OBJECTIVE To explore the potential mechanism of action of Gexia zhuyu decoction in the intervention of metabolic-associated fatty liver disease （MAFLD） based on ferroptosis. METHODS With the help of network pharmacology， the central targets of Gexia zhuyu decoction intervening in ferroptosis of MAFLD were screened， then gene ontology， Kyoto Encyclopedia Gene and Genomes enrichment analysis and molecular docking were performed. Juvenile zebrafish with normal development at 3 d post-fertilization were randomly divided into control group， model group （5 mmol/L thioacetamide）， magnesium isoglycyrrhizinate group （positive control， 5 mg/mL）， and Gexia zhuyu decoction low- ， medium- and high- concentration groups （20， 40， 80 μg/mL， calculated by crude drugs）. After cultured for 72 h， the contents of alanine transaminase （ALT）， aspartate transaminase （AST）， total cholesterol （TC）， triglyceride （TG）， malondialdehyde （MDA）， superoxide dismutase （SOD）， glutathione （GSH）， reactive oxygen species （ROS） and Fe2+ were determined； the cellular structure of the liver tissues and hepatic steatosis were observed； the protein expression of silence information regulator 1 （SIRT1）， nuclear factor- erythroid 2-related factor 2 （Nrf2） and glutathione peroxidase 4 （GPX4） were detected. RESULTS The central targets of potential active ingredients of Gexia zhuyu decoction that act on ferroptosis in MAFLD included tumor proteins p53， SIRT1， Nrf2， etc.， which were enriched in biological processes such as positive/negative regulation of RNA polymerase Ⅱ promoter transcription， cellular components such as nucleus and cytoplasm， molecular functions such as protein binding， as well as signaling pathways such as ferroptosis and the cancer pathway， and they might be tightly linked to the main active ingredients. Compared with model group， the contents of ALT， AST， TC， TG， MDA， ROS and Fe2+ were all decreased significantly in each administration group， while the contents of SOD and GSH were increased significantly （P＜0.05）； the pathological damage of liver tissue cells had improved， and the accumulation of liver lipids had decreased. The protein expressions of SIRT1， Nrf2 and GPX4 had been significantly upregulated （P＜0.05）. CONCLUSIONS Gexia zhuyu decoction can regulate lipid metabolism， improve the level of oxidative stress， maintain Fe2+ homeostasis， and inhibit the process of ferroptosis in juvenile zebrafish with MAFLD， and the above effects may be related to the activation of the SIRT1/Nrf2/GPX4 axis.

Pulmonary arterial hypertension(PAH)is a complex pulmonary vascular disease characterized by pro-gressive elevation of mean pulmonary artery pressure resulted from the pathological feature of pulmonary vascular re-modeling.Without medical intervention,PAH can eventually lead to right heart failure and death of patients.Up to the present,there are few treatment options for PAH are still mainly function through pulmonary vasodilation.Although these treatments can alleviate symptoms,the prognosis remains poor.In recent years,breakthroughs have been made in understanding the pathogenesis of PAH,thus support the development of new treatment strategies tar-geting at dysregulation of signaling pathways in PAH.This review focuses on five critical pathways and the relevant drugs those entered phase Ⅱ clinical trials and discusses their therapeutic potential,so to provide a basis for future research on targeting therapies for PAH patients.

Nonalcoholic fatty liver disease(NAFLD)has become the most common liver disease in the world and is an important risk factor for the progression to hepatocellular carcinoma.However,the pathogenesis of NAFLD remains unclear,and there is still a lack of specific treatment measures.Sterol regulatory element-binding proteins(SREBP)are an important nuclear transcription factor,which mainly maintains the balance of lipid metabolism inside the body by activating the genes associated with the synthesis and uptake of cholesterol,fatty acids,and triglycerides,and therefore,SREBP are a target for the treatment of metabolic diseases.This article reviews the latest advances in SREBP in the pathogenesis of NAFLD and the latest evidence of SREBP-targeted therapy for NAFLD.It is worth noting that recent studies have shown that SREBP inhibition can cause liver injury together with autophagy damage.Therefore,excessive inhibition of lipogenesis may exert a counterproductive effect on the treatment of NAFLD.In conclusion,SREBP is a promising therapeutic target for NAFLD;the molecular mechanism of SREBP in lipid metabolism is regulated by many factors,and these factors are being deeply explored and analyzed,which has an important clinical significance for the treatment of NAFLD.

