Hepatocyte nuclear factor 1β (HNF1β) is essential for biliary development, while its genetic defect triggers the dysplasia of interlobular bile ducts, leading to life-threatening hepatitis and cholestasis. To date, this disorder has mainly been documented in neonates. Here, we report a case of cholestasis in an adult patient caused by a de novo HNF1β mutation. A liver biopsy revealed remarkable shrinkage of the portal area accompanied by a decrease or absence of interlobular bile ducts, veins, and arteries in the portal area. Our case showed that an HNF1β defect could induce late-onset cholestasis with paucity of the portal area in adulthood.

Genetic polymorphisms of CYP2D6 and CYP2C19 affect both the effectiveness and the occurrence of side effects of many antidepressants. By drug-drug-gene interactions (also referred to as phenoconversion), the phenotype of the patient can be changed. Both pharmacogenetic testing, drug-drug, and drug-drug-gene interaction checks are essential to individualize the dose of the antidepressant or start an alternative drug in accordance with the pharmacogenetic guidelines. The aim of this study was to analyze the frequency of divergent phenotypes (i.e. divergent from the common phenotypes considered normal), of phenoconversion (a genotype–phenotype mismatch), and of actionable genotypes (genotypes where a prescribing change may be indicated) in psychiatric inpatients with a depressive disorder.

Genotyping of CYP2D6 and CYP2C19 was performed in 104 patients 18 years of age or older who received inpatient treatment in a German psychiatric university hospital for a depressive disorder. Representation of the frequencies of divergent phenotypes, of phenoconversion, and of actionable genotypes were analyzed.

A divergent phenotype in one or both CYP enzymes was seen in 83.5% of the patients. The rate of CYP2D6 poor metabolizers increased by 142.4% (from 5.9% to 14.3%, p = 0.013) at admission and by 183.1% (from 5.9% to 16.7%, p = 0.004) at discharge because of phenoconversion. At discharge, 22% of the patients (n = 104) received an antidepressant with a dosing recommendation based on their CYP2D6 phenotype and 15.4% on their CYP2C19 phenotype. When considering phenoconversion, the rate increased by 17.4 to 26.0% (p = 0.221) for patients with the CYP2D6 genotype.

The clinical relevance of the results of the study is that phenotype conversion is common in patients treated for depression with medication. The discrepancy between the clinically observed phenotype and the phenotype expected based on the patient genotype underscores the need for greater consideration of both genetic and nongenetic factors.

Targeted therapy and immunotherapy have emerged as treatment options for hepatocellular carcinoma (HCC) in recent years. The significance of serine and glycine metabolism in various cancers is widely acknowledged. This study aims to investigate their correlation with the prognosis and tumor immune microenvironment (TIME) of HCC.

Based on the public database, different subtypes were identified by cluster analysis, and the prognostic model was constructed through regression analysis. The gene expression omnibus (GEO) data set was used as the validation set to verify the performance of the model. The survival curve evaluated prognostic ability. CIBERSORT was used to evaluate the level of immune cell infiltration, and maftools analyzed the mutations. DsigDB screened small molecule compounds related to prognostic genes.

HCC was found to have two distinct subtypes. Subsequently, we constructed a risk score prognostic model through regression analysis based on serine and glycine metabolism-related genes (SGMGs). A nomogram was constructed based on risk scores and other clinical factors. HCC patients with a higher risk score showed a poor prognosis, and there were significant differences in immune cell infiltration between the high- and low-risk groups. In addition, three potential drugs associated with prognostic genes, streptozocin, norfloxacin, and hydrocotarnine, were identified.

This study investigated the expression patterns of SGMGs and their relationship with tumor characteristics, resulting in the development of a novel model for predicting the prognosis of HCC patients. The study provides a reference for clinical prognosis prediction and treatment of HCC patients.

