Objective To compare the effects of non-invasive intermittent oxygen-driven nebulization,non-invasive intermittent air-driven nebulization,and non-invasive simultaneous air-driven nebulization on the dynamic changes of partial pressure of carbon dioxide(PtCO2),pulse oxygen saturation(SpO2),and heart rate during nebulization,as well as the therapeutic effects in patients with acute exacerbation of chronic obstructive pulmonary disease(COPD).Methods A total of 99 patients with acute exacerbation of COPD requiring non-invasive mechanical ventilation and nebulization were randomly divided into a control group,an experimental group one,and an experimental group two,with 33 patients in each group.The control group was given non-invasive intermittent oxygen-driven nebulization,the experimental group one was given non-invasive intermittent air-driven nebulization,and the experimental group two was given non-invasive simultaneous air-driven nebulization.The changes in PtCO2,SpO2,and heart rate at 0 min,5 min,10 min,15 min during nebulization,5 min,10 min,and 15 min after nebulization were recorded.The values of arterial blood gas PaCO2 and PaO2 were recorded every morning from before treatment to the 7th day of treatment.The length of hospital stay in the three groups was also recorded.Results The comparison of PtCO2 during nebulization among the three groups showed that there were statistically significant differences in the main effect of time and the interaction effect of time and group(P<0.001).The PtCO2 values in the control group showed a linear relationship with time(F=10.166,P=0.003),increasing over time;the PtCO2 values in the experimental group one showed a linear relationship with time(F=10.544,P=0.003),decreasing over time;the PtCO2 values in the experimental group two showed a linear rela-tionship with time(F=20.003,P<0.001),decreasing over time.A one-way ANOVA was conducted on the PtCO2 values at each time point in the three groups.The PtCO2 value at 15 min of nebulization in the control group was higher than that in the experimental group one and the experimental group two.There were statistically signifi-cant differences in the difference in PtCO2 before and after nebulization(dPtCO2)between the experimental group one and the experimental group two and the control group(P<0.05).A one-way ANOVA was conducted on the PtCO2 values at each time point during the observation period after nebulization.The results showed that there were statistically significant differences in PtCO2 at 0 min and 5 min after nebulization among the three groups(P<0.05),while there were no statistically significant differences in PtCO2 at 10 min and 15 min after nebulization among the three groups(P>0.05).The comparison of SPO2 during nebulization among the three groups showed that there were statistically significant differences in the interaction effect of time and group(P<0.05).The SPO2 values in the experimental group one decreased over time.The SPO2 values at 10 min and 15 min of nebulization in the control group were higher than those in the experimental group one and the experimental group two.All three groups could improve PaCO2 in arterial blood gas with the treatment days(P<0.05).Conclusions All three nebu-lization treatment methods can achieve good therapeutic effects.However,non-invasive intermittent oxygen-driven nebulization can increase PtCO2 and SPO2 during nebulization;non-invasive intermittent air-driven nebulization can decrease PtCO2 and SPO2 during nebulization;non-invasive simultaneous air-driven nebulization can decrease PtCO2 and maintain stable SPO2 during nebulization.Therefore,non-invasive simultaneous air-driven nebulization is a relatively safer nebulization inhalation method and is worthy of clinical promotion.

