Hepatic sinusoidal obstruction syndrome (HSOS) is a life-threatening syndrome, and a cause is exposure to pyrrolizidine alkaloid (PA)-containing products. It is well-established that retrorsine (RTS), a representative Pas, insults hepatic sinusoidal endothelial cells and ensues congestion of hepatic sinusoids. However, little known about the impact of Pas on gut microbiota and intestinal barrier and inflammation in HSOS.

Mice were gavaged with or without nonabsorbable antibiotics (ABX), followed by a single dose of RTS. The gut microbiota was examined by 16S rDNA sequencing.

ABX pretreatment significantly reversed RTS-induced liver damage. RTS altered gut microbiota composition, increasing Gram-negative bacteria and resulting in a sharp elevation of circulating lipopolysaccharides (LPS) in HSOS mice. Gut decontamination with ABX alleviated RTS-induced intestine inflammation, protected against disruption of the intestinal epithelial barrier and gut vascular barrier (GVB), and suppressed hepatic LPS-NF-κB pathway activation in RTS-induced HSOS. Importantly, the LPS level was positively correlated with MELD score in patients with HSOS. Elevated LPS in patients with HSOS confirmed that Gram-negative bacteria were involved in the pathogenesis of HSOS.

RTS, a PA, cooperated with gut dysbiosis to cause intestinal inflammation and gut barrier compromise that increased transport of gut-derived LPS into the liver through the portal vein, which contributed to the pathology of HSOS. Modulating the gut microbiota, protecting the intestinal barrier, and suppressing intestinal inflammation with prebiotics or antibiotics might be a useful pharmacologic intervention in HSOS.

The aim was to determine if liver biochemistry indices can be used as biomarkers to help differentiate patients with neonatal Dubin–Johnson syndrome (nDJS) from those with biliary atresia (BA).

Patients with genetically-confirmed nDJS or cholangiographically confirmed BA were retrospectively enrolled and randomly assigned to discovery or verification cohorts. Their liver chemistries, measured during the neonatal period, were compared. Predictive values were calculated by receiver operating characteristic curve analysis.

A cohort of 53 nDJS patients was recruited, of whom 13 presented with acholic stools, and 14 underwent diagnostic cholangiography or needle liver biopsy to differentiate from BA. Thirty-five patients in the cohort, with complete biochemical information measured during the neonatal period, were compared with 133 infants with cholangiographically confirmed BA. Total and direct bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acids, alkaline phosphatase, and gamma-glutamyl transferase were significantly lower in nDJS than in BA. In the discovery cohort, the areas under the curve for ALT and AST were 0.908 and 0.943, respectively. In the validation cohort, 13/15 patients in the nDJS group were classified as nDJS, and 10/53 in the BA control group were positive (p<0.00001) with an ALT biomarker cutoff value of 75 IU/L. Thirteen of 15 patients were classified as nDJS and none were classified positive in the BA group (13/15 vs. 0/53, p<0.00001) with an AST cutoff of 87 IU/L.

Having assembled and investigated the largest cohort of nDJS patients reported to date, we found that nDJS patients could be distinguished from BA patients using the serum AST level as a biomarker. The finding may be clinically useful to spare cholestatic nDJS patients unnecessary invasive procedures.

The development of a multifunctional bionic prosthetic system to meet the daily activity needs of amputees has become a research hotspot in the field of international neuroengineering and rehabilitation technology. In order to reconstruct the muscle power supply related to the physiological activities of the lost limb, a method of targeted neural function replacement (TNFR) based on wavelet packet decomposition was proposed.

The TNFR rat model was established, and the necessary rehabilitation methods were used to restore the movement of rats as much as possible, in order to better collect the electromyography signals in the sham operation group, denervation group, TNFR group, 2-week delayed TNFR group, and 4-week delayed TNFR group. After signal acquisition, wavelet packet transformation was used in the analysis.

Compared to the first week, the average rectified values for the right biceps in the TNFR model group, and 2-week and 4-week delayed surgery groups significantly increased in the fourth week (p < 0.05). There was a significant difference between the fourth week TNFR group and 4-week delayed group (p < 0.05).

