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Objective To investigate the effects of morin on chronic obstructive pulmonary disease(COPD) animal and cell model through the regulation of matrix metalloproteinase-9(MMP9). Methods SwissTargetPrediction database was used to predict the genetargets of morin, GeneCards, OMIMand DisGenet databases were used to predict the risk genes of COPD, the intersection of COPD-related gene targets and morin gene targets was obtained by using Venny online website; Protein-protein interaction(PPI) analysis was performed using the String database, and topological analysis was performed by Cytoscape 3.8.2 software. Molecular docking was used to validate the interaction between the drug components and gene targets; COPD rat models were constructed to verify the therapeutic effects of morin om COPD rat models. The COPD cell model was established to interfere with the expression of MMP9 in the cells. COPD cell models were established and the expression ofMMP9in cells was intervened; flow cytometry was used to detect cell apoptosis rate; ELISA was used to measure the concentration of inflammatory factors. Results The Swiss Target Prediction database predicted 96 gene targets of morin. GeneCards, OMIM, and DisGenet databases predicted 7 122 gene targets of COPD, intersection analysis identified 67 common gene targets between morin and COPD. Topological analysis revealed that the top 5 gene targets with strongest interactions among the intersected targets wereSRC,MMP9,MMP2,PTGS2, andFURIN; Molecular docking results showed the best binding activity betweenMMP9and morin; animal experiments showed that morin improved respiratory function parameters and lung tissue pathological damage, and inhibited MMP9 expression in COPD rats(P<0.05); Cell experiments showed that morin increased cell viability in COPD cell models and inhibited MMP9 expression(P<0.05). In addition, morin inhibited cell apoptosis and expression of inflammatory factors in the COPD cell model, but this effect was reversed by overexpression of MMP9(P<0.05). Conclusion Morin can improve apoptosis and and expression of inflammatory cytokines in COPD cell model, reduce lung tissue pathological changes by inhibiting MMP9 expression.

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To investigate the structure of deoxyhypusine synthase(DHS) inSaccharomyces cerevisiae(Dys1) and unravel the molecular mechanism of hypusine lysine modification, providing a theoretical basis for the treatment of highly proliferative diseases such as human immunodeficiency virus type 1(HIV-1) replication.

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Objective To investigate the effect of inhibiting lipid synthesis on human skeletal rhabdomyosarcoma cells and its molecular mechanism. Methods The mRNA expression levels of lipid synthesis related genes sterol regulatory element binding protein 1(SREBP1) and squalene cyclooxygenase(SQLE) in human skeletal muscle cells(HSMC) and human skeletal rhabdomyosarcoma cells were detected by tumor gene expression database and verified by qRT-PCR. The concentration of methyl-β-cyclodextrin(mβCD) was determined by cell proliferation assay. The control group consisted of three human skeletal rhabdomyosarcoma cell lines(RD, SJCRH30, A673), while the experimental group comprised three human skeletal rhabdomyosarcoma cell lines treated with 1mmol/L mβCD. Plate clone formation assay, soft agar, colony formation assay, cell migration assay and cell invasion assay, and tumor formation in nude mice employed to assess changes in proliferation, migration, invasion, and tumor growth of human skeletal rhabdomyosarcoma cells between the control group and mβCD treatment group. The molecular mechanism of mβCD inhibiting the malignancy of human skeletal rhabdomyosarcoma cells was explored by lipoomics and triglyceride(TG) detection. Results Compared with HSMC, the expressions of lipid synthesis related genesSREBP1andSQLEsignificantly increased in human skeleton rhabdomyosarcoma cells(P<0.001). Compared with the control group, the proliferation, plate cloning, migration, invasion and colony formation ability of human skeleton rhabdomyosarcoma cells in the mβCD group significantly decreased(P<0.05). The growth of tumor volume and weight in nude mice was also significantly reduced(P<0.05). The lipidomics results and TG kit analysis revealed a significant reduction in TG content in the mβCD group compared to the control group(P<0.01). Conclusion mβCD may inhibit the malignant biological behaviors such as proliferation, migration and invasion of human skeleton rhabdomyosarcoma cells by reducing TG and other lipid metabolism.