Aim To identify the underlying target of bullatine A(BA)against rheumatoid arthritis(RA)u-sing limited proteolysis-small molecule mapping(LiP-SMap)drug target proteomics and to provide a scientif-ic basis for clinical application of Aconiti brachypodi Radix in the treatment of RA.Methods LiP-SMap drug target proteomics was employed to perform bioin-formatics analysis for comparing and validating the dif-ferential protein expression after BA intervention.A collagen-induced arthritis(CIA)model was estab-lished in DBA/1 mice using bovine type Ⅱ collagen.The mice were then divided into the CIA model group,methotrexate-positive control group(MTX group),and BA groups(10 mg·kg-1 and 20 mg·kg-1)based on their clinical scores.After drug intervention,the thera-peutic efficacy against RA was assessed by joint index scores and foot thickness measurements.Histopatholog-ical changes in the arthritic joints of CIA mice were e-valuated using hematoxylin and eosin(HE)staining.Enzyme-linked immunosorbent assay(ELISA)was employed to detect inflammatory cytokines interleukin-17(IL-17)and total IgG and IgG3 anti-collagen-spe-cific antibodies levels from the serum of CIA mice.Flow cytometry was used to detect the expression levels of intracellular Th17 cells(IL-17+CD4+T cells)and Th1 cells(IFN-γ+CD4+T cells).Fluorescent quanti-tative PCR was performed to detect the expression of genes related to differential proteins.Results The proteomic analysis identified Serpinb1a as a protein with strong binding affinity to BA,and KEGG enrich-ment analysis indicated IL-17 signaling pathway was a crucial pathway of BA in against RA.BA treatment significantly reduced clinical scores and foot thickness,improved local arthritis symptoms in CIA mice,and al-leviated inflammatory cell infiltration into arthritic joints(P＜0.05).Differential protein validation re-sults showed that BA had strong affinity with Serpinb1a(-5.92 kJ·mol-1)and downregulated the expres-sion of Serpinb1a mRNA.Furthermore,the administra-tion of BA markedly reduced serum IL-17 A levels from CIA mice,inhibited the expression of intracellular IL-17 A and IFN-γ cytokines in splenic CD4+T cells(P＜0.05),and significantly downregulated the transcrip-tional expression of IL-17F(P＜0.05).Conclusion BA exhibits therapeutic effects on collagen-induced arthritis,and its mechanism of action may involve the regulation of Serpinb1a and the IL-17 signaling path-way.

Gastric cancer remains one of the most prevalent and lethal malignancies of the digestive tract worldwide,underscoring the urgent need for more effective targeted therapeutic strategies.Poly(ADP-ri-bose)polymerase(PARP)inhibitors have demonstrated remarkable efficacy in tumors with homologous recombination repair(HRR)deficiency;however,their clinical application in gastric cancer remains limited.Clinical evidence suggests that patients harboring Helicobacter pylori infection in combination with HRR gene mutations exhibit a significantly elevated risk of developing gastric cancer,thereby supporting the potential benefit of PARP inhibition in this setting.In this study,a kinase inhibitor library was screened in combination with the PARP inhibitor olaparib in gastric cancer cells.And we identify the cy-clin-dependent kinase 8/19(CDK8/19)inhibitor Senexin A as a compound that synergistically enhances the cytotoxic effect of PARP inhibition(P<0.05).Phenotypic validation using CCK-8 and colony for-mation assays demonstrated that the combination treatment significantly suppressed cellular proliferation and clonogenic potential compared to either monotherapy(P<0.0001).Mechanistically,alkaline comet assays revealed a significant increase in DNA damage in the combination treatment group relative to either single-agent group(P<0.0001),suggesting that the synergistic effect results from the exacerbation of DNA damage via impaired DNA repair mechanisms.In addition,treatment with CDK8/19 inhibitors a-lone markedly increased the formation of γH2AX and 53BP1 foci in irradiated gastric cancer cells(P<0.0001),indicating inhibition of DNA damage repair pathways.Transcriptome sequencing further re-vealed that CDK8/19 inhibition impacts critical cellular pathways,including DNA repair,cell cycle reg-ulation,and RNA splicing.Co-immunoprecipitation assays confirmed that inhibition of CDK8/19 kinase activity significantly reduces the phosphorylation level of PARP1,suggesting a potential regulatory inter-action.Immunohistochemical analysis of tumor and adjacent non-tumor tissues from gastric cancer pa-tients demonstrated that CDK8 is significantly overexpressed in tumor tissues,supporting its potential as both a prognostic biomarker and a therapeutic target.Collectively,this study elucidates a mechanistic ba-sis by which CDK8/19 inhibition enhances the sensitivity of gastric cancer cells to PARP inhibitors.These findings provide a strong rationale for the combined use of CDK8/19 and PARP inhibitors as a tar-geted therapeutic strategy and offer promising translational implications for advancing personalized medi-cine in gastric cancer treatment.

