Portal hypertension in cirrhosis is defined as an increase in the portal pressure gradient (PPG) between the portal and hepatic veins and is traditionally estimated by the hepatic venous pressure gradient (HVPG), which is the difference in pressure between the free-floating and wedged positions of a balloon catheter in the hepatic vein. By convention, HVPG≥10 mmHg indicates clinically significant portal hypertension, which is associated with adverse clinical outcomes. Nonalcoholic fatty liver disease (NAFLD) is a common disorder with a heterogeneous clinical course, which includes the development of portal hypertension. There is increasing evidence that portal hypertension in NAFLD deserves special considerations. First, elevated PPG often precedes fibrosis in NAFLD, suggesting a bidirectional relationship between these pathological processes. Second, HVPG underestimates PPG in NAFLD, suggesting that portal hypertension is more prevalent in this condition than currently believed. Third, cellular mechanoresponses generated early in the pathogenesis of NAFLD provide a mechanistic explanation for the pressure-fibrosis paradigm. Finally, a better understanding of liver mechanobiology in NAFLD may aid in the development of novel pharmaceutical targets for prevention and management of this disease.

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with the metabolic syndrome and type 2 diabetes and independently contributes to long-term complications. Being often asymptomatic but reversible, it would require population-wide screening, but direct diagnostics are either too invasive (liver biopsy), costly (MRI) or depending on the examiner’s expertise (ultrasonography). Hepatosteatosis is usually accommodated by features of the metabolic syndrome (e.g. obesity, disturbances in triglyceride and glucose metabolism), and signs of hepatocellular damage, all of which are reflected by biomarkers, which poorly predict NAFLD as single item, but provide a cheap diagnostic alternative when integrated into composite liver fat indices. Fatty liver index, NAFLD LFS, and hepatic steatosis index are common and accurate indices for NAFLD prediction, but show limited accuracy for liver fat quantification. Other indices are rarely used. Hepatic fibrosis scores are commonly used in clinical practice, but their mandatory reflection of fibrotic reorganization, hepatic injury or systemic sequelae reduces sensitivity for the diagnosis of simple steatosis. Diet-induced liver fat changes are poorly reflected by liver fat indices, depending on the intervention and its specific impact of weight loss on NAFLD. This limited validity in longitudinal settings stimulates research for new equations. Adipokines, hepatokines, markers of cellular integrity, genetic variants but also simple and inexpensive routine parameters might be potential components. Currently, liver fat indices lack precision for NAFLD prediction or monitoring in individual patients, but in large cohorts they may substitute nonexistent imaging data and serve as a compound biomarker of metabolic syndrome and its cardiometabolic sequelae.

Over the last decade, epidemiological studies have discovered a link between hepatitis C virus (HCV) and hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL). The regression of HCV-associated NHL after HCV eradication is the most compelling proof supporting HCV infection’s role in lymphoproliferative diseases. HBV infection was found to significantly enhance the incidence of NHL, according to the epidemiological data. The exact mechanism of HCV leading to NHL has not been fully clarified, and there are mainly the following possible mechanisms: (1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HCV and cytokines; (2) Direct mechanisms: oncogenic effects mediated by intracellular HCV proteins; (3) hit-and-run mechanism: permanent genetic B lymphocytes damage by the transitional entry of HCV. The specific role of HBV in the occurrence of NHL is still unclear, and the research on its mechanism is less extensively explored than HCV, and there are mainly the following possible mechanisms: (1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HBV; (2) Direct mechanisms: oncogenic effects mediated by intracellular HBV DNA. In fact, it is reasonable to consider direct-acting antivirals (DAAs) as first-line therapy for indolent HCV-associated B-NHL patients who do not require immediate chemotherapy. Chemotherapy for NHL is affected by HBV infection and replication. At the same time, chemotherapy can also activate HBV replication. Following recent guidelines, all patients with HBsAg positive/HBV DNA≥2,000 IU/mL should be treated for HBV. The data on epidemiology, interventional studies, and molecular mechanisms of HCV and HBV-associated B-NHL are systematically summarized in this review.

