Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death. However, the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear. Here, we identified that the expression of sterile alpha and TIR motif containing 1 (SARM1), was increased significantly in the ischemic cardiomyopathy patients, dilated cardiomyopathy patients (GSE116250) and fibrotic heart tissues of mice. Additionally, inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction (MI) mice. Moreover, SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function. Mechanically, elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1. Notably, by using the Click-iT reaction, we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1, thereby accelerating the fibrosis process. Based on the fibrosis-promoting effect of SARM1, we screened several drugs with anti-myocardial fibrosis activity. In conclusion, we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis. Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis. The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.

Objective To analyze the expression of microRNA(miR)-200a and miR-4652-3p in cerebrospinal fluid of patients with tuberculous meningitis(TBM)and their predictive value for disease severity and prognosis.Methods A total of 187 patients with tuberculous meningitis who visited Qingdao Chest Hospital from January 2018 to December 2022 were regarded and separated into stage Ⅰ(n=62),stage Ⅱ(n=76)and stage Ⅲ(n=49)according to the severity of the condition.There were 131 cases in the good prognosis group and 56 cases in the poor prognosis group according to the prognosis.The qRT-PCR method was applied to detect the expression levels of miR-200a and miR-4652-3p in cerebrospinal fluid.Spearman method was used to analyze correlation among miR-200a,miR-4652-3p and clinical data.ROC curve was applied to analyze the predictive value of cerebrospinal fluid miR-200a and miR-4652-3p levels in evaluating the severity and prognosis of tuberculosis meningitis patients.Multivariate logistic regression was applied to analyze the influencing factors of poor prognosis in patients.Results The expression levels of miR-200a(1.05±0.14,0.91±0.14,0.76±0.13)and miR-4652-3p(0.92±0.11,0.78±0.11,0.65±0.10)in the cerebrospinal fluid of patients with stage Ⅰ,Ⅱ,and Ⅲ tuberculous meningitis were decreased sequentially,and the differences were significant(F=61.079,87.203,all P＜0.05).The expression levels of miR-200a(0.95±0.14)and miR-4652-3p(0.82±0.11)in cerebrospinal fluid of patients with good prognosis tuberculous meningitis were higher than those of patients with poor rognosis(0.84±0.13,0.73±0.10),and the differences were statistically significant(t=5.025,5.262,all P＜0.05),while the levels of cerebrospinal fluid adenosine deaminase,TNF-α,IL-23,LTB4,CRP and mRS scores in patients with good prognosis were lower than those in patients with poor prognosis(t=5.649,7.721,11.150,9.455,11.314,14.407,all P＜0.05).There was a positive correlation between the levels of miR-200a and miR-4652-3p in cerebrospinal fluid of patients with tuberculous meningitis(r=0.405,P＜0.001).The levels of miR-200a and miR-4652-3p in cerebrospinal fluid were negatively correlated with LTB4,TNF-ot,CRP,mRS scores,IL-23 and adenosine deaminase(r=-0.472,-0.466,-0.461,-0.435,-0.422,-0.419;-0.459,-0.531,-0.471,-0.417,-0.513,-0.408,all P＜0.05).The AUC(95％CI)of miR-200a and miR-4652-3p to assess disease severity were 0.881(0.825～0.923)and 0.878(0.822～0.921),respectively.The AUC(95％CI)of both combination in assessing the severity of patients was 0.945(0.902～0.973),which was higher than the single detection,and the differences were significant(Z=3.008,2.960,all P=0.003).The AUC(95％CI)of poor prognosis patients evaluated by cerebrospinal fluid miR-200a and miR-4652-3p levels were 0.749(0.681～0.809)and 0.756(0.688～0.816),and the AUC of poor prognosis patients evaluated by both combination was 0.839(0.778～0.889),which was higher than that measured separately,and the differences were significant(Z=2.994,2.697,P=0.003,0.007).Adenosine deaminase[OR(95％CI):1.106(1.033～1.185)],miR-200a[OR(95％CI):0.529(0.369～0.744)],miR-4652-3p[OR(95％CI):0.471(0.310～0.715)],C-reactive protein[OR(95％CI):4.423(1.459～13.412)],TNF-α[OR(95％CI):1.196(1.061～1.348)],IL-23[OR(95％CI):4.809(1.086～3.013)],and LTB4[OR(95％CI):1.327(1.064～1.655)]were influencing factors for poor prognosis in patients with tuberculous meningitis(all P＜0.05).Conclusion The expressions of miR-200a and miR-4652-3p in cerebrospinal fluid of patients with tuberculous meningitis were down-regulated,and they were closely related to the severity and prognosis of the disease.The combination of the miR-200a and miR-4652-3p could better predict the severity and prognosis of tuberculous meningitis,which may have a certain clinical value.

