Eastern Cooperative Oncology Group(ECOG)performance status and Gleason score are commonly investigated factors for overall survival(OS)in men with castration-resistant prostate cancer(CRPC).However,there is a lack of ...Eastern Cooperative Oncology Group(ECOG)performance status and Gleason score are commonly investigated factors for overall survival(OS)in men with castration-resistant prostate cancer(CRPC).However,there is a lack of consistency regarding their prognostic or predictive value for OS.Therefore,we performed this meta-analysis to assess the associations of ECOG performance status and Gleason score with OS in CRPC patients and compare the two markers in patients under different treatment regimens or with different chemotherapy histories.A systematic literature review of monotherapy studies in CRPC patients was conducted in the PubMed database until May 2019.The data from 8247 patients in 34 studies,including clinical trials and real-world data,were included in our meta-analysis.Of these,twenty studies reported multivariate results and were included in our main analysis.CRPC patients with higher ECOG performance statuses(≥2)had a significantly increased mortality risk than those with lower ECOG performance statuses(<2),hazard ratio(HR):2.10,95%confidence interval(CI):1.68-2.62,and P<0.001.The synthesized HR of OS stratified by Gleason score was 1.01,with a 95%CI of 0.62-1.67(Gleason score≥8 vs<8).Subgroup analysis showed that there was no significant difference in pooled HRs for patients administered taxane chemotherapy(docetaxel and cabazitaxel)and androgen-targeting therapy(abiraterone acetate and enzalutamide)or for patients with different chemotherapy histories.ECOG performance status was identified as a significant prognostic factor in CRPC patients,while Gleason score showed a weak prognostic value for OS based on the available data in our meta-analysis.展开更多
The roles of androgens on cardiovascular physiology and pathophysiology are controversial as both beneficial and detrimental effects have been reported. Although the reasons for this discrepancy are unclear, multiple ...The roles of androgens on cardiovascular physiology and pathophysiology are controversial as both beneficial and detrimental effects have been reported. Although the reasons for this discrepancy are unclear, multiple factors such as genetic and epigenetic variation, sex-specificity, hormone interactions, drug preparation and route of administration may contribute. Recently, growing evidence suggests that androgens exhibit beneficial effects on cardiovascular function though the mechanism remains to be elucidated. Endothelial cells （ECs） which line the interior surface of blood vessels are distributed throughout the circulatory system, and play a crucial role in cardiovascular function. Endothelial progenitor cells （EPCs） are considered an indispensable element for the reconstitution and maintenance of an intact endothelial layer. Endothelial dysfunction is regarded as an initiating step in development of atherosclerosis and cardiovascular diseases. The modulation of endothelial functions by androgens through either genornic or nongenomic signal pathways is one possible mechanism by which androgens act on the cardiovascular system. Obtaining insight into the mechanisms by which androgens affect EC and EPC functions will allow us to determine whether androgens possess beneficial effects on the cardiovascular system. This in turn may be critical in the prevention and therapy of cardiovascular diseases. This article seeks to review recent progress in androgen regulation of endothelial function, the sex-specificity of androgen actions, and its clinical applications in the cardiovascular system.展开更多
Objective The main aim of this meta-analysis is to compare the efficacy and safety of dual versus single antiplatelet therapy for pa- tients taking oral anticoagulation （OAC） after coronary intervention. Background ...Objective The main aim of this meta-analysis is to compare the efficacy and safety of dual versus single antiplatelet therapy for pa- tients taking oral anticoagulation （OAC） after coronary intervention. Background The optimal regimen remains controversial for patients taking OAC after coronary intervention. Methods PubMed, Embase and Cochrane Central Register of Controlled Trials were searched for eligible studies including data of triple therapy （TT） versus OAC plus