The present results revealed that the neural function reconstruction of the early TNFR operation is better, and that the average rectified values for the target muscle obtained after the operation were enhanced. These preliminary research results obtained from rats can be used as an exploratory basis, in order to provide reliable experimental data for clinical treatment and post-amputation research, which may be helpful in improving the quality of life of amputee patients and their control of the prosthesis.

The overexpression and mutation of EGFRs are associated with various types of human cancers. Epidermal growth factor receptor variant III (EGFRvIII) is one of the most notable EGFR mutations, and is exclusively present in cancer cells, making it a potential therapeutic target. The present study aims to determine whether recombinant immunotoxin 86 (rIT86) can effectively kill EGFRvIII-expressing cancer cells, while maintaining adequate levels of tolerance.

rIT86 consists of an antibody bivalent scFv obtained from EGFRvIII-targeting antibody mab806, combined with protein cytotoxin DT390. The in vitro and in vivo effects were evaluated in EGFRvIII-expressing tumor cell lines in culture and xenografts.

rIT86 inhibited the proliferation of several cancer cell lines, including U87, A549, Du145, MDA-MB231 and A431, with high selectivity towards the mutant EGFRvIII over wild-type EGFR. The in vivo pre-clinical studies revealed the better survival and greater inhibition of xenograft tumors, when compared to EGFRvIII-expressing tumor cells, and that these were achieved in mice treated with prolonged administration of low-dose rIT86, when compared to the control group.

The results demonstrated that rIT86 is very potent and highly selective for killing EGFRvIII-expressing cancer cells. However, its potential clinical application warrants further investigation.

Recognition of excessive activation of hepatic stellate cells (HSCs) in liver fibrosis prompted us to investigate the regulatory mechanisms of HSCs. We aimed to examine the role of O-GlcNAcylation modification of alanine, serine, cysteine transporter 2 (ASCT2) in HSCs and liver fibrosis.

The expression of O-GlcNAcylation modification in fibrotic mice livers and activated HSCs was analyzed by western blotting. Immunoprecipitation was used to assess the interaction of ASCT2 and O-GlcNAc transferase (OGT). In addition, ASCT2 protein stability was assayed after cycloheximide (CHX) treatment. The O-GlcNAcylation site of ASCT2 was predicted and mutated by site-directed mutagenesis. Real-time PCR, immunofluorescence, kit determinations and Seahorse assays were used to clarify the effect of ASCT2 O-GlcNAcylation on HSC glutaminolysis and HSC activation. Western blotting, immunochemistry, and immunohistofluorescence were used to analyze the effect of ASCT2 O-GlcNAcylation in vivo.

We observed significantly increased O-GlcNAcylation modification of ASCT2. ASCT2 was found to interact with OGT to regulate ASCT2 stability. We predicted and confirmed that O-GlcNAcylation of ASCT2 at Thr122 site resulted in HSCs activation. We found Thr122 O-GlcNAcylation of ASCT2 mediated membrane trafficking of glutamine transport and attenuated HSC glutaminolysis. Finally, we validated the expression and function of ASCT2 O-GlcNAcylation after injection of AAV8-ASCT2 shRNA in CCl4-induced liver fibrosis mice in vivo.

Thr122 O-GlcNAcylation regulation of ASCT2 resulted in stability and membrane trafficking-mediated glutaminolysis in HSCs and liver fibrosis. Further studies are required to assess its role as a putative therapeutic target.

Liver disease has long been a heavy health and economic burden worldwide. Once the disease is out of control and progresses to end-stage or acute organ failure, orthotopic liver transplantation (OLT) is the only therapeutic alternative, and it requires appropriate donors and aggressive administration of immunosuppressive drugs. Therefore, hepatocyte transplantation (HT) and bioartificial livers (BALs) have been proposed as effective treatments for acute liver failure (ALF) in clinics. Although human primary hepatocytes (PHs) are an ideal cell source to support these methods, the large demand and superior viability of PH is needed, which restrains its wide usage. Thus, a finding alternative to meet the quantity and quality of hepatocytes is urgent. In this context, human pluripotent stem cells (PSC), which have unlimited proliferative and differential potential, derived hepatocytes are a promising renewable cell source. Recent studies of the differentiation of PSC into hepatocytes has provided evidence that supports their clinical application. In this review, we discuss the recent status and future directions of the potential use of PSC-derived hepatocytes in treating ALF. We also discuss opportunities and challenges of how to promote such strategies in the common applications in clinical treatments.

