Ischemic stroke (IS) is a globally life-threatening disease. Presently, few therapeutic medicines are available for treating IS, and rt-PA is the only drug approved by the US Food and Drug Administration (FDA) in the US. In fact, many agents showing excellent neuroprotection but no blood flow-improving activity in animals have not achieved ideal clinical efficacy, while thrombolytic drugs only improving blood flow without neuroprotection have limited their wider application. To address these challenges and meet the huge unmet clinical need, we have designed and identified a novel compound AAPB with dual effects of neuroprotection and cerebral blood flow improvement. AAPB significantly reduced cerebral infarction and neural function deficit in tMCAO rats, pMCAO rats, and IS rhesus monkeys, as well as displayed exceptional safety profiles and excellent pharmacokinetic properties in rats and dogs. AAPB has now entered phase I of clinical trials fighting IS in China.

Objective To explore the current situation,hot spots and trends of clinical research on the treatment of carotid atherosclerosis(CAS)with traditional Chinese medicine.Methods Search CNKI,Wanfang,VIP,Web of Science core collection database related literature,using Python 3.9.6 cleaning data,using CiteSpace and VOSviewer for visual analysis of authors,institutions,keywords,etc.Results 910 Chinese literatures and 5 English literatures were included.The most published authors were Wang Changyin and Yin Chunping,and the institution was Handan Hospital of Traditional Chinese Medicine,Hebei Province.The cooperation between institutions was independent and regional.Research focus on:phlegm stasis interjunction,dyslipidemia,inflammatory factors,vascular endothelial function,nerve function defect,Banxia Baizhu Tianma decoction,coronary heart disease and so on;The treatment of CAS from"interjunction of phlegm and blood stasis"will continue to become a research hotspot in this field.Conclusion The clinical research of traditional Chinese medicine in the treatment of CAS should be closely combined with the observation of curative effect and the revelation of mechanism,and the law of traditional Chinese medicine in the treatment of CAS should be explored.In the future,the treatment of CAS should focus on the treatment of"phlegm and blood stasis",and the pathogenesis principle of"phlegm and blood stasis",the efficacy and mechanism of resolving phlegm and removing blood stasis in the treatment of CAS should be systematically and deeply explored.

Objective To explore the current situation,hot spots and trends of clinical research on the treatment of carotid atherosclerosis(CAS)with traditional Chinese medicine.Methods Search CNKI,Wanfang,VIP,Web of Science core collection database related literature,using Python 3.9.6 cleaning data,using CiteSpace and VOSviewer for visual analysis of authors,institutions,keywords,etc.Results 910 Chinese literatures and 5 English literatures were included.The most published authors were Wang Changyin and Yin Chunping,and the institution was Handan Hospital of Traditional Chinese Medicine,Hebei Province.The cooperation between institutions was independent and regional.Research focus on:phlegm stasis interjunction,dyslipidemia,inflammatory factors,vascular endothelial function,nerve function defect,Banxia Baizhu Tianma decoction,coronary heart disease and so on;The treatment of CAS from"interjunction of phlegm and blood stasis"will continue to become a research hotspot in this field.Conclusion The clinical research of traditional Chinese medicine in the treatment of CAS should be closely combined with the observation of curative effect and the revelation of mechanism,and the law of traditional Chinese medicine in the treatment of CAS should be explored.In the future,the treatment of CAS should focus on the treatment of"phlegm and blood stasis",and the pathogenesis principle of"phlegm and blood stasis",the efficacy and mechanism of resolving phlegm and removing blood stasis in the treatment of CAS should be systematically and deeply explored.

