and evaluating resistance to treatment.

The application of Chinese medicine in clinic is based on the classical theory of traditional Chinese medicine (TCM) syndrome differentiation, which remains not fully understood. This study aims to explore and interpret the associations between TCM syndromes and multiple clinical risk factors of hypertension.

A total of 203 patients with hypertension were retrospectively studied. After the regression analysis of confounding factors for different types of hypertension, the potential association between TCM syndrome and risk factors were analyzed.

The comorbidity of left ventricular hypertrophy was probably an independent risk factor for different types of hypertension. The correlation analysis indicated that the disease course was positively correlated with the syndrome differentiation degree (Spearman’s coefficient = 0.185, p < 0.05) and blood stasis syndrome (Spearman’s coefficient = 0.291, p < 0.05). tThe hypertension risk group was positively correlated with the blood stasis syndrome (Spearman’s coefficient = 0.207, p < 0.05). Age was positively correlated with the blood stasis syndrome (Spearman’s coefficient = 0.231, p < 0.05) and qi-deficiency syndrome (Spearman’s coefficient = 0.187, p < 0.05), but was negatively correlated with the liver-yang hyperactivity syndrome (Spearman’s coefficient = −0.167, p < 0.05).

There are correlations between TCM syndromes and the clinical risk factors of hypertension. These findings may help to interpret the TCM syndrome differentiation theory.