single antiplatelet therapy for patients requiring OAC after coronary intervention. The primary outcome was major adverse cardiac and cerebrovascular event （MACCE）. The safety outcome was major bleeding. Results Fourteen studies with 32,825 patients were included. Among prospective studies, patients with TT had a trend toward a higher risk of major bleeding [odds ratios （OR）： 1.56, 95% confidence interval （CI）： 0.98-2.49, P = 0.06] and a markedly higher risk of all-cause death （OR; 2.11, 95% CI： 1.10-4.06 P = 0.02） compared with OAC plus clopidogrel. Meanwhile, TT was associated with decreased risks of MACCE （OR： 0.63, 95% CI： 051-0.77 P 〈 0.0001）, all-cause death （OR： 0.45, 95% CI： 0.20-0.97, P = 0.04）, and stroke/transient ischemic attack （TIA）/peripheral embolism （PE） （OR= 0.29, 95% CI： 0.09~3.96, P = 0.04） compared with OAC plus aspirin. Conclusions For pa- tients requiring OAC after coronary intervention, OAC plus clopidogrel may bring more clinical net benefit than TT, whereas OAC plus aspirin should be the last choice. More large-size randomized control trials are needed to confirm these findings.展开更多
Pharmacogenomic landscapes and related databases are important for identifying the biomarkers of drug response and toxicity.However,these data are still lacking for the Chinese population.In this study,we constructed ...Pharmacogenomic landscapes and related databases are important for identifying the biomarkers of drug response and toxicity.However,these data are still lacking for the Chinese population.In this study,we constructed a pharmacogenomic landscape and an associated database using whole-genome sequencing data generated by non-invasive prenatal testing in 206,640 Chinese individuals.In total,1,577,513 variants(including 331,610 novel variants)were identified among 3,538 pharmacogenes related to 2,086 drugs.We found that the variant spectrum in the Chinese population differed among the seven major regions.Regional differences also exist among provinces in China.The average numbers of drug enzyme,transporter,and receptor variants were 258,557,and 632,respectively.Subsequent correlation analysis indicated that the pharmacogenes affecting multiple drugs had fewer variants.Among the 16 categories of drugs,we found that nervous system,cardiovascular system,and genitourinary system/sex hormone drugs were more likely to be affected by variants of pharmacogenes.Characteristics of the variants in the enzyme,transporter,and receptor subfamilies showed specificity.To explore the clinical utility of these data,a genetic association study was conducted on 1,019 lung cancer patients.Two novel variants,AKT2 chr19:40770621 C>G and SLC19A1 chr21:46934171 A>C,were identified as novel platinum response biomarkers.Finally,a pharmacogenomic database,named the Chinese Pharmacogenomic Knowledge Base(CNPKB:http://www.cnpkb.com.cn/),was constructed to collect all the data.In summary,a pharmacogenomic landscape and database for the Chinese population were constructed in this study,which could support personalized Chinese medicine in the future.展开更多
Background The preclinical experiments and studies of congener drugs show icotinib, a new epidermal growth factor receptor （EGFR） tyrosine kinase inhibitor, can specifically bind to the tyrosine kinase domain of the...Background The preclinical experiments and studies of congener drugs show icotinib, a new epidermal growth factor receptor （EGFR） tyrosine kinase inhibitor, can specifically bind to the tyrosine kinase domain of the EGFR, block the EGFR related signal, thereby inhibit the growth of tumor cell. The objective of this study was to investigate the safety, tolerability and dose-related biologic effects of icotinib in patients with non-small cell lung cancer （NSCLC） in a Chinese patient population. Methods This was an open-label, phase I, dose escalation, safety/tolerability trial of oral icotinib （100 to 400 mg）, administered twice per day for 28-continuous-day cycles until disease progression or undue toxicity. Results Forty patients with stage IIIB （15%） or IV （85%） NSCLC were included in the study. They had mainly adenocarcinoma （85%）, with a performance status （PS） of 0 （45%） or 1 （55%） and less than half the patients （45%） had histories of smoking and all were pretreated by at least one regimen of chemotherapy. Patients were assigned to three dose levels of 150 mg b.i.d, 200 mg b.i.d, or 125 mg t.i.d. The follow-up