Objective To investigate the cardiac protective effect of Taohong Tongluo granules on coronary microvascular dysfunction(CMD)rats.Methods SD rats were randomly assigned to sham-operated group,CMD group,nicorandil group(5 mg/kg),or Taohong Tongluo granule group(50 mg/kg).Animals were administered corresponding drugs for 7 d according to the grouping,and the CMD model was prepared 2 h after the last administration.The rat CMD model was induced by injecting embolization microspheres(diameter 40-120 μm,approximately 1 000 microspheres)into the left ventricular cavity.Twenty-four hours after modeling,echocardiography was performed to measure the left ventricular ejection fraction(EF),fractional shortening(FS),and end-diastolic volume(EDV).The damaged myocardial area was assessed by 2,3,5-triphenyltetrazolium chloride(TTC)staining.Myocardial morphological changes were observed by hematoxylin-eosin(H-E)staining.The protein expression levels of NOD-like receptor family pyrin domain containing protein 3(NLRP3),apoptosis-associated speck-like protein(ASC),and cysteine aspartic acid specific protease(caspase)-1 in rat myocardial tissue were detected by immunohistochemical staining and Western blotting.Results Echocardiography showed that the EF and FS values in the Taohong Tongluo granule group,CMD group,and nicorandil group were significantly lower than those in the sham-operated group(all P＜0.001).The EF and FS values in the Taohong Tongluo granule group and nicorandil group were significantly higher than those in the CMD group(all P＜0.01).However,there were no significant differences in EDV among the groups(all P＞0.05).H-E staining showed no abnormalities in the myocardium in the sham-operated group.The CMD group exhibited microsphere embolism in the myocardium,myocardial cell dissolution and rupture,and inflammatory infiltration.The lesions in the nicorandil group and the Taohong Tongluo granule group were relatively milder,and the number of thrombi in both groups was lower than that in the CMD group(both P＜0.01).The results of TTC staining indicated that the areas of damaged myocardial regions in both the nicorandil group and the Taohong Tongluo granule group were smaller than that in the CMD group(P＜0.05 or P＜0.01).Moreover,the area in the Taohong Tongluo granule group was smaller than that in the nicorandil group(P＜0.05).The results of immunohistochemical staining showed that in the CMD model,the expression of ASC and caspase-1 proteins,as well as the number of positive cells for these proteins,was increased and was distributed in myocardial and interstitial cells.The numbers of ASC and caspase-1 positive cells in the Taohong Tongluo granule group were lower than that in the CMD group(both P＜0.01).The Western blotting showed that the expression levels of NLRP3,ASC,and caspase-1 proteins in the Taohong Tongluo granule group were all lower than those in the CMD group(all P＜0.05).Conclusion Taohong Tongluo granules can improve cardiac function,ameliorate hemodynamic parameters,and reduce myocardial infarction area in rats with CMD induced by microsphere embolism.The mechanism is related to the inhibition of myocardial inflammasome activation,thereby attenuating the myocardial injuries.

Objective To construct evaluation indicators for the construction of key specialties in traditional Chinese medicine nursing at the provincial and municipal levels and conduct preliminary verification,providing references for evaluating the level of construction of key specialties in traditional Chinese medicine nursing.Methods From December 2022 to March 2023,based on the Wuli-Shili-Renli system methodology,the content and weight of the evaluation indicators for the construction of key specialties in traditional Chinese medicine nursing at the provincial and municipal levels were determined through literature review,semi-structured interviews,Delphi method,and analytic hierarchy process.Opinion consultation and satisfaction survey were conducted on 46 nursing managers of secondary and above traditional Chinese medicine hospitals in Chongqing in April 2023 to preliminarily verify the application effect of the indicators.Results After 2 rounds of consultation with 16 experts,the questionnaire response rates were 100％and 100％,respectively.The expert authority coefficients were 0.963 and 0.950,respectively,and the coordination coefficients were 0.216～0.307,0.134～0.144,respectively(P＜0.05).Ultimately,an evaluation index for the construction of key specialties in traditional Chinese medicine nursing at the provincial and municipal levels was formed,which includes 3 primary indicators,17 secondary indicators,and 76 tertiary indicators.97.83％nursing managers of hospitals are satisfied with the constructed indicators,believing that the indicator content is clear,comprehensive,professional,and has good practicality.Conclusion The evaluation indicators for the construction of key specialties in traditional Chinese medicine nursing at the provincial and municipal levels are scientific,reliable,which can provide references for the construction of key specialties in traditional Chinese medicine nursing and promote the development of traditional Chinese medicine nursing.