Objective To explore the application and prospects of artificial intelligence (AI) in metabolic associated fatty liver disease (MAFLD) based on bibliometrics. Methods Relevant literature on the application of AI technology in MAFLD was retrieved from the Web of Science Core Collection (WoSCC) database. Bibliometric analysis was conducted using CiteSpace, VOSviewer, R package "bibliometrix", and online bibliometric analysis was platformed to identify hotspots and trends in this field. Results A total of 303 eligible articles were obtained. Since 2017, the number of papers in this field had experienced explosive growth. The United States was leading the research on the application of AI in MAFLD and was the most frequent participant in international cooperation. San Diego of University of California was the institution with the highest number of publications. Rohit Loomba was the author with the highest number of publications, having published 14 articles. The co-cited keyword clustering labels revealed 10 major clusters: digital image analysis, machine learning, computer-aided diagnosis, fibrosis stage, automated quantitative analysis, metaproteomics, non-invasive diagnosis, ultrasonography, electronic health records, and knowledge representation. Current research on the application of AI in MAFLD mainly focused on the diagnosis, differential diagnosis, and staging of MAFLD. Image recognition and analysis, intelligent assisted diagnosis, AI algorithms, and monitoring disease progression will be important research directions for AI in MAFLD. Conclusion Research on the application of AI in MAFLD is experiencing exponential growth. Given enormous potential and clinical application prospects of this field, the application of AI in MAFLD-related areas will remain a research hotspot in the future.

Humans ; Hospital Mortality ; Pulmonary Embolism ; Comorbidity ; Registries ; Neoplasms/complications*

Objective:To study the correlation between the quartering of nerve root subsidence sign (NRS) and the cross-sectional area (CSA) of the narrow segment thecal sac in patients with lumbar spinal stenosis (LSS).Methods:The data of 203 LSS patients in the Fourth People′s Hospital of Hengshui from January 2020 to December 2021 were retrospectively analyzed. All patients underwent MRI cross sectional scanning. The patients were divided into positive type a group ( n=62), positive type b group ( n=32), positive type c group ( n=51), and negative group ( n=58) by NRS quartering method. The minimum CSA, median sagittal diameter (PAD), and lateral recess sagittal diameter of each group were compared. The correlation between NRS quartering classification and the minimum CSA and related indicators of lumbar spinal stenosis was analyzed. Results:The minimum CSA, PAD, and sagittal diameter of the lateral recess in the positive a group, positive b group, and positive c group were all smaller than those in the negative group, while the Visual Analogue Scale (VAS) score and Oswestry Disability Index (ODI) were higher than those in the negative group; The minimum CSA, PAD, and sagittal diameter of the lateral recess in the positive b type and positive c type groups were smaller than those in the positive a type group, while the VAS score and ODI index were higher than those in the positive a type group; The minimum CSA, PAD, and sagittal diameter of the lateral recess in the positive c type group were smaller than those in the positive b type group; The VAS score and ODI index were higher than those of the positive b type group; The differences were statistically significant (all P<0.05). 203 patients were divided into 54 normal cases, 58 mild stenosis cases, 49 moderate stenosis cases, and 42 severe stenosis cases based on the minimum CSA. The coincidence rate between negative NRS and minimal CSA diagnosis as normal was 94.44%(51/54), the coincidence rate between positive type a and minimal CSA diagnosis as mild stenosis was 84.48%(49/58), the coincidence rate between positive type b and minimal CSA diagnosis as moderate stenosis was 53.06%(26/49), and the coincidence rate between positive type c and minimal CSA diagnosis as severe stenosis was 90.48%(38/42). Using the kappa consistency test, the kappa value for quantitative diagnosis of minimum CSA stenosis in NRS and LSS patients was 0.743, indicating good consistency. The kappa values for quantitative diagnosis of NRS, sagittal diameter of lateral recess, and PAD stenosis were 0.271 and 0.335, with poor consistency. NRS typing was negatively correlated with CSA and PAD ( r=-0.723, -0.581, all P<0.001), and positively correlated with VAS score and ODI index ( r=0.473, 0.640, all P<0.001). Conclusions:The NRS quartering method has a good consistency in diagnosing the severity of LSS patients and the minimum CSA of stenosis segments, suggesting that the NRS quartering method can better reflect the degree of Spinal stenosis, which can not only be used as an auxiliary indicator for qualitative diagnosis of LSS, but also has a high value in quantitative diagnosis.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood-brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380).