periods ranged from 5 to 80 weeks. Adverse events were found in 35% patients, most of which were mild and reversible. The adverse events mainly occurred in the first 4 weeks and included rash （25%）, diarrhea, nausea and abdominal distention. One definite interstitial lung disease （ILD） was found in a patient in the dose of 200 mg b.i.d. According to an 8-week assessment, one （2.5%） patient receiving 150 mg gained complete response （CR） that persisted for 44 weeks, seven （17.50%） patients had partial remission （PR）, and 18 （45%） patients had stable disease （SD）. The objective response including CR＋PR was 20%. The median time of progression-free survival for the 40 patients was 20 weeks （range： 12 to 32 weeks）. The response was not affected by pathological type, history of smoking, or numbers of previous therapeutic regimens. No relationship between dose, response, adverse effect, or duration of the study was observed. Conclusions Icotinib, given as oral twice daily, showed favorable safety and tolerability. Mild and reversible rash, diarrhea, and nausea were the main adverse events. Antitumor activity was obvious at each dose in heavily pretreated patients. Pharmacodynamic evaluations and further phase II/III trials are in progress.展开更多
The spread of coronavirus disease 2019(COVID-19)throughout the world has resulted in stressful healthcare burdens and global health crises.Developing an effective measure to protect people from infection is an urgent ...The spread of coronavirus disease 2019(COVID-19)throughout the world has resulted in stressful healthcare burdens and global health crises.Developing an effective measure to protect people from infection is an urgent need.The blockage of interaction between angiotensin-converting enzyme 2(ACE2)and S protein is considered an essential target for anti-severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)drugs.A full-length ACE2 protein could be a potential drug to block early entry of SARS-Co V-2 into host cells.In this study,a therapeutic strategy was developed by using extracellular vesicles(EVs)with decoy receptor ACE2 for neutralization of SARS-Co V-2.The EVs embedded with engineered ACE2(EVs-ACE2)were prepared;the EVs-ACE2 were derived from an engineered cell line with stable ACE2 expression.The potential effect of the EVs-ACE2 on anti-SARS-Co V-2 was demonstrated by both in vitro and in vivo neutralization experiments using the pseudovirus with the S protein(S-pseudovirus).EVs-ACE2 can inhibit the infection of S-pseudovirus in various cells,and importantly,the mice treated with intranasal administration of EVs-ACE2 can suppress the entry of S-pseudovirus into the mucosal epithelium.Therefore,the intranasal EVs-ACE2 could be a preventive medicine to protect from SARS-Co V-2 infection.This EVs-based strategy offers a potential route to COVID-19 drug development.展开更多
eIF3a is a N^(6)-methyladenosine(m^(6)A)reader that regulates mRNA translation by recognizing m^(6)A modifications of these mRNAs.It has been suggested that eIF3a may play an important role in regulating translation i...eIF3a is a N^(6)-methyladenosine(m^(6)A)reader that regulates mRNA translation by recognizing m^(6)A modifications of these mRNAs.It has been suggested that eIF3a may play an important role in regulating translation initiation via m^(6)A during infection when canonical cap-dependent initiation is inhibited.However,the death of animal model studies impedes our understanding of the functional significance of eIF3a in immunity and regulation in vivo.In this study,we investigated the in vivo function of eIF3a using eIF3a knockout and knockdown mouse models and found that eIF3a deficiency resulted in splenic tissue structural disruption and multi-organ damage,which contributed to severe sepsis induced by Lipopolysaccharide(LPS).Ectopic eIF3a overexpression in the eIF3a knockdown mice rescued mice from LPS-induced severe sepsis.We further showed that eIF3a maintains a functional and healthy immune system by regulating B cell function and quantity through m^(6)A modification of mRNAs.These findings unveil a novel mechanism underlying sepsis,implicating the pivotal role of B cells in this complex disease process regulated by eIF3a.Furthermore,eIF3a may be used to develop a potential strategy for treating sepsis.展开更多
