Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver injuries, including steatosis to steatohepatitis (MASH), liver fibrosis, cirrhosis, and relevant complications. The liver mainly comprises hepatocytes, liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), immune cells (T cells, B cells), and hepatic stellate cells (HSCs). Crosstalk among these different liver cells, endogenous aberrant glycolipid metabolism, and altered gut dysbiosis are involved in the pathophysiology of MASLD. This review systematically examines advances in understanding the molecular pathogenesis of MASLD, with a focus on emerging therapeutic targets and translational clinical trials. We first delineate the crucial regulatory mechanisms involving diverse liver cells and the gut-liver axis in MASLD development. These cell-specific pathogenic insights offer valuable perspectives for advancing precision medicine approaches in MASLD treatment. Furthermore, we evaluate potential therapeutic targets and summarize clinical trials currently underway. By comprehensively updating the MASLD pathophysiology and identifying promising strategies, this review aims to facilitate the development of novel pharmacotherapies for this increasingly prevalent condition.
Humans ; Fatty Liver/therapy* ; Animals ; Liver/pathology* ; Kupffer Cells/metabolism* ; Hepatocytes/metabolism* ; Hepatic Stellate Cells/metabolism*

BACKGROUND: Double-stranded RNA-specific adenosine deaminase 1 (ADAR1) binds to double-stranded RNA and catalyzes the deamination of adenosine (A) to inosine (I). The functional mechanism of ADAR1 in non-small cell lung cancer (NSCLC) remains incompletely understood. This study aimed to investigate the prognostic significance of ADAR1 in NSCLC and to elucidate its potential role in regulating tumor cell proliferation and migration. METHODS: Data from The Cancer Genome Atlas (TCGA) and cBioPortal were analyzed to assess the correlation between high ADAR1 expression and clinicopathological features as well as prognosis in lung cancer. We performed Western blot (WB), cell proliferation assays, Transwell invasion/migration assays, and nude mouse xenograft modeling to examine the phenotypic changes and molecular mechanisms induced by ADAR1 knockdown. Furthermore, the ADAR1 p150 overexpression model was utilized to validate the proposed mechanism. RESULTS: ADAR1 expression was significantly elevated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tissues compared with adjacent non-tumor tissues (LUAD: P=3.70×10-15, LUSC: P=0.016). High ADAR1 expression was associated with poor prognosis (LUAD: P=2.03×10-2, LUSC: P=2.81×10-2) and distant metastasis (P=0.003). Gene Set Enrichment Analysis (GSEA) indicated that elevated ADAR1 was associated with mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway activation, matrix metalloproteinase-9 (MMP-9) expression, and cell adhesion. ADAR1 and MMP-9 levels showed a strongly positive correlation (P=6.45×10-34) in 10 lung cancer cell lines, highest in H1581. Knockdown of ADAR1 in H1581 cells induced a rounded cellular morphology with reduced pseudopodia. Concomitantly, it suppressed cell proliferation, invasion, migration, and in vivo tumorigenesis. It also suppressed ERK phosphorylation and downregulated cellular Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog (c-FOS), MMP-9, N-cadherin, and Vimentin. Conversely, ADAR1 p150 overexpression in PC9 cells enhanced ERK phosphorylation and increased c-FOS and MMP-9 expression. CONCLUSIONS High ADAR1 expression is closely associated with poor prognosis and distant metastasis in NSCLC patients. Mechanistically, ADAR1 may promote proliferation, invasion, migration, and tumorigenesis in lung cancer cells via the ERK/c-FOS/MMP-9 axis.
Humans ; Lung Neoplasms/physiopathology* ; Adenosine Deaminase/genetics* ; Matrix Metalloproteinase 9/genetics* ; Cell Proliferation ; Carcinoma, Non-Small-Cell Lung/physiopathology* ; Cell Movement ; Animals ; Mice ; RNA-Binding Proteins/genetics* ; Female ; Male ; Cell Line, Tumor ; Proto-Oncogene Proteins c-fos/genetics* ; Middle Aged ; MAP Kinase Signaling System ; Gene Expression Regulation, Neoplastic ; Mice, Nude ; Extracellular Signal-Regulated MAP Kinases/genetics*

