Objective This study aimed to investigate the therapeutic effects and underlying mechanisms of the combination of Yinchenhao decoction(YCHD)and praziquantel(PZQ)in a Schistosoma japonicum(S.japonicum)-induced mouse mo...Objective This study aimed to investigate the therapeutic effects and underlying mechanisms of the combination of Yinchenhao decoction(YCHD)and praziquantel(PZQ)in a Schistosoma japonicum(S.japonicum)-induced mouse model of schistosomiasis.Methods Six-week-old male BALB/c mice were randomly divided into five groups:control group,infected group,infected-PZQ group(I-PZQ),infected-YCHD group(I-YCHD),and infected-PZQ+YCHD group(I-PZQ+YCHD).The mice were infected with S.japonicum cercariae in infected group,I-PZQ group,I-YCHD group,and I-PZQ+YCHD group(n=6 per group)and maintained for 63 days.From day 43 to day 63 postinfection,the mice received PZQ(150 mg/kg,intragastric gavage),YCHD(10 mL/kg,intragastric gavage),or a combination of both.The control and infected groups received equal amounts of sterile double-distilled water for the same period.At the end of the experiment,the mice were anesthetized with pentobarbital sodium and sacrificed.Serum alanine transaminase(ALT)and aspartate transaminase(AST)levels were measured.Network pharmacology analysis was used to predict the targets of YCHD in the treatment of schistosomiasis.Histopathological analysis,Western blotting,immunofluorescence,quantitative polymerase chain reaction and flow cytometry were employed to evaluate liver pathology and molecular changes.Results Compared with the other groups,the I-PZQ+YCHD group presented significantly decreased serum ALT and AST levels(P<0.001).The I-PZQ+YCHD group exhibited improved pathological changes in the liver,as evidenced by reduced area of single granuloma(P<0.01),granuloma area(P<0.01),and Ishak score of liver fibrosis(P<0.01).Network pharmacology analysis suggested that YCHD may alleviate schistosomiasis-related liver injury through the modulation of the endoplasmic reticulum stress(ERS)pathway.Western blot analysis revealed that ERS-related markers,including glucose-regulated protein 78(GRP78),inositol-requiring enzyme 1 alpha(IRE1α),X-box binding protein 1(XBP-1),and C/EBP homologous protein(CHOP),were significantly downregulated in the I-PZQ+YCHD group(P<0.05).Furthermore,the I-PZQ+YCHD group presented reduced hepatocyte apoptosis(P<0.05),diminished hepatic macrophage infiltration(P<0.05)and downregulated expression of proinflammatory cytokines(TNF-α,IL-1βand IL-6)(P<0.05).Conclusion YCHD combined with PZQ reduced schistosomiasis-associated hepatic granulomatous inflammation and fibrosis by inhibiting hepatic apoptosis and ERS.展开更多
Objective:Osimertinib(OSI)therapy,a cornerstone in treating non-small cell lung cancer(NSCLC),has been severely limited by rapidly developing acquired resistance.Inhibition of bypass activation using a combination str...Objective:Osimertinib(OSI)therapy,a cornerstone in treating non-small cell lung cancer(NSCLC),has been severely limited by rapidly developing acquired resistance.Inhibition of bypass activation using a combination strategy holds promise in overcoming this resistance.Biguanides,with excellent anti-tumor effects,have recently attracted much attention for this potential.The current study investigated whether novel biguanide compounds developed by our team could overcome OSI resistance and the underlying mechanisms were explored.Methods:A comprehensive screening assay using OSI-resistant cells identified the optimal combination of biguanide compounds with OSI.Proteomics,co-immunoprecipitation mass spectrometry,RNA sequencing,and homologous recombination assays were used to elucidate the molecular mechanisms underlying combination therapy.NSCLC tumor tissues,especially OSI-resistant tissues,obtained from our clinic were used to assess the correlations between key proteins and OSI resistance.Results:SMK-010,a highly potent biguanide compound,effectively overcame OSI resistance in vitro and in vivo.Mechanistical studies showed that BMI1/FGFR1 pathway activation is responsible for OSI resistance.Specifically,silencing BMI1 promoted NEDD4-mediated FGFR1 ubiquitination and proteasomal degradation,whereas SMK-010 treatment induced FGFR1 lysosomal degradation.This reduction in FGFR1 levels impaired homologous recombination,increased DNA damage,and surmounted OSI resistance.Analysis of clinical samples revealed overexpression of BMI1 and FGFR1 in NSCLC tissues and represented potential biomarkers for OSI resistance.Conclusions:These findings highlight the crucial role of the BMI1/FGFR1 axis in OSI resistance and provide a rational basis for the future clinical application of the biguanide,SMK-010,in combination with OSI.展开更多
