Tumor drug resistance is an important problem in the failure of chemotherapy and targeted drug therapy, which is a complex process involving chromatin remodeling. SWI/SNF is one of the most studied ATP-dependent chromatin remodeling complexes in tumorigenesis, which plays an important role in the coordination of chromatin structural stability, gene expression, and post-translation modification. However, its mechanism in tumor drug resistance has not been systematically combed. SWI/SNF can be divided into 3 types according to its subunit composition: BAF, PBAF, and ncBAF. These 3 subtypes all contain two mutually exclusive ATPase catalytic subunits (SMARCA2 or SMARCA4), core subunits (SMARCC1 and SMARCD1), and regulatory subunits (ARID1A, PBRM1, and ACTB, etc.), which can control gene expression by regulating chromatin structure. The change of SWI/SNF complex subunits is one of the important factors of tumor drug resistance and progress. SMARCA4 and ARID1A are the most widely studied subunits in tumor drug resistance. Low expression of SMARCA4 can lead to the deletion of the transcription inhibitor of the BCL2L1 gene in mantle cell lymphoma, which will result in transcription up-regulation and significant resistance to the combination therapy of ibrutinib and venetoclax. Low expression of SMARCA4 and high expression of SMARCA2 can activate the FGFR1-pERK1/2 signaling pathway in ovarian high-grade serous carcinoma cells, which induces the overexpression of anti-apoptosis gene BCL2 and results in carboplatin resistance. SMARCA4 deletion can up-regulate epithelial-mesenchymal transition (EMT) by activating YAP1 gene expression in triple-negative breast cancer. It can also reduce the expression of Ca²⁺ channel IP3R3 in ovarian and lung cancer, resulting in the transfer of Ca²⁺ needed to induce apoptosis from endoplasmic reticulum to mitochondria damage. Thus, these two tumors are resistant to cisplatin. It has been found that verteporfin can overcome the drug resistance induced by SMARCA4 deletion. However, this inhibitor has not been applied in clinical practice. Therefore, it is a promising research direction to develop SWI/SNF ATPase targeted drugs with high oral bioavailability to treat patients with tumor resistance induced by low expression or deletion of SMARCA4. ARID1A deletion can activate the expression of ANXA1 protein in HER2+ breast cancer cells or down-regulate the expression of progesterone receptor B protein in endometrial cancer cells. The drug resistance of these two tumor cells to trastuzumab or progesterone is induced by activating AKT pathway. ARID1A deletion in ovarian cancer can increase the expression of MRP2 protein and make it resistant to carboplatin and paclitaxel. ARID1A deletion also can up-regulate the phosphorylation levels of EGFR, ErbB2, and RAF1 oncogene proteins.The ErbB and VEGF pathway are activated and EMT is increased. As a result, lung adenocarcinoma is resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Although great progress has been made in the research on the mechanism of SWI/SNF complex inducing tumor drug resistance, most of the research is still at the protein level. It is necessary to comprehensively and deeply explore the detailed mechanism of drug resistance from gene, transcription, protein, and metabolite levels by using multi-omics techniques, which can provide sufficient theoretical basis for the diagnosis and treatment of poor tumor prognosis caused by mutation or abnormal expression of SWI/SNF subunits in clinical practice.

