Hyperglycemia in individuals with diabetes causes cognitive impairment,called diabetic encephalopathy(DE).The pathogenesis of DE is closely related to angiopathy,and effective treatment is highly desirable.The botanic...Hyperglycemia in individuals with diabetes causes cognitive impairment,called diabetic encephalopathy(DE).The pathogenesis of DE is closely related to angiopathy,and effective treatment is highly desirable.The botanical agent berberine(BBR)effectively lowers blood glucose in diabetic patients.Here,we show for the first time that BBR significantly improved cognitive function in type 2 diabetic encephalopathy KK-Ay(2DEK)mice.High-resolution imaging via fluorescence micro-optical sectioning tomography(fMOST)revealed that the integrity of brain vessels was improved by BBR treatment.The improvements in average vessel diameter,vessel length,and total vessel volume were significant in the parietal association cortex(PtA),as well as in the CA1 and CA3 regions.A mechanistic study revealed that oral BBR inhibited δ-valerobetaine(δ-VB,a metabolite of the gut microbiota)production in the intestine.As intestinal δ-VB can enter the circulation and activate the Toll-like receptor-4(TLR-4)/myeloid differentiation factor 88(MyD88)/nuclear factor kappa B(NF-jB)inflammatory pathway in the epithelial cells of blood vessels through interacting with TLR-4,BBR might reduce the intestinal level of δ-VB to protect the cerebral blood vessels of DE mice and improve their brain function.Fecal microbiota transplantation(FMT)using the gut microbiota from BBR-treated mice confirmed the vital role of the gut microbiota.BBR showed a wide range of effects on the gut flora,also increasing short-chain fatty acid(SCFA)production and decreasing lipopolysaccharide(LPS)levels in the intestine by adjusting the abundance of SCFA-or LPS-producing bacteria.The observed therapeutic efficacy in vivo revealed a synergistic effect of BBR on the gut microbiota.Conclusively,we found an association between the gut microbiota and blood vessels,of which intestinal δ-VB might be a chemical link.Mainly through downregulating δ-VB in the intestine,BBR protected cerebral vessels and alleviated DE.展开更多
Specnuezhenide(SNZ)is among the main components of Fructus Ligustri Lucidi,which has antiinflammation,anti-oxidation,and anti-tumor effect.The low bioavailability makes it difficult to explain the mechanism of pharmac...Specnuezhenide(SNZ)is among the main components of Fructus Ligustri Lucidi,which has antiinflammation,anti-oxidation,and anti-tumor effect.The low bioavailability makes it difficult to explain the mechanism of pharmacological effect of SNZ.In this study,the role of the gut microbiota in the metabolism and pharmacokinetics characteristics of SNZ as well as the pharmacological meaning were explored.SNZ can be rapidly metabolized by the gut microbiome,and two intestinal bacterial metabolites of SNZ,salidroside and tyrosol,were discovered.In addition,carboxylesterase may be the main intestinal bacterial enzyme that mediates its metabolism.At the same time,no metabolism was found in the incubation system of SNZ with liver microsomes or liver homogenate,indicating that the gut microbiota is the main part involved in the metabolism of SNZ.In addition,pharmacokinetic studies showed that salidroside and tyrosol can be detected in plasma in the presence of gut microbiota.Interestingly,tumor development was inhibited in a colorectal tumor mice model administered orally with SNZ,which indicated that SNZ exhibited potential to inhibit tumor growth,and tissue distribution studies showed that salidroside and tyrosol could be distributed in tumor tissues.At the same time,SNZ modulated the structure of gut microbiota and fungal group,which may be the mechanism governing the antitumoral activity of SNZ.Furthermore,SNZ stimulates the secretion of short-chain fatty acids by intestinal flora in vitro and in vivo.In the future,targeting gut microbes and the interaction between natural products and gut microbes could lead to the discovery and development of new drugs.展开更多