Disease severity across the different diagnostic categories of metabolic dysfunction-associated fatty liver disease (MAFLD) remains elusive. This study assessed the fibrosis stages and features of MAFLD between different items. We also aimed to investigate the associations between advanced fibrosis and risk factors.

This multicenter cross-sectional study enrolled adults participating in liver disease screening in the community. Patients were stratified following MAFLD diagnostic criteria, to group A (395 patients) for type 2 diabetes, group B (1,818 patients) for body mass index (BMI)>23 kg/m2, and group C (44 patients) for BMI≤23 kg/m2 with at least two metabolic factors. Advanced fibrosis was defined as a fibrosis-4 index>2.67.

Between 2009 and 2020, 1,948 MAFLD patients were recruited, including 478 with concomitant liver diseases. Advanced fibrosis was observed in 125 patients. A significantly larger proportion of patients in group C (25.0%) than in group A (7.6%) and group B (5.8%) had advanced fibrosis (p<0.01). Logistic regression analysis found that hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfection (odds ratio [OR]: 12.14, 95% confidence interval [CI]: 4.04–36.52; p<0.01), HCV infection (OR: 7.87, 95% CI: 4.78–12.97; p<0.01), group C (OR: 6.00, 95% CI: 2.53–14.22; p<0.01), and TC/LDL-C (OR: 1.21, 95% CI: 1.06–1.38; p<0.01) were significant predictors of advanced fibrosis.

A higher proportion of lean MAFLD patients with metabolic abnormalities had advanced fibrosis. HCV infection was significantly associated with advanced fibrosis.

Ferroptosis is a programmed cell death mainly manifested as accumulation of ferrous ions and cell lipid peroxidation. Ferroptosis is well regulated by multiple signaling pathways, of which SLC7A11/GPX4 axis is the key pathway negatively regulating ferroptosis by eliminating lipid peroxidation. While disorder of iron homeostasis catalyzes the lipid peroxidation by supplying ferrous iron. Lipid metabolism participates in ferroptosis by offering lipid substrates. In addition, transsulfuration pathway and FSP1/CoQ10 also involve in ferroptosis. Evading ferroptosis is one strategy that cancer bypasses cell death and develops resistance to chemotherapy or radiotherapy, making ferroptosis inducers the potential treatment for cancer. The objective of this review is to summarize the ferroptosis signaling pathways and ferroptosis inducers, thus exploring the opportunities and challenges of inducing ferroptosis in cancer.

Donors with fatty livers are considered to address the shortage of livers for transplantation, but those livers are particularly sensitive to ischemia-reperfusion injury (IRI), and an increased incidence of graft failure is observed. Kupffer cells account for 20–35% of liver nonparenchymal cells, and have been shown to participate in the process of IRI and inflammatory reactions of hepatic steatosis. NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) is an intracellular sensor activated by Kupffer cells to promote generation and participates in IRI. Dynamics-associated protein 1 (Drp1) is one of the main proteins regulating mitochondrial division and exacerbates IRI by affecting mitochondrial dynamics. The mechanism of interaction of Kupffer cells with Drp1 and NLRP3 to aggravate IRI has not been clarified.

A mouse model of hepatic steatosis was established by feeding the mice with a high-fat diet. In vitro experiments were performed using AML12 normal mouse liver cells and RAW264.7 mononuclear macrophage cells cultured in medium with palmitate and oleic acid. Western blotting and immunohistochemical (IHC) staining were used to detect the expression of NLRPP3 and Drp1 in IRI in the control and high-fat diet groups. The expression of F4/80+ cells during IRI in hepatic steatosis was verified by IHC staining, and the role of NLRPP3 and Drp1 in Kupffer-cell mediated IRI was investigated by targeting Drp-1 inhibition.