Objective To investigate the mechanism of Tojapride,a Chinese herbal formula extract,on strengthening the barrier function of esophageal epithelium in rats with reflux esophagitis(RE).Methods Ten out of 85 SD rats wer...Objective To investigate the mechanism of Tojapride,a Chinese herbal formula extract,on strengthening the barrier function of esophageal epithelium in rats with reflux esophagitis(RE).Methods Ten out of 85 SD rats were randomly selected as the sham group(n10),and 75 rats were developed a reflux esophagitis model(RE)by the esophageal and duodenal side-to-side anastomosis.Fifty successful modeling rats were divided into different medicated groups through a random number table including the model,low-,medium-,and high-dose of Tojapride as well as omeprazole groups(n10).Three doses of Tojapride[5.73,11.46,22.92 g/(kg•d)]and omeprazole[4.17 mg/(kg•d)]were administrated intragastrically twice daily for 3 weeks.And the rats in the sham and model groups were administered 10 mL/kg distilled water.Gastric fluid was collected and the supernatant was kept to measure for volume,pH value and acidity.Esophageal tissues were isolated to monitor the morphological changes through hematoxylin-eosin(HE)staining,and esophageal epithelial ultrastructure was observed by transmission electron microscopy.The expressions of nuclear factor kappa-light-chain-enhancer of activated B cells p65(NF-KBp65),κB kinase beta(IKKß),occludin,and zonula occludens-1(ZO-1)in the esophageal tissues were measured by immunohistochemistry and Western blot,respectively.Results The gastric pH value in the model group was significantly lower than the sham group(P<0.05).Compared with the model group,gastric pH value in the omeprazole and medium-dose of Tojapride groups were significantly higher(P<0.05).A large area of ulceration was found on the esophageal mucosa from the model rats,while varying degrees of congestion and partially visible erosion was observed in the remaining groups.Remarkable increase in cell gap width and decrease in desmosome count was seen in RE rats and the effect was reversed by Tojapride treatment.Compared with the sham group,the IKKßlevels were significantly higher in the model group(P<0.05).However,the IKKßlevels were down-regulated after treatment by all doses of Tojapride(P<0.01 or P<0.05).The occluding and ZO-1 levels decreased in the model group compared with the sham group(Ps0.01 or Ps0.05),while both indices were significantly up-regulated in the Tojapride-treated groups(P<0.01 or P<0.05).Conclusions Tojapride could improve the pathological conditions of esophageal epithelium in RE rats.The underlying mechanisms may involve in down-regulating the IKKßexpression and elevating ZO-1 and occludin expression,thereby alleviating the inflammation of the esophagus and strengthening the barrier function of the esophageal epithelium.展开更多
文摘Eastern Cooperative Oncology Group(ECOG)performance status and Gleason score are commonly investigated factors for overall survival(OS)in men with castration-resistant prostate cancer(CRPC).However,there is a lack of consistency regarding their prognostic or predictive value for OS.Therefore,we performed this meta-analysis to assess the associations of ECOG performance status and Gleason score with OS in CRPC patients and compare the two markers in patients under different treatment regimens or with different chemotherapy histories.A systematic literature review of monotherapy studies in CRPC patients was conducted in the PubMed database until May 2019.The data from 8247 patients in 34 studies,including clinical trials and real-world data,were included in our meta-analysis.Of these,twenty studies reported multivariate results and were included in our main analysis.CRPC patients with higher ECOG performance statuses(≥2)had a significantly increased mortality risk than those with lower ECOG performance statuses(<2),hazard ratio(HR):2.10,95%confidence interval(CI):1.68-2.62,and P<0.001.The synthesized HR of OS stratified by Gleason score was 1.01,with a 95%CI of 0.62-1.67(Gleason score≥8 vs<8).Subgroup analysis showed that there was no significant difference in pooled HRs for patients administered taxane chemotherapy(docetaxel and cabazitaxel)and androgen-targeting therapy(abiraterone acetate and enzalutamide)or for patients with different chemotherapy histories.ECOG performance status was identified as a significant prognostic factor in CRPC patients,while Gleason score showed a weak prognostic value for OS based on the available data in our meta-analysis.