OBJECTIVES: To investigate the synergistic inhibitory effects of AKBA and doxorubicin on malignant phenotype of triple-negative breast cancer (TNBC) MDA-MB-231 cells. METHODS: CCK-8 assay was used to determine the 48-h IC₅₀ of AKBA and doxorubicin in MDA-MB-231 cells, and SynergyFinder was employed to calculate the synergistic index and the optimal concentrations of the two agents. MDA-MB-231 cells treated with AKBA (22.5 μmol/L), doxorubicin (0.84 μmol/L) or their combination were examined for changes in cell proliferation, migration, invasion and apoptosis using Transwell migration, scratch assay, clone generation, RT-qPCR and Western blotting. Network pharmacology analysis was conducted to identify the downstream targets of AKBA in TNBC. In nude mouse models bearing subcutaneous MDA-MB-231 cell xenografts, the effects of normal saline, AKBA (50 mg/kg), doxorubicin (2.5 mg/kg), and AKBA combined with doxorubicin on xenograft growth and histopathology were observed. RESULTS: The IC₅₀ of AKBA and doxorubicin in MDA-MB-231 cells at 48 h was 45.15±0.97 μmol/L and 0.42±0.99 μmol/L, respectively. SynergyFinder confirmed the synergistic effect of AKBA and ADR with a ZIP>10. The combined treatment with AKBA and doxorubicin significantly inhibited the proliferation, migration and invasion, promoted apoptosis of MDA-MB-231 cells, and effectively suppressed xenograft growth in nude mice. Network pharmacology analysis predicted that AKBA affects the progression of TNBC through its downstream target AKBA. CONCLUSIONS AKBA combined with doxorubicin inhibits proliferation, migration and invasion, promotes apoptosis of MDA-MB-231 cells and suppresses MDA-MB-231 cell xenograft growth in nude mice. The combined use of AKBA can attenuate the toxic effects of doxorubicin in nude mice.
Animals ; Doxorubicin/pharmacology* ; Triple Negative Breast Neoplasms/pathology* ; Mice, Nude ; Mice ; Cell Proliferation/drug effects* ; Cell Line, Tumor ; Humans ; Female ; Apoptosis/drug effects* ; Cell Movement/drug effects* ; Xenograft Model Antitumor Assays ; Drug Synergism ; MDA-MB-231 Cells