BACKGROUND Borrmann classification(types I-IV)for the detection of advanced gastric cancer has been accepted worldwide,and lymphatic and/or blood vessel invasion(LBVI)status is related to the poor prognosis after gast...BACKGROUND Borrmann classification(types I-IV)for the detection of advanced gastric cancer has been accepted worldwide,and lymphatic and/or blood vessel invasion(LBVI)status is related to the poor prognosis after gastric cancer.AIM To evaluate the significance of Borrmann type combined with LBVI status in predicting the prognosis of advanced gastric cancer.METHODS We retrospectively studied the clinicopathological characteristics and long-term survival data of 2604 patients who were diagnosed with advanced gastric adenocarcinoma at Harbin Medical University Cancer Hospital from January 2009 to December 2013.Categorical variables were evaluated by the Pearson’sχ^2 test,the Kaplan-Meier method was used to identify differences in cumulative survival rates,and the Cox proportional hazards model was used for multivariate prognostic analysis.RESULTS A total of 2604 patients were included in this study.The presence of LVBI[LBVI(+)]and Borrmann type(P=0.001),tumor location(P<0.001),tumor size(P<0.001),histological type(P<0.001),tumor invasion depth(P<0.001),number of metastatic lymph nodes(P<0.001),and surgical method(P<0.001)were significantly correlated with survival.When analyzing the combination of the Borrmann classification and LBVI status,we found that patients with Borrmann type Ⅲ disease and LBVI(+)had a similar 5-year survival rate to those with Borrmann IV+LBVI(-)(16.4%vs 13.1%,P=0.065)and those with Borrmann IV+LBVI(+)(16.4%vs 11.2%,P=0.112).Subgroup analysis showed that the above results were true for any pT stage and any tumor location.Multivariate Cox regression analysis showed that Borrmann classification(P=0.023),vascular infiltration(P<0.001),tumor size(P=0.012),pT stage(P<0.001),pN stage(P<0.001),and extent of radical surgery(P<0.001)were independent prognostic factors for survival.CONCLUSION Since patients with Borrmann Ⅲ disease and LBVI(+)have the same poor prognosis as those with Borrmann IV disease,more attention should be paid to patients with Borrmann Ⅲ disease and LBVI(+)during diagnosis and treatment,regardless of the pT stage and tumor location,to obtain better survival results.展开更多
BACKGROUND Through analyzing the data from a single institution in Northeast China,this study revealed the possible clinicopathologic characteristics that influence the prognosis of patients with gastric cancer(GC).AI...BACKGROUND Through analyzing the data from a single institution in Northeast China,this study revealed the possible clinicopathologic characteristics that influence the prognosis of patients with gastric cancer(GC).AIM To evaluate the changing trends of clinicopathologic features and survival duration after surgery in patients with GC in Northeast China,which is a highprevalence area of GC.METHODS The study analyzed the difference in clinicopathologic features and survival duration after surgery of 5887 patients who were histologically diagnosed with GC at the Harbin Medical University Cancer Hospital.The study mainly analyzed the data in three periods,2000 to 2004(Phase 1),2005 to 2009(Phase 2),and 2010 to 2014(Phase 3).RESULTS Over time,the postoperative survival rate significantly increased from 2000 to 2014.In the past 15 years,compared with Phases 1 and 2,the tumor size was smaller in Phase 3(P<0.001),but the proportion of high-medium differentiated tumors increased(P<0.001).The proportion of early GC gradually increased from 3.9%to 14.4%(P<0.001).A surprising improvement was observed in the mean number of retrieved lymph nodes,ranging from 11.4 to 27.5(P<0.001).The overall 5-year survival rate increased from 24%in Phase 1 to 43.8%in Phase 3.Through multivariate analysis,it was found that age,tumor size,histologic type,tumor-node-metastasis stage,depth of invasion,lymph node metastasis,surgical approach,local infiltration,radical extent,number of retrieved lymph nodes,and age group were independent risk factors that influenced the prognosis of patients with GC.CONCLUSION The clinical features of GC in Northeast China changed during the observation period.The increasing detection of early GC and more standardized surgical treatment effectively prolonged lifetimes.展开更多