基金The researches described in this article were partially supported by grants from the National Natural Science Foundation of China （No. 81570271 and 81400357） and NIH （UL1 RR024996）. We are very grateful to John R Lee （Assistant Professor of Medicine, Weill Comell Medical College, New York）, and Jeff J Zhu （Research Manager, Weill Comell Medical College, New York） for critical review of the article. The authors have nothing to disclosure.
文摘The roles of androgens on cardiovascular physiology and pathophysiology are controversial as both beneficial and detrimental effects have been reported. Although the reasons for this discrepancy are unclear, multiple factors such as genetic and epigenetic variation, sex-specificity, hormone interactions, drug preparation and route of administration may contribute. Recently, growing evidence suggests that androgens exhibit beneficial effects on cardiovascular function though the mechanism remains to be elucidated. Endothelial cells （ECs） which line the interior surface of blood vessels are distributed throughout the circulatory system, and play a crucial role in cardiovascular function. Endothelial progenitor cells （EPCs） are considered an indispensable element for the reconstitution and maintenance of an intact endothelial layer. Endothelial dysfunction is regarded as an initiating step in development of atherosclerosis and cardiovascular diseases. The modulation of endothelial functions by androgens through either genornic or nongenomic signal pathways is one possible mechanism by which androgens act on the cardiovascular system. Obtaining insight into the mechanisms by which androgens affect EC and EPC functions will allow us to determine whether androgens possess beneficial effects on the cardiovascular system. This in turn may be critical in the prevention and therapy of cardiovascular diseases. This article seeks to review recent progress in androgen regulation of endothelial function, the sex-specificity of androgen actions, and its clinical applications in the cardiovascular system.
文摘Objective The main aim of this meta-analysis is to compare the efficacy and safety of dual versus single antiplatelet therapy for pa- tients taking oral anticoagulation （OAC） after coronary intervention. Background The optimal regimen remains controversial for patients taking OAC after coronary intervention. Methods PubMed, Embase and Cochrane Central Register of Controlled Trials were searched for eligible studies including data of triple therapy （TT） versus OAC plus single antiplatelet therapy for patients requiring OAC after coronary intervention. The primary outcome was major adverse cardiac and cerebrovascular event （MACCE）. The safety outcome was major bleeding. Results Fourteen studies with 32,825 patients were included. Among prospective studies, patients with TT had a trend toward a higher risk of major bleeding [odds ratios （OR）： 1.56, 95% confidence interval （CI）： 0.98-2.49, P = 0.06] and a markedly higher risk of all-cause death （OR; 2.11, 95% CI： 1.10-4.06 P = 0.02） compared with OAC plus clopidogrel. Meanwhile, TT was associated with decreased risks of MACCE （OR： 0.63, 95% CI： 051-0.77 P 〈 0.0001）, all-cause death （OR： 0.45, 95% CI： 0.20-0.97, P = 0.04）, and stroke/transient ischemic attack （TIA）/peripheral embolism （PE） （OR= 0.29, 95% CI： 0.09~3.96, P = 0.04） compared with OAC plus aspirin. Conclusions For pa- tients requiring OAC after coronary intervention, OAC plus clopidogrel may bring more clinical net benefit than TT, whereas OAC plus aspirin should be the last choice. More large-size randomized control trials are needed to confirm these findings.