Drp1 and NLRP3 expression was increased during IRI in hepatic steatosis, and the expression of Drp1 and NLRP3 were decreased after the elimination of Kupffer cells. That indicated Kupffer cells were involved in the process of IRI in hepatic steatosis through the action of Drp1 and NLRP3. After Drp1 inhibition, liver function was restored and NLRP3 expression level was reduced.

Kupffer cells aggravated IRI in hepatic steatosis via NLRP3 and Drp1. Drp1 inhibitors might be useful as specific therapeutics to alleviate IRI in hepatic steatosis and may have promise in case of liver donor shortage.

This study aimed to analyze the effects of baicalin (BC) and geniposide (GP) in combination (7:3) on the activation of microglia (MG) and 5-lipoxygenase (5-LOX) expression in rats during the recovery period after cerebral ischemia and to determine whether inhibition of the 5-LOX pathway is beneficial for M1-to-M2 polarization of MG.

Sprague Dawley rats were divided into five groups: control, model, and BC/GP (7:3) at 30, 45, and 60 mg/kg. A permanent middle artery occlusion model was established using the thread embolism method, and recovery after cerebral ischemia was monitored for 5 weeks. The effects on microglial activation and 5-LOX expression were evaluated by the neurofunctional score and immunofluorescence double labeling. The gene expression of 5-LOX in MG was determined by quantitative polymerase chain reaction before and after drug administration. The gene expression of tumor necrosis factor alpha, inducible nitric oxide synthase, interleukin 10, and cluster of differentiation 206 in MG was determined after the administration of zileuton (depressor). Western blotting was performed to determine the protein expression of 5-LOX, cysteinyl leukotriene receptor 1, cysteinyl leukotriene receptor 2, leukotriene B4 receptor 1, and leukotriene B4 receptor 2 before and after the administration of zileuton.

The activation of MG and the expression of 5-LOX were both increased after cerebral ischemia. BC/GP in combination inhibited the activation of microglia-reduced expression of 5-LOX and induced M2 polarization of MG.

The combination of BC and GP downregulates the 5-LOX inflammatory pathway by inhibiting activation of MG and promotes M1-to-M2 polarization of MG. Neurons are protected by the M2-type polarization, resulting in alleviation of cerebral ischemia.

This study aimed to determine the key points in the design of clinical trial protocols for coronavirus disease 2019 (COVID-19) following the PICOS principle.

A randomized, double-blind, placebo-controlled study of Cangma Huadu Granules in the treatment of mild COVID-19 will be carried out.

We recommend a randomized controlled trial as the study type. The inclusion criteria should not only define the diagnostic criteria of Western medicine and the syndrome types of Chinese medicine but also define the course of the disease. The definition of high-risk groups in the exclusion criteria needs to specify the diseases and laboratory test indicators to avoid excluding patients with common underlying diseases. Preclinical studies on the experimental product and the traditional Chinese medicine theory of indications should be outlined to clarify the trial rationale. A placebo combined with basic treatment is recommended as a control. Outcomes can refer to the core outcome set for clinical trials on COVID-19, and it is recommended to set the main outcome indicators around the clinical symptoms. In addition, homogeneous Chinese medicine during the experiment should be avoided, and the online registration should be completed in a timely manner.

Chinese Clinical Trial Registry, ChiCTR2300070933. Registered on 26 April 2023, www.chictr.org.cn .

Hepatocellular carcinoma (HCC) is a common tumor. Although the diagnosis and treatment of HCC have made great progress, the overall prognosis remains poor. As the core component of artificial intelligence, machine learning (ML) has developed rapidly in the past decade. In particular, ML has become widely used in the medical field, and it has helped in the diagnosis and treatment of cancer. Different algorithms of ML have different roles in diagnosis, treatment, and prognosis. This article reviews recent research, explains the application of different ML models in HCC, and provides suggestions for follow-up research.

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) have common features and differences. This real-life study investigated their characteristics, treatment modalities, and prognoses.