Pyridyl-based ketones and 1,6-diketones are both attractive and invaluable scaffolds which play pivotal roles in the construction and structural modification of a plethora of synthetically paramount natural products,p...Pyridyl-based ketones and 1,6-diketones are both attractive and invaluable scaffolds which play pivotal roles in the construction and structural modification of a plethora of synthetically paramount natural products,pharmaceuticals,organic materials and fine chemicals.In this context,we herein demonstrate an unprecedented,robust and generally applicable synthetically strategy to deliver these two crucial ketone frameworks via visible-light-induced ring-opening coupling reactions of cycloalcohols with vinylazaarenes and enones,respectively.A plausible mechanism involves the selectiveβ-C-C bond cleavage of cycloalcohols enabled by proton-coupled electron transfer and ensuing Giese-type addition followed by single electron reduction and protonation.The synthetic methodology exhibits broad substrate scope,excellent functional group compatibility as well as operational simplicity and environmental friendliness.展开更多
BACKGROUND The methylated septin 9(mSEPT9) assay was the first blood-based test approved by the United States Food and Drug Administration as a colorectal screening test.However, the diagnostic and prognostic role of ...BACKGROUND The methylated septin 9(mSEPT9) assay was the first blood-based test approved by the United States Food and Drug Administration as a colorectal screening test.However, the diagnostic and prognostic role of preoperative mSEPT9 for colorectal cancer(CRC) in Chinese patients is still unknown.AIM To improve the understanding of diagnostic and prognostic factors, serum m SEPT9 was detected in Chinese CRC patients.METHODS A retrospective analysis of 354 cases, of which 300 had CRC and 54 were normal,was performed in China. Patients' characteristics, treatments, and laboratory data, including age, the date of surgery, Union for International Cancer Control(UICC) stages, distant metastasis(M), and so on, were collected. Methylation levels of SEPT9 were quantified by quantitative, methylation-specific polymerase chain reaction before surgery. In addition, the effects of mSEPT9 on the occurrence and prognosis of 330 CRC cases from The Cancer Genome Atlas(TCGA) database were evaluated using bioinformatics analyses. Potential prognostic factors for overall survival(OS) and progression-free survival(PFS)were evaluated by Kaplan-Meier univariate analysis.RESULTSIn Chinese CRC patients, positive mSEPT9 was strongly associated with advanced UICC stages, deeper invasion by the primary tumor, and more distant metastasis. Methylation levels of SEPT9 were stage-dependent and showed a stepwise increase in UICC stages(I–IV), primary tumor categories(T1–T4),regional node categories(N0–N2), and distant metastasis categories(M0–M1).The patients with positive mSEPT9 showed a tendency toward lower PFS. After analyzing TCGA clinical data, the high mSEPT9 group was found to be obviously correlated only with more distant metastasis. The patients with high mSEPT9 levels showed a tendency toward lower OS. Besides, nine meaningful mSEPT9 sites were found to provide guidance for the follow-up studies.CONCLUSION MSEPT9 analysis may add valuable information to current tumor staging. Serum m SEPT9 in Chinese CRC patients appears to offer promising novel prognostic markers and might be considered for monitoring CRC recurrence.展开更多
Artificial intelligence(AI)is playing an increasingly important role in medicine,especially in the field of medical imaging.It can be used to diagnose diseases and predict certain statuses and possible events that may...Artificial intelligence(AI)is playing an increasingly important role in medicine,especially in the field of medical imaging.It can be used to diagnose diseases and predict certain statuses and possible events that may happen.Recently,more and more studies have confirmed the value of AI based on ultrasound in the evaluation of diffuse liver diseases and focal liver lesions.It can assess the severity of liver fibrosis and nonalcoholic fatty liver,differentially diagnose benign and malignant liver lesions,distinguish primary from secondary liver cancers,predict the curative effect of liver cancer treatment and recurrence after treatment,and predict microvascular invasion in hepatocellular carcinoma.The findings from these studies have great clinical application potential in the near future.The purpose of this review is to comprehensively introduce the current status and future perspectives of AI in liver ultrasound.展开更多