In recent decades,the prevalence of hyperuricemia and gout has increased dramatically due to lifestyle changes.The drugs currently recommended for hyperuricemia are associated with adverse reactions that limit their c...In recent decades,the prevalence of hyperuricemia and gout has increased dramatically due to lifestyle changes.The drugs currently recommended for hyperuricemia are associated with adverse reactions that limit their clinical use.In this study,we report that berberine(BBR)is an effective drug candidate for the treatment of hyperuricemia,with its mechanism potentially involving the modulation of gut microbiota and its metabolite,succinic acid.BBR has demonstrated good therapeutic effects in both acute and chronic animal models of hyperuricemia.In a clinical trial,oral administration of BBR for 6 months reduced blood uric acid levels in 22 participants by modulating the gut microbiota,which led to an increase in the abundance of Bacteroides and a decrease in Clostridium sensu stricto_1.Furthermore,Bacteroides fragilis was transplanted into ICR mice,and the results showed that Bacteroides fragilis exerted a therapeutic effect on uric acid similar to that of BBR.Notably,succinic acid,a metabolite of Bacteroides,significantly reduced uric acid levels.Subsequent cell and animal experiments revealed that the intestinal metabolite,succinic acid,regulated the upstream uric acid synthesis pathway in the liver by inhibiting adenosine monophosphate deaminase 2(AMPD2),an enzyme responsible for converting adenosine monophosphate(AMP)to inosine monophosphate(IMP).This inhibition resulted in a decrease in IMP levels and an increase in phosphate levels.The reduction in IMP led to a decreased downstream production of hypoxanthine,xanthine,and uric acid.BBR also demonstrated excellent renoprotective effects,improving nephropathy associated with hyperuricemia.In summary,BBR has the potential to be an effective treatment for hyperuricemia through the gut-liver axis.展开更多
Inter-basin Water Transfer Projects require the appropriate financing model to attract large amounts of social investment.Therefore,financing model decision becomes the key of engineering construction.In three aspects...Inter-basin Water Transfer Projects require the appropriate financing model to attract large amounts of social investment.Therefore,financing model decision becomes the key of engineering construction.In three aspects,such as the subject,the object and the target of the financing model,Grey Target Model is established in this paper.First,the complex financing mode decision problems of Inter-basin Water Transfer Projects are decomposed by using hierarchical decomposition method.Then Analytical Hierarchy Process(AHP) method is used to calculate the comprehensive weight of evaluation index.Experts' opinions financing model are transformed into the evaluation matrix based on the Dephi method.The Weighted Grey Target Model is used to calculate the approaching degree of financing model and assists financing mode decision.In addition,this paper takes the water diversion project from the Han to the Wei River of Shaanxi Province as a verification example for the model.For other water diversion projects,the evaluation results are also reliable and provide theoretical references for the financing model decision of Inter-basin Water Transfer Projects.展开更多
Engineering project management is the whole process of project construction management activities up to the point of achieving the goals of engineering construction, which adopts the means of planning, organizing,lead...Engineering project management is the whole process of project construction management activities up to the point of achieving the goals of engineering construction, which adopts the means of planning, organizing,leading, and controlling. In addition, engineering project management modes are the works of project management and the technical guarantee of project success. For the quality and efficient transformation demands of the Chinese construction industry in the process of marketization, internationalization and informatization, based on the connotation and development path of engineering project management modes, the 16 main and new kinds of project management modes both domestically and abroad are divided into trading mode, financing mode and management mode. These have led to comparative analysis and brief commentary. Finally, it will be pointed out that the engineering project management modes move throughout the whole management process, the combined model and the expansion development of financing model. This work will provide reference for project participants to choose the appropriate project management modes and better understand building company transformation.展开更多
基金funded by the National Key Research and Devel-opment Program of China(2022YFA0806400)the CAMS Innova-tion Fund for Medical Sciences(CIFMS)(2023-I2M-2-006,2021-1-I2M-027,and 2021-1-I2M-028)+1 种基金the National Natural Science Foundation of China(82173888 and 81973290)the Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study(Z141102004414062).