Objective:To investigate the factors influencing the prognosis of critically ill patients and the predictive value of the C-reactive protein-albumin-lymphocyte (CALLY) index.Methods:A retrospective analysis was conducted on the clinical data of 122 critically ill patients admitted to Guoyao Dongfeng General Hospital affiliated with Hubei University of Medicine from June 2022 to December 2023. Patients were divided into a death group and a survival group based on their 28-day prognosis. Clinical data were compared between the two groups to analyze the factors influencing prognosis and assess the predictive value of various indicators. Normally distributed measurement data were expressed as Mean±SD, and intergroup comparisons were performed by independent samples t-test; non-normally distributed measurement data were expressed as M( Q1,Q3), and intergroup comparisons were performed by the Mann-Whitney U test. Counting data were expressed as case (%), and intergroup comparisons were performed by the χ2 test. Multivariate logistic regression was used to analyze factors influencing patient prognosis, and receiver operating characteristic (ROC) curves were plotted to analyze the predictive value of each indicator. Results:The Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score, blood lactate, CRP, and B-type natriuretic peptide levels in the death group were higher than those in the survival group [22 (17, 30) points vs. 17 (14, 22) points, (4.8±1.4) mmol/L vs. (3.3±1.0) mmol/L, 134 (83, 2 381) mg/L vs. 13 (10, 27) mg/L, 259 (111, 592) ng/L vs. 108 (40, 247) ng/L; Z=3.04, P=0.002; t=5.79, P<0.001; Z=8.57, P<0.001; Z=3.28, P=0.001, respectively]. Albumin, neutrophil count, lymphocyte count (LYC), and the CALLY index were lower in the death group than in the survival group [(31±5) g/L vs. (37±6) g/L, (58±9)×10 9/L vs. (63±10)×10 9/L, 0.6 (0.4, 0.8)×10 9/L vs. 1.3 (0.8, 1.7)×10 9/L, 0.03 (0.02, 0.11) vs. 0.26 (0.13, 0.49); t=6.05, P<0.001; t=3.04, P=0.003; Z=5.82, P<0.001; Z=6.52, P<0.001, respectively]. Multivariate logistic regression analysis indicated that the APACHE Ⅱ score and CRP were risk factors for poor prognosis in critically ill patients ( OR=1.349, 95% CI: 1.004-1.821, P=0.048; OR=1.006, 95% CI: 1.003-1.010, P=0.001, respectively), while LYC and the CALLY index were protective factors ( OR=0.297, 95% CI: 0.111-0.795, P=0.016; OR=0.989, 95% CI: 0.955-0.999, P=0.001, respectively). The area under the ROC curve for the CALLY index predicting 28-day mortality in critically ill patients was 0.872 (95% CI: 0.800-0.926), which was higher than that of the APACHE Ⅱ score, LYC, and CRP [0.673 (95% CI: 0.582-0.756), 0.664 (95% CI: 0.573-0.748), 0.576 (95% CI: 0.482-0.665), respectively]. The cut-off values were 0.06, 20 points, 0.8×10 9/L, and 50 mg/L, respectively. When the CALLY index was 0.06, the specificity was 97.65%, the sensitivity was 72.97%, and the Youden index was 0.706. Conclusions:The APACHE Ⅱ score, CRP, LYC, and CALLY index are all factors influencing the prognosis of critically ill patients. The CALLY index has certain predictive value, but its false negative rate is relatively high. Further combination with other indicators is needed to improve its predictive value.

Eight butyl-phthalides, senkyunolide K(1), senkyunolide N(2), butylphthalide(3), senkyunolide I(4), senkyunolide H(5),(Z)-butylidenephthalide(6),(Z)-ligustilide(7), and 3-butylidene-7-hydroxyphthalide(8) were isolated from the aerial part of Ligusticum sinense by column chromatography on silica gel column, ODS, Sephadex LH-20 and semi-preparative HPLC. Their structures were elucidated on the basis of spectroscopic and chemical data, especially NMR and MS. Compound 1 was a new butyl-phthalide and compounds 2-8 were isolated from the aerial part of L. sinense for the first time. Furthermore, the inhibitory activities of compounds 1-8 against the nitric oxide(NO) production induced by lipopolysaccharide(LPS) in mouse RAW264.7 macrophages in vitro were evaluated. The results showed that compounds 1-8 exerted inhibitory activities on NO production with IC_(50) of 19.34-42.16 μmol·L~(-1).