Objective: To define the conditions of hepatitis C vi- rus (HCV) infections, and geographic and demo- graphic distributions of genotypes in China. Methods: HCV infected patients were selected from individuals with dif...Objective: To define the conditions of hepatitis C vi- rus (HCV) infections, and geographic and demo- graphic distributions of genotypes in China. Methods: HCV infected patients were selected from individuals with different patterns of liver diseases and high risk populations in different parts of China. Genotypes of HCV in some isolates were further ana- lyzed, based on the data from our laboratory studies and some carefully selected published literatures. Results: The anti-HCV positive rates were 9.7% in patients with acute hepatitis, 13.3% in patients with chronic hepatitis, 18.3% in patients with hepatocel- lular carcinoma, 33.0% in patients with liver cirrho- sis, and 43.2% in patients with posttransfusional hepatitis (average, 16.2% in patients with liver di- seases). The anti-HCV positive rates in the high risk populations were 36.4% in leukemic patients, 43.0% in hemodialysis patients, 12.7% in blood do- nors, 64.1% in drug abusers, 13.1% in prostitutes, and 2.57% in naturally healthy people. At least 4 clades (clades 1, 2, 3 and 6) of HCV were found in China with different geographic and demographic distributions. Genotype 1b was the most widely dis- tributed genotype, and genotype 3 was mainly found in Yunnan Province, Southwest China. Conclusion: China has a high incidence of HCV in- fection. Our results will provide a strategic basis for diagnosis, treatment and possibly prophylaxis of he- patitis C virus diseases.展开更多
基金supported by the National Natural Science Foundation of China(No.81802036 and No.81876182).
文摘Objective This study aimed to investigate the therapeutic effects and underlying mechanisms of the combination of Yinchenhao decoction(YCHD)and praziquantel(PZQ)in a Schistosoma japonicum(S.japonicum)-induced mouse model of schistosomiasis.Methods Six-week-old male BALB/c mice were randomly divided into five groups:control group,infected group,infected-PZQ group(I-PZQ),infected-YCHD group(I-YCHD),and infected-PZQ+YCHD group(I-PZQ+YCHD).The mice were infected with S.japonicum cercariae in infected group,I-PZQ group,I-YCHD group,and I-PZQ+YCHD group(n=6 per group)and maintained for 63 days.From day 43 to day 63 postinfection,the mice received PZQ(150 mg/kg,intragastric gavage),YCHD(10 mL/kg,intragastric gavage),or a combination of both.The control and infected groups received equal amounts of sterile double-distilled water for the same period.At the end of the experiment,the mice were anesthetized with pentobarbital sodium and sacrificed.Serum alanine transaminase(ALT)and aspartate transaminase(AST)levels were measured.Network pharmacology analysis was used to predict the targets of YCHD in the treatment of schistosomiasis.Histopathological analysis,Western blotting,immunofluorescence,quantitative polymerase chain reaction and flow cytometry were employed to evaluate liver pathology and molecular changes.Results Compared with the other groups,the I-PZQ+YCHD group presented significantly decreased serum ALT and AST levels(P<0.001).The I-PZQ+YCHD group exhibited improved pathological changes in the liver,as evidenced by reduced area of single granuloma(P<0.01),granuloma area(P<0.01),and Ishak score of liver fibrosis(P<0.01).Network pharmacology analysis suggested that YCHD may alleviate schistosomiasis-related liver injury through the modulation of the endoplasmic reticulum stress(ERS)pathway.Western blot analysis revealed that ERS-related markers,including glucose-regulated protein 78(GRP78),inositol-requiring enzyme 1 alpha(IRE1α),X-box binding protein 1(XBP-1),and C/EBP homologous protein(CHOP),were significantly downregulated in the I-PZQ+YCHD group(P<0.05).Furthermore,the I-PZQ+YCHD group presented reduced hepatocyte apoptosis(P<0.05),diminished hepatic macrophage infiltration(P<0.05)and downregulated expression of proinflammatory cytokines(TNF-α,IL-1βand IL-6)(P<0.05).Conclusion YCHD combined with PZQ reduced schistosomiasis-associated hepatic granulomatous inflammation and fibrosis by inhibiting hepatic apoptosis and ERS.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82172653 and 82472728)the Key Project of Developmental Biology and Breeding from Hunan Province(Grant No.2022XKQ0205)+1 种基金the Research Team for Reproduction Health and Translational Medicine of Hunan Normal University(Grant No.2023JC101)the Natural Science Foundation of Hunan Province(Grant No.2025JJ80150).