基金supported by the National Natural Science Foundation of China(82073943,82373962,and 82450103 to J-Y.Y. and 82204533 to J.J.C.)a Scientific Research Project of the Furong Laboratory of Central South University (2023SK2083 to J-Y.Y.)+4 种基金the Natural Science Foundation of Hunan Province(2023JJ40931 to JJ.C 2023JU50251 to J.-C.W,and 2024JJ6633 to Y.W.)the Postdoctoral Fellowship Programof CPSF (GZB20240878 to Y.W.)the Hunan Innovation platform and talent program(2020RC3086 to C.-P.L)the Non-profit Central Research Institute Fund of the Chinese Academyof Medical Scienoes (2020 PT320-004to J.-G.L)the Open Fund for ScientificResearch ofNHC Key Laboratory of Personalized Diagnosis and Treatment of Nasopharyn-geal Carcinoma (2021NPCK01 to J.-Y.Y.).
文摘Pharmacogenomic landscapes and related databases are important for identifying the biomarkers of drug response and toxicity.However,these data are still lacking for the Chinese population.In this study,we constructed a pharmacogenomic landscape and an associated database using whole-genome sequencing data generated by non-invasive prenatal testing in 206,640 Chinese individuals.In total,1,577,513 variants(including 331,610 novel variants)were identified among 3,538 pharmacogenes related to 2,086 drugs.We found that the variant spectrum in the Chinese population differed among the seven major regions.Regional differences also exist among provinces in China.The average numbers of drug enzyme,transporter,and receptor variants were 258,557,and 632,respectively.Subsequent correlation analysis indicated that the pharmacogenes affecting multiple drugs had fewer variants.Among the 16 categories of drugs,we found that nervous system,cardiovascular system,and genitourinary system/sex hormone drugs were more likely to be affected by variants of pharmacogenes.Characteristics of the variants in the enzyme,transporter,and receptor subfamilies showed specificity.To explore the clinical utility of these data,a genetic association study was conducted on 1,019 lung cancer patients.Two novel variants,AKT2 chr19:40770621 C>G and SLC19A1 chr21:46934171 A>C,were identified as novel platinum response biomarkers.Finally,a pharmacogenomic database,named the Chinese Pharmacogenomic Knowledge Base(CNPKB:http://www.cnpkb.com.cn/),was constructed to collect all the data.In summary,a pharmacogenomic landscape and database for the Chinese population were constructed in this study,which could support personalized Chinese medicine in the future.
文摘Background The preclinical experiments and studies of congener drugs show icotinib, a new epidermal growth factor receptor （EGFR） tyrosine kinase inhibitor, can specifically bind to the tyrosine kinase domain of the EGFR, block the EGFR related signal, thereby inhibit the growth of tumor cell. The objective of this study was to investigate the safety, tolerability and dose-related biologic effects of icotinib in patients with non-small cell lung cancer （NSCLC） in a Chinese patient population. Methods This was an open-label, phase I, dose escalation, safety/tolerability trial of oral icotinib （100 to 400 mg）, administered twice per day for 28-continuous-day cycles until disease progression or undue toxicity. Results Forty patients with stage IIIB （15%） or IV （85%） NSCLC were included in the study. They had mainly adenocarcinoma （85%）, with a performance status （PS） of 0 （45%） or 1 （55%） and less than half the patients （45%） had histories of smoking and all were pretreated by at least one regimen of chemotherapy. Patients were assigned to three dose levels of 150 mg b.i.d, 200 mg b.i.d, or 125 mg t.i.d. The follow-up periods ranged from 5 to 80 weeks. Adverse events were found in 35% patients, most of which were mild and reversible. The adverse events mainly occurred in the first 4 weeks and included rash （25%）, diarrhea, nausea and abdominal distention. One definite interstitial lung disease （ILD） was found in a patient in the dose of 200 mg b.i.d. According to an 8-week assessment, one （2.5%） patient receiving 150 mg gained complete response （CR） that persisted for 44 weeks, seven （17.50%） patients had partial remission （PR）, and 18 （45%） patients had stable disease （SD）. The objective response including CR＋PR was 20%. The median time of progression-free survival for the 40 patients was 20 weeks （range： 12 to 32 weeks）. The response was not affected by pathological type, history of smoking, or numbers of previous therapeutic regimens. No relationship between dose, response, adverse effect, or duration of the study was observed. Conclusions Icotinib, given as oral twice daily, showed favorable safety and tolerability. Mild and reversible rash, diarrhea, and nausea were the main adverse events. Antitumor activity was obvious at each dose in heavily pretreated patients. Pharmacodynamic evaluations and further phase II/III trials are in progress.
