Pharmacophore is a commonly used method for molecular simulation,including ligand-based pharmacophore(LBP)and structure-based pharmacophore(SBP).LBP can be utilized to identify active compounds usual with lower accura...Pharmacophore is a commonly used method for molecular simulation,including ligand-based pharmacophore(LBP)and structure-based pharmacophore(SBP).LBP can be utilized to identify active compounds usual with lower accuracy,and SBP is able to use for distin-guishing active compounds from inactive compounds with frequently higher missing rates.Merged pharmacophore(MP)is presented to integrate advantages and avoid shortcomings of LBP and SBP.In this work,LBP and SBP models were constructed for the study of per-oxisome proliferator receptor-alpha(PPARα)agonists.According to the comparison of the two types of pharmacophore models,mainly and secondarily pharmacological features were identified.The weight and tolerance values of these pharmacological features were adjusted to construct MP models by single-factor explorations and orthogonal experimental design based on SBP model.Then,the reliability and screening efficiency of the best MP model were validated by three databases.The best MP model was utilized to compute PPARαactivity of compounds from traditional Chinese medicine.The screening efficiency of MP model outperformed individual LBP or SBP model for PPARαagonists,and was similar to combinatorial screening of LBP and SBP.However,MP model might have an advantage over the combination of LBP and SBP in evaluating the activity of compounds and avoiding the inconsistent prediction of LBP and SBP,which would be beneficial to guide drug design and optimization.展开更多
BACKGROUND Obesity and comorbidities onset encompass gut dysbiosis,altered intestinal permeability,and endotoxemia.Treatments that target gut dysbiosis can cope with obesity and nonalcoholic fatty liver disease(NAFLD)...BACKGROUND Obesity and comorbidities onset encompass gut dysbiosis,altered intestinal permeability,and endotoxemia.Treatments that target gut dysbiosis can cope with obesity and nonalcoholic fatty liver disease(NAFLD)management.Peroxisome proliferator-activated receptor(PPAR)-alpha activation and dipeptidyl-peptidase-4(DPP-4)inhibition alleviate NAFLD,but the mechanism may involve gut microbiota modulation and merits further investigation.AIM To address the effects of PPAR-alpha activation and DPP-4 inhibition(isolated or combined)upon the gut-liver axis,emphasizing inflammatory pathways in NAFLD management in high-fat-fed C57BL/6J mice.METHODS Male C57BL/6J mice were fed a control diet(C,10%of energy as lipids)or a highfat diet(HFD,50%of energy as lipids)for 12 wk,when treatments started,forming the groups:C,HF,HFA(HFD+PPAR-alpha agonist WY14643,2.5 mg/kg body mass),HFL(HFD+DPP-4 inhibitor linagliptin,15 mg/kg body mass),and HFC(HFD+the combination of WY14643 and linagliptin).RESULTS The HFD was obesogenic compared to the C diet.All treatments elicited significant body mass loss,and the HFC group showed similar body mass to the C group.All treatments tackled oral glucose intolerance and raised plasma glucagon-like peptide-1 concentrations.These metabolic benefits restored Bacteroidetes/Firmicutes ratio,resulting in increased goblet cells per area of the large intestine and reduced lipopolysaccharides concentrations in treated groups.At the gene level,treated groups showed higher intestinal Mucin 2,Occludin,and Zo-1 expression than the HFD group.The reduced endotoxemia suppressed inflammasome and macrophage gene expression in the liver of treated animals.These observations complied with the mitigation of liver steatosis and reduced hepatic triacylglycerol,reassuring the role of the proposed treatments on NAFLD mitigation.CONCLUSION PPAR alpha activation and DPP-4 inhibition(isolated or combined)tackled NAFLD in dietinduced obese mice by restoration of gut-liver axis.The reestablishment of the intestinal barrier and the rescued phylogenetic gut bacteria distribution mitigated liver steatosis through antiinflammatory signals.These results can cope with NAFLD management by providing pre-clinical evidence that drugs used to treat obesity comorbidities can help to alleviate this silent and harmful liver disease.展开更多
Background: Cytokines are mediators of diseases. Expression levels in the blood could be of clinical relevance. Objective: sIL-2Rα is used as a marker for different malignancies in human medicine. The aim of this stu...Background: Cytokines are mediators of diseases. Expression levels in the blood could be of clinical relevance. Objective: sIL-2Rα is used as a marker for different malignancies in human medicine. The aim of this study was to show if sIL-2Rα is detectable and if there is any correlation to different diseases in dogs. Methods: For this purposes sIL-2Rα concentrations in the blood were measured in healthy dogs, in dogs with different non-neoplastic diseases and benign tumors and in dogs with malignant tumors. Serum levels of sIL-2Rα were measured by using a human specific enzyme linked immunosorbent assay (ELISA). Results: Measurement of sIL-2Rα was successful in most of the samples. Dogs with diseases have significantly increased serum levels of sIL-2Rα compared to healthy controls. sIL-2Rα serum levels are higher in patients with non-neoplastic diseases and benign tumors than in those with malignant neoplasia. There is a strong correlation between sIL-2Rα and leukocyte count. Conclusion: Measurements of sIL-2Rα in serum may be helpful in detecting stages and grades of inflammation in the progression of disease. sIL-2Rα could actually not be used as an indicator for malignant diseases in dogs like in humans. The strong correlation between sIL-2Rα and the leukocyte count indicates the inflammatory response to the disease. This could be helpful in giving a prognosis in some cases, because the inflammatory reaction is of prognostic relevance in different diseases including malignant and non-malignant neoplasia. Although the results of our research studies were very promising, further studies should be performed with a canine ELISA.展开更多