文摘Hyperglycemia in individuals with diabetes causes cognitive impairment,called diabetic encephalopathy(DE).The pathogenesis of DE is closely related to angiopathy,and effective treatment is highly desirable.The botanical agent berberine(BBR)effectively lowers blood glucose in diabetic patients.Here,we show for the first time that BBR significantly improved cognitive function in type 2 diabetic encephalopathy KK-Ay(2DEK)mice.High-resolution imaging via fluorescence micro-optical sectioning tomography(fMOST)revealed that the integrity of brain vessels was improved by BBR treatment.The improvements in average vessel diameter,vessel length,and total vessel volume were significant in the parietal association cortex(PtA),as well as in the CA1 and CA3 regions.A mechanistic study revealed that oral BBR inhibited δ-valerobetaine(δ-VB,a metabolite of the gut microbiota)production in the intestine.As intestinal δ-VB can enter the circulation and activate the Toll-like receptor-4(TLR-4)/myeloid differentiation factor 88(MyD88)/nuclear factor kappa B(NF-jB)inflammatory pathway in the epithelial cells of blood vessels through interacting with TLR-4,BBR might reduce the intestinal level of δ-VB to protect the cerebral blood vessels of DE mice and improve their brain function.Fecal microbiota transplantation(FMT)using the gut microbiota from BBR-treated mice confirmed the vital role of the gut microbiota.BBR showed a wide range of effects on the gut flora,also increasing short-chain fatty acid(SCFA)production and decreasing lipopolysaccharide(LPS)levels in the intestine by adjusting the abundance of SCFA-or LPS-producing bacteria.The observed therapeutic efficacy in vivo revealed a synergistic effect of BBR on the gut microbiota.Conclusively,we found an association between the gut microbiota and blood vessels,of which intestinal δ-VB might be a chemical link.Mainly through downregulating δ-VB in the intestine,BBR protected cerebral vessels and alleviated DE.
基金supported by the National Key R&D Program of China(Grant No.:2022YFA0806400)the CAMS Innovation Fund for Medical Sciences(Grant Nos.:2022-I2M-1-028,2022-I2M-2-002,and 2021-I2M-1-007)+1 种基金the National Natural Science Foundation of China(Grant Nos.:81973290 and 82173888)Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study,China(Grant No.:Z141102004414062)。
文摘Specnuezhenide(SNZ)is among the main components of Fructus Ligustri Lucidi,which has antiinflammation,anti-oxidation,and anti-tumor effect.The low bioavailability makes it difficult to explain the mechanism of pharmacological effect of SNZ.In this study,the role of the gut microbiota in the metabolism and pharmacokinetics characteristics of SNZ as well as the pharmacological meaning were explored.SNZ can be rapidly metabolized by the gut microbiome,and two intestinal bacterial metabolites of SNZ,salidroside and tyrosol,were discovered.In addition,carboxylesterase may be the main intestinal bacterial enzyme that mediates its metabolism.At the same time,no metabolism was found in the incubation system of SNZ with liver microsomes or liver homogenate,indicating that the gut microbiota is the main part involved in the metabolism of SNZ.In addition,pharmacokinetic studies showed that salidroside and tyrosol can be detected in plasma in the presence of gut microbiota.Interestingly,tumor development was inhibited in a colorectal tumor mice model administered orally with SNZ,which indicated that SNZ exhibited potential to inhibit tumor growth,and tissue distribution studies showed that salidroside and tyrosol could be distributed in tumor tissues.At the same time,SNZ modulated the structure of gut microbiota and fungal group,which may be the mechanism governing the antitumoral activity of SNZ.Furthermore,SNZ stimulates the secretion of short-chain fatty acids by intestinal flora in vitro and in vivo.In the future,targeting gut microbes and the interaction between natural products and gut microbes could lead to the discovery and development of new drugs.