Breast cancer is the most prevalent malignancy and the leading cause of cancer-related death in women. Breast cancer is still an extremely difficult cancer to treat due to its significant metastasis. Mis-regulation of Notch signaling components such as Notch receptors/ligands and their interaction in breast cancer sparks tumor initiation, maintenance, and progression through induction of abnormal tumorigenesis while modulating vascular integrity, drug resistance, invasion, and migration. Numerous studies have shown that non-coding RNAs can regulate Notch signaling and accordingly impact breast cancer pathobiology. MiRNAs could regulate Notch signaling components directly or indirectly via sponging or suppressing other genes involved in the pathway. Further, lncRNAs interact with miRNAs and mRNAs, and lncRNA-miRNA-mRNA interaction networks function as substantial mediators in various pathways, including the Notch signaling pathway. Also, by targeting and sponging other genes, circRNAs could induce tumorigenic properties via the Notch signaling pathway. Due to the intricacy of human physiology, it is challenging for standard drugs to be effective, and cancer cells can develop resistance to treatment and have a significant self-renewal capacity. Moreover, because non-specific Notch signaling intervention targets both tumor cells and immune cells, it may have the reverse effect of regulating the formation of tumors. Thus, an in-depth understanding of the mechanisms could be useful in diagnosis, prognosis, and the development of novel medications that specifically target Notch signaling, improving the efficacy of cancer immunotherapy in the treatment of breast cancer. This review will discuss and clarify the mechanisms by which miRNAs, lncRNAs, and circRNAs affect the Notch signaling pathway leading to BC development.

Gastric cancer (GC) is a prevalent gastrointestinal malignancy, yet its early detection remains hindered due to the lack of available genetic markers. This study aimed to identify alternative genetic markers for the early prognosis and prevention of GC.

This objective was achieved through the analysis of differentially expressed genes (DEGs) from three datasets obtained from the Gene Expression Omnibus (GEO). By doing so, our goal was to identify hub genes associated with gastric adenocarcinoma that could serve as potential biomarkers for the early detection and management of GC. Three GEO datasets (GSE172032, GSE179581, and GSE181492), consisting of 10 normal and 10 GC samples were analyzed using the Galaxy web server. The visualizations of DEGs, including heatmaps, volcano plots, and MD plots, were generated via the same tool. ShinyGO performed Gene Ontology and KEGG enrichment analysis, while NetworkAnalyst identified a protein-protein interaction (PPI) network and screened 10 potential hub genes. Kaplan Meier plotter was used to analyze overall survival analysis for key hub genes, and NetworkAnalyst was used to assess protein-drug interactions for the top 10 hub genes.

A total of 1,079 common DEGs emerged across datasets, concentrating on significant GC-related pathways. Ten hub genes (H2BC21, H3C12, H2BC17, H3C2, H3C10, ERBB4, H2AC8, H3C8, H2BC14, and MAPT) were found to be linked to GC via PPI analysis. Survival analysis revealed that higher expression levels of ERBB4 and MAPT were associated with poor overall survival in GC patients. Furthermore, protein-drug interaction analysis revealed that the protein product of the MAPT gene exhibited a robust connection with drug compounds, specifically docetaxel and paclitaxel. These findings suggested that these drugs have the potential to inhibit the function of MAPT.

In summary, our findings provide putative candidate biomarkers, provide insights into GC treatment strategies, and highlight avenues for further research, contributing to a better understanding of the pathogenesis of GC.

Acetaminophen (APAP)-induced liver injury (AILI) has an increasing incidence worldwide. However, the mechanisms contributing to such liver injury are largely unknown and no targeted therapy is currently available. The study aimed to investigate the effect of BTF3L4 overexpression on apoptosis and inflammation regulation in vitro and in vivo.

We performed a proteomic analysis of the AILI model and found basic transcription factor 3 like 4 (BTF3L4) was the only outlier transcription factor overexpressed in the AILI model in mice. BTF3L4 overexpression increased the degree of liver injury in the AILI model.

