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.

BACKGROUND:Whether coiled-coil-helix-coiled-coil-helix domain-containing 2(CHCHD2)can regulate the neuroprotective role of PINK1/Parkin-mediated mitochondrial autophagy in Parkinson's disease remains unknown.OBJECTIVE:To explore the role and mechanisms of CHCHD2 in the 6-hydroxydopamine-induced Parkinson's disease cell model in mediating the PINK1/Parkin signaling pathway and its involvement in mitochondrial autophagy.METHODS:Utilizing recombinant plasmid transfection technology to overexpress or knockdown CHCHD2,SH-SY5Y cells were constructed with a Parkinson's disease model using 6-hydroxydopamine,and divided into control group,model group,overexpression negative control+6-hydroxydopamine group,knockdown negative control+6-hydroxydopamine group,overexpression CHCHD2+6-hydroxydopamine group,and knockdown CHCHD2+6-hydroxydopamine group.Western blot assay and RT-qPCR were used to detect CHCHD2 expression.Western blot assay was utilized to detect the protein expression of LC3Ⅰ/Ⅱ,p62,MFN1,COXIV,DRP1,PINK1,Parkin,TIM23,Bax,Bcl-2,and cleaved-caspase 3.CCK-8 assay,JC-1,and reactive oxygen species assay kits were used to measure cell viability,mitochondrial membrane potential,and reactive oxygen levels.Monodansylcadaverine staining was used to observe cell autophagy.Transmission electron microscopy was used to observe autophagolysosomes.RESULTS AND CONCLUSION:(1)Compared with the control group,cell activity,mitochondrial membrane potential,and the protein expression levels of CHCHD2,PINK1,and Parkin were decreased,and the levels of reactive oxygen species,apoptosis,and LC3Ⅰ/Ⅱ and p62 proteins were increased(P＜0.05),and the presence of autophagic lysosomes was observed in the model group.(2)Compared with the model group,overexpression of CHCHD2 could reduce the level of cellular reactive oxygen species,increase the mitochondrial membrane potential,and the expression levels of PINK1,Parkin,and MFN1 proteins,and observed an increase in mitochondrial autolysosomes,and the knockdown of CHCHD2 had the opposite effect with the increase of COXIV,TIM23 and p-DRP1 protein expression(P＜0.05).(3)Compared with the model group,overexpression of CHCHD2 reduced apoptosis,up-regulated Bcl-2,and down-regulated the expression of Bax and cleaved-caspase3 proteins,while knockdown of CHCHD2 had the opposite effect(P＜0.05).(4)The results suggest that CHCHD2 can play a neuroprotective role by promoting PINK1/Parkin-mediated mitochondrial autophagy,improving mitochondrial function,and alleviating apoptosis in 6-hydroxydopamine-induced Parkinson's disease cell models.

