This study aims to reveal the effect and mechanism of Gentianella turkestanorum total extract(GTI) in ameliorating non-alcoholic steatohepatitis(NASH). UPLC-Q-TOF-MS was employed to identify the chemical components in GTI. SwissTarget-Prediction, GeneCards, OMIM, and TTD were utilized to screen the targets of GTI components and NASH. The common targets shared by GTI components and NASH were filtered through the STRING database and Cytoscape 3.9.0 to identify core targets, followed by GO and KEGG enrichment analysis. AutoDock was used for molecular docking of key components with core targets. A mouse model of NASH was established with a methionine-choline-deficient high-fat diet. A 4-week drug intervention was conducted, during which mouse weight was monitored, and the liver-to-brain ratio was measured at the end. Hematoxylin-eosin staining, Sirius red staining, and oil red O staining were employed to observe the pathological changes in the liver tissue. The levels of various biomarkers, including aspartate aminotransferase(AST), alanine aminotransferase(ALT), hydroxyproline(HYP), total cholesterol(TC), triglycerides(TG), low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol(HDL-C), malondialdehyde(MDA), superoxide dismutase(SOD), and glutathione(GSH), in the serum and liver tissue were determined. RT-qPCR was conducted to measure the mRNA levels of interleukin 1β(IL-1β), interleukin 6(IL-6), tumor necrosis factor α(TNF-α), collagen type I α1 chain(COL1A1), and α-smooth muscle actin(α-SMA). Western blotting was conducted to determine the protein levels of IL-1β, IL-6, TNF-α, and potential drug targets identified through network pharmacology. UPLC-Q-TOF/MS identified 581 chemical components of GTI, and 534 targets of GTI and 1 157 targets of NASH were screened out. The topological analysis of the common targets shared by GTI and NASH identified core targets such as IL-1β, IL-6, protein kinase B(AKT), TNF, and peroxisome proliferator activated receptor gamma(PPARG). GO and KEGG analyses indicated that the ameliorating effect of GTI on NASH was related to inflammatory responses and the phosphoinositide 3-kinase(PI3K)/AKT pathway. The staining results demonstrated that GTI ameliorated hepatocyte vacuolation, swelling, ballooning, and lipid accumulation in NASH mice. Compared with the model group, high doses of GTI reduced the AST, ALT, HYP, TC, and TG levels(P<0.01) while increasing the HDL-C, SOD, and GSH levels(P<0.01). RT-qPCR results showed that GTI down-regulated the mRNA levels of IL-1β, IL-6, TNF-α, COL1A1, and α-SMA(P<0.01). Western blot results indicated that GTI down-regulated the protein levels of IL-1β, IL-6, TNF-α, phosphorylated PI3K(p-PI3K), phosphorylated AKT(p-AKT), phosphorylated inhibitor of nuclear factor kappa B alpha(p-IκBα), and nuclear factor kappa B(NF-κB)(P<0.01). In summary, GTI ameliorates inflammation, dyslipidemia, and oxidative stress associated with NASH by regulating the PI3K/AKT/NF-κB signaling pathway.
Animals ; Non-alcoholic Fatty Liver Disease/genetics* ; Mice ; Network Pharmacology ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Chromatography, High Pressure Liquid ; Liver/metabolism* ; Mice, Inbred C57BL ; Humans ; Mass Spectrometry ; Tumor Necrosis Factor-alpha/metabolism* ; Disease Models, Animal ; Molecular Docking Simulation

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Body weight abnormalities, including overweight, obesity, and underweight, have become a dual public health challenge in Chinese adults: overweight and obesity lead to a variety of chronic complications, while underweight increases the risks of malnutrition, sarcopenia, and organ dysfunction. To systematically address these issues, multidisciplinary experts in endocrinology, sports science, nutrition, and psychiatry from various regions have held multiple weight management seminars. Based on the latest epidemiological data and clinical evidence, they expanded the guideline to include assessment and intervention strategies for underweight, in addition to the core content of obesity management. This guideline outlines the etiological mechanisms, evaluation methods, and multidimensional management strategies for overweight and obesity, covering key areas such as diagnosis and assessment, medical nutrition therapy, exercise prescription, pharmacological intervention, and psychological support. It is intended to provide a scientific and standardized approach to weight management across the adult population, aiming to curb the rising prevalence of obesity, mitigate complications associated with abnormal body weight, and improve nutritional status and overall quality of life.