Acute liver failure (ALF) is associated with high mortality. Gasdermin D (GSDMD) is the executioner of pyroptosis and is involved in the pathophysiology of immune dysregulation This study investigated the role of the GSDMD inhibitor necrosulfonamide (NSA) in ALF.

An ALF model was established by lipopolysaccharide/D-galactosamine challenge in C57BL/6J mice. Mice were divided into four groups: normal controls (control group), ALF group (ALF group), dimethyl sulfoxide group (DMSO group), and NSA intervention group (NSA group). Survival was monitored, liver damage was determined by hematoxylin and eosin staining, and serum alanine aminotransferase (ALT). Underlying mechanisms were explored by quantitative real-time PCR, western blotting, and enzyme-linked immunosorbent assays.

Pyroptosis was activated in ALF model mice. Mice treated with GSDMD inhibitor NSA developed less severe liver failure. NSA reduced the expression of GSDMD, NLRP3, cleaved caspase-1, cleaved caspase-11, and secretion of interleukin-1 beta in ALF mice model.

Pyroptosis was activated in ALF. NSA alleviated ALF via the pyroptosis pathway.

Chronic diseases affect many people and have become the leading cause of death and loss of health worldwide. The etiology of chronic diseases is complex. They are usually incurable and require continual medical management. Many chronic diseases deteriorate with time, resulting in an enormous burden on society and patients’ families. During the past years, targeted agents have made improved the management of various chronic diseases. An optimal drug delivery system can improve the therapeutic efficacy of these targeted drugs and reduce systemic adverse effects, bringing benefits to patients with chronic diseases. Here, we highlight recent research progress in the development of targeted therapeutic drugs for chronic diseases and improved delivery systems.

Krüppel-like factor (KLF) has a role in the occurrence, development and metabolism of cancer. We aimed to explore the role and potential molecular mechanism of KLF13 in the growth and migration of liver cancer cells.

The expression of KLF13 in hepatocellular carcinoma (HCC) tissues was higher than that in normal tissues according to analysis of The Cancer Genome Atlas (TCGA) database. Lentiviral plasmids were used for overexpression and plasmid knockdown of KLF13. Real-time quantitative polymerase chain reaction (qPCR) and western blotting were used to detect mRNA and protein expression in HCC tissues and cells. Cell counting kit-8 (CCK-8), colony formation, cell migration and invasion, and flow cytometry assays were used to assess the in vitro function of KLF13 in HCC cells. The effect of KLF13 on xenograft tumor growth in vivo was evaluated. The cholesterol content of HCC cells was determined by an indicator kit. A dual-luciferase reporter assay and chromatin immunoprecipitation sequencing (ChIP-seq) revealed the binding relationship between KLF13 and HMGCS1.

The expression of KLF13 was upregulated in HCC tissues and TCGA database. KLF13 knockdown inhibited the proliferation, migration and invasion of HepG2 and Huh7 cells and increased the apoptosis of Huh7 cells. The opposite effects were observed with the overexpression of KLF13 in SK-Hep1 and MHCC-97H cells. The overexpression of KLF13 promoted the growth of HCC in nude mice and KLF13 transcription promoted the expression of HMGCS1 and the biosynthesis of cholesterol. KLF13 knockdown inhibited cholesterol biosynthesis mediated by HMGCS1 and inhibited the growth and metastasis of HCC cells.

KLF13 acted as a tumor promoter in HCC by positively regulating HMGCS1-mediated cholesterol biosynthesis.