Objective To construct evaluation indicators for the construction of key specialties in traditional Chinese medicine nursing at the provincial and municipal levels and conduct preliminary verification,providing references for evaluating the level of construction of key specialties in traditional Chinese medicine nursing.Methods From December 2022 to March 2023,based on the Wuli-Shili-Renli system methodology,the content and weight of the evaluation indicators for the construction of key specialties in traditional Chinese medicine nursing at the provincial and municipal levels were determined through literature review,semi-structured interviews,Delphi method,and analytic hierarchy process.Opinion consultation and satisfaction survey were conducted on 46 nursing managers of secondary and above traditional Chinese medicine hospitals in Chongqing in April 2023 to preliminarily verify the application effect of the indicators.Results After 2 rounds of consultation with 16 experts,the questionnaire response rates were 100％and 100％,respectively.The expert authority coefficients were 0.963 and 0.950,respectively,and the coordination coefficients were 0.216～0.307,0.134～0.144,respectively(P＜0.05).Ultimately,an evaluation index for the construction of key specialties in traditional Chinese medicine nursing at the provincial and municipal levels was formed,which includes 3 primary indicators,17 secondary indicators,and 76 tertiary indicators.97.83％nursing managers of hospitals are satisfied with the constructed indicators,believing that the indicator content is clear,comprehensive,professional,and has good practicality.Conclusion The evaluation indicators for the construction of key specialties in traditional Chinese medicine nursing at the provincial and municipal levels are scientific,reliable,which can provide references for the construction of key specialties in traditional Chinese medicine nursing and promote the development of traditional Chinese medicine nursing.

This study aims to analyze the differentiating factors between only allergic rhinitis and allergic rhinitis combined with other allergic diseases in pre-school children and to explore the impact of relevant family and maternal factors during pregnancy on pediatric allergic diseases.The study employed an epidemiological cross-sectional survey design, conducted from January to June 2022 at the Helong Street Health Service Center in Baiyun District, Guangzhou City, China. This cross-sectional investigation focused on 15 preschool education centers within the jurisdiction. It encompassed a total of 4 661 pre-school children aged 3-6 years within the district, resulting in the collection of 3 437 valid questionnaires. The study utilized an online survey, covering aspects such as children′s birth conditions, early living environment, maternal lifestyle and emotional state during pregnancy, and paternal information. The questionnaire was designed by an expert team and incorporated advanced logic functions to ensure data accuracy. Diagnosis of allergic diseases included evaluation of symptoms such as rhinitis, asthma, eczema and along with collecting family member′s allergy information. Factors like maternal emotional stress during pregnancy, premature birth, and breastfeeding were also considered. The analysis of frequency differences between groups was conducted using the Chi-square test. The distribution differences between two groups were examined using the t-test or Mann-Whitney U test. Additionally, binary logistic regression analysis was employed to identify risk factors for the occurrence of allergic diseases. To illustrate the distribution and co-occurrence of different allergic diseases in children, upset plots were created. Furthermore, forest plots were utilized to analyze the risk factors. The study included 455 children with only allergic rhinitis and 759 children with rhinitis combined with other allergic diseases. The results showed no significant demographic differences between the two groups. Logistic model results indicated that children with allergic rhinitis who had suffered from severe eczema within the first 12 months had a OR(95% CI):19.818 times (2.670-147.095) higher probability of developing combined allergic diseases than those without eczema, while the probability increased 2.345 times (1.825-3.013) for those with mild to moderate eczema. A higher level of maternal education was also identified as a risk factor, increasing the risk by about 1.5 times. Additionally, the risk of developing combined allergic diseases in children with one allergic parent was OR(95% CI):1.662 times (1.273-2.170) higher than in those with non-allergic parents, and 2.181 times (1.504-3.163) higher if both parents had allergies. Moreover, negative maternal emotional stress during pregnancy was more significant in children with combined allergic diseases. In conclusion, severe eczema in the first 12 months, mild to moderate eczema; allergies in one or both parents; parents′ educational level, household disposable income level; firstborn status; and negative maternal emotions during pregnancy are risk factors for children with allergic rhinitis combined with other allergic diseases.