Objective To investigate the relationship between the radial-ulnar ratio,lateral lunate angle of radius and height loss of radius after palmar locking plate internal fixation for distal radius fractures.Methods A total of 158 patients with distal radius fractures treated with palmar locking plate internal fixation in our hospital from March 2020 to September 2023 were selected.According to the height of radius loss after operation,the patients were divided into non-radius loss group(41 cases,<2 mm),mild to moderate radius loss group(32 cases,2 to 5 mm)and severe radius loss group(85 cases,>5 mm),and the clinical data of patients in the three groups were compared.Multivariate Logistic regression analysis was used to analyze the risk factors affecting height loss of radius.Locally weighted scatterplot smoothing(LOWESS)method was used to analyze the two-dimensional curve relationship of continuous variables.Restricted cubic spline(RCS)and threshold effect were used to analyze the relationship between the radial-ulnar ratio,lateral lunate angle of radius and height loss of radius after operation.Results The age of patients in the severe radius loss group was significantly higher than those in the non-radius loss group and the mild to moderate radius loss group(P<0.05),and the age of patients in the mild to moderate radius loss group was significantly higher than that in the non-radius loss group(P<0.05).Female patients and patients with osteoporosis and fracture type C were more likely to have height loss of radius(P<0.05).There were significant differences in patient-rated wrist evaluation(PRWE)score,disabilities of the arm,shoulder and hand(DASH)score,dorsal extension,palmar curvature,ulnar deviation,radial deviation,radial-ulnar ratio,and lateral lunate angle of radius of patients at 3 and 6 months after operation among three groups(P<0.001).The first prediction model based on age,gender,osteoporosis,fracture type,PRWE score,DASH score,dorsal extension,palmar curvature,ulnar deviation,and radial deviation and the second prediction model based on age,gender,osteoporosis,fracture type,PRWE score,DASH score,dorsal extension,palmar curvature,ulnar deviation,radial deviation,radial-ulnar ratio,and lateral lunate angle of radius were subjected to Hosmer-Lemeshow test showed good goodness of fit.LOWESS analysis showed that age,PRWE score,DASH score,dorsal extension,palmar curvature,ulnar deviation,radial deviation,radial-ulnar ratio,and lateral lunate angle of radius had a certain nonlinear relationship with the height loss of radius.RCS and threshold effect analysis showed that the probability of postoperative radius loss increased with the increase of radial-ulnar ratio in patients with distal radius fractures and radial-ulnar ratio≥13.254(P<0.001).The probability of postoperative radius loss decreased with the increase of the lateral lunate angle of radius in patients with distal radius fractures and lateral lunate angle of radius≤11.068°(P<0.001).Conclusion There was a positive correlation between the radial-ulnar ratio and the height loss of radius,and a negative correlation between the lateral lunate angle of radius and the height loss of radius after palmar locking plate internal fixation for distal radius fractures.

Detection of poor-water-soluble substances typically requires an organic solvent containing solution,and therefore,the biosensors that can operate in such conditions are highly promising for practical applications.However,most existing biosensors have been developed in aqueous solution and it is hard to work effectively in organic solvent systems.In this work,we uncovered that the G-quadruplex(G4)/hemin DNAzyme(G4HD)could be strongly reactivated by NH4 in organic solvents at concentration up to 30％,and the activity was significantly higher than that in aqueous solutions containing K+.Based on this discovery,a biosensing system was developed for small molecule in 40％methanol by coupling G4HD with our previously identified RNA-cleaving DNAzyme(E3).This system comprised an ATP-activated aptazyme that was made of E3 and a G4HD that was activated by the cleavage product of the aptazyme.By using a manmade pipette tip filter to separate the reaction products,the subsequent colorimetric reaction of the G4HD could be triggered.This biosensing system enabled the visualization of target molecules in organic cosolvents without any other instruments.The activable DNAzyme-cascade sensing system had potential in point-of-care detection of poor-water-soluble pollutants,thereby enhancing the practical values of functional nucleic acid-based biosensors in real-world detection conditions.

Objective To estimate the prevalence of calcified nodule(CN)among patients with coronary artery disease(CAD)and identify the possible risk factors associated with an increased CN risk.Methods Databases include PubMed,Web of Science and Embase was conducted to identify studies reporting the prevalence and/or risk factors of CN.For this databases,the search was from inception to January 1,2024.Data analyses was performed using R statistical Software 4.2.2.Results A total of 46 studies involving 17 926 patients were included.Among them,13 studies with 4 187 patients reported both the prevalence and associated risk factors.The overall prevalence of CN was found to be 5.72％(95％CI 4.47％-7.31％),while in studies reporting both the prevalence and risk factors,the CN prevalence was slightly higher at 8.72％(95％CI 6.43％-11.71％).Hypertension(OR 1.75,95％CI 1.29-2.37),diabetes(OR 1.84,95％CI 1.46-2.33),chronic kidney disease(OR 2.50,95％CI 1.67-3.74),and hemodialysis(OR 7.77,95％CI 4.77-12.67)were associated with an elevated CN risk(all P＜0.001).Conversely,obesity(OR 0.39,95％CI 0.18-0.83)and history of smoking(OR 0.61,95％CI 0.47-0.80)were linked to a decreased CN risk(both P＜0.05).Conclusions The overall prevalence of CN is relatively low among patients with CAD.However,the prevalence of CN is influenced by a variety of clinical factors.Further research is warranted to elucidate the underlying mechanisms.