Silicosis is a leading cause of occupational disease-related morbidity and mortality worldwide, but the molecular basis underlying its development remains unclear. An accumulating body of evidence supports gasdermin D (GSDMD)-mediated pyroptosis as a key component in the development of various pulmonary diseases. However, there is little experimental evidence connecting silicosis and GSDMD-driven pyroptosis. In this work, we investigated the role of GSDMD-mediated pyroptosis in silicosis. Single-cell RNA sequencing of healthy and silicosis human and murine lung tissues indicated that GSDMD-induced pyroptosis in macrophages was relevant to silicosis progression. Through microscopy we then observed morphological alterations of pyroptosis in macrophages treated with silica. Measurement of interleukin-1β release, lactic dehydrogenase activity, and real-time propidium iodide staining further revealed that silica induced pyroptosis of macrophages. Additionally, we verified that both canonical (caspase-1-mediated) and non-canonical (caspase-4/5/11-mediated) signaling pathways mediated silica-induced pyroptosis activation, in vivo and in vitro. Notably, Gsdmd knockout mice exhibited dramatically alleviated silicosis phenotypes, which highlighted the pivotal role of pyroptosis in this disease. Taken together, our results demonstrated that macrophages underwent GSDMD-dependent pyroptosis in silicosis and inhibition of this process could serve as a viable clinical strategy for mitigating silicosis.

Objective To investigate the effect of moderate treadmill exercise together with modified hydroxyapatite chitosan composite hydrogel (CS/HA-g-CS) implantation on repair of full-thickness defects of articular cartilage in rats.Methods Full-thickness cartilage defects were drilled in the patellar groove of bilateral femoral condyles in a total of 24 male SD rats before they were randomly assigned into 4 groups.The control group (BC group) was subjected to no exercise or CS/HA-g-CS implantation;the chitosan group (CHI group) to CS/HA-g-CS implantation without exercise;the moderate treadmill exercise group (MIR group) to exercise 4 weeks after modeling without CS/HA-g-CS implantation;the CHI + MIR group to moderate treadmill exercise plus CS/HA-g-CS implantation 4 weeks after modeling.Half of the animals were sacrificed at week 8 and half at week 16 after operation.Femoral condyles were harvested for gross observation and histochemical measurement by O' Driscoll scoring system.mRNA expressions of glycosaminoglycan,collagen type Ⅱ and BMP-2 were detected by RT-PCR.Results Gross observation revealed:at 8 weeks after modeling,the CHI + MIR group was significantly better than the other 3 groups,with the BC group in the poorest (P ＜ 0.05);at 16 weeks after modeling,the BC group was significantly poorer than the other 3 groups (P ＜0.05) among which there were no significant differences (P ＞ 0.05).O 'Driscoll scoring revealed:at both 8 and 16 weeks after modeling,the CHI + MIR group was significantly better than the other 2 groups and the BC group significantly poorer than the other 3 groups (P ＜ 0.05) but there was no significant difference between the MIR and CHI + MIR groups(P ＞ 0.05).The expressions of collagen type Ⅱ,glycosaminoglycan and BMP-2 were significantly higher in the CHI + MIR group than in the other 3 groups (P ＜ 0.05) and significantly lower in the BC group than in the other 3 groups (P ＜ 0.05).Conclusions Moderate treadmill exercise together with CS/HA-g-CS implantation has significant positive effects on repair of full-thickness defects of articular cartilage in rats than merely moderate treadmill exercise or CS/HA-g-CS implantation alone.The defective cartilage repaired by moderate treadmill exercise together with CS/HA-g-CS implantation contains more collagen type Ⅱ and glycosaminoglycan and shows morphology of nearly normal cartilage.

Objective To make a comparison for the neutrophils prepared either by induction of differentiation of myeloid leuke-mia cell line,or by separation and purification of peripheral blood cells,or by induction of myeloid differentiation of peripheral blood stem cells.Methods NB4 cells were induced differentiation by 1μmol/L all-trans retinoic acid (ATRA)to mature granulo-cytes;neutrophils were separated and purified from peripheral blood by lysis of red blood cells followed by negative selection using magnetic bead-labeled antibodies;hematopoietic stem cells were separated and purified from peripheral blood by Percoll gradient centrifugation followed by negative selection using magnetic bead-labeled antibodies,and were induced to myeloid differentiation by GM-CSF and G-CSF.Morphology and purity of neutrophils prepared by these three methods were studied by means of MGG stai-ning.CD18 protein expression and subcellular distribution were studied by means of immunofluorescence staining.Results Purity of neutrophil was above 40% by induction of differentiation of NB4 cells,and was about 90% if purified from peripheral blood,and was above 70% if induced by myeloid differentiation of peripheral blood stem cells.There was no obvious difference for CD18 ex-pression in neutrophils prepared by these three methods,and staining of CD18 had a dotted pattern distributed in these cells.Con-clusion Peripheral blood neutrophils prepared by lysis of red blood cells followed by negative selection using magnetic bead-labeled antibodies are with high purity and viability which is suitable for immediate test of neutrophils from fresh blood.Neutrophils pre-pared by myeloid differentiation of hematopoietic stem cell are with high viability and last for days,which can be used in long test for neutrphils.