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Objective To investigate the effect of aspirin-induced Gasdermin E(GSDME) dependent pyroptosis and the related mechanism of colorectal cancer cell proliferation. Methods The colorectal cancer cells Caco2 were culturedin vitro. MTT assay was used to detect the effects of aspirin intervention with different concentrations(1.0, 2.5, 5.0, 10.0, 15.0, 20.0 mmol/L)on the proliferation activity of colorectal cancer cells. The effect of aspirin intervention on the morphology of colorectal cancer cells was observed under the microscope. Lactate dehydrogenase(LDH) release assay was used to investigate the effect of aspirin intervention on cell membrane integrity. The protein expression levels of NOD-like receptor protein(NLRP3), cysteinyl aspartate and specific proteinase 1(Caspase-1), Gasdermin E-N(GSDME-N) in colorectal cancer cells were detected by Western blot. The contents of interleukin-1β(IL-1β) and interleukin-18(IL-18) in cell supernatant after GSDME silencing were detected by ELISA. After silencing GSDME, cell morphological changes were observed under a microscope, and cell membrane integrity was observed by LDH release assay; The contents of IL-1β and IL-18 in cell supernatant were determined by ELISA after GSDME silencing. Results MTT results showed that aspirin could decrease the proliferation activity of Caco-2 in a concentration-dependent manner(P<0.01). Morphological observation and LDH experiment showed that aspirin could promote the occurrence of pyroptosis(P<0.05). Western blot showed that aspirin could increase the expression levels of NLRP3, Caspase-1, GSDME-N of pyroptosis-related pathway genes(P<0.05). ELISA showed that aspirin could significantly increase the concentration of IL-1β and IL-18 in Caco-2 cells(P<0.01). After GSDME silencing, the pyroptosis was significantly inhibited(P<0.05) and the expression of IL-1β and IL-18 decreased significantly(P<0.01). Conclusion Aspirin can inhibit the proliferation of Caco-2 by inducing the pyroptosis of GSDME-dependent cells, thus inhibiting colon cancer.

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Objective To analyze the effects of Porphyromonas gingivalis(Pg) infection and expression of vitamin D pathway-related proteins on the survival and prognosis of patients with esophageal squamous cell carcinoma(ESCC).Methods Pg infection and the expression of 24 hydroxylase(CYP24A1), 1α hydroxylase(CYP27B1) and vitamin D receptor(VDR) in 173 ESCC tissues were detected by immunohistochemistry. The correlation between each index and the survival time of patients was analyzed.Results The positive rates of Pg, CYP24A1, CYP27B1 and VDR in ESCC were 43. 35%, 37. 57%, 20. 23% and 21. 97%, respectively. The 5-year survival time of ESCC patients in the Pg+CYP24A1+CYP27B-VDR-high-risk group was shortened(P<0. 05).Conclusion Pg infection and vitamin D pathway-associated proteins can be used as reliable indicators to predict the survival and prognosis of ESCC patients.

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Objective To investigate the expression of Specific protein1(SP1) in esophageal squamous cell carcinoma(ESCC) and adjacent normal tissues and its effect on the proliferation and apoptosis of ESCC cells. Methods The expression of SP1 protein in 121 ESCC tissues and 74 adjacent normal tissues was detected by immunohistochemistry. Chi-square test and Cox regression analysis were used to analyze the relationship between SP1 and clinicopathological parameters and survival prognosis of ESCC patients. SP1 siRNA(small interfering RNA) was constructed and transfected into esophageal squamous cell carcinoma Eca109 and EC9706 cell lines. Western blot was used to detect the expression of SP1 after transfection. The effects of SP1 on the proliferation and apoptosis of esophageal squamous cell carcinoma cells were detected by cloning assay, CCK-8 cell proliferation assay and flow cytometry. Results SP1 protein was expressed in the nucleus of esophageal squamous cell carcinoma tissues, and the expression rate of SP1 protein in esophageal squamous cell carcinoma tissues was significantly higher than that in adjacent normal tissues(χ2=20.568,P<0.01).Comparison between groups showed that the high expression rate of SP1 was higher in female(P=0.041), moderately or poorly differentiated(P=0.038) and T3-T4 invasion depth(P=0.041) ESCC(esophageal squamous cell carcinoma) patients. Log-rank test showed that the survival time of patients with high expression of SP1 was shorter than that of patients with low expression of SP1(P=0.048). Multivariate Cox regression analysis showed that TNM(tumor node metastasis classification) stage(Ⅲ+Ⅳ) was a potential risk factor for shorter survival time in patients with esophageal squamous cell carcinoma(P<0.001). Cell biological experiments showed that compared with the control group, the proliferation ability of esophageal squamous cell carcinoma cell lines decreased(P<0.05) and the apoptosis index increased(P<0.05) after silencing SP1. Conclusion SP1 protein is highly expressed in human esophageal squamous cell carcinoma tissues and is associated with poor prognosis in patients. Silencing SP1 can inhibit the proliferation of esophageal squamous cell carcinoma cells and promote their apoptosis.