Animals ; Mice ; Nitric Oxide/biosynthesis* ; Ligusticum/chemistry* ; Benzofurans/isolation & purification* ; Drugs, Chinese Herbal/isolation & purification* ; Macrophages/immunology* ; RAW 264.7 Cells ; Molecular Structure

Objective:To investigate the factors influencing the prognosis of critically ill patients and the predictive value of the C-reactive protein-albumin-lymphocyte (CALLY) index.Methods:A retrospective analysis was conducted on the clinical data of 122 critically ill patients admitted to Guoyao Dongfeng General Hospital affiliated with Hubei University of Medicine from June 2022 to December 2023. Patients were divided into a death group and a survival group based on their 28-day prognosis. Clinical data were compared between the two groups to analyze the factors influencing prognosis and assess the predictive value of various indicators. Normally distributed measurement data were expressed as Mean±SD, and intergroup comparisons were performed by independent samples t-test; non-normally distributed measurement data were expressed as M( Q1,Q3), and intergroup comparisons were performed by the Mann-Whitney U test. Counting data were expressed as case (%), and intergroup comparisons were performed by the χ2 test. Multivariate logistic regression was used to analyze factors influencing patient prognosis, and receiver operating characteristic (ROC) curves were plotted to analyze the predictive value of each indicator. Results:The Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score, blood lactate, CRP, and B-type natriuretic peptide levels in the death group were higher than those in the survival group [22 (17, 30) points vs. 17 (14, 22) points, (4.8±1.4) mmol/L vs. (3.3±1.0) mmol/L, 134 (83, 2 381) mg/L vs. 13 (10, 27) mg/L, 259 (111, 592) ng/L vs. 108 (40, 247) ng/L; Z=3.04, P=0.002; t=5.79, P<0.001; Z=8.57, P<0.001; Z=3.28, P=0.001, respectively]. Albumin, neutrophil count, lymphocyte count (LYC), and the CALLY index were lower in the death group than in the survival group [(31±5) g/L vs. (37±6) g/L, (58±9)×10 9/L vs. (63±10)×10 9/L, 0.6 (0.4, 0.8)×10 9/L vs. 1.3 (0.8, 1.7)×10 9/L, 0.03 (0.02, 0.11) vs. 0.26 (0.13, 0.49); t=6.05, P<0.001; t=3.04, P=0.003; Z=5.82, P<0.001; Z=6.52, P<0.001, respectively]. Multivariate logistic regression analysis indicated that the APACHE Ⅱ score and CRP were risk factors for poor prognosis in critically ill patients ( OR=1.349, 95% CI: 1.004-1.821, P=0.048; OR=1.006, 95% CI: 1.003-1.010, P=0.001, respectively), while LYC and the CALLY index were protective factors ( OR=0.297, 95% CI: 0.111-0.795, P=0.016; OR=0.989, 95% CI: 0.955-0.999, P=0.001, respectively). The area under the ROC curve for the CALLY index predicting 28-day mortality in critically ill patients was 0.872 (95% CI: 0.800-0.926), which was higher than that of the APACHE Ⅱ score, LYC, and CRP [0.673 (95% CI: 0.582-0.756), 0.664 (95% CI: 0.573-0.748), 0.576 (95% CI: 0.482-0.665), respectively]. The cut-off values were 0.06, 20 points, 0.8×10 9/L, and 50 mg/L, respectively. When the CALLY index was 0.06, the specificity was 97.65%, the sensitivity was 72.97%, and the Youden index was 0.706. Conclusions:The APACHE Ⅱ score, CRP, LYC, and CALLY index are all factors influencing the prognosis of critically ill patients. The CALLY index has certain predictive value, but its false negative rate is relatively high. Further combination with other indicators is needed to improve its predictive value.