This retrospective comparative study was performed in 1,075 patients seen at one tertiary center between January 2008 and December 2020. Overall survival (OS) was estimated by the Kaplan-Meier method. Subclassification of iCCAs after histological and radiological review, and molecular profiling was performed.

HCCs patients were more likely to have early-stage disease than iCCA patients. iCCA patients were more likely to be female, especially those patients without cirrhosis (43% vs. 17%). Cirrhosis was prominent among HCC patients (89% vs. 34%), but no difference in underlying liver disease among cirrhotic patients was found. OS of HCC patients was 18.4 (95% CI: 6.4, 48.3) months, that of iCCA patients was 7.0 (95% CI: 3.4, 20.1) months. OS of Barcelona Clinic Liver Cancer C HCC patients was 7.8 (95% CI: 4.3, 14.2) months, that of advanced/metastatic iCCA patients was 8.5 (95% CI: 5.7, 12.3) months. In patients treated with sorafenib, OS was longer in HCC patients who received subsequent tyrosine kinase inhibitor therapies. No significant OS difference was found between iCCA patients with and without cirrhosis or according to histological subtype. A targetable molecular alteration was detected in 50% of the iCCA patients.

In this French series, cirrhosis was common in iCCA, which showed etiological factors comparable to those of HCC, implying a distinct oncogenic pathway. Both entities had a dismal prognosis at advanced stages. However, systemic therapies sequencing in HCC and molecular profiling in iCCA offer new insights.

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide. Recently, accumulating evidence has revealed hepatic mediators, termed as liver-derived secretory factors (LDSFs), play an important role in regulating CVDs such as atherosclerosis, coronary artery disease, thrombosis, myocardial infarction, heart failure, metabolic cardiomyopathy, arterial hypertension, and pulmonary hypertension. LDSFs presented here consisted of microbial metabolite, extracellular vesicles, proteins, and microRNA, they are primarily or exclusively synthesized and released by the liver, and have been shown to exert pleiotropic actions on cardiovascular system. LDSFs mainly target vascular endothelial cell, vascular smooth muscle cells, cardiomyocytes, fibroblasts, macrophages and platelets, and further modulate endothelial nitric oxide synthase/nitric oxide, endothelial function, energy metabolism, inflammation, oxidative stress, and dystrophic calcification. Although some LDSFs are known to be detrimental/beneficial, controversial findings were also reported for many. Therefore, more studies are required to further explore the causal relationships between LDSFs and CVDs and uncover the exact mechanisms, which is expected to extend our understanding of the crosstalk between the liver and cardiovascular system and identify potential therapeutic targets. Furthermore, in the case of patients with liver disease, awareness should be given to the implications of these abnormalities in the cardiovascular system. These studies also underline the importance of early recognition and intervention of liver abnormalities in the practice of cardiovascular care, and a multidisciplinary approach combining hepatologists and cardiologists would be more preferable for such patients.

Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver disease. The worldwide increasing prevalence of NAFLD has become a cause of concern for clinicians. Furthermore, the molecular mechanism of NAFLD pathogenesis remains poorly understood. Moreover, therapeutic interventions are presently limited. Balanced diet, physical exercise and lifestyle modifications have been recommended. Several studies have revealed that vitamin D deficiency is correlated with NAFLD, and its supplementation may play a vital role in this regard. Sufficient information was obtained from full articles written in the English language, and accessible in PubMed, Google Scholar, Web of Science, and Scopus. The increasing prevalence of vitamin D deficiency remains as a global health risk factor, and this is linked to NAFLD pathogenesis. In vitro and in vivo studies, and clinical trials have revealed the beneficial role of vitamin D supplementation to control NAFLD. Vitamin D potentially regulates the molecular pathways associated with NAFLD risk factors, such as obesity, insulin resistance, and diabetes. It acts on adipocytes to control free fatty acid (FFA) trafficking, lipogenesis, and inflammation. Similarly, vitamin D acts on hepatocytes to reduce de novo lipogenesis and cellular FFA trafficking. Furthermore, it acts on pancreatic β-cells to improve insulin secretion, cell survival, and cellular functions. Vitamin D supplementation improves glucose uptake and insulin sensitivity. In addition, it decreases inflammation and liver injury, and acts on mitochondria to control reactive oxygen species (ROS)-mediated cellular toxicity. Vitamin D deficiency is a major risk factor for NAFLD pathogenesis. Thus, there is an urgent need to conduct molecular level analysis for further discernment.