Sarcomatoid carcinoma is a rare tumor that is composed of a mixture of malignant epithelial cells and mesenchymal cells. Many studies have reported that sarcomatoid carcinoma occurs in multiple organs including the liver. Sarcomatoid intrahepatic cholangiocarcinoma (S-iCCA) is an extremely rare tumor that primarily occurs in the liver. This case occurred in a middle-aged man who was admitted to our hospital with abdominal pain. Enhanced computed tomography of the abdomen showed a low-density mass in the upper right posterior lobe of the liver with enhancement in the periphery. Histological and immunohistochemical examination indicated that the tumor was malignant, with both cancer and sarcoma components, and was positive for cytokeratin and vimentin. The patient was diagnosed with S-iCCA. Metastases appeared in the liver and lung 4 months after surgery. Two cycles of chemotherapy were administered. Because of enlargement of the tumor, anti-angiogenic agents combined with immunotherapy were subsequently given to achieve disease control. To the best of our knowledge, this is the first reported case of a programmed cell death-1 inhibitor used in a S-iCCA patient. The purpose of this case report and literature review is to enhance clinician understanding of S-iCCA and to explore safe and effective treatment methods.

Objective measurements of dysautonomia in children with psychosomatic disease and more recently in SARS-CoV-2-related disorders may clarify current uncertainties by using heart rate analysis for diagnostics and therapy control.

We analyzed the data of 181 children who had an active standing test, among which 131 had an additional 24-h Holter echocardiogram. The children suffered from dysautonomia due to postural orthostatic tachycardia (n = 48), inappropriate sinus tachycardia (n = 74), or clinical vasovagal syncope (n = 12). We investigated the effect of our treatment on heart rate and heart rate variability, including beta blocker (low dose propranolol 20–20–0 mg, n = 15), ivabradine 5–5–0 mg (n = 11), midodrine 2.5–2.5–0 mg (n = 6), and omega-3-fatty acid supplementation (n = 7).

Lowering increases in heart rate while standing was achieved by low dose propranolol (from 41.7 ± 17.5 to 29.5 ± 17.8 beats per minute) and ivabradine (from 37.5 ± 16.4 to 23.6 ± 8.1 beats per minute). We further found a significant reduction of heart rate while standing after omega-3-fatty acid supplementation (from 44.0 ± 11.9 to 25.6 ± 8.4 beats per minute). Heart rate variability was useful for determining pathophysiology but was not necessary for diagnosis.

Vagus weakness was more common in children with dysautonomia compared to those with inappropriate sinus tachycardia and in the upright position in children with postural orthostatic tachycardia. Dysautonomia was related to autoimmunity in nine cases, including in children following SARS-CoV-2 infection. The current study demonstrates that assessing dysautonomia could be beneficial in the treatment of psychosomatic and SARS-CoV-2-related disorders.

Radiation-induced liver fibrosis (RILF), delayed damage to the liver (post-irradiation) remains a major challenge for the radiotherapy of liver malignancies. This study investigated the potential function and mechanism of circTUBD1 in the development of RILF.

By using a dual luciferase assay, RNA pull-down assays, RNA sequencing, chromatin immunoprecipitation (known as ChIP) assays, and a series of gain- or loss-of-function experiments, it was found that circTUBD1 regulated the activation and fibrosis response of LX-2 cells induced by irradiation via a circTUBD1/micro-203a-3p/Smad3 positive feedback loop in a 3D system.

Knockdown of circTUBD1 not only reduced the expression of α-SMA, as a marker of LX-2 cell activation, but also significantly decreased the levels of hepatic fibrosis molecules, collagen type I alpha 1 (COL1A1), collagen type III alpha 1 (COL3A1), and connective tissue growth factor (CTGF) in a three-dimensional (3D) culture system and RILF model in vivo. Notably, knockdown of circTUBD1 alleviated early liver fibrosis induced by irradiation in mice models.

This study is the first to reveal the mechanism and role of circTUBD1 in RILF via a circTUBD1/micro-203a-3p/Smad3 feedback loop, which provides a novel therapeutic strategy for relieving the progression of RILF.

Metabolic associated fatty liver disease (MAFLD) is a serious condition, and a simple method is needed for practitioners to identify patients with the disease and have a high risk of disease progression.

We developed and validated a nomogram for fatty liver disease and reclassified the risk factors for MAFLD. The development cohort had 335 patients who received bioelectrical impedance analysis and liver ultrasound attenuation measurements at Shenzhen People’s Hospital between September 2020 and June 2021. The validation cohort had 200 patients from other hospitals who received the same evaluation. A random forest procedure and binary logistic analysis were used to screen for risk factors, establish a fatty liver disease predictive model, and forecast the risk of MAFLD. The performance of the nomogram was evaluated by measurement of discrimination, calibration, and clinical usefulness.