BTF3L4 exerts its pathogenic effect by inducing an inflammatory response and damaging mitochondrial function. Increased BTF3L4 expression increases the degree of apoptosis, reactive oxygen species generation, and oxidative stress, which induces cell death and liver injury. The damage of mitochondrial function by BTF3L4 triggers a cascade of events, including reactive oxygen species accumulation and oxidative stress. According to the available AILI data, BTF3L4 expression is positively associated with inflammation and may be a potential biomarker of AILI.

Our results suggest that BTF3L4 is a pathogenic factor in AILI and may be a potential diagnostic maker for AILI.

Gallstone (GS) disease is common and arises from a combination of genetic and environmental factors. Although genetic abnormalities specifically leading to cholesterol GSs are rare, there are clinically significant gene variants associated with cholesterol GSs. In contrast, most bilirubin GSs can be attributed to genetic defects. The pathogenesis of cholesterol and bilirubin GSs differs greatly. Cholesterol GSs are notably influenced by genetic variants within the ABC protein superfamily, including ABCG8, ABCG5, ABCB4, and ABCB11, as well as genes from the apolipoprotein family such as ApoB100 and ApoE (especially the E3/E3 and E3/E4 variants), and members of the MUC family. Conversely, bilirubin GSs are associated with genetic variants in highly expressed hepatic genes, notably UGT1A1, ABCC2 (MRP2), ABCC3 (MRP3), CFTR, and MUC, alongside genetic defects linked to hemolytic anemias and conditions impacting erythropoiesis. While genetic cases constitute a small portion of GS disease, recognizing genetic predisposition is essential for proper diagnosis, treatment, and genetic counseling.

The correlation between gut, secreted metabolites, and hepatic diseases has strengthened over the last decade. Interactions of intestinal permeability, gut microbes, and derived metabolites influence the development and progression of nonalcoholic fatty liver disease (NAFLD), a prevalent disease that affects more than 30% of the global population. NAFLD is now called metabolic dysfunction-associated steatotic liver disease (MASLD) to better reflect the disease process. Here, we describe mechanisms of NAFLD development, the role of gut bacteria, gut metabolites, interventions for diagnosis, and the prognosis of NAFLD. We discuss new paradigms that challenge the conventional, addressing disease etiology and translational approaches in a new dimension. Previous studies shed light on intricate relationships of the gut microbiome with the liver, or the gut-liver axis. Bidirectional communication between the gut and the liver involves exchange of metabolites, immune signaling, and inflammatory responses that has potential for novel NAFLD/nonalcoholic steatohepatitis (NASH) treatments. In this review, we propose exploring functional metagenomics to develop NAFLD diagnostic methods and risk assessment. The prospects of genetic engineering, fecal transplants, and specialized diet as targets of novel therapeutic regimes to combat NAFLD/NASH are discussed. Changes in lifestyle and diet in the population, combined with genetic predisposition, have led to an increasing number of cases of NAFLD. The microbiome responds to diet, exercise, and the environment, and can modulate NAFLD in cases with surgical impediments. It is thus vital to explore its emerging roles in human healthcare and not only liver disease.

Cancer is a significant global health issue and a primary cause of death. Extensive research has led to the development of various anticancer medications, driven by an improved knowledge and comprehension of the molecular pathways involved in cancer growth. However, there is a need for new approaches to enhance the effectiveness of existing cancer therapies. Dietary phytochemicals have gained increasing attention due to their potential role in tumor prevention. These bioactive compounds derived from plants exhibit a wide range of beneficial effects on human health, including their ability to inhibit carcinogenesis and promote anticancer activities. Examples of dietary phytochemicals with promising properties include vitamin D, vitamin E, lycopene, fisetin, genistein, epigallocatechin gallate, crocetin, curcumin, cyanidins, and gingerol. These compounds often exert their effects by regulating interconnected molecular pathways associated with cancer development and progression. Some of these pathways include the apoptosis pathway, cyclooxygenase-2 pathway, ATP-dependent chromatin remodeling pathway, DNA methylation-epigenetic pathway, Hedgehog signaling pathway, signal transducer and activator of transcription protein-3 pathway, tumor angiogenesis inhibition pathway, and Wnt pathway. This comprehensive review aims to summarize the current knowledge on the role of dietary phytochemicals in tumor prevention, highlighting their mechanisms of action and potential therapeutic applications.