International registration of herbal drugs is a necessary prerequisite for the internationalization of Chinese materia medica. North America and European Union occupy an important position in the world herbal drugs market, and their drug administration and quality supervision requirements are relatively complete and progressiveness. By summarizing the definition of herbal drugs in North America and European Union, combing and interpreting the relevant laws, regulations and policy documents, this article constructed the registration path of herbal drugs, and discussed the current status of market registration of herbal drugs in North America and European Union based on the examples of successful marketing of herbal drugs under current application and approval in overseas markets. This article believed that in the future, an internationally matched TCM quality standard evidence system should be built, clinical trials of TCM products in line with international standards should be carried out, standards that are the same or higher than international mainstream GMP should be developed, the registration path of TCM compounds should be explored, and professionals to establish an international registration application team should be recruited to provide theoretical and practical support for China's overseas registration of Chinese TCM products, promote TCM products to enter the world mainstream market, and achieve high-quality development of TCM internationalization.

Objective To explore the ideas,methods and pathways for the registration of Chinese medicine prescriptions in overseas countries,to form a strategy for overseas registration of Chinese medicine,and to provide technical support and reference for China's Chinese medicine prescriptions to go abroad.Methods Five representative countries were selected to form corresponding expert teams and exchange platforms for international cooperation.The laws,regulations,rules,standards,specifications and technical guidance documents related to Chinese medicine prescription preparations of the target countries were used as pathway research materials,and the documents were translated directly,naturalized,proofread and diagrammed,and a problem-oriented mechanism for consultation with domestic and international experts was established to form a pathway for overseas registration of Chinese medicine prescription preparations.Results The path for standardization of overseas registration of Chinese medicines was clarified,and the detailed registration paths and corresponding work strategies of Chinese medicines in five countries were formulated with flow charts,tables and explanatory texts.Conclusion By developing standardized registration pathways for traditional Chinese medicine in target countries,reference can be provided for the internationalization of Chinese herbal formula preparations.

Objective To investigate the role of miRNAs in maternal amniotic fluid exosomes in development of isolated ventriculomegaly(VM)in fetuses.Methods Amniotic fluid samples were collected from 9 cases of moderate isolated VM and 8 normal control cases to extract exosomal miRNA,and miRNA sequencing technique was used to identify differentially expressed miRNAs between the two groups.Three miRNAs with significant differential expression between the two groups,whose high expression was associated with VM,were selected for verification with RT-qPCR.Dual luciferase reporter assays were used to verify the regulatory effect of miR-122-5p on its predicted target genes AKT3 and CCDC88C.Gene ontology(GO)and KEGG pathway analyses were performed to explore the possible roles of the top 40 significant differential miRNAs in the pathophysiology of VM.Results We identified a total of 272 differentially expressed miRNAs in VM cases,including 43 up-regulated and 229 down-regulated miRNAs.The target genes of these differential miRNAs were associated with DNA and transcription factor binding,transmembrane transporter and nucleic acid binding transcription factor activity,and cell developmental process.These miRNAs were mostly enriched in the MAPK,cGMP-PKG and Wnt signaling pathways.Verification with RT-qPCR showed that miR-122-5p expression level was significantly lower in VM group than in the control group(P<0.05),which was consistent with miRNA sequencing results;let-7b-5p expression level was significantly lower in VM group,which was contrary to miRNA sequencing result.Dual luciferase reporter assays showed that miR-122-5p was not capable of regulating AKT3 or CCDC88C expressions.Conclusions The highly abundant differentially expressed miRNAs in maternal amniotic fluid exosomes play important roles in the occurrence of fetal VM possibly by regulating the MAPK,PI3K-Akt,Wnt and cGMP-PKG signaling pathways.