BACKGROUND:Various proteins,signaling pathways,and inflammatory mediators are involved in the pathophysiological process of osteoarthritis.The development of small molecule drugs targeting these proteins,signaling pathways,and inflammatory mediators can effectively delay the progression of osteoarthritis and ameliorate its clinical manifestations. OBJECTIVE:To review the research progress of small molecule drugs in the treatment of osteoarthritis based on the pathogenesis of osteoarthritis. METHODS:PubMed,CNKI,and WanFang databases were searched with English search terms"osteoarthritis,arthritis,osteoarthrosis,degenerative,arthritides,deformans,small molecule drugs,small molecule inhibitors,small molecule agents"and Chinese search terms"osteoarthritis,small molecule drugs,small molecule inhibitors."A total of 68 articles were included for review according to the inclusion and exclusion criteria. RESULTS AND CONCLUSION:(1)Currently,studies concerning the pathogenesis of osteoarthritis remain unclear.The occurrence and development of osteoarthritis are strongly associated with proteins,cytokines,and signal transduction pathways,so its therapeutic mechanism is relatively complex.Currently,targeting proteins,cytokines,and signal transduction pathways related to osteoarthritis with small molecule drugs has become a major research focus.(2)Small molecule drugs frequently possess visible intracellular or extracellular targets and efficacy,containing enhancing cartilage repair,resisting joint degradation,attenuating inflammation,and relieving pain.Other anti-osteoarthritis small molecule drugs have shown promise in promoting stem cell chondrogenic differentiation and cartilage matrix reconstruction.(3)At present,small molecule drugs targeting the pathophysiological process of osteoarthritis to delay the progression of osteoarthritis are still in the experimental stage,but most of these small molecule drugs have shown the expected results in the experimental process,and there are no relevant studies to illustrate the efficacy of small molecule drugs in the treatment of osteoarthritis.(4)Small molecule drugs for the treatment of osteoarthritis have reached the expected experimental results in the basic experimental stage.Numerous studies have exhibited that small molecule drugs can target the suppression of specific proteins,cytokines,and signal transduction pathways that cause osteoarthritis,so as to treat osteoarthritis.Nevertheless,its safety and effectiveness still need to be identified by further basic and clinical studies.This process needs to be investigated and studied by more scholars.(5)At present,many scholars in and outside China have made contributions to the treatment of osteoarthritis.Compared with traditional treatment methods,small molecule drugs reveal better efficacy and safety in the basic experimental stage,and it is expected to become an emerging method for the treatment of osteoarthritis in the future to rid patients of pain.

Objective To compare the clinical efficacy and safety of transarterial chemoembolization(TACE)plus apatinib(Apa)and camrelizumab(Cam)and TACE plus Apa in treating CNLC stage Ⅲ hepatocellular carcinoma(HCC).Methods A total of 54 patients in Affiliated Yancheng No.1 People's Hospital,School of Medicine,Nanjing University with CNLC stage Ⅲ HCC were enrolled in this study.The patients were divided into triple treatment group(n=25,receiving TACE plus Apa and Cam)and dual treatment group(n=29,receiving TACE plus Apa).The overall survival(OS)and progression-free survival(PFS)were compared between the two groups.Univariate analysis and multivariate analysis were used to determine the independent influencing factors for OS and PFS.The target immunotherapy-related adverse reactions(TRAE)were analyzed.Results The median OS and PFS in the triple treatment group were 23.2 months and 10.9 months respectively,which were higher than 15.2 months and 5.8 months respectively in the dual treatment group(both P＜0.001).Multivariate analysis indicated that the therapeutic regimen and the type of portal vein tumor thrombosis(PVTT)were the independent factors affecting OS,while only the therapeutic regimen was the independent factor affecting PFS.The incidence of≥grade Ⅲ TRAE in the triple treatment group and the dual treatment group was 20％(5/25)and 17.2％(5/29)respectively,the difference between the two groups was not statistically significant(P＞0.05).Conclusion For the treatment of patients with CNLC stage Ⅲ HCC,TACE plus Apa and Cam is superior to TACE plus Apa in OS and PFS,and the type of PVTT and the therapeutic regimen are the independent prognostic factors associated with patient's survival.