Gastric cancer remains one of the most prevalent and lethal malignancies of the digestive tract worldwide,underscoring the urgent need for more effective targeted therapeutic strategies.Poly(ADP-ri-bose)polymerase(PARP)inhibitors have demonstrated remarkable efficacy in tumors with homologous recombination repair(HRR)deficiency;however,their clinical application in gastric cancer remains limited.Clinical evidence suggests that patients harboring Helicobacter pylori infection in combination with HRR gene mutations exhibit a significantly elevated risk of developing gastric cancer,thereby supporting the potential benefit of PARP inhibition in this setting.In this study,a kinase inhibitor library was screened in combination with the PARP inhibitor olaparib in gastric cancer cells.And we identify the cy-clin-dependent kinase 8/19(CDK8/19)inhibitor Senexin A as a compound that synergistically enhances the cytotoxic effect of PARP inhibition(P<0.05).Phenotypic validation using CCK-8 and colony for-mation assays demonstrated that the combination treatment significantly suppressed cellular proliferation and clonogenic potential compared to either monotherapy(P<0.0001).Mechanistically,alkaline comet assays revealed a significant increase in DNA damage in the combination treatment group relative to either single-agent group(P<0.0001),suggesting that the synergistic effect results from the exacerbation of DNA damage via impaired DNA repair mechanisms.In addition,treatment with CDK8/19 inhibitors a-lone markedly increased the formation of γH2AX and 53BP1 foci in irradiated gastric cancer cells(P<0.0001),indicating inhibition of DNA damage repair pathways.Transcriptome sequencing further re-vealed that CDK8/19 inhibition impacts critical cellular pathways,including DNA repair,cell cycle reg-ulation,and RNA splicing.Co-immunoprecipitation assays confirmed that inhibition of CDK8/19 kinase activity significantly reduces the phosphorylation level of PARP1,suggesting a potential regulatory inter-action.Immunohistochemical analysis of tumor and adjacent non-tumor tissues from gastric cancer pa-tients demonstrated that CDK8 is significantly overexpressed in tumor tissues,supporting its potential as both a prognostic biomarker and a therapeutic target.Collectively,this study elucidates a mechanistic ba-sis by which CDK8/19 inhibition enhances the sensitivity of gastric cancer cells to PARP inhibitors.These findings provide a strong rationale for the combined use of CDK8/19 and PARP inhibitors as a tar-geted therapeutic strategy and offer promising translational implications for advancing personalized medi-cine in gastric cancer treatment.