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Objective To investigate the expression of Member RAS Oncogene Family(RAB10) in pancreatic cancer(PAAD) and its effects on the proliferation, migration, invasion and apoptosis of SW1990 cells(human pancreatic cancer cells). Methods The expression ofRAB10mRNA in PAAD tissues wasanalyzed by the cancer gene database GEPIA(Gene Expression Profiling Interactive Analysis) and TCGA(The Cancer Genome Atlas). Cox regression analysis was used to detect relationship betweenRAB10mRNA expression and the prognosis of pancreatic cancer patients. We targeted small interfering RNA(RAB10-siRNA) targetingRAB10as the silence group, and constructed an overexpression plasmid(RAB10-OE) for overexpression ofRAB10as the overexpression group. The effects of silencing and overexpressionweredetected by Q-PCR; protein expression levelsweredetected by Western blot.EdUcellproliferation test, wound healing test, Transwelltestand flow cytometry test were used to determine the effects ofRAB10on the proliferation, migration, invasion and apoptosis of SW1990 pancreatic cancer cells. Results RAB10mRNA expression in PAAD tissues was higher than that innormal pancreatic tissues(P<0.05). The results of EdUcellproliferation testshowed that the proliferation rate of SW1990 cells in the RAB10-OE group was higher thanthat in the control group, and the proliferation rate of SW1990 cells in the RAB10-siRNA group was lower than that inthe control group(P<0.05). The results of the Transwell test and wound healing test showed that the invasion rate and mobility rate of RAB10-OE group were higher thanthose of the control group, and the mobility and invasion rate of RAB10-siRNA group were lower than those of the control group(P<0.05). The results of flow cytometry test showed that the apoptosis rate was lower in the RAB10-OE group than the control group, and the apoptosis rate in the RAB10-siRNA group was higher than the control group(P<0.05). The median survival time ofRAB10high expression group was significantly lower than that ofRAB10low expression group(P<0.05). Cox regression analysis showed that clinical grade, T stage, M stage andRAB10mRNA expression were related to survival and prognosis of pancreatic cancerpatients(P<0.05). Multivariate Cox regression analysis showed that the expression level ofRAB10mRNA was the independent risk factor affecting the prognosis of pancreatic cancer patients(P<0.05). Conclusion RAB10is highly expressed in PAAD tissues andRAB10can promote the proliferation of pancreatic cancer cells, accelerate the ability to invade and migrate, and inhibit the apoptosis of pancreatic cancer cells.RAB10is an independent risk factor for survival prognosis in patients with pancreatic cancer.

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Objective To investigate the effect of sirtuin 3(SIRT3) on the oxidative stress response and hypoxia inducible factor-1α(HIF-1α) expression in lung cancer cells through reactive oxygen species(ROS) under hypoxic conditions and its mechanism. Methods Human non-small cell lung cancer A549 cells were exposed to hypoxia for 0 h, 12 h, 24 h and 48 h. The mRNA and protein expressions of HIF-1α and SIRT3 were detected by RT-PCRand Western blot to determine the optimal time of hypoxia induction. A549 cells were divided into 5 groups: control group, hypoxia group, hypoxia+ROS inhibitor n-acetylcysteine(NAC) group, hypoxia+(SIRT3 overexpression) SIRT3-OE group and hypoxia+SIRT3-OE+NAC group. Cell proliferation was detected by MTT assay. Cell apoptosis was detected by flow cytometry. The mRNA and protein expressions of HIF-1α and SIRT3 in each group were detected by RT-PCR and Western blot. ROS content in each group was detected by flow cytometry. The contents of malondialdehyde(MDA), superoxide dismutase(SOD) and glutathione(GSH) in the cells of each group were detected by biochemical kits. Results The optimal induction time of hypoxia was 24 h. Compared with the control group, the apoptosis rate, SIRT3 mRNA and protein levels, SOD and GSH contents in the hypoxia group significantly decreased(P<0.01), the cell proliferation ability, HIF-1α mRNA and protein levels, ROS and MDA content in cells significantly increased(P<0.01). Compared with the hypoxia group, the apoptosis rate, SIRT3 mRNA and protein levels, SOD and GSH contents in the hypoxia+NAC and hypoxia+SIRT3-OE groups increased(P<0.05), the cell proliferation ability, HIF-1α mRNA and protein levels, ROS and MDA content in cells decreased(P<0.05). Compared with the hypoxia+NAC group, the apoptosis rate, SIRT3 mRNA and protein levels, SOD and GSH contents in the hypoxia+SIRT3-OE+NAC group significantly increased(P<0.01), the cell proliferation ability, HIF-1α mRNA and protein levels, ROS and MDA content in cells significantly decreased(P<0.01). Conclusion Under hypoxic conditions, SIRT3 can promote cell apoptosis and inhibit lung cancer progression by mediating ROS to inhibit oxidative stress response and HIF-1α expression in lung cancer cells.