This study aims to analyze the differentiating factors between only allergic rhinitis and allergic rhinitis combined with other allergic diseases in pre-school children and to explore the impact of relevant family and maternal factors during pregnancy on pediatric allergic diseases.The study employed an epidemiological cross-sectional survey design, conducted from January to June 2022 at the Helong Street Health Service Center in Baiyun District, Guangzhou City, China. This cross-sectional investigation focused on 15 preschool education centers within the jurisdiction. It encompassed a total of 4 661 pre-school children aged 3-6 years within the district, resulting in the collection of 3 437 valid questionnaires. The study utilized an online survey, covering aspects such as children′s birth conditions, early living environment, maternal lifestyle and emotional state during pregnancy, and paternal information. The questionnaire was designed by an expert team and incorporated advanced logic functions to ensure data accuracy. Diagnosis of allergic diseases included evaluation of symptoms such as rhinitis, asthma, eczema and along with collecting family member′s allergy information. Factors like maternal emotional stress during pregnancy, premature birth, and breastfeeding were also considered. The analysis of frequency differences between groups was conducted using the Chi-square test. The distribution differences between two groups were examined using the t-test or Mann-Whitney U test. Additionally, binary logistic regression analysis was employed to identify risk factors for the occurrence of allergic diseases. To illustrate the distribution and co-occurrence of different allergic diseases in children, upset plots were created. Furthermore, forest plots were utilized to analyze the risk factors. The study included 455 children with only allergic rhinitis and 759 children with rhinitis combined with other allergic diseases. The results showed no significant demographic differences between the two groups. Logistic model results indicated that children with allergic rhinitis who had suffered from severe eczema within the first 12 months had a OR(95% CI):19.818 times (2.670-147.095) higher probability of developing combined allergic diseases than those without eczema, while the probability increased 2.345 times (1.825-3.013) for those with mild to moderate eczema. A higher level of maternal education was also identified as a risk factor, increasing the risk by about 1.5 times. Additionally, the risk of developing combined allergic diseases in children with one allergic parent was OR(95% CI):1.662 times (1.273-2.170) higher than in those with non-allergic parents, and 2.181 times (1.504-3.163) higher if both parents had allergies. Moreover, negative maternal emotional stress during pregnancy was more significant in children with combined allergic diseases. In conclusion, severe eczema in the first 12 months, mild to moderate eczema; allergies in one or both parents; parents′ educational level, household disposable income level; firstborn status; and negative maternal emotions during pregnancy are risk factors for children with allergic rhinitis combined with other allergic diseases.

Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival. Targeting CDK9 has shown potent anti-tumor activity in clinical trials among different cancers. However, the study and knowledge on drug resistance to CDK9 inhibitors are very limited. In this study, we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor BAY1251152. Through genomic sequencing, we identified in the kinase domain of CDK9 a mutation L156F, which is also a coding SNP in the CDK9 gene. By knocking in L156F into cancer cells using CRISPR/Cas9, we found that single CDK9 L156F could drive the resistance to CDK9 inhibitors, not only ATP competitive inhibitor but also PROTAC degrader. Mechanistically, CDK9 L156F disrupts the binding with inhibitors due to steric hindrance, further, the mutation affects the thermal stability and catalytic activity of CDK9 protein. To overcome the drug resistance mediated by the CDK9-L156F mutation, we discovered a compound, IHMT-CDK9-36 which showed potent inhibition activity both for CDK9 WT and L156F mutant. Together, we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors.

Angiogenesis is an essential process in tumor growth, invasion and metastasis. VEGF receptor 2 (VEGFR2) inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment. However, most of currently used VEGFR2 kinase inhibitors are multi-target inhibitors which might result in target-associated side effects and therefore limited clinical toleration. Highly selective VEGFR inhibitors are still highly demanded from both basic research and clinical application point of view. Here we report the discovery and characterization of a novel VEGFR2 inhibitor (CHMFL-VEGFR2-002), which exhibited high selectivity among structurally closed kinases including PDGFRs, FGFRs, CSF1R, etc. CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay (IC = 66 nmol/L) and VEGFR2 autophosphorylation in cells (ECs ∼100 nmol/L) as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells (GI = 150 nmol/L). In addition, CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy and exhibited good PK (pharmacokinetics) profile with bioavailability over 49% and anti-angiogenesis efficacy in both zebrafish and mouse models without apparent toxicity. These results suggest that CHMFL-VEGFR2-002 might be a useful research tool for dissecting new functions of VEGFR2 kinase as well as a potential anti-angiogenetic agent for the cancer therapy.