ObjectiveTo compare the differences in color， odor， coumarin content and microbial community composition of Angelicae Dahuricae Radix（ADR） during different drying processes， and to explore the correlation between changes in microbial community composition and changes in quality indexes of ADR. MethodsThe fresh ADR was processed at three drying temperatures（50， 70， 100 ℃） by drying and steaming cutting， semi-fresh cutting and drying， fresh cutting and drying， and sulfur fumigation methods. The color values of samples were extracted by Adobe Photoshop 2022 software and subjected to principal component analysis（PCA）， electronic nose was used to identify the odor information of medicinal powders and subjected to loadings analysis， PCA， and linear discriminant analysis（LDA）， and high performance liquid chromatography（HPLC） was used to determine the contents of five coumarins（bergapten， oxypeucedanin， imperatorin， phellopterin， isoimperatorin）. The samples for microbial detection were taken from fresh dried samples， 50 ℃（dried and steamed cut， sulfur fumigated） samples， and 100 ℃（dried and steamed cut） samples when the water content was 50% and 14%， respectively. And the changes of microbial community composition during processing were determined by high-throughput sequencing method. The relationship between the changes of microbial community composition and the changes of odor， color and active component content of ADR during drying process was analyzed by Pearson correlation analysis. ResultsThe color quantification results showed that an increase in drying temperature led to the decrease of brightness value（L）， and the increases of red-green value（a） and yellow-blue value（b）， and the change of processing method had no obvious effect on the color of medicinal materials. The results of odor quantification showed that W1S， W2S， W5S， W2W and W1W sensor were sensitive to the odor changes of ADR and could be used to distinguish ADR decoction pieces from different processing methods. The results of HPLC showed that the coumarin content of ADR decreased with the increase of drying temperature and the delay of processing time， the optimal processing method was drying and steaming cutting method， and the optimal temperature was 50 ℃. High-throughput sequencing results showed that the dominant bacteria in ADR during processing were Achromobacter， Agrobacterium， Nocardioides， Mycobacterium and Enterobacter， the dominant fungi were Coprinopsis， Meyerozyma and Apiotrichum. The results of correlation analysis showed that the quality indexes of ADR were positively correlated with Agrobacterium， Mycobacterium in bacteria， Candida in fungi， and negatively correlated with Bacillus in bacteria. ConclusionThere are significant differences in the color， odor， coumarin content and microbial community composition of ADR in different drying processes， and the best drying method is drying and steaming cutting at 50 ℃. The relative abundance changes of 9 bacterial genera and 4 fungal genera are closely related to the quality formation of ADR during the drying process.

Objective To assess the global and Chinese disease burden of early-onset lung cancer(di-agnosed in patients aged 15-49 years)and its major risk factors.Methods Based on the GLOBOCAN 2022 and Global Burden of Disease(GBD)2021 datasets,we evaluated the disease burden and associated risk fac-tors of early-onset lung cancer globally and in China,stratified by age,sex,geographic location,and human development index(HDI).Key indicators included age-standardized incidence rate(ASIR),age-standardized mortality rate(ASMR),and disability adjusted life years(DALYs)attributable to risk factors.Results In 2022,there were 137 705 new cases and 72 646 deaths from early-onset lung cancer globally,with ASIR and ASMR of 3.43 per 100 000 and 1.82 per 100 000 population,respectively.The disease burden was higher in males than in females(ASIR:3.72 per 100 000 vs.3.14 per 100 000;ASMR:2.31 per 100 000 vs.1.33 per 100 000).High-HDI regions exhibited the highest ASIR(5.51 per 100 000)and ASMR(2.57 per 100 000),with health inequality analysis revealing a concentration of disease burden in higher-HDI areas.China bore the heaviest burden,accounting for 48.69%of global new cases and 35.77%of deaths.China's ASIR(8.21 per 100 000)and ASMR(3.17 per 100 000)exceeded global averages,with incidence higher in fe-males(8.78 per 100 000 vs.7.67 per 100 000)but mortality higher in males(4.01 per 100 000 vs.2.29 per 100 000).Smoking and ambient particulate matter pollution were the leading risk factors globally(DALYs contribution:42.01%and15.62%)and in China(DALYs contribution:46.78%and 20.84%).Globally,household air pollution ranked third,whereas in China,secondhand smoke replaced it as the third leading risk factor,with household air pollution dropping to fifth.Risk factor profiles varied significantly across age groups,with modifiable risks contributing less to disease burden in the 15-24 age group.Conclusions The burden of early-onset lung cancer varies markedly by sex,region,and HDI,with China facing a disproportionately high burden.Policymakers should prioritize equitable resource allocation and targeted interventions,particularly in tobacco control and air pollution mitigation,to enhance cancer prevention and control efforts.