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Objective To investigate the role of miR-125b on hepatic angiogenesis, with the hope of providing new targets for the prevention and treatment of liver fibrosis. Methods The human hepatic sinusoidal endothelial cells were transfected with miR-125b mimics and inhibitors, and the mRNA and protein expression of vascular endothelial growth factor(VEGF), cluster of differentiation antigens 31(CD31), von Willebrand factor(vWF), collagen IV, and laminin(LN) were detected by qRT-PCR and ELISA, and the expression of nitric oxide(NO) was detected by fluorescent probe, scanning electron microscopy detected the alteration of the window holes on the surface of human hepatic sinusoidal endothelial cells, angiogenesis assay was performed to observe the neovascularization of each group, and dual luciferase reporter gene assay was performed to validate the targeting relationship between miR-125b and VEGF. Results qRT-PCR and ELISA showed that compared with the negative control group, the mRNA and protein expressions of VEGF, CD31, vWF, Collagen Ⅳ, and LN significantly decreased after miR-125b mimic transfection(P<0.05), while the mRNA and protein expressions of VEGF, CD31, vWF, Collagen Ⅳ, and LN were significantly increased after transfection with miR-125b mimics(P<0.05); fluorescent probe detection showed that compared with the negative control group, the average fluorescence of intensity expression NO decreased significantly(P<0.05), while the average fluorescence intensity expression of NO increased significantly after miR-125b inhibitor transfection(P<0.05); the number of fenestrations on the surface of human liver sinusoidal endothelial cells significantly increased after miR-125b mimic transfection(P<0.05), while the number of fenestrations on the surface of human liver sinusoidal endothelial cells decreased significantly after miR-125b inhibitor transfection(P<0.05); angiogenesis assay showed that compared with the negative control group, the number of angiogenesis significantly decreased after miR-125b mimic transfection(P<0.05), while the number of angiogenesis significantly increased after miR-125b inhibitor transfection(P<0.05); dual luciferase reporter gene assay showed that compared with negative control group, the expression of relative fluorescence intensity after transfection of miR-125b mimics in VEGF wild-typ significantly decreased(P<0.05), while the expression of relative fluorescence intensity after transfection of miR-125b mimics in VEGF mutant significantly decreased(P>0.05). Conclusion miR-125b can inhibit liver angiogenesis and thus play an anti-fibrosis role, which can provide a new reference for the prevention and treatment of chronic liver disease and the development of new drugs.

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Objective To investigate the protective effect of hyperoside(Hyp) on transverse aortic constriction-induced cardiac hypertrophy and its possible mechanism. Methods Forty 8-week-old male C57BL/6J mice were randomly divided into four groups: Sham group, TAC group, Hyp+TAC group and Hyp+ML385+TAC group. Four weeks after operation, cardiac function including left ventricular ejection fraction(LVEF), left ventricular fractional shortening(LVFS) and left ventricular end-diastolic posterior wall thickness(LVPWd) were measured with echocardiography. HE staining was used to evaluate the myocyte cross-sectional area. Masson staining was used to determine myocardial fibrosis. The ratio of heart weight/body weight was calculated. DHE staining was used to assess reactive oxygen species(ROS) production. The mRNA levels of atrial natriuretic peptide(ANP), brain natriuretic peptide(BNP) and β-myosin heavy chain(β-MHC) were detected by qRT-PCR. The protein levels of NF-E2-related factor 2(Nrf2), heme oxygenase-1(HO-1), superoxide dismutase2(SOD2) and NADPH-Oxidase 2(gp91phox) were detected by Western blot. Differences among groups were compared by one-way analysis of variance, and LSD-ttest was used for comparison between the two groups. Results Compared with the Sham group, the values of LVEF and LVFS in the TAC group decreased(P<0.01). The value of LVPWd, the cross-sectional area, fibrosis and the ratio of HW/BW increased(P<0.01). The mRNA levels ofANP,BNPandβ-MHCwere upregulated(P<0.01). The ROS production and gp91phox protein level were elevated in the TAC group(P<0.01), while the protein levels of Nrf2, HO-1 and SOD2 decreased(P<0.01). Compared with the TAC group, the values of LVEF and LVFS in the Hyp+TAC group increased(P<0.01). The value of LVPWd, the cross-sectional area, fibrosis and the ratio of HW/BW decreased(P<0.01). The mRNA levels ofANP,BNPandβ-MHCwere downregulated(P<0.01). The ROS production and gp91phox protein levels were reduced in the Hyp+TAC group(P<0.01), while the protein levels of Nrf2, HO-1 and SOD2 increased(P<0.01). However, ML385 could partially reverse the protective effects of Hyp on TAC-induced cardiac hypertrophy. Conclusion Hyp alleviates pressure overload-induced cardiac hypertrophy by inhibiting oxidative stress and fibrosis, and its mechanism may be related to Nrf2/HO-1 signaling.

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Objective To explore the effect of miR-23b-3p regulation on osteogenic differentiation of renal interstitial fibroblasts(hRIFs) on the formation of Randall plaque and its possible mechanism. Methods qRT-PCR was used to detect the expression levels of miR-23b-3p and osteogenic marker: myocyte enhancer factor 2C(MEF2C), osteocalcin(OCN), osteopontin(OPN), runt-related transcription factor 2(Runx2) mRNA in Randall plaque tissue of CaOx stone patients(RP) and normal papillary tissue of kidney tumor patients undergoing nephrectomy(nRP). Isolation and culture of human normal hRIFs were isolated and cultured in vitro. The miR-23b-3p overexpression plasmid pSi-miR-23b-3p and its negative no-load plasmid pSi-NC, the MEF2C lentivirus overexpression plasmid Lv-MEF2C and the no-load plasmid Lv-NC were transfected into hRIFs cells, and the cells were induced to osteogenic differentiation for 14 days. The activity of alkaline phosphatase(ALP) was determined by ELISA. Alizarin red staining was used to observe the formation of mineralized nodules. The expression levels of miR-23b-3p and MEF2C, OCN, OPN, Runx2 mRNA were detected by qRT-PCR. The expression level of MEF2C protein was detected by Western blot. Dual luciferase reporter gene assay verified the targeting relationship between miR-23b-3p and MEF2C. Results (1) Compared with the nRP group, miR-23b-3p was low expressed and MEF2C, OCN, OPN, and Runx2 were highly expressed in the RP group.(2) 14 days after osteogenic induction of hRIFs cells, the activity of ALP in cells significantly increased, the ability of cells to form mineralized nodules was enhanced, the expression level of miR-23b-3p significantly decreased, the mRNA expression levels of MEF2C, OCN, OPN, and Runx2 significantly increased, and the expression level of MEF2C protein significantly increased.(3) Overexpression of miR-23b-3p decreased the activity of ALP in hRIFs cells after osteogenic induction, inhibited the formation of mineralized nodules in cells, and down-regulated the mRNA expression levels of OCN, OPN, and Runx2 in cells.(4) Overexpression of MEF2C reversed the inhibitory effect of miR-23b-3p overexpression on osteoblast differentiation of hRIFs cells.(5) MEF2C was the downstream target gene of miR-23b-3p. Conclusion miR-23b-3p is underexpressed in RP tissues and during osteoblastic differentiation of hRIFs cells. Up-regulation of miR-23b-3p inhibits osteogenic differentiation of hRIFs cells, and its mechanism may be related to targeted silencing MEF2C.

