Alagille syndrome (AGS) is an autosomal dominant multisystem disorder caused by mutations in the JAG1 and NOTCH2 genes. AGS has been rarely reported in adult patients, mainly because its characteristics in adults are subtle. The study aimed to improve the understanding of adult AGS by a descriptive case series.

Eight adults diagnosed with AGS at our hospital between June 2016 and June 2019 were included in the study. Clinical data, biochemical results, imaging results, liver histopathology, and genetic testing were analyzed.

Three female and five male patients with a median age of 24.5 years at the time of diagnosis were included in the analysis. The clinical manifestations were adult-onset (62.5%, 5/8), cholestasis (50%, 4/8), butterfly vertebrae (62.5%, 5/8), systolic murmurs (12.5%, 1/8), typical facies (12.5%, 1/8), posterior embryotoxon, and renal abnormalities (0/8). Genetic sequencing showed that all patients had mutations, with four occurring in the JAG1 gene and four in the NOTCH2 gene. Six were substitution mutations, one was a deletion mutation, and one was a splicing mutation. Five had been previously reported; but the others, one JAG1 mutation and two NOTCH2 mutations were unique and are reported here for the first time.

The clinical manifestations highlighted by the current diagnostic criteria for most adults with AGS are atypical. Those who do not meet the criteria but are highly suspicious of having AGS need further evaluation, especially genetic testing.

Alanine aminotransferase (ALT) is a common clinical indicator of liver inflammation. The current Chinese guidelines for the management of chronic hepatitis B (CHB) recommend antiviral treatment for patients with detectable hepatitis B virus (HBV) DNA and persistent ALT levels (ALTs) exceeding the upper limit of normal. However, it has been recently reported that patients with chronic HBV infection, especially HBeAg-negative patients with persistently normal ALTs, may have liver biopsy findings of significant inflammation and fibrosis. For HBeAg-negative patients with chronic HBV infection and normal ALTs, many controversial questions have been asked. To treat or not? When to initiate the treatment? Which drug is appropriate? In this review, we summarize the available data on the management of HBeAg-negative patients with chronic HBV infection and normal ALTs with the aim of improving the current clinical management.

The recent histologic subtyping of lung adenocarcinoma has demonstrated the prognostic values of histologic patterns in this malignancy. However, the histological features of lung squamous cell carcinoma (SCC) are much less established. This short review discusses several promising histological prognostic markers for SCC, including tumor budding, tumor cell nesting, and the spreading of tumors through air spaces. Wherever appropriate, the biological significance of these morphological features was also discussed. The investigators consider that histological prognostic markers are highly valuable in understanding the cancer biology of SCC, and in guiding clinical treatment. However, larger clinical cohorts are needed to better establish the prognostic values of the aforementioned histological markers. The application of modern technologies, including machine-learning, would make the histological analysis accurate and reproducible.

Morphologic variants of well-differentiated pancreatic neuroendocrine tumors (PanNETs) are uncommon. These variants may mimic non-PanNETs, and when under recognized, it would lead to misdiagnosis by fine-needle aspiration (FNA) biopsy. The present report describes the unique cytomorphologic features and diagnostic clues of pigmented, pleomorphic, clear cell/lipid-rich and oncocytic variants of well-differentiated PanNETs. The differential diagnoses of each morphologic variant are also discussed. Ancillary immunohistochemical studies with appropriate markers are crucial in the diagnostic work-up. Raising the awareness of PanNET morphologic variants is essential for preventing diagnostic pitfalls, and rendering an accurate diagnosis during the FNA diagnostic work-up of pancreatic lesions.

Hridayarnava Rasa is traditionally used cardio tonic in Ayurveda. This drug was selected for the evaluation of stabilization of erythrocyte membrane (EM) in high-fat diet induced atherosclerosis via rabbit model.

A total of 24 male white New Zealand rabbits were randomly divided into 6 groups (n = 4 each). Rabbits in group 1 were fed a standard pellet diet, those in group II rabbits a high-fat diet (HFD), those in groups III, IV and V increasing doses of H. Rasa and an HFD, and those in group VI an HFD diet plus Atorvastatin.

There was a significant reduction in rabbit sodium/potassium adenosine triphosphatase (Na+/K+ ATPase) at 30 (58.51%), 60 (61.40%), and 90 (64.92%) days of an HFD diet compared to the control group. Upon treatment with H. Rasa, the activity of Na+/K+ ATPase in groups III, IV, and V increased at 30, 60 and 90 days, respectively, compared to HFD induced rabbits. The Na+ concentration also increased significantly in HFD-administered rabbits at 30, 60 and 90 days as compared to controls. Serum K+ concentration was reduced at days 30, 60 and 90 in the HFD group and was increased in group V as compared to the control group. These levels improved with H. Rasa treatment whereas the atorvastatin-treated group exhibited an improvement only between dose levels 2 and 3.

These results suggest that HFD diminishes EM stabilization in atherosclerosis whereas H. Rasa protects EM by maintaining the Na+/K+ ATPase activity through a Na+/K+ pump. In atherosclerosis, an HFD reduces EM stabilization after administration of H. Rasa, which maintains Na+/K+ ATPase activity through a Na+/K+ pump.

Hepatic ischemic reperfusion injury (IRI) occurring during surgery seriously affects patient prognosis. The specific mechanism of IRI has not been fully elucidated. The study aim was to explore the changes of inflammatory environment, and the relationship of the Th17/Treg cell ratio and FOXO1 expression in hepatic IRI.

Liver samples at different ischemic times were collected from patients and mice. The expression of inflammatory markers and FOXO1 in the liver was detected by western blotting and qPCR. Phenotypic changes of liver lymphocytes were analyzed by flow cytometry. The AKT/Stat3/FOXO1 pathway was verified by targeting AKT with GSK2141795. The role of FOXO1 in liver inflammation and changes in lymphocyte phenotype was confirmed by upregulating FOXO1 with resveratrol.