Objective To assess the global and Chinese disease burden of early-onset lung cancer(di-agnosed in patients aged 15-49 years)and its major risk factors.Methods Based on the GLOBOCAN 2022 and Global Burden of Disease(GBD)2021 datasets,we evaluated the disease burden and associated risk fac-tors of early-onset lung cancer globally and in China,stratified by age,sex,geographic location,and human development index(HDI).Key indicators included age-standardized incidence rate(ASIR),age-standardized mortality rate(ASMR),and disability adjusted life years(DALYs)attributable to risk factors.Results In 2022,there were 137 705 new cases and 72 646 deaths from early-onset lung cancer globally,with ASIR and ASMR of 3.43 per 100 000 and 1.82 per 100 000 population,respectively.The disease burden was higher in males than in females(ASIR:3.72 per 100 000 vs.3.14 per 100 000;ASMR:2.31 per 100 000 vs.1.33 per 100 000).High-HDI regions exhibited the highest ASIR(5.51 per 100 000)and ASMR(2.57 per 100 000),with health inequality analysis revealing a concentration of disease burden in higher-HDI areas.China bore the heaviest burden,accounting for 48.69%of global new cases and 35.77%of deaths.China's ASIR(8.21 per 100 000)and ASMR(3.17 per 100 000)exceeded global averages,with incidence higher in fe-males(8.78 per 100 000 vs.7.67 per 100 000)but mortality higher in males(4.01 per 100 000 vs.2.29 per 100 000).Smoking and ambient particulate matter pollution were the leading risk factors globally(DALYs contribution:42.01%and15.62%)and in China(DALYs contribution:46.78%and 20.84%).Globally,household air pollution ranked third,whereas in China,secondhand smoke replaced it as the third leading risk factor,with household air pollution dropping to fifth.Risk factor profiles varied significantly across age groups,with modifiable risks contributing less to disease burden in the 15-24 age group.Conclusions The burden of early-onset lung cancer varies markedly by sex,region,and HDI,with China facing a disproportionately high burden.Policymakers should prioritize equitable resource allocation and targeted interventions,particularly in tobacco control and air pollution mitigation,to enhance cancer prevention and control efforts.

BACKGROUND:Whether coiled-coil-helix-coiled-coil-helix domain-containing 2(CHCHD2)can regulate the neuroprotective role of PINK1/Parkin-mediated mitochondrial autophagy in Parkinson's disease remains unknown.OBJECTIVE:To explore the role and mechanisms of CHCHD2 in the 6-hydroxydopamine-induced Parkinson's disease cell model in mediating the PINK1/Parkin signaling pathway and its involvement in mitochondrial autophagy.METHODS:Utilizing recombinant plasmid transfection technology to overexpress or knockdown CHCHD2,SH-SY5Y cells were constructed with a Parkinson's disease model using 6-hydroxydopamine,and divided into control group,model group,overexpression negative control+6-hydroxydopamine group,knockdown negative control+6-hydroxydopamine group,overexpression CHCHD2+6-hydroxydopamine group,and knockdown CHCHD2+6-hydroxydopamine group.Western blot assay and RT-qPCR were used to detect CHCHD2 expression.Western blot assay was utilized to detect the protein expression of LC3Ⅰ/Ⅱ,p62,MFN1,COXIV,DRP1,PINK1,Parkin,TIM23,Bax,Bcl-2,and cleaved-caspase 3.CCK-8 assay,JC-1,and reactive oxygen species assay kits were used to measure cell viability,mitochondrial membrane potential,and reactive oxygen levels.Monodansylcadaverine staining was used to observe cell autophagy.Transmission electron microscopy was used to observe autophagolysosomes.RESULTS AND CONCLUSION:(1)Compared with the control group,cell activity,mitochondrial membrane potential,and the protein expression levels of CHCHD2,PINK1,and Parkin were decreased,and the levels of reactive oxygen species,apoptosis,and LC3Ⅰ/Ⅱ and p62 proteins were increased(P＜0.05),and the presence of autophagic lysosomes was observed in the model group.(2)Compared with the model group,overexpression of CHCHD2 could reduce the level of cellular reactive oxygen species,increase the mitochondrial membrane potential,and the expression levels of PINK1,Parkin,and MFN1 proteins,and observed an increase in mitochondrial autolysosomes,and the knockdown of CHCHD2 had the opposite effect with the increase of COXIV,TIM23 and p-DRP1 protein expression(P＜0.05).(3)Compared with the model group,overexpression of CHCHD2 reduced apoptosis,up-regulated Bcl-2,and down-regulated the expression of Bax and cleaved-caspase3 proteins,while knockdown of CHCHD2 had the opposite effect(P＜0.05).(4)The results suggest that CHCHD2 can play a neuroprotective role by promoting PINK1/Parkin-mediated mitochondrial autophagy,improving mitochondrial function,and alleviating apoptosis in 6-hydroxydopamine-induced Parkinson's disease cell models.