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Objective To investigate the effect of bone marrow mesenchymal stem cells(BMSCs) on the inflammatory response of lipopolysaccharide(LPS) induced acute lung injury(ALI) in mice. Methods 32 SPF KM mice, aged 4 weeks were randomly divided into four groups, control group, LPS group, dexamethasone treatment group(LPS+DEX) and BMSCs treatment group(LPS+BMSCs). The latter three groups were injected with LPS by tracheal puncture to establish mouse ALI model 24 h after modeling, BMSCs isolated from the femur of mice were injected into the caudal vein, and DEX were injected into caudal vein at the same time in LPS+DEX group for 3 consecutive days. On the 4th day after cell transplantation or 24 h after DEX injection, the survival quantity of mice was recorded, lung function was detected, and the wet/dry weight ratio(W/D) of lung was measured. Then inflammatory cells in bronchoalveolar lavage fluid(BALF), lung pathological changes and serum inflammatory cytokines were collected. Green fluorescent protein(GFP) staining was used to observe the homing of BMSCs in lung tissues. The mRNA and protein expression of TLR4, MyD88 and NF-κB in lung tissues were detected by RT-PCR and Western blot assay respectively. Results Compared with the control group, LPS model group showed decreased lung function, significantly increase in the W/D weight ratio of lung, inflammatory cytokines in serum and inflammatory cells in BALF, and severe damage in lung tissue. Compared with LPS group, LPS+DEX group and LPS+BMSCs group showed improved lung function, reduced lung tissue damage, significantly decrease in the W/D weight ratio of lung, inflammatory cytokines in serum and inflammatory cells in BALF. And the expression of TLR4-MyD88-NF-κB signaling pathway-related genes and proteins decreased, the survival quantity increased. Conclusion Homologous BMSCs transplantation can effectively treat LPS-induced acute lung injury, and the mechanism may be related to the regulation of TLR4-MyD88-NF-κB signaling pathway and the reduction of inflammatory response. These findings provide the experimental basis for BMSCs homologous transplantation for ALI.

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Objective To investigate the possible mechanism of circ RNA in the pathogenesis of epilepsy. Methods In this study, circRNA expression profiles in peripheral venous blood of epileptic patients and healthy controls were studied by using circRNA gene chip technology, and differentially expressed circrnas were screened. Bioinformatics databases such as circPrimer, circMir and TargetScan were used to analyze its possible role in epilepsy and adenovirus vector was constructed. Thirty male adult C57BL/6 mice were randomly divided into control group, empty vector group and circ＿0017178 overexpressed group(10 mice/group). Normal saline, empty plasmid adenovirus vector and circ＿0017178 overexpressed adenovirus vector were injected into the hippocampus of the three groups respectively. The change of animal behavior of mice in each group was observed after the establishment of pentetrazole epilepsy model, and the apoptosis of hippocampal tissue cells of mice in each group was analyzed by Tunel staining. Results The results of gene microarray showed that circ＿0069272, circ＿0033065, circ＿0017178, circ＿0073442, circ＿0033063 and circ＿0049415 in epilepsy group were up-regulated significantly compared with the control group. And circ＿0083773, circ＿0088262, circ＿0016396 decreased significantly. Circ＿0017178 might be the most associated with epilepsy. Through bioanalysis, circ＿0017178 might regulate 39 epilepsy genes by combining 20 miRNA and possess potential m6A, IRES and ORF1 binding sites. In the experiment of pentatetrazole epileptic mice, compared with the empty carrier group and the control group, the latency period of epilepsy in the circ＿0017178 overexpression group was shortened(P<0.05), the seizure time was prolonged(P<0.05), and the seizure frequency increased(P<0.05). There was no statistical significance between the empty carrier group and the control group(P>0.05). In animal experiments, compared with the empty vector group and the control group, the apoptosis degree of hippocampal tissue of epileptic mice in the circ＿0017178 overexpression group significantly increased(P<0.05), but there was no statistical significance between the empty vector group and the control group(P>0.05). Conclusion Circ＿0017178 significantly increases in the expression profile of peripheral blood mononuclear cells in patients with epilepsy, which may act as a "molecular sponge" of miRNA in epilepsy and has the potential of m6A methylation and protein translation. Circ＿0017178 may increase the susceptibility and severity of epilepsy by promoting apoptosis in penetetrazole epileptic mice.