Objective To investigate the role of miRNAs in maternal amniotic fluid exosomes in development of isolated ventriculomegaly(VM)in fetuses.Methods Amniotic fluid samples were collected from 9 cases of moderate isolated VM and 8 normal control cases to extract exosomal miRNA,and miRNA sequencing technique was used to identify differentially expressed miRNAs between the two groups.Three miRNAs with significant differential expression between the two groups,whose high expression was associated with VM,were selected for verification with RT-qPCR.Dual luciferase reporter assays were used to verify the regulatory effect of miR-122-5p on its predicted target genes AKT3 and CCDC88C.Gene ontology(GO)and KEGG pathway analyses were performed to explore the possible roles of the top 40 significant differential miRNAs in the pathophysiology of VM.Results We identified a total of 272 differentially expressed miRNAs in VM cases,including 43 up-regulated and 229 down-regulated miRNAs.The target genes of these differential miRNAs were associated with DNA and transcription factor binding,transmembrane transporter and nucleic acid binding transcription factor activity,and cell developmental process.These miRNAs were mostly enriched in the MAPK,cGMP-PKG and Wnt signaling pathways.Verification with RT-qPCR showed that miR-122-5p expression level was significantly lower in VM group than in the control group(P<0.05),which was consistent with miRNA sequencing results;let-7b-5p expression level was significantly lower in VM group,which was contrary to miRNA sequencing result.Dual luciferase reporter assays showed that miR-122-5p was not capable of regulating AKT3 or CCDC88C expressions.Conclusions The highly abundant differentially expressed miRNAs in maternal amniotic fluid exosomes play important roles in the occurrence of fetal VM possibly by regulating the MAPK,PI3K-Akt,Wnt and cGMP-PKG signaling pathways.

Abstract: Objective To analyze the epidemiological characteristics of human brucellosis in Hebei Province, and to explore strategies and measures for its prevention and control. Methods Data on brucellosis cases reported in Hebei Province were collected from the National Notifiable Infectious Disease Reporting Information System. The total situation of brucellosis was described, and the epidemiological characteristics of brucellosis in Hebei Province were analyzed. The spatial autocorrelation analysis method was used to explore the spatial distribution characteristics of brucellosis incidence at the county level in Hebei Province. Results From 2018 to 2023, a total of 21 718 cases of brucellosis were reported in Hebei Province, with 1 death (in 2021). The annual incidence rate fluctuated between 3.91/100 000 to 6.26/100 000, with an average annual reported incidence rate of 4.84/100 000. The epidemic peak was from April to July, showing obvious seasonal characteristics. The incidence in males was higher than in females, with a male-to-female ratio of 2.81∶1. The incidence age was concentrated 30-<70 years, accounting for 85.33% of the total cases. The primary occupational group affected was farmers, accounting for 88.59%. The top three cities with the highest average annual incidence rate were Zhangjiakou, Chengde, and Hengshui, which reported a total of 7 801 cases, representing 35.92% of the total cases in the province. From the perspective of spatial distribution: the global spatial autocorrelation analysis showed clustering distribution in Hebei Province from 2018 to 2023, and there were hot spots in local spatial autocorrelation analysis. The high-incidence areas of brucellosis were mainly concentrated in Zhangjiakou (13.651 3/100 000) and Chengde (13.116 7/100 000) in the north of Hebei Province during the past six years. The "low-low" clustering areas were mainly distributed in Tangshan, Shijiazhuang, and Handan. The "low-high" clustering areas were mainly located around the "high-high" cluster areas, in some counties of Zhangjiakou and Chengde. Conclusions The situation of human brucellosis prevention and control in Hebei Province remains challenging. It is recommended to strengthen the management of infection sources, enhance the surveillance of human brucellosis, focus on health education and behavior intervention in high-risk groups, and intensify prevention and control efforts in the hotspot areas.