Methylenetetrahydrofolate Reductase (MTHFR) is the critical enzyme in folate and 1-carbon metabolism. MTHFR polymorphisms may result in increased homocysteine levels, and be associated with abnormal lipid metabolism in the liver. This study aims to explore the association between the gene polymorphisms of MTHFR rs1801131 and rs1801133 and the susceptibility to nonalcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD).

This case-control study included 103 NAFLD patients, 176 CAD patients, 94 patients with NAFLD complicated with CAD, and 183 healthy controls. Basic clinical information was collected, and all participants were genotyped using polymerase chain reaction. Data were analyzed by SPSS 26.0.

The genotype distribution of MTHFR rs1801131 does not exhibit a significant difference in the four groups (NAFLD, CAD, NAFLD+CAD, and Healthy controls) with all p values greater than 0.05. The genotype distribution of MTHFR rs1801133 is significantly different in the four groups (p0 = 0.014), while the allele distribution was not significant (p0 = 0.139). In both the dominant model (TT vs CT+CC) and co-dominant model (TT+CC vs CT), the genotype distribution of rs1801133 is statistically significant between the CAD and NAFLD+CAD, healthy controls and NAFLD+CAD, and NAFLD and NAFLD+CAD groups (all p < 0.05). In the NAFLD+CAD group, there are statistically significant differences in fasting plasma glucose (FPG) levels among carriers with different genotypes (TT vs CT+CC: p = 0.047, TT+CC vs CT: p = 0.002).

The C allele of MTHFR rs1801133 is a risk factor for NAFLD+CAD. The CT genotype of MTHFR rs1801133 is associated with FPG level in patients with NAFLD complicated with CAD.

Although anemia may cause angiogenesis and neovascularization, especially in ocular situations, neither published nonrandomized clinical trials nor registered clinical trials have reported the anemia status as inclusion or exclusion criteria in their design. Increases in the circulating levels of erythropoietin and vascular endothelial growth factor are proportional to the levels of tissue hypoxia, which are influenced by hematocrit. Erythropoietin is a potent retinal angiogenic factor that is independent of endothelial growth factor and is capable of stimulating ischemia-induced retinal angiogenesis. We suggest that clinical trials investigating anti-vascular endothelial growth factor treatment for retinal neovascularization should measure appropriate variables such as serum erythropoietin, vascular endothelial growth factor, hemoglobin, and hematocrit to yield preliminary data for future trials of angiogenesis inhibitors. Ignoring the anemia status, serum erythropoietin, and/or vascular endothelial growth factor levels could create clinical uncertainty and subtle statistical bias in both systematic reviews and nonrandomized clinical trials that aim to evaluate the efficiency of angiogenesis inhibitors in several medical situations, including but not limited to ocular alterations, rheumatoid arthritis, and many types of cancer, just to mention a few. Implications of this type of bias could be involved in other disease situations in which angiogenesis inhibitors are used for medication, such as different carcinomas as well as metastases. In this hypothesis paper, we suggest that clinical trials of angiogenesis inhibitors should measure appropriate variables such as serum erythropoietin, hemoglobin, and hematocrit and match their participants by anemia and its severity to avoid a game-changing bias in their data analysis.