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Objective To investigate the mechanism by which Nicotinamide adenine dinucleotide(NADH) regulates anti-tuberculosis drug-induced liver injury and apoptosis in mice through SIRT1/Nrf2 pathway. Methods Twenty-four six-week-old SPF male mice were randomly divided into four groups according to body weight, ADLI group[90 mg/(kg·d) Isoniazid, 135 mg/(kg·d) Rifampicin, 315 mg/(kg·d) Pyrazinamide were given by gavage], control group[thesame volume of saline was given by gavage as antituberculosis drug-induced liver injury(ADLI) group], NADH group(30 mg/kg NADH wasgiven by gavage on the basis of control group) and NADH intervention group(30 mg/kg NADH wasgiven by gavage on the basis of ADLI group), with sixmice in each group. They were gavaged continuously for seven days, and their seruand liver tissues were collected. The mRNA and protein expression of silence information regulator 1(SIRT1), nuclear factor erythroid 2-related factor 2(Nrf2) in SIRT1/Nrf2 pathway, apoptosis indicators B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax) and caspase-3 were detected by qRT-PCR and Western blot, respectively. HE staining was performed to observe the morphology of liver tissue. The liver was weighedandthe liver index was obtained by dividingweight by body weight.The levels of glutamate aminotransferase( ALT), aspartate aminotransferase( AST) and lactate dehydrogenase(LDH), which are indicators of liver injury, were detected by microplate method.Results Compared with control group, the protein and mRNA expression of SIRT1, Nrf2decreased significantly in ADLI group. Liver tissue structure wasdisturbed, hepatocytes were obviously swollen, and their boundary was unclear. The weight of mice decreased, but liver index increased. The mRNA and protein expression level of anti-apoptotic factor Bcl-2 decreased,while that of Bax and caspase-3 was raised. The level of ALT, AST and LDH were also elevated. The differences above were statistically significant(P<0. 05). Compared with ADLI group, the protein and mRNA expression of SIRT1, Nrf2 were higher after NADH intervention. Liver tissue structure became clear, and hepatocytes were polygonal. The protein and mRNA expression of anti-apoptosis factor Bcl-2 was elevated and while that of Bax and caspase-3 was lower. The weight of mice increased and liver index decreased. The expression of ALT, AST and LDH decreased. The differences above were statistically significant(P<0. 05).Conclusion NADH may alleviate anti-tuberculosis drug-induced liver injury and apoptosis in mice by regulating SIRT1/Nrf2 pathway.

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Objective To investigate whether Andrographolide(AG) can alleviate intestinal injury in sepsis by activating the SLC7A11/GPX4 axis in ferroptosis. Methods Forty rats were randomly divided into sham group(sham group), sepsis group(CLP group), AG low, medium and high dose groups(5, 10 and 20 mg/kg). HE staining was used to observe the pathological changes of Intestinal tract. ELISA method was used to determine Interleukin 6(IL-6), tumour necrosis factor α(TNF-α), intestinal fatty acid binding protein(I-FABP), D-lactate content. The mechanism of ferroptosis was explored with AG high dose group(AG20 group), forty rats were randomly divided into sham group, CLP group, ferroptosis inhibitor(Fer-1) group, AG20+Fer-1 group. HE staining and transmission electron microscopy were used to observe the pathological changes of Intestinal tract. The kits were used to determine oxidative stress MDA, GSH levels and Fe3+content. Western blot was used to detect the protein levels of solute carrier family 7 member 11(SLC7A11),glutathione peroxidase 4(GPX4), and ferritin heavy polypeptide 1(FTH-1). Results Compared with the sham group, the CLP group showed severe morphological damage to the small intestine, with significantly higher levels of inflammation, I-FABP and D-lactate(allP<0.05), the AG group reversed these changes in a concentration-dependent manner(allP<0.05). Compared with the CLP group, the AG20 and Fer-1 groups showed improved pathological damage to the small intestine, with lower levels of MDA and Fe3+and higher levels of GSH, SLC7A11, GPX4 and FTH-1 protein expression increased(allP<0.05), and pathological injury and oxidative stress were reduced in the AG20+Fer-1 group, and SLC7A11, GPX4 and FTH-1 protein expression increased more significantly(allP<0.05). Conclusion The mechanism by which AG attenuates intestinal injury in sepsis may be related to SLC7A11/GPX4 axis activation in ferroptosis.