Objective To analyze the clinical characteristics of collagenous gastritis (CG) and provide evidence for the precise diagnosis and treatment of CG.Methods Published case reports and case series were collected from PubMed,CNKI,and Wanfang Med Online with the key words of collagenous gastritis,collagenous gastroduodenitis,collagenous gastrointestinal diseases,and gastric mucosal nodules.The demographic and clinical information of each case was collected.Results According to the extent of collagen deposition in the digestive tract,94 CG cases included in this study were assigned into upper digestive tract (UDT)-CG,total digestive tract (TDT)-CG and other groups.The UDT-CG group included 52 cases (57.69% females and 42.31% males) with a median age of 14.50 (11.00,25.75) years old.There were 17 cases in the TDT-CG group,including 70.59% females and 29.41% males,with a median age of 15.00 (9.50,48.50) years old.The other group contained 25 cases,(64.00% females and 36.00% males) with a median age of 25.00 (15.50,59.50) years old.The main clinical manifestations in the UDT-CG group were anemia (59.62%) and diarrhea (17.31%),and those in the TDT-CG group were anemia (29.41%) and diarrhea (94.12%).The nodular appearance of gastric mucosa was observed in 75.00% cases in the UDT-CG group and 35.29% cases in the TDT-CG group.In the initial treatment,symptomatic therapy and hormonal therapy respectively relieved the symptoms in 75.00% (30/40) and 100% (3/3) cases in the UDT-CG group and 57.14% (4/7) and 83.33% (5/6) cases in the TDT-CG group.In the retreatment,symptomatic therapy and hormone therapy respectively achieved the remission rates of 100.00% (3/3) and 88.89% (8/9) in the UDT-CG group and 80.00% (4/5) and 66.67% (2/3) in the TDT-CG group.Conclusions CG,a rare disease of gastric collagen deposition,mainly occurs in young patients,and females are more susceptible than males.The clinical manifestations of CG are nonspecific,and anemia,abdominal pain,diarrhea,weight loss,and gastrointestinal bleeding are the common symptoms of CG.Nodular appearance of gastric mucosa is a relatively specific endoscopic feature of CG.There is no standardized treatment for CG.Symptomatic treatment is commonly adopted to improve the quality of life of the patients,and hormones can be added when necessary.
Male ; Female ; Humans ; Quality of Life ; Gastritis/diagnosis* ; Gastric Mucosa ; Collagen ; Anemia/etiology* ; Diarrhea/complications*

ObjectiveTo explore the active ingredients， therapeutic targets， and relative signaling pathways of Tripterygium wilfordii in the treatment of triple negative breast cancer （TNBC） based on network pharmacology， and to verify the mechanism through in vitro cell model. MethodThe active ingredients of T. wilfordii were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）. The targets of TNBC were obtained from DisGeNET and GeneCards. Venny was used to identify the potential therapeutic targets of T. wilfordii against TNBC. Protein-protein interaction （PPI） network was constructed with String database. Gene ontology （GO） annotation and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment were carried out with DAVID to predict the mechanisms of potential targets. The molecular docking between triptolide and key targets were performed with AutoDock Vina. The effect of triptolide （0， 5， 10， 20， 30， 40， 50， 60， 80 nmol·L^-1） on the proliferation of MDA-MB-231 cells was determined through methyl thiazolyl tetrazolium （MTT） assay. The effect of triptolide （0， 12.5， 25， 50 nmol·L^-1） on the apoptosis of MDA-MB-231 cells was detected with Hoechst 33342 staining. Western blot was performed to detect the effect of triptolide （0， 25， 50 nmol·L^-1） on the expression levels of key targets. ResultT. wilfordii had 23 active ingredients related to 55 potential targets of TNBC. GO and KEGG enrichment revealed that the potential targets were associated with 103 biological processes， 15 cellular components， and 35 molecular functions， and were involved in 140 signaling pathways including atherosclerosis and apoptosis. The results of molecular docking demonstrated that triptolide could bind with the targets including threonine kinase 1 （Akt1）， vascular endothelial growth factor A （VEGFA）， cellular tumor antigen p53 （p53）， transcription factor AP-1 （JUN）， signal transducer and activator of transcription 3 （STAT3）， tumor necrosis factor （TNF）， mitogen-activated protein kinase 8 （MAPK8）， prostaglandin G/H synthase 2 （PTGS2）， and Caspase-3. According to the results of MTT assay， triptolide （20， 30， 40， 50， 60， 80 nmol·L^-1） inhibited the proliferation of MDA-MB-231 cells compared with blank control （P<0.05， P<0.01）. Hoechst 33342 staining showed that triptolide （12， 25， 50 nmol·L^-1） induced the apoptosis of MDA-MB-231 cells compared with black control （P<0.05， P<0.01）. Western blot showcased that 50 nmol·L^-1 triptolide down-regulated the relative expression levels of p-Akt， TNF-α， and VEGFA， while 25 and 50 nmol·L^-1 triptolide up-regulated the relative expression level of p53 in a dose-dependent manner compared with the blank control （P<0.05， P<0.01）. ConclusionT. wilfordii has multiple ingredients， targets， and pathways in the treatment of TNBC. It may regulate p53， VEGFA， TNF-α and other key targets to induce cell apoptosis and suppress angiogenesis and inflammatory response， which provides a scientific basis for the further investigation and clinical application of T. wilfordii.