Cannabis is a commonly used recreational and therapeutic substance in our society. There are a variety of established physical, social, and mental health impacts associated with cannabis use. However, there is no overview of the impact cannabis use has on the genitourinary system. Thus, this scoping review aims to present data on the impact of cannabis on the genitourinary system.

A scoping review search was undertaken on Embase, Medline, and Web of Science. There were no date restrictions applied. Studies that included data from humans, exposure to cannabis, and outcomes related to the genitourinary system were included. Opinion pieces, commentaries, perspectives, and studies not available in English were excluded.

A total of 50 articles met this review’s inclusion criteria. The various studies were thematically organized into four themes: adverse outcomes related to cancer (n = 4), non-cancerous urogenital illness (n = 31), kidney transplant (n = 4), and therapeutic use of cannabis (n = 11). There were several non-cancerous urogenital illnesses associated with cannabis use, including acute kidney injury, urinary retention, rhabdomyolysis, and renal infarcts. The data found in this review suggest that cannabis use may not be a contraindication to receiving a kidney transplant. Finally, several studies highlighted some of the therapeutic applications cannabis may have on the genitourinary system.

This review brings forward conflicting findings on the association between cannabis use and genitourinary malignancies. Moving forward, data from well-designed long-term research studies are needed to understand the impact cannabis use has on the genitourinary system.

Liver iron overload can induce hepatic expression of bone morphogenic protein (BMP) 6 and activate the BMP/SMAD pathway. However, serum iron overload can also activate SMAD but does not induce BMP6 expression. Therefore, the mechanisms through which serum iron overload activates the BMP/SMAD pathway remain unclear. This study aimed to clarify the role of SMURF1 in serum iron overload and the BMP/SMAD pathway.

A cell model of serum iron overload was established by treating hepatocytes with 2 mg/mL of holo-transferrin (Holo-Tf). A serum iron overload mouse model and a liver iron overload mouse model were established by intraperitoneally injecting 10 mg of Holo-Tf into C57BL/6 mice and administering a high-iron diet for 1 week followed by a low-iron diet for 2 days. Western blotting and real-time PCR were performed to evaluate the activation of the BMP/SMAD pathway and the expression of hepcidin.

Holo-Tf augmented the sensitivity and responsiveness of hepatocytes to BMP6. The E3 ubiquitin-protein ligase SMURF1 mediated Holo-Tf-induced SMAD1/5 activation and hepcidin expression; specifically, SMURF1 expression dramatically decreased when the serum iron concentration was increased. Additionally, the expression of SMURF1 substrates, which are important molecules involved in the transduction of BMP/SMAD signaling, was significantly upregulated. Furthermore, in vivo analyses confirmed that SMURF1 specifically regulated the BMP/SMAD pathway during serum iron overload.

SMURF1 can specifically regulate the BMP/SMAD pathway by augmenting the responsiveness of hepatocytes to BMPs during serum iron overload.

The results of new randomized clinical trials show that immunotherapy is the preferred treatment for a small proportion of metastatic colorectal cancers (mCRCs). For microsatellite instability-high mCRC, pembrolizumab, nivolumab, and ipilimumab are currently authorized as first- and second-line immune checkpoint agents. However, the problem concerns tumors with microsatellite stability where the “cold” microenvironment does not allow immunotherapy to function properly. All efforts are now aimed at ensuring that this microenvironment is inflamed and “hot”. In this review, we examine recent studies on immunotherapy for mCRC and assess novel drivers of immunotherapy response.