The nomogram provided good predictions in a model that included body mass index (BMI) and waist circumference. The areas under the curve of the nomogram were 0.793 in the development cohort and 0.774 in the validation cohort. The nomogram performed well for calibration, category-free net reclassification improvement, and integrated discrimination improvement. Decision curve analysis indicated the nomogram performed better than BMI for predicting net outcome.

The nomogram was an effective screening tool for fatty liver disease, and for those overweight individuals, may help physicians make appropriate decisions regarding treatment of MAFLD.

Monocyte/macrophage-associated CD163 is an indicator of the severity of liver inflammation and cirrhosis, but the difference of soluble CD163 (sCD163) levels in chronic hepatitis B (CHB) patients and hepatitis B surface antigen (HBsAg)-loss patients is unclear. Herein, we aimed to compare the sCD163 levels in CHB patients and HBsAg-loss patients with or without antiviral treatment.

sCD163 and CD163 expression on monocytes were compared among four groups, healthy subjects, treatment-naïve CHB patients, spontaneous HBsAg-loss patients, and treatment-related HBsAg-loss patients. The correlation between sCD163 levels and clinical parameters in CHB patients was analyzed. A group of 80 patients with hepatitis B virus (HBV) infection and liver biopsy were recruited.

sCD163 levels were higher in the CHB group than in the other three groups. sCD163 levels were higher in treatment-related HBsAg-loss patients than in spontaneous HBsAg-loss patients. sCD163 levels were negatively correlated with hepatitis B e-antigen (HBeAg) and HBsAg levels in HBeAg-positive patients. Liver biopsy results further demonstrated that sCD163 levels were elevated in CHB patients with substantial inflammation (A≥2) or fibrosis (F≥2). The sCD163 model was more sensitive in predicting inflammation than other noninvasive models. Its levels were higher in patients with normal alanine aminotransferase levels and significant inflammation (A≥2) than in patients with no or mild inflammation.

sCD163 and CD163 expression on monocytes were associated with CHB inflammation and HBsAg loss, and may be used as markers to predict HBV-specific immune activation.

Darwinian/evolutionary medicine is a nascent but rapidly developing field that applies the principles of evolutionary biology to help explain and prevent human disease. This article examines selected topics in Darwinian medicine, including diet-culture coevolution and health, developmental origins of health and disease, ageing (life history evolution and disease), nutrigenomics/pharmacogenomics, and the hygiene hypothesis (microbiota, pathogens and parasites within the Darwinian perspective of human health). It also looks at the future and how Darwinian medicine fits into anthropogenic changes at the planetary level. Although Darwinian medicine has a very broad domain, encompassing ageing, immunity, reproductive health, cancer, infectious disease, diet-culture interactions, the application of personalised medicine, the microbiome, and behavioural conditions, there are several core principles drawn from evolutionary biology that it applies, and that are integrated into this review. These include selection, drift, plasticity, mismatch, cultural practices, trade-offs, life history traits, antagonistic pleiotropy, heterozygote advantage, constraints, biological defences, co-evolution (i.e., microbiome), adaptation/maladaptation, novel environments, and the genome-phenome relationship.

The governors of New Jersey, New York, California, Connecticut, Delaware and Oregon announced early in the week of February 7 that selecting mask mandates in their states would end in two to six weeks. These states together account for 77.9 million Americans, or ∼23.5% of the U.S. population, and therefore, these changes in policy could have a significant impact on the U.S. economy, as well as education and healthcare systems in each state. As counts of COVID-19 cases, hospitalizations and deaths decrease, mask mandates should be reassessed. We propose that a data-driven, dynamic and flexible approach may help lift mask mandates safely and facilitate a smooth transition to post-pandemic normalcy.