基金Supported by Nn10 Program of Harbin Medical University Cancer Hospital,China,No.Nn10 PY 2017-03.
文摘BACKGROUND Borrmann classification(types I-IV)for the detection of advanced gastric cancer has been accepted worldwide,and lymphatic and/or blood vessel invasion(LBVI)status is related to the poor prognosis after gastric cancer.AIM To evaluate the significance of Borrmann type combined with LBVI status in predicting the prognosis of advanced gastric cancer.METHODS We retrospectively studied the clinicopathological characteristics and long-term survival data of 2604 patients who were diagnosed with advanced gastric adenocarcinoma at Harbin Medical University Cancer Hospital from January 2009 to December 2013.Categorical variables were evaluated by the Pearson’sχ^2 test,the Kaplan-Meier method was used to identify differences in cumulative survival rates,and the Cox proportional hazards model was used for multivariate prognostic analysis.RESULTS A total of 2604 patients were included in this study.The presence of LVBI[LBVI(+)]and Borrmann type(P=0.001),tumor location(P<0.001),tumor size(P<0.001),histological type(P<0.001),tumor invasion depth(P<0.001),number of metastatic lymph nodes(P<0.001),and surgical method(P<0.001)were significantly correlated with survival.When analyzing the combination of the Borrmann classification and LBVI status,we found that patients with Borrmann type Ⅲ disease and LBVI(+)had a similar 5-year survival rate to those with Borrmann IV+LBVI(-)(16.4%vs 13.1%,P=0.065)and those with Borrmann IV+LBVI(+)(16.4%vs 11.2%,P=0.112).Subgroup analysis showed that the above results were true for any pT stage and any tumor location.Multivariate Cox regression analysis showed that Borrmann classification(P=0.023),vascular infiltration(P<0.001),tumor size(P=0.012),pT stage(P<0.001),pN stage(P<0.001),and extent of radical surgery(P<0.001)were independent prognostic factors for survival.CONCLUSION Since patients with Borrmann Ⅲ disease and LBVI(+)have the same poor prognosis as those with Borrmann IV disease,more attention should be paid to patients with Borrmann Ⅲ disease and LBVI(+)during diagnosis and treatment,regardless of the pT stage and tumor location,to obtain better survival results.
基金Nn10 Program of Harbin Medical University Cancer Hospital,China,No.Nn10 PY 2017-03.
文摘BACKGROUND Through analyzing the data from a single institution in Northeast China,this study revealed the possible clinicopathologic characteristics that influence the prognosis of patients with gastric cancer(GC).AIM To evaluate the changing trends of clinicopathologic features and survival duration after surgery in patients with GC in Northeast China,which is a highprevalence area of GC.METHODS The study analyzed the difference in clinicopathologic features and survival duration after surgery of 5887 patients who were histologically diagnosed with GC at the Harbin Medical University Cancer Hospital.The study mainly analyzed the data in three periods,2000 to 2004(Phase 1),2005 to 2009(Phase 2),and 2010 to 2014(Phase 3).RESULTS Over time,the postoperative survival rate significantly increased from 2000 to 2014.In the past 15 years,compared with Phases 1 and 2,the tumor size was smaller in Phase 3(P<0.001),but the proportion of high-medium differentiated tumors increased(P<0.001).The proportion of early GC gradually increased from 3.9%to 14.4%(P<0.001).A surprising improvement was observed in the mean number of retrieved lymph nodes,ranging from 11.4 to 27.5(P<0.001).The overall 5-year survival rate increased from 24%in Phase 1 to 43.8%in Phase 3.Through multivariate analysis,it was found that age,tumor size,histologic type,tumor-node-metastasis stage,depth of invasion,lymph node metastasis,surgical approach,local infiltration,radical extent,number of retrieved lymph nodes,and age group were independent risk factors that influenced the prognosis of patients with GC.CONCLUSION The clinical features of GC in Northeast China changed during the observation period.The increasing detection of early GC and more standardized surgical treatment effectively prolonged lifetimes.