Aim To identify the underlying target of bullatine A(BA)against rheumatoid arthritis(RA)u-sing limited proteolysis-small molecule mapping(LiP-SMap)drug target proteomics and to provide a scientif-ic basis for clinical application of Aconiti brachypodi Radix in the treatment of RA.Methods LiP-SMap drug target proteomics was employed to perform bioin-formatics analysis for comparing and validating the dif-ferential protein expression after BA intervention.A collagen-induced arthritis(CIA)model was estab-lished in DBA/1 mice using bovine type Ⅱ collagen.The mice were then divided into the CIA model group,methotrexate-positive control group(MTX group),and BA groups(10 mg·kg-1 and 20 mg·kg-1)based on their clinical scores.After drug intervention,the thera-peutic efficacy against RA was assessed by joint index scores and foot thickness measurements.Histopatholog-ical changes in the arthritic joints of CIA mice were e-valuated using hematoxylin and eosin(HE)staining.Enzyme-linked immunosorbent assay(ELISA)was employed to detect inflammatory cytokines interleukin-17(IL-17)and total IgG and IgG3 anti-collagen-spe-cific antibodies levels from the serum of CIA mice.Flow cytometry was used to detect the expression levels of intracellular Th17 cells(IL-17+CD4+T cells)and Th1 cells(IFN-γ+CD4+T cells).Fluorescent quanti-tative PCR was performed to detect the expression of genes related to differential proteins.Results The proteomic analysis identified Serpinb1a as a protein with strong binding affinity to BA,and KEGG enrich-ment analysis indicated IL-17 signaling pathway was a crucial pathway of BA in against RA.BA treatment significantly reduced clinical scores and foot thickness,improved local arthritis symptoms in CIA mice,and al-leviated inflammatory cell infiltration into arthritic joints(P＜0.05).Differential protein validation re-sults showed that BA had strong affinity with Serpinb1a(-5.92 kJ·mol-1)and downregulated the expres-sion of Serpinb1a mRNA.Furthermore,the administra-tion of BA markedly reduced serum IL-17 A levels from CIA mice,inhibited the expression of intracellular IL-17 A and IFN-γ cytokines in splenic CD4+T cells(P＜0.05),and significantly downregulated the transcrip-tional expression of IL-17F(P＜0.05).Conclusion BA exhibits therapeutic effects on collagen-induced arthritis,and its mechanism of action may involve the regulation of Serpinb1a and the IL-17 signaling path-way.

Objective To compare the effects of non-invasive intermittent oxygen-driven nebulization,non-invasive intermittent air-driven nebulization,and non-invasive simultaneous air-driven nebulization on the dynamic changes of partial pressure of carbon dioxide(PtCO2),pulse oxygen saturation(SpO2),and heart rate during nebulization,as well as the therapeutic effects in patients with acute exacerbation of chronic obstructive pulmonary disease(COPD).Methods A total of 99 patients with acute exacerbation of COPD requiring non-invasive mechanical ventilation and nebulization were randomly divided into a control group,an experimental group one,and an experimental group two,with 33 patients in each group.The control group was given non-invasive intermittent oxygen-driven nebulization,the experimental group one was given non-invasive intermittent air-driven nebulization,and the experimental group two was given non-invasive simultaneous air-driven nebulization.The changes in PtCO2,SpO2,and heart rate at 0 min,5 min,10 min,15 min during nebulization,5 min,10 min,and 15 min after nebulization were recorded.The values of arterial blood gas PaCO2 and PaO2 were recorded every morning from before treatment to the 7th day of treatment.The length of hospital stay in the three groups was also recorded.Results The comparison of PtCO2 during nebulization among the three groups showed that there were statistically significant differences in the main effect of time and the interaction effect of time and group(P<0.001).The PtCO2 values in the control group showed a linear relationship with time(F=10.166,P=0.003),increasing over time;the PtCO2 values in the experimental group one showed a linear relationship with time(F=10.544,P=0.003),decreasing over time;the PtCO2 values in the experimental group two showed a linear rela-tionship with time(F=20.003,P<0.001),decreasing over time.A one-way ANOVA was conducted on the PtCO2 values at each time point in the three groups.The PtCO2 value at 15 min of nebulization in the control group was higher than that in the experimental group one and the experimental group two.There were statistically signifi-cant differences in the difference in PtCO2 before and after nebulization(dPtCO2)between the experimental group one and the experimental group two and the control group(P<0.05).A one-way ANOVA was conducted on the PtCO2 values at each time point during the observation period after nebulization.The results showed that there were statistically significant differences in PtCO2 at 0 min and 5 min after nebulization among the three groups(P<0.05),while there were no statistically significant differences in PtCO2 at 10 min and 15 min after nebulization among the three groups(P>0.05).The comparison of SPO2 during nebulization among the three groups showed that there were statistically significant differences in the interaction effect of time and group(P<0.05).The SPO2 values in the experimental group one decreased over time.The SPO2 values at 10 min and 15 min of nebulization in the control group were higher than those in the experimental group one and the experimental group two.All three groups could improve PaCO2 in arterial blood gas with the treatment days(P<0.05).Conclusions All three nebu-lization treatment methods can achieve good therapeutic effects.However,non-invasive intermittent oxygen-driven nebulization can increase PtCO2 and SPO2 during nebulization;non-invasive intermittent air-driven nebulization can decrease PtCO2 and SPO2 during nebulization;non-invasive simultaneous air-driven nebulization can decrease PtCO2 and maintain stable SPO2 during nebulization.Therefore,non-invasive simultaneous air-driven nebulization is a relatively safer nebulization inhalation method and is worthy of clinical promotion.