Objective To compare the differences in lipid metabolism between platinum-resistant and platinum-sensitive ovarian cancer patients at stage Ⅲ-Ⅳ,to analyze the differential intestinal flora using 16S rRNA sequen-cing,and to explore the associations among intestinal flora,lipid metabolism characteristics and platinum resistance in ovarian cancer.Methods Patients diagnosed with ovarian cancer at stage Ⅲ-Ⅳ through surgical pathology were selected,including a platinum-resistant group(11 cases)and a platinum-sensitive group(11 cases).The differences in lipid metabolism between the two groups were compared.The differences in gut microbiota between the two groups were investigated using fecal 16S rRNA sequencing.The association among gut microbiota,lipid metabolism characteristics,and platinum resistance in ovarian cancer was analyzed.Results Significant differ-ences were observed in lipid metabolism-related indicators[total cholesterol(TC),high-density lipoprotein choles-terol(HDL-C),non-high-density lipoprotein cholesterol(n-HDL),low-density lipoprotein cholesterol(LDL-C),apolipoprotein(B)]between the two groups,with higher levels in the platinum-resistant group.The Shannon in-dex(P=0.008 3)and Simpson index(P=0.008 2)both showed higher diversity of gut microbiota in platinum-resistant ovarian cancer patients compared to the platinum-sensitive group.However,based on OTUs species clus-tering and relative abundance statistics,certain bacterial abundances differed significantly between the groups.Spe-cies such as Parabacteroides,Akkermansia,Blautia,Lachnoclostridium,Fusicatenibacter,and Megamonas had sig-nificantly higher abundances in the platinum-sensitive ovarian cancer group,and Akkermansia(a lipid metabolism-related bacterial group)was the most prevalent.Conclusion The platinum-resistant group of ovarian cancer ex-hibits significantly higher levels of lipid metabolism and gut microbiota diversity compared to the platinum-sensitive group.This suggests that the increase in lipid metabolism levels and fecal microbiota diversity may be associated with the development of platinum resistance.However,certain microbial taxa are reduced in abundance in the plat-inum-resistant group,such as the distinct Akkermansia genus(a lipid metabolism-related microbial community),which may serve as one of the factors inducing platinum-resistance in ovarian cancer.

Objective To provide a longitudinal evaluation tool based on the frequency of aggressive be-havior for the aggression assessment of schizophrenia patients.Methods The Life History of Aggression was translated and revised to form the Life History of Aggression-Chinese Version(LHA-CV)based on 369 patients diagnosed with schizophrenia in the Chengdu community and compulsory medical insti-tution.The reliability of LHA-CV was analyzed by means of split-half reliability,test-retest reliability and inter-evaluator consistency.The validity was analyzed by item analysis,construct validity and crite-rion validity.Results Item analysis found that LHA-CV had good homogeneity and discriminant validity.Exploratory factor analysis found that the Kaiser-Meyer-Olkin(KMO)test value was 0.80,and the Bartlett's sphericity test χ2=1203.46(P<0.05),and it revealed four factors including non-physical ag-gression,physical aggression,self-directed aggression and antisocial behavior/consequences.The factor loadings for all 11 items were greater than 0.40.Confirmatory factor analysis was performed on the factor model,Chi-square degree of freedom(χ2/df)was 3.61,root mean square error of approxima-tion(RMSEA)was 0.07,goodness-of-fit index(GFI)was 0.92,comparative fit index(CFI)was 0.90,incremental fit index(IFI)was 0.90,and the discriminant validity of each factor was good.The criterion validity test showed the total score of LHA-CV was positively correlated with the aggressive behavior level of MacArthur Community Violence Instrument,the total score of Buss-Perry Aggression Scale,and the score of Antisocial Personality Disorder Subscale of Personality Diagnostic Question-naire-4th Edition Plus(PDQ-4+_ASPD,P<0.05).The Cronbach's α coefficient of non-physical aggres-sion,physical aggression,self-directed aggression,antisocial behavior/consequences and LHA-CV total score were 0.82,0.73,0.74,0.56 and 0.79,respectively.The test-retest reliability,Spearman-Brown split-half reliability and intra-class correlation coefficient of LHA-CV total score were 0.82(P<0.05),0.66 and 0.99,respectively.Conclusion LHA-CV has good reliability and validity,and can be used as an evaluation tool for longitudinally assessing aggressive behavior in schizophrenia patients.