基金Jiandong Jiang,Yan Wang,and Linbin Pan have a patent related to this work(CN201810788495.7).
文摘In recent decades,the prevalence of hyperuricemia and gout has increased dramatically due to lifestyle changes.The drugs currently recommended for hyperuricemia are associated with adverse reactions that limit their clinical use.In this study,we report that berberine(BBR)is an effective drug candidate for the treatment of hyperuricemia,with its mechanism potentially involving the modulation of gut microbiota and its metabolite,succinic acid.BBR has demonstrated good therapeutic effects in both acute and chronic animal models of hyperuricemia.In a clinical trial,oral administration of BBR for 6 months reduced blood uric acid levels in 22 participants by modulating the gut microbiota,which led to an increase in the abundance of Bacteroides and a decrease in Clostridium sensu stricto_1.Furthermore,Bacteroides fragilis was transplanted into ICR mice,and the results showed that Bacteroides fragilis exerted a therapeutic effect on uric acid similar to that of BBR.Notably,succinic acid,a metabolite of Bacteroides,significantly reduced uric acid levels.Subsequent cell and animal experiments revealed that the intestinal metabolite,succinic acid,regulated the upstream uric acid synthesis pathway in the liver by inhibiting adenosine monophosphate deaminase 2(AMPD2),an enzyme responsible for converting adenosine monophosphate(AMP)to inosine monophosphate(IMP).This inhibition resulted in a decrease in IMP levels and an increase in phosphate levels.The reduction in IMP led to a decreased downstream production of hypoxanthine,xanthine,and uric acid.BBR also demonstrated excellent renoprotective effects,improving nephropathy associated with hyperuricemia.In summary,BBR has the potential to be an effective treatment for hyperuricemia through the gut-liver axis.
基金partly supported by the National Natural Science Foundation of China (Grant Nos.51209170,and 51479160)the foundation for the Plan Projects of Water Conservancy Science and Technology of Shaanxi Province (Grant No.2013SLKJ05)the Project Supported by Natural Science Basic Research Plan in Shaanxi Province of China (Grant No.2016JQ5061)
文摘Inter-basin Water Transfer Projects require the appropriate financing model to attract large amounts of social investment.Therefore,financing model decision becomes the key of engineering construction.In three aspects,such as the subject,the object and the target of the financing model,Grey Target Model is established in this paper.First,the complex financing mode decision problems of Inter-basin Water Transfer Projects are decomposed by using hierarchical decomposition method.Then Analytical Hierarchy Process(AHP) method is used to calculate the comprehensive weight of evaluation index.Experts' opinions financing model are transformed into the evaluation matrix based on the Dephi method.The Weighted Grey Target Model is used to calculate the approaching degree of financing model and assists financing mode decision.In addition,this paper takes the water diversion project from the Han to the Wei River of Shaanxi Province as a verification example for the model.For other water diversion projects,the evaluation results are also reliable and provide theoretical references for the financing model decision of Inter-basin Water Transfer Projects.
文摘Engineering project management is the whole process of project construction management activities up to the point of achieving the goals of engineering construction, which adopts the means of planning, organizing,leading, and controlling. In addition, engineering project management modes are the works of project management and the technical guarantee of project success. For the quality and efficient transformation demands of the Chinese construction industry in the process of marketization, internationalization and informatization, based on the connotation and development path of engineering project management modes, the 16 main and new kinds of project management modes both domestically and abroad are divided into trading mode, financing mode and management mode. These have led to comparative analysis and brief commentary. Finally, it will be pointed out that the engineering project management modes move throughout the whole management process, the combined model and the expansion development of financing model. This work will provide reference for project participants to choose the appropriate project management modes and better understand building company transformation.