Aim To investigate the therapeutic effect of the MW-9 on ulcerative colitis(UC)and reveal the underlying mechanism, so as to provide a scientific guidance for the MW-9 treatment of UC. Methods The model of lipopolysaccharide(LPS)-stimulated RAW264.7 macrophage cells was established. The effect of MW-9 on RAW264.7 cells viability was detected by MTT assay. The levels of nitric oxide(NO)in RAW264.7 macrophages were measured by Griess assay. Cell supernatants and serum levels of inflammatory cytokines containing IL-6, TNF-α and IL-1β were determined by ELISA kits. Dextran sulfate sodium(DSS)-induced UC model in mice was established and body weight of mice in each group was measured. The histopathological damage degree of colonic tissue was assessed by HE staining. The protein expression of p-p38, p-ERK1/2 and p-JNK was detected by Western blot. Results MW-9 intervention significantly inhibited NO release in RAW264.7 macrophages with IC50 of 20.47 mg·L-1 and decreased the overproduction of inflammatory factors IL-6, IL-1β and TNF-α(P<0.05). MW-9 had no cytotoxicity at the concentrations below 6 mg·L-1. After MW-9 treatment, mouse body weight was gradually reduced, and the serum IL-6, IL-1β and TNF-α levels were significantly down-regulated. Compared with the model group, MW-9 significantly decreased the expression of p-p38 and p-ERK1/2 protein. Conclusions MW-9 has significant anti-inflammatory activities both in vitro and in vivo, and its underlying mechanism for the treatment of UC may be associated with the inhibition of MAPK signaling pathway.

Aim To investigate the mechanisms of Ke-chuanting granules(KCT)inhibiting the IL-33/ILC2s pathway and pathogenic T cells to intervene in allergic airway inflammation.Methods Network pharmacolo-gy was utilized to analyze the potential targets and mechanisms of KCT-treated asthma.Allergic asthma models were induced in mice using OVA.Lung histo-pathology was conducted to observe injury changes.ELISA and quantitative PCR were utilized to measure key inflammatory factors and their mRNA expression levels in Th2-type asthma.Western blot was used to detect the phosphorylation levels of relevant proteins in the MAPK pathway.Flow cytometry was performed to evaluate the proportions of ILC2s,Th1,Th 17,Th2 and Treg cells.Results Network pharmacology iden-tified 227 main active components and 143 key targets of KCT in treating asthma,primarily enriched in signa-ling pathways such as MAPK and IL-17.Further vali-dation experiments demonstrated that KCT significantly alleviated lung inflammatory injury in asthmatic mice,reduced the number of B cells,production of I L-4,TNF-α and TGF-β,downregulated JNK phosphoryla-tion levels in lung tissue,as well as mRNA levels of Il-33,Bcl11b,Rorα,Tcf-7,Jun,Mapk3 and Mapk14.KCT intervention reduced the numbers of ILC2s and Th 17 cells in lungs and spleens of mice,and inhibited Th2 cell infiltration in lungs.Conclusions KCT ex-hibits therapeutic effects on allergic airway inflamma-tion in asthma,closely associated with the inhibition of the IL-33/ILC2s pathway,pathogenic T cell subsets,and JNK-MAPK signaling pathway.

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.