Our recent work has focused on the application of infinite group theory and related algebraic geometric tools in the context of transcription factors and microRNAs. We were able to differentiate between “healthy” nucleotide sequences and disrupted sequences that may be associated with various diseases. In this paper, we extend our efforts to the study of messenger RNA (mRNA) metabolism, showcasing the power of our approach. We investigate (1) mRNA translation in prokaryotes and eukaryotes, (2) polyadenylation in eukaryotes, which is crucial for nuclear export, translation, stability, and splicing of mRNA, (3) microRNAs involved in RNA silencing and post-transcriptional regulation of gene expression, and (4) identification of disrupted sequences that could lead to potential illnesses. To achieve this, we used: (a) infinite (finitely generated) groups fp, with generators representing the r + 1 distinct nucleotides and a relation between them [e.g., the consensus sequence in the mRNA translation (i), the poly (A) tail in item (ii), and the microRNA seed in item (iii)]; (b) aperiodicity theory, which connects healthy groups fp to free groups Fr of rank r and their profinite completion F ^ r , and (c) the representation theory of groups fp over the space-time-spin group SL2(C), highlighting the role of surfaces with isolated singularities in the character variety. Our approach could potentially contribute to the understanding of the molecular mechanisms underlying various diseases and help develop new diagnostic or therapeutic strategies.

Non-alcoholic fatty liver disease (NAFLD) is an extremely prevalent disease, and the presence and severity of liver fibrosis are considered one of the most important factors determining its prognosis. Hepatic stellate cells (HSCs) are essential in hepatic fibrogenesis associated with NAFLD. A number of factors underlying NAFLD pathogenesis may promote HSCs activation, leading to the development of profibrotic and proinflammatory signs. In addition, for the fibrogenic transdifferentiation of quiescent HSCs, alterations in multiple genes are necessary, where epigenetic regulation plays a defining role. Epigenetic regulation induces changes in gene activity without altering the coding sequence, and these changes are stably inherited after the factor causing the alteration has disappeared. Epigenetic modifications comprise several regulatory mechanisms, including DNA methylation, covalent histone modification, chromatin remodeling, and non-coding RNAs. Since the mechanisms underlying epigenetic regulation of HSCs fibrogenic activation are reversible and dynamic, molecular targeted therapies aimed at correcting these mechanisms provide promising prospects for novel therapeutic approaches for treating liver fibrosis associated with NAFLD.

The impact of the characteristics of extrahepatic organ failure (EHOF) including the onset time, number, type, and sequence on the prognosis of acute-on-chronic liver failure (ACLF) patients remains unknown. This study aimed to identify the association between the characteristics of EHOF and the prognosis of ACLF patients.

ACLF subjects enrolled at six hospitals in China were included in the analysis. The risk of mortality based on the characteristics of EHOF was evaluated. Survival of study groups was compared by Kaplan–Meier analysis and log-rank tests.

A total of 736 patients with ACLF were included. EHOF was observed in 402 patients (54.6%), of which 295 (73.4%) developed single EHOF (SEHOF) and 107 (26.6%) developed multiple EHOF (MEHOF). The most commonly observed EHOF was coagulation failure (47.0%), followed by renal (13.0%), brain (4.9%), respiratory (4.3%), and circulatory (2.3%) failure. Survival analysis found that MEHOF or SEHOF patients with brain failure had a worse prognosis. However, no significant outcome was found in the analysis of the effect of onset time and sequence of failed organs on prognosis. Patients were further divided into three risk subgroups by the EHOF characteristics. Kaplan–Meier analysis showed that risk stratification resulted in the differentiation of patients with different risks of mortality both in the training and validation cohorts.

The mortality of ACLF patients was determined by the number and type, but not the onset time and sequence of EHOF. Risk stratification applicable to clinical practice was established.