Prolonged ischemic time aggravates liver injury in both humans and mouse models of hepatic IRI. IR-stress caused Th17/Treg imbalance and FOXO1 down-regulation by activating the AKT/Stat3/FOXO1 signaling pathway. Upregulation of FOXO1 reversed the Th17/Treg cytokine imbalance and altered the inflammation environment in the liver.

Liver IRI induced Th17/Treg imbalance. Upregulation of FOXO1 reversed the imbalance and alleviated liver inflammation.

Rosemary (Rosmarinus officinalis L.) extract is widely used in food, cosmetic and pharmaceutical industries. This study centered on the optimization of ethanolic extraction of rosemary leaves and evaluated the bioactivity of the extract.

The optimized rosemary extract was analyzed using high-performance liquid chromatography. The antioxidant activity of the rosemary extract was measured using 2,2′-Azinobis-(3-ethylBenzoThiazoline-6-Sulfonic) acid, 2,2-DiPhenyl-1-Picryl-Hydrazyl-hydrate, and ferric reducing antioxidant power assays. The antibacterial activity of the rosemary extract was tested using the disk diffusion method. Toxicity was tested using mice. Nitrite production by RAW 264.7 cells was used to determine the anti-inflammatory activity of the rosemary extract. The construction and statistical analysis of the experimental design was done using NemrodW (LPRAI, version 2000) software.

Optimization studies of rosemary leaf extract for carnosic and rosmarinic acid yields revealed a significant interaction between extraction temperature and time. A mathematical model was established, showing that the optimal conditions for maximum yields of carnosic acid (86.28 mg/g DW) and rosmarinic acid (8.37 mg/g DW) were at 155°C and 120 minutes. Biochemical analysis confirmed the extract’s richness in phenolic compounds, with carnosic acid and rosmarinic acid being the most abundant. Antioxidant assays demonstrated the extract’s efficacy, with notable anti-radical activity surpassing the standard Trolox in the DPPH assay. Additionally, the extract exhibited significant antibacterial activity against various pathogens, suggesting its potential as a natural food preservative.

The research successfully identified optimal extraction parameters for carnosic and rosmarinic acids from rosemary leaves, contributing to their efficient utilization. The extract showed potent antioxidant and antibacterial activities, which are attributed to the high content of active phenolic compounds. Furthermore, the absence of acute toxicity in mice and anti-inflammatory effects in macrophage cells support rosemary leaf extract’s safety and therapeutic potential. These findings pave the way for the application of rosemary extract as a natural additive in food and pharmaceutical industries.

There is an unmet need for new biomarkers to improve diagnostics and prognostics in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Inter-α-inhibitor heavy chain 4 (ITIH4) is an abundant, liver-produced protein, and its synthesis may be altered in liver diseases. We investigated whether ITIH4 plasma concentrations were affected in PBC and PSC patients.

We developed an immunoassay specific for ITIH4 and determined ITIH4 plasma concentrations in 66 PBC, 126 PSC, 92 autoimmune hepatitis (AIH), 67 chronic hepatitis C (CHC), 33 alcoholic hepatitis (AH) patients and 138 healthy controls (HCs). Hepatic ITIH4 expression was investigated by immunohistochemistry in PBC.

The mean plasma concentration of ITIH4 was almost doubled in PBC [409 µg/mL (95% CI: 388–431)] and 35% higher in PSC [308 µg/mL, (95% CI: 296–319)] compared with HCs [226 µg/mL (95% CI: 221–231); p<0.001]. In PBC patients, ITIH4 correlated with IgM (rho=0.49, p<0.001). Responders to ursodeoxycholic acid treatment (UDCA) had lower levels of ITIH4 than incomplete responders [395 µg/mL (95% CI: 364–425)] vs. 460 µg/mL (95% CI: 421–498); p=0.02]. Four weeks of UDCA treatment had no effect (p=0.19). Increased ITIH4 immunohistochemical staining was seen in a liver biopsy from a PBC patient. ITIH4 levels in AIH [224 µg/mL (95% CI: 208–241)] and HCs were similar (p=0.8). ITIH4 levels were lower in AH [199 µg/mL (95% CI: 175–223)] and CHC [202 µg/mL (192–212)] patients than in HCs (p<0.05).

The plasma concentration of ITIH4 was highly elevated in patients with PBC and PSC, suggesting that ITIH4 should be further investigated as a biomarker in cholestatic liver disease.

Although whole body vibration (WBV) has been used to reduce pain, some studies have indicated that WBV can cause low back pain (LBP). This study provides an overview of the current literature on the use of WBV to treat LBP and its effects on muscle strength, postural stability, and quality of life.

A literature research was conducted using the search terms “Whole Body Vibration” and “Low Back Pain” in the PubMed, PEDro, OVID, Cochrane Library, Web of Science, Google Scholar, and Scopus databases. All articles published up to November 2021 were included. Articles that did not have WBV as a treatment were excluded. The PEDro score was used to test methodological quality.

Of the 1,686 publications identified in the literature search, 21 studies focused on WBV as treatment for LBP, including 18 original studies, two reviews, and one meta-analysis. Ten of these 21 studies had good methodological quality. Five studies had a WBV duration of 12 weeks and were included in the meta-analysis (muscle strength, postural stability, and quality of life). Standardized mean differences and 95% confidence intervals were calculated. The effects range was from −0.86 to 0.84, favoring experimental groups.

Many positive effects of WBV on LBP were found. Given the effect sizes of the high-quality studies, it is reasonable to assume that WBV is effective for treating LBP.

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.