Background::Lung cancer is the most common cancer and a leading cause of cancer-related deaths globally. The aim of this study was to evaluate the incidence and mortality of lung cancer worldwide in 2022 and to project the number of new cases and deaths due to lung cancer in China and the United States in 2050.Methods::In this study, data from the GLOBCAN 2022 database were used to analyze lung cancer incidence and mortality. The current status of lung cancer incidence and deaths was described by country/region, sex, age, and the human development index (HDI), and future lung cancer incidence and deaths in China and the United States were projected for 2050.Results::Globally, an estimated 2,480,675 new lung cancer cases and 1,817,469 lung cancer-related deaths occurred in 2022, with age-standardized incidence rates (ASIRs) and age-standardized mortality rates (ASMRs) of 23.6/100,000 and 16.8/100,000, respectively. In China, the ASIR and ASMR for male lung cancer patients were approximately 1.7 times and 2.7 times greater than those for female lung cancer patients, respectively. The ASIR and ASMR in high-HDI countries were approximately 8.5 times and 6.5 times those in low-HDI countries, respectively. It is estimated that in 2050, there will be approximately 1120 thousand new cases and 960 thousand deaths among Chinese men, 680 thousand new cases and 450 thousand deaths among Chinese women, approximately 170 thousand new cases and 110 thousand deaths among American men, and 160 thousand new cases and 90 thousand deaths among American women.Conclusions::There are significant differences in the incidence and mortality of lung cancer among different regions and sexes. Therefore, sex factors need to be considered in the prevention, screening, and treatment strategies of lung cancer, and the implementation of tertiary prevention measures for lung cancer, especially primary and secondary prevention, needs to be actively promoted.

Objective:This paper provides a brief overview of the epidemiology of colorectal cancer in China and around the world, and discusses how to prevent colorectal cancer to reduce its disease burden.Method:Using the official database of GLOBOCAN 2020, the China Cancer Registry Annual Report compiled by the National Cancer Center, and data from CONCORD-3.Data management was performed by Microsoft Excel 2016 and R 4.2.1 Relevant graphs were generated using the ggplot2 package for result visualization.Result:An estimated 1 931 590 people were diagnosed with colorectal cancer worldwide in 2020 with an age-standardized incidence rate of 19.5 per 100 000. There were about 935 173 deaths caused by colorectal cancer internationally, with an age-standardized mortality rate of 9.0 per 100 000. Overall, colorectal cancer was the fourth most commonly diagnosed cancer and the third leading cause of cancer-related death worldwide in 2020. In China, the age-standardized incidence rate and mortality rate of colorectal cancer was 17.3 per 100 000 and 7.8 per 100 000, respectively. Gender differences in trends were observed, with a decreasing trend in incidence and mortality among females and an increasing trend in incidence and mortality among males. The primary risk factors for colorectal cancer include age, genetic factors, gastrointestinal disorders, dietary habits, and lifestyle et al.Conclusions:Colorectal cancer poses a significant burden globally and in China. The occurrence of colorectal cancer is closely related to physiology, genetics, behavioral habits, lifestyle, and disease factors. To better control the colorectal cancer burden with the lowest cost, specific measures should be taken to reduce exposure to established risk factors. By combining the disease prevention and control strategies of tertiary prevention in China with the characteristic factors of colorectal cancer, the incidence and mortality of colorectal cancer may be effectively controlled.