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Objective To investigate the effect of Danhuangsan on high glucose-induced vascular endothelial cell injury based on PINK 1/Parkin signaling pathway, and to explore its specific mechanism. Methods Human umbilical vein endothelial cells were cultured in vitro and randomly divided into control group, growth factor group, Danhuangsan group, high glucose group, high glucose + growth factor group, high glucose + Danhuangsan group, with 3 cases in each group, treated for 48 hours. Cell scratch test was used to detect cell migration rate, and Transwell test was used to detect cell invasion rate. Immunofluorescence was used to detect the expression of anti-apoptotic protein Bcl-2, Beclin-1 and pro-apoptotic protein Bax. Western blot was used to detect the protein expression levels of PINK 1, Parkin and LC 3-Ⅱ. Results Cell scratch test and Transwell test showed that under normal environment and high glucose treatment, Danhuangsan could reduce the cell migration and invasion rate(P<0.05).Immunofluorescence assay showed that under normal environment and high glucose treatment, Danhuangsan up-regulated the expression levels of Bcl-2 and Beclin-1 protein in cells(P<0.05).Western blot results showed that under normal environment and high glucose treatment, Danhuangsan increased the protein expression levels of PINK 1, Parkin and LC 3-Ⅱ in cells and down-regulated the expression levels of Bax protein(P<0. 05),and the effects of Danhuang powder were significantly better than those of blank serum and growth factor(P<0. 05).Conclusion Danhuangsan can alleviate high glucose-induced endothelial cell injury by activating PINK 1/Parkin pathway, and the mechanism may be related to promoting mitophagy and enhancing the repair of damage.

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Objective To investigate the role and possible mechanism of curcumin(Cur) regulating Peroxiredoxin-6(Prdx6) expression in inhibiting Erastin-induced ferroptosis in C28/I2 chondrocytes. Methods Safranin O/Fast Green and hematoxylin-eosin(HE) staining were performed to observe the pathological changes in the knee joint of rats with osteoarthritis(OA). The expression levels of Prdx6 and GPX4 proteins in cartilage tissues with OA were detected by immunohistochemistry and Western blot. C28/I2 chondrocytes were treated with different concentrations of Cur, cell viability was detected by thiazolyl blue tetrazolium bromide(MTT) assay and cytotoxicity was measured by lactic dehydrogenase(LDH) assay. The production of lipid reactive oxygen species(ROS) in chondrocytes was detected by flow cytometry, and the total glutathione(GSH) assay kit was used to detect the GSH level in chondrocytes. Western blot was performed to detect the expression level of Prdx6 and ferroptosis-related proteins in chondrocytes. The interaction between the Cur molecule and Prdx6 was analyzed through the molecular docking technique. Results During the OA progression, OA rats and OA patients showed pathological changes such as damage to the cartilage and a decrease in the number of chondrocytes. The expression levels of Prdx6 and GPX4 were reduced in the cartilage tissues of OA patients compared with healthy people. Further study revealed that the treatment of Erastin-induced ferroptosis in C28/I2 chondrocytes in a mouse model with 20 μmol/L of Cur could improve cell viability, decrease cytotoxicity, inhibit lipid ROS production, and increase the level of intracellular GSH. Western blot results showed decreased expression of Prdx6, SLC7A11, FTH, and GPX4 and increased expression of ACSL4. In addition, Cur molecules interacted with Prdx6 protein by van der Waals forces and π bond. Conclusion Cur may inhibit Erastin-induced ferroptosis in C28/I2 chondrocytes by upregulating the Prdx6 expression level.

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Objective To analyze the risk factors of repeated admissions for community-acquired pneumonia(CAP)in adults, and to build a nomogram model to predict individual risk. Methods A total of 2 306 adult hospitalized patients with CAP in Beijing Shijitan Hospital affiliated to Capital Medical University from January 2018 to December 2020 were retrospectively selected and divided into repeated admission group and control group according to whether they were readmitted within one year after discharge. Univariate logistic analysis and multivariate logistic analysis were used to determine the risk factors. The risk factors were introduced into R 3.5.3 software to construct the nomogram prediction model. The calibration curve was drawn and the Hosmer-Lemeshow goodness of fit test was performed to evaluate the accuracy of the nomogram prediction model. The receiver operating characteristic(ROC) curve was drawn to evaluate the discrimination of the nomogram prediction model. The decision analysis curve was drawn to measure patient benefits. Results The age, gender, length of stay, total score of comorbidity index, use of special grade antibiotics, history of blood transfusion, and Vaccination history were risk factors of repeated hospital admissions for CAP in adults. The nomogram prediction model of adult CAP repeated admission was constructed based on the above risk factors. The Hosmer-Lemeshow goodness of fit test showed that the fitting effect of the nomogram prediction model was good(χ2=8.873,P=0.353). The ROC curve analysis showed that the area under the curve of the test dataset was 0.775. The results of the decision analysis curve showed that when the threshold was 0.21, the model could generate a net profit of 0.104. Conclusion The nomogram model established in this study has good discrimination and accuracy in predicting the risk of adult CAP repeated admissions and has high clinical application value.