Drug addiction, a disorder characterized by chronic relapse and compulsive drug use, poses a significant threat to public safety and human health. Addictive substances can be categorized as natural, semi-synthetic, or synthetic based on their origin. Additionally, they can be classified into three groups according to their pharmacological targets: opioids, hallucinogens, and cannabinoids that act on G-protein-coupled receptors (GPCRs); alcohols, nicotine, ketamine, barbiturates, and benzodiazepines (BDZs) that affect ligand-gated ion channel-type receptors; and psychostimulants that interact with monoamine transporters. Current treatments for drug addiction primarily include substitution therapy and non-pharmacological approaches. However, these methods have limitations, particularly in addressing the underlying causes of relapse. Several drugs in clinical trials have demonstrated potential therapeutic effects for addiction to opioids, heroin, cocaine, and other substances. This review examines the origins and pharmacological mechanisms of addiction to naturally-derived psychoactive substances (NPS) and provides an overview of recent advancements in pharmacotherapy for drug addiction.
Humans ; Substance-Related Disorders/drug therapy* ; Psychotropic Drugs/therapeutic use* ; Animals

Objective To analyze the distribution of common allergens in children with allergic rhinitis(AR)in Hangzhou,and to provide reference for its prevention and treatment.Methods From January 2020 to December 2022,13 521 children who were diagnosed with AR and underwent in vitro serum specific immunoglobulin E(sIgE)detection in Affiliated Hangzhou First People's Hospital,School of Medicine,Westlake University were selected as the research objects.The positive rates of allergens in children with AR of different genders,ages and seasons were compared.Results Among 13 521 children,the positive rate of sIgE was 54.49%(7367/13 521),of which 64.82%were allergic to only one allergen.Among the 19 common allergens,the top three overall positive rates were household dust mite(44.27%),milk(14.62%),and mixed grass(4.82%).The positive rates of allergens of house dust mites,cat hair dander,mulberry,mold combination,tree pollen combination,amaranth,cockroach,milk,shrimp,crab,pineapple,shellfish and mango in male children were significantly higher than those in female children(P<0.05).The positive rates of allergens of house dust mite,mixed grass,cat hair dander,mulberry,mold combination,egg white,shrimp,crab,pineapple,cashew nuts and shellfish in different age groups were statistically significant(P<0.05).July and August were the two months with the highest allergen positive rate.The allergen positive rates of house dust mite,dog and cat hair dander were the highest in summer,and the allergen positive rate of plants was consistent with the flowering season.The sIgE concentration of house dust mite(77.87%)was mainly grade 3 and above.The sIgE concentration of other allergens was mainly grade 1 and 2.Conclusion Dust mites and milk are the most common allergens in children with AR in Hangzhou,and the distribution of allergens varies with gender,age and season.Allergen detection can provide a more accurate plan for the diagnosis,prevention and treatment of AR.

Glioma is the most common primary tumor of the brain,accounting for 81%of central nervous system(CNS)malignant tumors.The degree of malignancy is high,and the current treatment methods are limited.In recent years,with the in-depth study of intestinal flora and brain-gut axis,it has been found that the diversity of gut microbiota plays an important role in the regulation of glioma.The mechanism is that the intestinal flora affects the development of glioma through the role of immune regulation and metabolites.In addition,it has been con-firmed that there is a certain correlation between some probiotics and glioma,which provides a new application prospect for the treatment of glioma.This paper discusses the main intestinal bacteria that regulate gliomas as well as the role and regulatory mechanisms of intestinal flora in the development of gliomas,and provides ideas for the discovery of new targets for glioma treatment and further improvement of treatment options.

Objective To explore the effectiveness of Failure Modes and Effects Analysis(FMEA)in emergency man-agement of sudden incidents involving outpatient and emergency patients in general hospitals,to provide references for the optimi-zation of emergency response process for such incidents.Methods Based on FMEA,we identified and evaluated risks in the e-mergency response procedures for sudden incidents involving outpatient and emergency patients in general hospitals.Potential fail-ure modes were analyzed to identify key risks with a Risk Priority Number(RPN)greater than 125.Continuous quality improve-ment measures were implemented to control these risks,and the effectiveness of these controls was evaluated using chi-square tests for statistical analysis.Results A total of 16 risk points in 4 major areas were identified.After implementing continuous quality improvement measures,the RPNs of these high-risk points decreased to below 125,effectively controlling the potential risks.This intervention significantly improved the utilization rate of emergency equipment,the timely reporting rate of sudden in-cidents,the timely feedback rate of emergency response,with statistically significant differences(P＜0.01).Conclusion The application of FMEA to outpatient and emergency management of sudden incidents helps optimize the emergency response process,thus enhancing the emergency response capability of general hospitals and ensuring effective handling of such incidents.