There is a high prevalence rate of malnutrition in patients with end-stage liver disease, which often promotes disease progression and has a negative impact on the prognosis of patients. This article briefly describes the etiology of malnutrition in end-stage liver disease and introduces the research advances in nutrition screening, evaluation, and treatment in end-stage liver disease in China and globally, hoping to provide inspiration for nutritional support in patients with end-stage liver disease in China.

Objective    To analyze the correlation between folate receptor-positive circulating tumor cells (FR+CTC) and the benign or malignant lesions of the lung, and to establish a malignant prediction model for pulmonary neoplasm based on clinical data, imaging and FR+CTC tests. Methods    A retrospective analysis was done on 1 277 patients admitted to the Affiliated Hospital of Qingdao University from September 2018 to December 2019, including 518 males and 759 females, with a median age of 57 (29-85) years. They underwent CTC examination of peripheral blood and had pathological results of pulmonary nodules and lung tumors. The patients were randomly divided into a trial group and a validation group. Univariate and multivariate analyses were performed on the data of the two groups. Then the nomogram prediction model was established and verified internally and externally. Receiver operating characteristic (ROC) curve was used to test the differentiation of the model and calibration curve was used to test the consistency of the model. Results    Totally 925 patients suffered non-small cell lung cancer and 113 patients had benign diseases in the trial group; 219 patients suffered non-small cell lung cancer and 20 patients had benign diseases in the verification group. The FR+CTC in the peripheral blood of non-small cell lung cancer patients was higher than that found in the lungs of the patients who were in favorite conditions (P<0.001). Multivariate analysis showed that age≥60 years, female, FR+CTC value>8.7 FU/3 mL, positive pleural indenlation sign, nodule diameter, positive burr sign, consolidation/tumor ratio<1 were independent risk factors for benign and malignant lung tumors with a lesion diameter of ≤4 cm. Thereby, the nomogram prediction model was established. The area under the ROC curve (AUC) of the trial group was 0.918, the sensitivity was 86.36%, and the specificity was 83.19%. The AUC value of the verification group was 0.903, the sensitivity of the model was 79.45%, and the specificity was 90.00%, indicating nomogram model discrimination was efficient. The calibration curve also showed that the nomogram model calibration worked well. Conclusion    FR+CTC in the peripheral blood of non-small cell lung cancer patients is higher than that found in the lungs of the patients who carry benign pulmonary diseases. The diagnostic model of clinical stage Ⅰ non-small cell lung cancer established in this study owns good accuracy and can provide a basis for clinical diagnosis.

Objective:To explore the clinical characteristics of lung adenocarcinoma patients with exon 21 L858R deletion mutation.Methods:The data of 112 patients who were diagnosed with lung adenocarcinoma and positive genetic mutations in the People's Hospital of Xinjiang Uygur Autonomous Region from January 2015 to December 2018 was retrospectively analyzed, and the patients were divided into the exon 21 L858R deletion mutation group (52 cases) and the non-exon 21 L858R deletion mutation group (60 cases). The clinical characteristics, imaging characteristics, expressions of tumor markers and smoking history of patients were compared between the two groups.Results:There was no statistical difference in the gender, age and ethnicity between the exon 21 L858R deletion mutation group and the non-exon 21 L858R deletion mutation group (P values were 0.488, 0.238 and 0.191). There was no statistical difference in the imaging features (including primary tumor site, lobulation, burr, pleural depression and small vacuoles) between the two groups (all P > 0.05). There was no statistical difference in the expressions of tumor markers (including carcinoembryonic antigen, squamous cell carcinoma antigen, neuron-specific enolase, cytokeratin 19 fragment, and gastrin-releasing peptide precursor) between the two groups (all P > 0.05). There were 20 patients (38.5%, 20/52) with smoking history in the exon 21 L858R deletion mutation group, and 4 patients (6.7%, 4/60) with smoking history in the non-exon 21 L858R deletion mutation group, the difference between the two groups was statistically significant (χ 2 = 4.182, P = 0.041). Conclusions:There is no significant difference in clinical characteristics, imaging features and expressions of tumor markers between the patients with exon 21 L858R deletion mutation and the patients without exon 21 L858R deletion mutation. Smoking may be the influencing factor of exon 21 L858R deletion mutation.