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Objective To investigate the clinical and pathological features and risk factors of primary IgA nephropathy(IgAN) with foot process effacement(FPE). Methods The clinical and Oxford-type pathological data of 300 patients diagnosed with primary IgAN by renal biopsy were retrospectively analyzed, and the influential factors of IgAN foot process fusion were analyzed by multivariate logistic regression with significant clinical indicators. Results 300 cases of adult IgAN diagnosed by renal puncture biopsy were included, the extensive FPE group accounted for 15%. 156 cases(52%) were female and 144 cases(48%) were male. The median age of onset was 36(30,50) years. The median duration of renal biopsy was 8(1,24) months. The proportion of nephrotic syndrome in the extensive fusion group was higher(55.6%vs6.7%,P<0.05). There was no significant difference in the proportion of IgAN with hypertension among different degrees of FPE(P=0.092), but the systolic and diastolic blood pressure in the extensive FPE group were higher than those in the mild FPE group(P<0.05). The levels of total cholesterol(TC), triglyceride(TG), low-density lipoprotein cholesterol(LDL-c), and 24-hour urinary protein in the extensive FPE group were higher(P<0.05), but the levels of albumin, estimated glomerular filtration rate(eGFR) and hyperuricemia were low(P<0.05). There were no significant differences in hemoglobin, creatinine, and uric acid levels between the two groups(P>0.05). There was a higher proportion of endothelial cell proliferation(E1), segmental sclerosis or adhesion(S1), and cellular or cellular fibrous crescents(C1-2) in the extensive FPE group(P<0.05), while there was no significant difference in tubular atrophy or interstitial fibrosis(T1-2) between the two groups(P>0.05). Univariate logistic regression analysis showed that diastolic blood pressure, eGFR, TC, TG, and LDL-c were associated with extensive FPE in IgAN patients. Multivariate logistic regression analysis showed that elevated TC(OR=2.135,95%CI1.095-4.164,P=0.026) was an independent risk factor for extensive fusion of the foot process. Conclusion Compared with mild FPE, IgAN patients with extensive FPE had higher rates of blood pressure, blood lipid, nephrotic syndrome and hyperuricemia, slightly worse renal function, and more severe pathological manifestations of the Oxford-type. Elevated TC is an independent risk factor for extensive FPE in IgAN patients.

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Objective To explore whether the capacity of decision-making under ambiguity in adult patients with moyamoya disease(MMD) is impaired and its association with executive function. Methods Neuropsychological scales were used to measure the executive function of forty-one adult patients with MMD and forty-one healthy controls(HC), The Iowa Gambling Task(IGT) was utilized to study the capacity of decision-making under ambiguity of the two groups. Correlation analysis was performed between the two types of data. Results (1) The total number of favorable choices in the MMD group was significantly lower than that in the HC group, with a statistically significant difference(Z=-2.782,P<0.01), and the total number of unfavorable choices was significantly higher than that of the controls, with a statistically significant difference(Z=-2.782,P<0.01). The results of ANOVA showed that the net residual value of Block4 and Block5 in MMD group was lower than that of Block4 and Block5 in HC group, respectively, and the differences were statistically significant(t=-3.433,P=0.001;t=-5.271,P<0.001), the net residual value of Block1 was higher than that of Block1 in HC group, the difference was statistically significant(t=2.715,P=0.008).(2) Spearman correlation analysis revealed no association between the net score of IGT, the total number of favorable choices, the total number of unfavorable choices, and executive function. Conclusion The capacity of decision-making under ambiguity in adult patients with MMD is impaired possibly, which is not correlated with executive cognition.

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Objective To construct and appraise a new model for predicting the prognosis of rectal cancer patients using the Lasso-Cox strategy. Methods The clinical pathological data of 599 rectal cancer patients who underwent radical resection were analyzed. Comparison between groups, Lasso and Cox regression were used to select variables and construct a model, and its discrimination, consistency, and clinical benefits were appraised by the receiver operating characteristic(ROC), calibration curve, and decision curve analysis. Results Comparison between groups showed that age, body mass index(BMI), preoperational nutrition status, carbohydrate antigen199(CA199), preoperative chemotherapy, intraoperative blood transfusion, vascular or nerve invasion, cancer nodules, pathologic T, N, and TNM stages, tumor recurrence or metastasis, radiotherapy and postoperative survival time were associated with grouping of death or survival in rectal cancer patients. Among them, 8 variables were selected by lasso and contained into the Cox regression model. Age(HR=1.04,P<0.05), BMI(HR=0.89,P<0.05), blood transfusion(HR=2.29,P<0.05), postoperative chemotherapy(HR=0.16,P<0.01), recurrence(HR=43.67,P<0.01), and metastasis(HR=2.75,P<0.05) were identified as independent prognostic factors, which were used to construct a nomogram model. The area under the curve(AUC) and the 95% confidence interval of the receiver operating characteristic(ROC) curve of the predictive model was 0.95(0.91-0.99),P<0.01. The predicted probability of 1-year and 3-year survival was close to the actual probability. The DCA curve of the model was far away from a decision line parallel to the X-axis and another line with a negative slope. Conclusion The newly established nomogram has good discrimination, consistency and clinical benefits, which help predict the prognosis of rectal cancer after surgery.