文摘Objective:Osimertinib(OSI)therapy,a cornerstone in treating non-small cell lung cancer(NSCLC),has been severely limited by rapidly developing acquired resistance.Inhibition of bypass activation using a combination strategy holds promise in overcoming this resistance.Biguanides,with excellent anti-tumor effects,have recently attracted much attention for this potential.The current study investigated whether novel biguanide compounds developed by our team could overcome OSI resistance and the underlying mechanisms were explored.Methods:A comprehensive screening assay using OSI-resistant cells identified the optimal combination of biguanide compounds with OSI.Proteomics,co-immunoprecipitation mass spectrometry,RNA sequencing,and homologous recombination assays were used to elucidate the molecular mechanisms underlying combination therapy.NSCLC tumor tissues,especially OSI-resistant tissues,obtained from our clinic were used to assess the correlations between key proteins and OSI resistance.Results:SMK-010,a highly potent biguanide compound,effectively overcame OSI resistance in vitro and in vivo.Mechanistical studies showed that BMI1/FGFR1 pathway activation is responsible for OSI resistance.Specifically,silencing BMI1 promoted NEDD4-mediated FGFR1 ubiquitination and proteasomal degradation,whereas SMK-010 treatment induced FGFR1 lysosomal degradation.This reduction in FGFR1 levels impaired homologous recombination,increased DNA damage,and surmounted OSI resistance.Analysis of clinical samples revealed overexpression of BMI1 and FGFR1 in NSCLC tissues and represented potential biomarkers for OSI resistance.Conclusions:These findings highlight the crucial role of the BMI1/FGFR1 axis in OSI resistance and provide a rational basis for the future clinical application of the biguanide,SMK-010,in combination with OSI.
基金financial support from National Natural Science Foundation of China(Nos.21801129,22078153 and22378201)National Key Research and Development Program of China(No.2022YFB3805603)+3 种基金Natural science research projects in Jiangsu Higher Education Institutions(No.18KJB150018)Open Research Fund of School of Chemistry and Chemical EngineeringHenan Normal University(No.2024Y16)Nanjing Tech University(Start-up Grant Nos.39837137,39837101 and 3827401739)for financial support。
文摘Pyridyl-based ketones and 1,6-diketones are both attractive and invaluable scaffolds which play pivotal roles in the construction and structural modification of a plethora of synthetically paramount natural products,pharmaceuticals,organic materials and fine chemicals.In this context,we herein demonstrate an unprecedented,robust and generally applicable synthetically strategy to deliver these two crucial ketone frameworks via visible-light-induced ring-opening coupling reactions of cycloalcohols with vinylazaarenes and enones,respectively.A plausible mechanism involves the selectiveβ-C-C bond cleavage of cycloalcohols enabled by proton-coupled electron transfer and ensuing Giese-type addition followed by single electron reduction and protonation.The synthetic methodology exhibits broad substrate scope,excellent functional group compatibility as well as operational simplicity and environmental friendliness.