基金support of National Special Project for Significant Drugs Development(2018ZX09711002-010-002,China)National Natural Science Foundation of China(81925035 and 81521005,China)+3 种基金Shanghai Sci-Tech Innovation Initiative(19431903100,18430740800,China)the Shanghai Collaborative Innovation Group of Early Diagnosis and Precise Treatment of Hemangiomas and Vascular Malformations(SSMUZDCX20180701,China)the Sanofi-SIBS Yong Faculty Award,and The Youth Innovation Promotion Association。
文摘The spread of coronavirus disease 2019(COVID-19)throughout the world has resulted in stressful healthcare burdens and global health crises.Developing an effective measure to protect people from infection is an urgent need.The blockage of interaction between angiotensin-converting enzyme 2(ACE2)and S protein is considered an essential target for anti-severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)drugs.A full-length ACE2 protein could be a potential drug to block early entry of SARS-Co V-2 into host cells.In this study,a therapeutic strategy was developed by using extracellular vesicles(EVs)with decoy receptor ACE2 for neutralization of SARS-Co V-2.The EVs embedded with engineered ACE2(EVs-ACE2)were prepared;the EVs-ACE2 were derived from an engineered cell line with stable ACE2 expression.The potential effect of the EVs-ACE2 on anti-SARS-Co V-2 was demonstrated by both in vitro and in vivo neutralization experiments using the pseudovirus with the S protein(S-pseudovirus).EVs-ACE2 can inhibit the infection of S-pseudovirus in various cells,and importantly,the mice treated with intranasal administration of EVs-ACE2 can suppress the entry of S-pseudovirus into the mucosal epithelium.Therefore,the intranasal EVs-ACE2 could be a preventive medicine to protect from SARS-Co V-2 infection.This EVs-based strategy offers a potential route to COVID-19 drug development.
基金supported by the National Natural Science Foundation of China(82450103,82373962,82073943 to Jiye Yin,and 82173901 to Zhaoqian Liu,82204533 to Jiajia Cui)Scientific research project of Furong laboratory of Central South University(No.2023SK2083,China)+10 种基金The Natural Science Foundation of Hunan Province of China(2023JJ40931 to Jiajia Cui,2023JJ30822 to Chengxian Guo,2024JJ6633 to Yang Wang,2021JJ30428,2024JJ8180 to Juan Chen,2024JJ9245 to Cenhui Luo,2021JJ80087 to Liansheng Wang)Major Project of Natural Science Foundation of Hunan Province of China(Open competition,2021 JC0002 to Zhaoqian Liu)Hunan Province key research and development plan of China(2023SK2007 to Zhaoqian Liu)Science and Technology Program of Changsha of China(kh2003010 to Zhaoqian Liu)the Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University(YX202110 to Chengxian Guo,China)China Postdoctoral Science Foundation(2023M733973 to Juan Chen)and the Hunan Cancer Hospital Climb Plan(YF2020011 to Chenhui Luo,China)Health Research Project of Hunan Provincial Health Commission(B202305017863 to Chenhui Luo,China)the Association Foundation Program of Yunnan Provincial Science and Technology Department and Kunming Medical University(202001AY070001-282 to Jianming Xia,China)Open Fund of Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research(ZDSYS20220606100801003 to Jiajia Cui,China)The Postdoctoral Fellowship Program of CPSF(GZB20240878 to Yang Wang,China)supported by the High Performance Computing Center of Central South University.