To investigate the cardioprotective effect of formononetin (FMN) on no-reflow (NR) after myocardial ischemia-reperfusion and its molecular mechanism based on integrated pharmacology and experimental verification, firstly, human breast cancer MCF-7 cells and myocardial NR rats were used to confirm the estrogenic activity and the effect of alleviating NR of FMN, respectively. Male SD rats were divided into Sham, NR, FMN (20 mg·kg^-1) and sodium nitroprusside (SNP, 5.0 mg·kg^-1) groups, which were administered once a day for one week, the experiment was approved by the Ethics Committee of Tianjin University of Traditional Chinese Medicine (TCM-LAEC2019095). The pharmacological analysis and in vivo study of NR rats were integrated to reveal the mechanism of FMN improving NR. The results showed that FMN had estrogenic effect and reduced NR by improving cardiac structure and function, reducing NR, ischemic myocardial area and pathological injury of cardiomyocytes. Integrated pharmacology predicts that the mechanism of FMN improving NR is mainly related to phosphatidyinositol-3-kinase-protein kinase B (PI3K-Akt) signal pathway. Phytoestrogens play a role in cardiovascular protection mainly by activating G protein-coupled estrogen receptor (GPER). GPER is also an important regulator in the upstream of PI3K-Akt signaling pathway. This study found that FMN can significantly activate GPER, p-PI3K, p-Akt and phospho-endothelial nitric oxide synthase (p-eNOS). It has good binding ability with GPER and eNOS protein. In this study, through the integration of pharmacology and experimental evaluation, it is revealed that FMN activates PI3K/Akt/eNOS signal pathway by activating GPER, thus significantly improving NR.

Humans ; Stroke, Lacunar ; Mendelian Randomization Analysis ; Leukocytes ; Telomere/genetics* ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide

Objective: To obtain the diversity and abundance of fast-growing bacteria in the surface water of the northeast coast of Hainan Island in China, different cultivation methods were employed. This study also aims to provide a reference for isolating bacterial samples from seawater sources and preventing marine-derived pathogens. Methods: Based on the principles of taxonomic design, surface seawater samples were collected from six locations along the northeast coast of Hainan Island in China in March, June, October, and December 2021. Then, bacterial enrichment was performed based on traditional cultivation methods for Salmonella, Vibrio, Burkholderia pseudomallei, Actinomycetes, and general marine bacteria. After that, bacterial species identification was conducted by 16S rDNA amplicon sequencing and metagenomic sequencing. Results: A total of 1 151 fast-growing cultivable bacteria belonging to 66 genera and 213 species were identified using five different culture protocols. In different cultivation protocols, Bacillus and Klebsiella demonstrated extensive discriminatory advantages and ranked among the top genera in terms of abundance. Protocol 1 had Escherichia, Klebsiella, and Citrobacter as dominant genera. Pathogenic bacteria detected by protocol 1 included Klebsiella pneumoniae and Escherichia coli, with 37 and 29 strains respectively, while Salmonella enterica was uniquely detected with seven isolates. Proteus, Enterococcus, and Providencia were the dominant genera in protocol 2, and Proteus mirabilis was the most abundant pathogenic bacteria detected with 66 isolates. Vibrio cholerae was uniquely detected with six isolates at a higher abundance. Klebsiella, Escherichia, and Acinetobacter were the dominant genera in protocol 3, and Klebsiella pneumoniae was the most abundant pathogenic bacteria detected with 53 isolates, while Acinetobacter nosocomialis was uniquely detected with seven isolates. Vibrio and Pseudoalteromonas were the dominant genera in protocol 4, and they showed advantages in isolating and cultivating Marine-derived Vibrio. Exiguobacterium, Staphylococcus, and Bacillus were the dominant genera in protocol 5. Bacillus cereus and Lactococcus lactis were the most abundant pathogenic bacteria detected with 20 and 15 isolates, respectively, while Lactococcus lactis was uniquely detected at higher abundance. Metagenomic sequencing showed that Klebsiella pneumoniae was significantly dominant with a gene abundance of 51.11%, followed by Alcanivorax sp. at 12.57%. Conclusion: The surface water of the northeast coast of Hainan Island in China exhibits a rich diversity of bacteria, with Klebsiella pneumoniae being highly abundant in the studied area. Different cultivation methods demonstrate distinct selective advantages in culturing bacterial genera and pathogens. Therefore, it is necessary to optimize cultivation conditions for specific marine bacteria.