Head and neck cancers (including cancers of the oral cavity, oropharynx, hypopharynx, and larynx) are the sixth most common type of cancer worldwide. Almost all of these cancers are squamous cell carcinomas that develop from the mucosal lining. Due to the lack of specificity of the symptoms and inadequate screening methods, less than half of these tumors are currently discovered, albeit at an early stage. These cancers, therefore, constitute a real public health problem. Smoking, alcohol consumption, certain HPV infections, and chronic betel nut consumption are the main risk factors for developing squamous cell carcinoma of the upper aerodigestive tract. Early diagnosis depends on performing a complete and systematic physical examination of the oral cavity, pharynx, and larynx with a nasofibroscope in populations at risk. However, there are no strict criteria, in terms of alcohol and tobacco consumption, to trigger a physical examination by an ENT specialist, and there are no indications concerning the frequency with which such “screening” should be performed in at-risk populations. Even if such “screening strategies” are used in the absence of an alternative, different approaches are used in practice, depending on the medical system and country, and their efficacy and ideal modes of implementation remain unknown.

Qingfei Paidu decoction (QFPD) is a compounded Chinese herbal medicine used to treat mild and severe cases of COVID-19. Acute lung injury (ALI) is a common clinical manifestation of COVID-19, and this mainly manifests through lung inflammation and epithelial cell damage. However, the mechanism by which QFPD ameliorates ALI remains unclear. The present study aims to determine the role and molecular mechanism of QFPD in lipopolysaccharide (LPS)-induced ALI in mice.

After the administration of QFPD treatment in LPS-induced ALI mice, the therapeutic effect was evaluated through the H&E staining of lung tissues and the level of inflammatory factors in vivo. The RNA sequencing in mouse peritoneal macrophages and subsequent network pharmacological analysis were used to explore the molecular mechanisms of QFPD. Experimental validation was also performed by immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), and western blot.

QFPD inhibited the LPS-induced inflammatory cytokines in macrophages, ameliorated ALI in mice, and prolonged its survival at the lethal dose of LPS. Furthermore, the complement-related pathway was enriched through the network pharmacology and transcriptome analysis of the gene expression. The quantitative real-time PCR and apoptotic analysis further confirmed that QFPD inhibited ALI through the classical complement pathway as no additive changes were observed when its key components were silenced plus QFPD treatment.

QFPD applied for the treatment of COVID-19 can attenuate ALI through the classical complement pathway. The present study provides a practical basis and directional guide for the further exploration of the use of QFPD in treating ALI.

In this paper, the features of ductular reaction (DR) and remodeling of the biliary tract are discussed in models of total and selective biliary occlusion. It has been shown that the intensity of DR, as well as the shape, number, and topography of ductular profiles following common bile duct occlusion (CBDO), are closely related to the duration of the biliary obstruction. In addition, the formation of new ductular profiles can occur by the widening of existing bile ducts/ductules as a result of cholangiocyte proliferation, hepatocyte transdifferentiation, and/or activation and differentiation of stem/progenitor cells. It has been concluded that DR induced by CBDO encompasses the components of all types of DRs, including I, II (A and B), and III, thereby increasing the interest in further studies of this model. In the DR following CBDO, the subsequent “preproliferative” and “proliferative” phases develop alongside cellular differentiation and transdifferentiation (the “para-proliferative” phase) should be distinguished. The dynamics of these phases are crucial for further detailed classification of DRs. During selective biliary obstruction, the full spectrum of DR characteristics for CBDO has not been determined (mainly the events of biliary proliferation and fibrosis are noted). However, the great compensatory potential of the biliary bed has been confirmed, as evidenced by the formation of new collaterals between congested and noncongested bile ducts

Liver biopsy is historically the gold standard for liver fibrosis assessment of chronic hepatitis C patients. However, with the introduction and validation of noninvasive tests (NITs) to evaluate advanced fibrosis, and the direct-acting antiviral agents for treatment of chronic hepatitis C virus (HCV), the role of NITs have become even more complex. There is now need for longitudinal monitoring and elucidation of cutoff values for prediction of liver-related complication after sustained virological response. The aim of this report is to provide a critical overview of the various NITs available for the assessment of liver fibrosis in HCV patients.