[Objective]To investigate the protective effect of herbal enema formula on dextran sodium sulfate(DSS)-induced ulcerative colitis (UC) and its mechanism of action.[Methods]C57BL/6J mice were given 2.5％ DSS aqueous solution for 7 d to induce UC.After 2 d,mice in herbal enema formula low,medium and high dose groups were given 1.3 g/kg,2.6 g/kg and 5.2 g/kg herbal enema formula for edema;0.2 g/kg sulfasalazine were given to positive control group for enema;mice in model group and normal group were given equal volumes of 0.9％ sodium chloride solution for enema,respectively.The degree of lesions was observed by hematoxylin-eosin(HE) staining in mice colon tissue sections;serum inflammatory factor tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),interleukin-1β(IL-1β) and interleukin-18(IL-18) were determined by enzyme linked immunosorbent assay(ELISA);myeloperoxidase(MPO) and superoxide dismutase (SOD) activities,nitric oxide(NO) and malondialdehyde(MDA) levels were detected by physiological and biochemical assay kits;protein expression levels of zonula occludens protein-1(ZO-1),occludin,nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3),and sirtuin 6(SIRT6) in mouse colon tissues were detected by western blot.[Results]Compared with normal group,DSS induced colonic inflammation,crypt loss,cuprocyte depletion and inflammatory infiltration;serum TNF-α,IL-6,IL-1β,and IL-18 inflammatory factor levels,MPO activity,NO and MDA levels were significantly increased(P<0.01,P<0.001),and SOD activity was significantly decreased(P<0.01).After treatment,the herbal enema formula significantly improved the DSS-induced colonic inflammation of crypt loss,cuprocyte depletion,and inflammatory infiltration.The levels of serum TNF-α,IL-6,IL-1β and IL-18 inflammatory factors,MPO activity and NO and MDA levels were significantly decreased(P<0.01,P<0.001),and SOD activity were significantly increased in medium dose and high dose groups(P<0.05).The protein expression levels of ZO-1,occludin and SIRT6 in the colonic tissues of mice in herbal enema formula group were significantly higher(P<0.001,P<0.01,P<0.05),and the protein expression levels of NLRP3 in medium dose and high dose groups were significantly lower(P<0.01).[Conclusion]The herbal enema formula has a protective effect against DSS-induced UC,and its mechanism includes alleviating inflammation,reducing oxidative stress,improving intestinal barrier permeability,and regulating the NLRP3/SIRT6 signaling pathway.

[Objective]To investigate the protective effect of herbal enema formula on dextran sodium sulfate(DSS)-induced ulcerative colitis (UC) and its mechanism of action.[Methods]C57BL/6J mice were given 2.5％ DSS aqueous solution for 7 d to induce UC.After 2 d,mice in herbal enema formula low,medium and high dose groups were given 1.3 g/kg,2.6 g/kg and 5.2 g/kg herbal enema formula for edema;0.2 g/kg sulfasalazine were given to positive control group for enema;mice in model group and normal group were given equal volumes of 0.9％ sodium chloride solution for enema,respectively.The degree of lesions was observed by hematoxylin-eosin(HE) staining in mice colon tissue sections;serum inflammatory factor tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),interleukin-1β(IL-1β) and interleukin-18(IL-18) were determined by enzyme linked immunosorbent assay(ELISA);myeloperoxidase(MPO) and superoxide dismutase (SOD) activities,nitric oxide(NO) and malondialdehyde(MDA) levels were detected by physiological and biochemical assay kits;protein expression levels of zonula occludens protein-1(ZO-1),occludin,nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3),and sirtuin 6(SIRT6) in mouse colon tissues were detected by western blot.[Results]Compared with normal group,DSS induced colonic inflammation,crypt loss,cuprocyte depletion and inflammatory infiltration;serum TNF-α,IL-6,IL-1β,and IL-18 inflammatory factor levels,MPO activity,NO and MDA levels were significantly increased(P<0.01,P<0.001),and SOD activity was significantly decreased(P<0.01).After treatment,the herbal enema formula significantly improved the DSS-induced colonic inflammation of crypt loss,cuprocyte depletion,and inflammatory infiltration.The levels of serum TNF-α,IL-6,IL-1β and IL-18 inflammatory factors,MPO activity and NO and MDA levels were significantly decreased(P<0.01,P<0.001),and SOD activity were significantly increased in medium dose and high dose groups(P<0.05).The protein expression levels of ZO-1,occludin and SIRT6 in the colonic tissues of mice in herbal enema formula group were significantly higher(P<0.001,P<0.01,P<0.05),and the protein expression levels of NLRP3 in medium dose and high dose groups were significantly lower(P<0.01).[Conclusion]The herbal enema formula has a protective effect against DSS-induced UC,and its mechanism includes alleviating inflammation,reducing oxidative stress,improving intestinal barrier permeability,and regulating the NLRP3/SIRT6 signaling pathway.