文摘目的 :比较改良牙支持式上颌骨前部牵引成骨术(anterior maxillary segmental distraction osteogenesis,AMSDO)及上颌骨Le Fort I型截骨术对唇腭裂(cleft lip palate,CLP)患者腭咽部结构的影响。方法:选择32例唇腭裂继发上颌骨发育不足患者,分为AMSDO组(16例)和上颌骨Le Fort I型截骨术组(16例)。治疗前(T1)和治疗后6个月(T2)拍摄头颅定位侧位片,对腭咽部结构进行测量。采用SPSS 12.0软件包对数据进行统计学分析。结果:AMSDO组治疗前、后腭咽部结构测量参数变化无显著差异,Le Fort I型组咽腔深度平均增加3.13 mm、软硬腭交角增加4.3°,腭咽闭合需值(need ratio)平均值大于术前0.11,差异有统计学意义(P<0.05)。结论:AMSDO对腭咽部结构的影响微小,腭咽闭合基本无变化。Le Fort I组术后结果提示可能造成腭咽闭合功能恶化及腭咽部结构适应性代偿。
基金Supported by the National Natural Science Foundation of China,No.81803035,No.81703036,and No.81572946the China Postdoctoral Science Foundation,No.2017M610510the Youth Fund of Xiangya Hospital,No.2017Q17
文摘BACKGROUND The methylated septin 9(mSEPT9) assay was the first blood-based test approved by the United States Food and Drug Administration as a colorectal screening test.However, the diagnostic and prognostic role of preoperative mSEPT9 for colorectal cancer(CRC) in Chinese patients is still unknown.AIM To improve the understanding of diagnostic and prognostic factors, serum m SEPT9 was detected in Chinese CRC patients.METHODS A retrospective analysis of 354 cases, of which 300 had CRC and 54 were normal,was performed in China. Patients' characteristics, treatments, and laboratory data, including age, the date of surgery, Union for International Cancer Control(UICC) stages, distant metastasis(M), and so on, were collected. Methylation levels of SEPT9 were quantified by quantitative, methylation-specific polymerase chain reaction before surgery. In addition, the effects of mSEPT9 on the occurrence and prognosis of 330 CRC cases from The Cancer Genome Atlas(TCGA) database were evaluated using bioinformatics analyses. Potential prognostic factors for overall survival(OS) and progression-free survival(PFS)were evaluated by Kaplan-Meier univariate analysis.RESULTSIn Chinese CRC patients, positive mSEPT9 was strongly associated with advanced UICC stages, deeper invasion by the primary tumor, and more distant metastasis. Methylation levels of SEPT9 were stage-dependent and showed a stepwise increase in UICC stages(I–IV), primary tumor categories(T1–T4),regional node categories(N0–N2), and distant metastasis categories(M0–M1).The patients with positive mSEPT9 showed a tendency toward lower PFS. After analyzing TCGA clinical data, the high mSEPT9 group was found to be obviously correlated only with more distant metastasis. The patients with high mSEPT9 levels showed a tendency toward lower OS. Besides, nine meaningful mSEPT9 sites were found to provide guidance for the follow-up studies.CONCLUSION MSEPT9 analysis may add valuable information to current tumor staging. Serum m SEPT9 in Chinese CRC patients appears to offer promising novel prognostic markers and might be considered for monitoring CRC recurrence.
基金Supported by National Natural Science Foundation of China,No.820719532020 Hunan Province Clinical Medical Technology Innovation Guidance Project.
文摘Artificial intelligence(AI)is playing an increasingly important role in medicine,especially in the field of medical imaging.It can be used to diagnose diseases and predict certain statuses and possible events that may happen.Recently,more and more studies have confirmed the value of AI based on ultrasound in the evaluation of diffuse liver diseases and focal liver lesions.It can assess the severity of liver fibrosis and nonalcoholic fatty liver,differentially diagnose benign and malignant liver lesions,distinguish primary from secondary liver cancers,predict the curative effect of liver cancer treatment and recurrence after treatment,and predict microvascular invasion in hepatocellular carcinoma.The findings from these studies have great clinical application potential in the near future.The purpose of this review is to comprehensively introduce the current status and future perspectives of AI in liver ultrasound.
文摘Objective: To define the conditions of hepatitis C vi- rus (HCV) infections, and geographic and demo- graphic distributions of genotypes in China. Methods: HCV infected patients were selected from individuals with different patterns of liver diseases and high risk populations in different parts of China. Genotypes of HCV in some isolates were further ana- lyzed, based on the data from our laboratory studies and some carefully selected published literatures. Results: The anti-HCV positive rates were 9.7% in patients with acute hepatitis, 13.3% in patients with chronic hepatitis, 18.3% in patients with hepatocel- lular carcinoma, 33.0% in patients with liver cirrho- sis, and 43.2% in patients with posttransfusional hepatitis (average, 16.2% in patients with liver di- seases). The anti-HCV positive rates in the high risk populations were 36.4% in leukemic patients, 43.0% in hemodialysis patients, 12.7% in blood do- nors, 64.1% in drug abusers, 13.1% in prostitutes, and 2.57% in naturally healthy people. At least 4 clades (clades 1, 2, 3 and 6) of HCV were found in China with different geographic and demographic distributions. Genotype 1b was the most widely dis- tributed genotype, and genotype 3 was mainly found in Yunnan Province, Southwest China. Conclusion: China has a high incidence of HCV in- fection. Our results will provide a strategic basis for diagnosis, treatment and possibly prophylaxis of he- patitis C virus diseases.