This study aimed to investigate the effect and possible mechanism of Bidens pilosa decoction on non-alcoholic fatty liver disease(NAFLD) induced by high fat and high glucose in mice. Bald/c mice were randomly divided into normal group, model group, metformin(200 mg·kg~(-1)) treatment group, Bidens pilosa decoction(10 g·kg~(-1)) treatment group, metformin and B. pilosa decoction(100 mg·kg~(-1)+5 g·kg~(-1)) treatment group. Except for the normal group, mice in the other four groups were fed with high-fat and high-glucose diet for 8 weeks to establish the non-alcoholic fatty liver model. After 4 weeks of treatment, blood was collected from the eyeballs, the mice were sacrificed, and relevant indicators were detected. The results showed that compared with the model group, blood lipid and blood glucose levels of each treatment group were significantly lower(P<0.05); HE staining results showed that liver pathological damage in each treatment group was significantly improved; oil red O staining results showed fat distribution in each treatment group significantly reduced(P<0.01); immunohistochemical staining showed that glucose regulated the protein expression of protein 78(GRP78) in liver tissues of each treatment group was also significantly reduced(P<0.01); Western blot results showed that endoplasmic reticulum stress signal pathway-related factors GRP78, phosphorylated-protein kinase R-like ER kinase(p-PERK), eukaryotic translation-initiation factor 2α(eIF2α), activating transcription factor 4(ATF4), C/EBP homologous protein(Chop), inositol requiring 1α(IRE1α), and cleaved-cysteinyl aspartate specific proteinase 12(cleaved-caspase-12) were significantly reduced(P<0.01). The results of the combined drug treatment group were better than those of the single drug treatment group. These results showed that B. pilosa decoction had the effect in improving non-alcoholic fatty liver, and its mechanism may be related to the down-regulation of the expression of endoplasmic reticulum stress(ERS)-related factors, and the reduction of the apoptosis of hepatocytes caused by ERS and the down-regulation of blood lipid and blood glucose levels.
Animals ; Apoptosis ; Bidens ; Endoplasmic Reticulum Stress ; Endoribonucleases ; Glucose ; Mice ; Non-alcoholic Fatty Liver Disease ; Protein-Serine-Threonine Kinases

Objective To study fluid flow within alveolar bone under orthodontic and occlusal loading, so as to provide references for understanding the regulatory mechanism of bone remodeling during orthodontics. Methods An animal model for orthodontic tooth movement on rats was first constructed. The finite element model of tooth-periodontal ligament-alveolar bone was established based on micro-CT images and the strain field in alveolar bone under orthodontic or constant occlusal loading was analyzed. Then finite element model of alveolar bone was constructed from the bone near the cervical margin or apical root of mesial root. The fluid flow in this model under orthodontic and cyclic occlusal loading was further predicted by using fluid-solid coupling numerical simulation. Results The fluid velocity within alveolar bone cavity mainly distributed at 0-10 μm/s, and the fluid shear stress (FSS) was mainly distributed at 0-10 Pa. FSS on the surface of alveolar bone near the apical root was higher than that close to the cervical margin. Conclusions FSS at different levels could be produced at different location within alveolar bone cavity under orthodontic and cyclic occlusal loading, which might further activate biological response of bone cells on the surface of trabeculae and finally regulate the remodeling of alveolar bone and orthodontic movement of tooth. The results provide theoretical guidance for the clinical treatment of orthodontics.