To summarize the clinical manifestations of a case with 46, XY sex development disorder caused by myelin regulatory factor(MYRF) gene mutation and review the literature to deepen the specialists′ understanding of the clinical disease spectrum resulting from MYRF gene variations. The child had a female phenotype with mild masculinity, chromosome 46, XY, sex-determining region of Y gene(SRY gene) positive, laboratory tests were consistent with primary hypogonadism, ultrasound did not detect the gonads, but the residual reproductive tract was visible, and echocardiography suggested coarctation of the aorta, MYRF gene c. 2518C>T(p.R840*) heterozygous variant. The father did not carry this variant. The mother was untraceable, and genetic testing had not been completed. It was analyzed as pathogenic variation according to American College of Medical Genetics and Genomics(ACMG) guidelines. Sixteen cases of disorders of sex development caused by MYRF gene variation reported from 2018 to 2021 were reviewed, MYRF gene variants, 46, XY, and 46, XX individuals can be pathogenic, can affect the gonad and reproductive tract at the same time, and can also affect multiple systems. In this case, the patient presents with 46, XY sex development disorder due to MYRF gene mutation, accompanied by rare cardiovascular complications. When encountering 46, XY primary hypogonadism without well-developed Müllerian duct structures, this condition should be considered. Following confirmation, a comprehensive assessment of multi-organ function is necessary.

The secondary motor cortex (M2) encodes choice-related information and plays an important role in cue-guided actions. M2 neurons innervate the dorsal striatum (DS), which also contributes to decision-making behavior, yet how M2 modulates signals in the DS to influence perceptual decision-making is unclear. Using mice performing a visual Go/No-Go task, we showed that inactivating M2 projections to the DS impaired performance by increasing the false alarm (FA) rate to the reward-irrelevant No-Go stimulus. The choice signal of M2 neurons correlated with behavioral performance, and the inactivation of M2 neurons projecting to the DS reduced the choice signal in the DS. By measuring and manipulating the responses of direct or indirect pathway striatal neurons defined by M2 inputs, we found that the indirect pathway neurons exhibited a shorter response latency to the No-Go stimulus, and inactivating their early responses increased the FA rate. These results demonstrate that the M2-to-DS pathway is crucial for suppressing inappropriate responses in perceptual decision behavior.
Mice ; Animals ; Motor Cortex ; Corpus Striatum/physiology* ; Neostriatum ; Neurons/physiology* ; Reaction Time

The formation of learning and memory is regulated by synaptic plasticity in hippocampal neurons. Here we explored how gestational exposure to dexamethasone, a synthetic glucocorticoid commonly used in clinical practice, has lasting effects on offspring's learning and memory. Adult offspring rats of prenatal dexamethasone exposure (PDE) displayed significant impairments in novelty recognition and spatial learning memory, with some phenotypes maintained transgenerationally. PDE impaired synaptic transmission of hippocampal excitatory neurons in offspring of F1 to F3 generations, and abnormalities of neurotransmitters and receptors would impair synaptic plasticity and lead to impaired learning and memory, but these changes failed to carry over to offspring of F5 and F7 generations. Mechanistically, altered hippocampal miR-133a-3p-SIRT1-CDK5-NR2B signaling axis in PDE multigeneration caused inhibition of excitatory synaptic transmission, which might be related to oocyte-specific high expression and transmission of miR-133a-3p. Together, PDE affects hippocampal excitatory synaptic transmission, with lasting consequences across generations, and CDK5 in offspring's peripheral blood might be used as an early-warning marker for fetal-originated learning and memory impairment.

Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia, which results in atherosclerosis and cardiovascular disease (CVD). ATP-citrate lyase (ACLY) is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle (TCA cycle) to acetyl-CoA in the cytoplasm. Therefore, ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis. In this study, we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor, and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC₅₀ = 5.31 ± 1.2 μmol/L in vitro. 326E treatment reduced de novo lipogenesis, and increased cholesterol efflux in vitro and in vivo. 326E was rapidly absorbed after oral administration, exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid (BA) used for hypercholesterolemia. Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia. Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE^-/- mice to a greater extent than that of BA treatment. Taken together, our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.