Biliary atresia (BA) is a congenital cholestatic disease that can seriously damage children’s liver function. It is one of the main reasons for liver transplantation in children. Early diagnosis of BA is crucial to the prognosis of patients, but there is still a lack of reliable non-invasive diagnostic methods. Additionally, as some children are in urgent need of liver transplantation, evaluating the stage of liver fibrosis and postoperative native liver survival in children with BA using a straightforward, efficient, and less traumatic method is a major focus of doctors. In recent years, an increasing number of BA-related biomarkers have been identified and have shown great potential in the following three aspects of clinical practice: diagnosis, evaluation of the stage of liver fibrosis, and prediction of native liver survival. This review focuses on the pathophysiological function and clinical application of three novel BA-related biomarkers, namely MMP-7, FGF-19, and M2BPGi. Furthermore, progress in well-known biomarkers of BA such as gamma-glutamyltransferase, circulating cytokines, and other potential biomarkers is discussed, aiming to provide a reference for clinical practice.

Sarcopenia is a well-known complication of chronic liver disease (CLD), and it is almost always observed in patients with cirrhosis, at least in those with decompensated disease. Since nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is becoming the leading cause of end-stage liver disease, a new scenario characterized by the frequent coexistence of NAFLD, obesity, and sarcopenia is emerging. Although it is not yet resolved whether the bidirectional relationship between sarcopenia and NAFLD subtends causal determinants, it is clear that the interaction of these two conditions is associated with an increased risk of poor outcomes. Notably, during the course of CLD, deregulation of the liver-muscle-adipose tissue axis has been described. Unfortunately, owing to the lack of properly designed studies, specific therapeutic guidelines for patients with sarcopenia in the context of NAFLD-related CLD have not yet been defined. Strategies aimed to induce the loss of fat mass together with the maintenance of lean body mass seem most appropriate. This can be achieved by properly designed diets integrated with specific nutritional supplementations and accompanied by adequate physical exercise. Future studies aiming to add to the knowledge of the correct assessment and approach to sarcopenia in the context of NAFLD-related CLD are eagerly awaited.

Hepatic lipid homeostasis is not only essential for maintaining normal cellular and systemic metabolic function but is also closely related to the steatosis of the liver. The controversy over the nomenclature of non-alcoholic fatty liver disease (NAFLD) in the past three years has once again sparked in-depth discussions on the pathogenesis of this disease and its impact on systemic metabolism. Pituitary-targeted gland axes (PTGA), an important hormone-regulating system, are indispensable in lipid homeostasis. This review focuses on the roles of thyroid hormones, adrenal hormones, sex hormones, and their receptors in hepatic lipid homeostasis, and summarizes recent research on pituitary target gland axes-related drugs regulating hepatic lipid metabolism. It also calls on researchers and clinicians to recognize the concept of endocrine-associated fatty liver disease (EAFLD) and to re-examine human lipid metabolism from the macroscopic perspective of homeostatic balance.

China accounts for 14.9% of total cirrhosis deaths worldwide. A detailed and comprehensive understanding of the contemporary status of cirrhosis mortality in China is crucial for establishing strategies for intervention and decreasing the disease burden of cirrhosis worldwide. The study aimed to report the cirrhosis mortality rates in our whole country or province over time.

Mortality data from 2008 to 2020 were retrieved from the Disease Surveillance Point System (DSPs) of the Chinese Center for Disease Control and Prevention. The crude mortality rate and age-standardized mortality rate of patients with cirrhosis were stratified by sex, residential location, and region. The average annual percentage change (AAPC) in cirrhosis mortality rates from 2008 to 2020 was also calculated.

The crude mortality rate of cirrhosis was 4.57/100,000 people in 2020. Compared with females and individuals living in urban areas, males and people living in rural areas had greater age-standardized mortality. The crude mortality rate and age-standardized mortality rate in provinces in Southwest China (Guangxi, Yunnan, Guizhou, and Qinghai) were greater than those in other provinces. Moreover, with increasing age, the age-specific mortality rate increased significantly. From 2008 to 2020, the mortality rate of cirrhosis in China decreased except for in males aged 50–59 years, females aged 45–49 years and females aged 80–84 years.

The mortality rate of patients with cirrhosis in China decreased from 2008 to 2020. In the future, interventions of cirrhosis mortality control need to pay more attention to all males, females aged 45–49 and 80–84 years, and people living in rural areas and in provinces in Southwest China.