文摘eIF3a is a N^(6)-methyladenosine(m^(6)A)reader that regulates mRNA translation by recognizing m^(6)A modifications of these mRNAs.It has been suggested that eIF3a may play an important role in regulating translation initiation via m^(6)A during infection when canonical cap-dependent initiation is inhibited.However,the death of animal model studies impedes our understanding of the functional significance of eIF3a in immunity and regulation in vivo.In this study,we investigated the in vivo function of eIF3a using eIF3a knockout and knockdown mouse models and found that eIF3a deficiency resulted in splenic tissue structural disruption and multi-organ damage,which contributed to severe sepsis induced by Lipopolysaccharide(LPS).Ectopic eIF3a overexpression in the eIF3a knockdown mice rescued mice from LPS-induced severe sepsis.We further showed that eIF3a maintains a functional and healthy immune system by regulating B cell function and quantity through m^(6)A modification of mRNAs.These findings unveil a novel mechanism underlying sepsis,implicating the pivotal role of B cells in this complex disease process regulated by eIF3a.Furthermore,eIF3a may be used to develop a potential strategy for treating sepsis.
基金Supported by Natural Science Foundation of China(No.81503560)“Ten Diseases and Ten Drugs”Program and the Cultivation Research of Biological Medicine and Life Science Innovation of Beijing Municipal Science and Technology Commission(No.Z141100002214012,Z161100000116046)。
文摘Objective To investigate the mechanism of Tojapride,a Chinese herbal formula extract,on strengthening the barrier function of esophageal epithelium in rats with reflux esophagitis(RE).Methods Ten out of 85 SD rats were randomly selected as the sham group(n10),and 75 rats were developed a reflux esophagitis model(RE)by the esophageal and duodenal side-to-side anastomosis.Fifty successful modeling rats were divided into different medicated groups through a random number table including the model,low-,medium-,and high-dose of Tojapride as well as omeprazole groups(n10).Three doses of Tojapride[5.73,11.46,22.92 g/(kg•d)]and omeprazole[4.17 mg/(kg•d)]were administrated intragastrically twice daily for 3 weeks.And the rats in the sham and model groups were administered 10 mL/kg distilled water.Gastric fluid was collected and the supernatant was kept to measure for volume,pH value and acidity.Esophageal tissues were isolated to monitor the morphological changes through hematoxylin-eosin(HE)staining,and esophageal epithelial ultrastructure was observed by transmission electron microscopy.The expressions of nuclear factor kappa-light-chain-enhancer of activated B cells p65(NF-KBp65),κB kinase beta(IKKß),occludin,and zonula occludens-1(ZO-1)in the esophageal tissues were measured by immunohistochemistry and Western blot,respectively.Results The gastric pH value in the model group was significantly lower than the sham group(P<0.05).Compared with the model group,gastric pH value in the omeprazole and medium-dose of Tojapride groups were significantly higher(P<0.05).A large area of ulceration was found on the esophageal mucosa from the model rats,while varying degrees of congestion and partially visible erosion was observed in the remaining groups.Remarkable increase in cell gap width and decrease in desmosome count was seen in RE rats and the effect was reversed by Tojapride treatment.Compared with the sham group,the IKKßlevels were significantly higher in the model group(P<0.05).However,the IKKßlevels were down-regulated after treatment by all doses of Tojapride(P<0.01 or P<0.05).The occluding and ZO-1 levels decreased in the model group compared with the sham group(Ps0.01 or Ps0.05),while both indices were significantly up-regulated in the Tojapride-treated groups(P<0.01 or P<0.05).Conclusions Tojapride could improve the pathological conditions of esophageal epithelium in RE rats.The underlying mechanisms may involve in down-regulating the IKKßexpression and elevating ZO-1 and occludin expression,thereby alleviating the inflammation of the esophagus and strengthening the barrier function of the esophageal epithelium.