The diagnosis of severe acute flares of chronic hepatitis B is guided by raised alanine aminotransferase enzyme levels almost five times the upper limit of normal during the chronic phase of hepatitis B virus (HBV) infection preceded by elevated levels of hepatitis B surface antigen and hepatitis B virus deoxyribonucleic acid (HBV DNA). Elevation of HBV DNA levels during acute flares indicates an ineffective immune clearance mechanism in the host, which is associated with the lytic activity of hepatocytes with or without hepatic decompensation that might require urgent intervention with antiviral drug therapy. Bridging hepatic necrosis associated with alpha-fetoprotein levels >100 ng/mL or decreasing HBV DNA levels during acute flares are pathognomics of better immune clearance of HBV that eventually progresses to seroclearance. The clinical manifestation of acute hepatitis flares can be asymptomatic or might begin with symptomatic acute hepatitis, which subsequently might progress to hepatic decompensation. It occurs due to the immune response against HBV, which is cytotoxic T-lymphocyte mediated and human leukocyte antigen-1 specific. Certain precipitating factors for the occurrence of acute flares in the case of chronic hepatitis B infected patients include the initiation or the end of treatment with antiviral drug therapy, immunosuppressive or chemotherapy treatment, or spontaneous reactivation with or without concurrent reinfection with HBV or any other hepatotropic viruses. Severe or repeated acute flares might progress to hepatic decompensation and liver cirrhosis. Therefore, it is important to prevent acute hepatitis B flares with the appropriate administration of antiviral drug therapy.

The redefinition of metabolic-associated fatty liver disease (MAFLD) from nonalcoholic fatty liver disease (NAFLD) has caused a revolution in clinical practice, and the characteristics of patients with steatosis but not MAFLD remain unclear. The aims were to compare the diagnosis rate of MAFLD in NAFLD using different steatosis methods and explore the features of non-MAFLD–NAFLD and MAFLD–non-NAFLD.

A cross-sectional study enrolling consecutive individuals was conducted at three medical centers in southern China from January 2015 to September 2020. Steatosis was evaluated by liver biopsy or magnetic resonance imaging-based proton density fat fraction (MRI-PDFF), ultrasound, controlled attenuation parameter (CAP), and fatty liver index (FLI). Fibrosis was assessed by the NAFLD fibrosis score, transient elastography, or shear wave elastography.

The study enrolled 14,985 Chinese adults. The agreement of MAFLD and NAFLD diagnoses were 83% for FLI, 95% for ultrasound, 94% for both CAP and MRI-PDFF, and 95% for liver biopsy. The body mass index, blood pressure and lipid levels among non-MAFLD–NAFLD patients were similar metabolic parameters (p>0.05 for all), but not the alanine aminotransferase and the proportion of patients with insulin resistance, which were significantly higher in non-MAFLD–NAFLD with significant fibrosis.

The new MAFLD definition ruled out 5–17% of NAFLD cases. NAFLD and MAFLD–NAFLD involved more severe metabolic abnormalities than MAFLD and MAFLD–non-NAFLD. Non-MAFLD–NAFLD patients with significant fibrosis had more severe liver injury and increased glycemic dysregulation within the normal range. Attention should be paid to its progression.

The Quzhi formula, a Chinese medicine compound prescription, relieves nonalcoholic steatohepatitis (NASH) symptoms. This study aimed to explore the mechanism of the Quzhi formula against NASH.

A choline-deficient, L-amino acid-defined, high-fat diet induced a NASH mouse model and a free fatty acid-induced mouse hepatocyte cell model were used to evaluate the function of Quzhi formula in vivo and in vitro. Network pharmacology and molecular docking technology were performed to uncover the possible protective mechanisms of the Quzhi formula against NASH. Key factors in liver lipid metabolism and endoplasmic reticulum (ER) stress pathway were evaluated to verify the mechanism.

The positive contribution of the Quzhi formula on NASH was confirmed in vivo and in vitro. Abnormal accumulation of lipid in the liver and inflammatory responses were significantly decreased by the Quzhi formula. Network pharmacological analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that the Quzhi formula protected against NASH by regulating ER stress and inflammatory responses, which was enhanced by further molecular docking analysis. In addition, mechanism exploration showed that Quzhi formula mainly reduced ER stress by downregulating Bip/eIF2α signaling.

The Quzhi formula protected against NASH by inhibiting lipid accumulation, ER stress, and inflammatory responses, which supports the potential use of Quzhi formula as an alternative treatment for NASH.