Humans ; Water ; Bacteria/genetics* ; Seawater/microbiology* ; Escherichia coli ; Enterococcus ; Klebsiella pneumoniae ; China

Objective: To obtain the diversity and abundance of fast-growing bacteria in the surface water of the northeast coast of Hainan Island in China, different cultivation methods were employed. This study also aims to provide a reference for isolating bacterial samples from seawater sources and preventing marine-derived pathogens. Methods: Based on the principles of taxonomic design, surface seawater samples were collected from six locations along the northeast coast of Hainan Island in China in March, June, October, and December 2021. Then, bacterial enrichment was performed based on traditional cultivation methods for Salmonella, Vibrio, Burkholderia pseudomallei, Actinomycetes, and general marine bacteria. After that, bacterial species identification was conducted by 16S rDNA amplicon sequencing and metagenomic sequencing. Results: A total of 1 151 fast-growing cultivable bacteria belonging to 66 genera and 213 species were identified using five different culture protocols. In different cultivation protocols, Bacillus and Klebsiella demonstrated extensive discriminatory advantages and ranked among the top genera in terms of abundance. Protocol 1 had Escherichia, Klebsiella, and Citrobacter as dominant genera. Pathogenic bacteria detected by protocol 1 included Klebsiella pneumoniae and Escherichia coli, with 37 and 29 strains respectively, while Salmonella enterica was uniquely detected with seven isolates. Proteus, Enterococcus, and Providencia were the dominant genera in protocol 2, and Proteus mirabilis was the most abundant pathogenic bacteria detected with 66 isolates. Vibrio cholerae was uniquely detected with six isolates at a higher abundance. Klebsiella, Escherichia, and Acinetobacter were the dominant genera in protocol 3, and Klebsiella pneumoniae was the most abundant pathogenic bacteria detected with 53 isolates, while Acinetobacter nosocomialis was uniquely detected with seven isolates. Vibrio and Pseudoalteromonas were the dominant genera in protocol 4, and they showed advantages in isolating and cultivating Marine-derived Vibrio. Exiguobacterium, Staphylococcus, and Bacillus were the dominant genera in protocol 5. Bacillus cereus and Lactococcus lactis were the most abundant pathogenic bacteria detected with 20 and 15 isolates, respectively, while Lactococcus lactis was uniquely detected at higher abundance. Metagenomic sequencing showed that Klebsiella pneumoniae was significantly dominant with a gene abundance of 51.11%, followed by Alcanivorax sp. at 12.57%. Conclusion: The surface water of the northeast coast of Hainan Island in China exhibits a rich diversity of bacteria, with Klebsiella pneumoniae being highly abundant in the studied area. Different cultivation methods demonstrate distinct selective advantages in culturing bacterial genera and pathogens. Therefore, it is necessary to optimize cultivation conditions for specific marine bacteria.
Humans ; Water ; Bacteria/genetics* ; Seawater/microbiology* ; Escherichia coli ; Enterococcus ; Klebsiella pneumoniae ; China