Background： Systemic lupus eiLythenaatosus （SLE） is a prototypic autoimmune disease wida complex genetic inheritance. This study was conducted to examine whether the association ofa proliferation-inducing ligand （...Background： Systemic lupus eiLythenaatosus （SLE） is a prototypic autoimmune disease wida complex genetic inheritance. This study was conducted to examine whether the association ofa proliferation-inducing ligand （APRIL）, spermatogenesis associated 8 （SPATA8）, platelet-derived growth lhctor receptor-alpha （PDGFRA）, and DNA polymerase beta （POLB） with SLE can be replicated in a Chinese Han population. Methods： Chinese SLE patients （n = 1247） and ethnically and geographically matched healthy controls （n 1440） were genotyped for the APRI L, SPATAS. PDGFRA, and POLB single-nucleotide polymorphisms （SN Ps）, rs3803800 rs8023715, rs1364089 and rsl2678588 using the Sequenom MassARRAY System. Results： The Chinese Hart SLE patients and controls had statistically similar liequencies of alleles and genotypes of four gene polynlorphisms. Moreover, no association signal was detected on different genetic models （additive, dominant, and recessive, all, P〉 0.05） or in SLE subgroups stratified by various clinical nlanifestations （all, P 〉 0.05）. Conclusions： Different genetic backgrounds from different ancestries and various populations may result in different genetic risk litctors for SLE. We did not detect any significant association with SNPs of APRIL SPATAS, PDGFRA, and POLB.展开更多
Background Estrogen receptor （ER）-negative breast cancer cells are more aggressive than ER-positive cells. Elevated levels of cyclooxygenase-2 （COX-2） and vascular endothelial growth factor-C （VEGF-C） expression...Background Estrogen receptor （ER）-negative breast cancer cells are more aggressive than ER-positive cells. Elevated levels of cyclooxygenase-2 （COX-2） and vascular endothelial growth factor-C （VEGF-C） expression have been detected in cultured human breast cancer cells and are associated with negative hormone receptor status. In this study, we created ERα stable transfectants in MDA-MB-231 cells to explore the effect of ERα on cell growth and COX-2 and VEGF-C expression.Methods The green fluorescent protein （GFP）-ERα plasmids were stably transfected into ER-negative MDA-MB-231 cells. The proliferation and migration of untransfected MDA-MB-231 cells, ERα-transfected MDA-MB-231 cells and ER-positive MCF-7 cells were determined. The expression of COX-2, and the levels of VEGF-C mRNA and the VEGF-C secretion concentration were assayed in these cell lines.Results The proliferation and migration capacities of ERα-tranfected MDA-MB-231 cells were significantly decreased （P 〈0.05）. The expression of COX-2 was significantly lower in ERa-tranfected MDA-MB-231 cells than in untranfected MDA-MB-231 cells. The mRNA and protein levels of VEGF-C were lower in ERa-tranfected MDA-MB-231 cells than in untransfected MDA-MB-231 cells （P〈0.05）.Conclusions ERα stable transfection inhibits proliferation and migration capacities of MDA-MB-231 cells and decreases expression of COX-2 and VEGF-C. The decreases of proliferation and migration capacities may be related to suppression of COX-2 and VEGF-C expression.展开更多
基金supported by the National Natural Science Foundation of China(No.81173522,No.81430094,and No.81573831)the Joint Construction Project of the Beijing Municipal Commission of Education
文摘Pharmacophore is a commonly used method for molecular simulation,including ligand-based pharmacophore(LBP)and structure-based pharmacophore(SBP).LBP can be utilized to identify active compounds usual with lower accuracy,and SBP is able to use for distin-guishing active compounds from inactive compounds with frequently higher missing rates.Merged pharmacophore(MP)is presented to integrate advantages and avoid shortcomings of LBP and SBP.In this work,LBP and SBP models were constructed for the study of per-oxisome proliferator receptor-alpha(PPARα)agonists.According to the comparison of the two types of pharmacophore models,mainly and secondarily pharmacological features were identified.The weight and tolerance values of these pharmacological features were adjusted to construct MP models by single-factor explorations and orthogonal experimental design based on SBP model.Then,the reliability and screening efficiency of the best MP model were validated by three databases.The best MP model was utilized to compute PPARαactivity of compounds from traditional Chinese medicine.The screening efficiency of MP model outperformed individual LBP or SBP model for PPARαagonists,and was similar to combinatorial screening of LBP and SBP.However,MP model might have an advantage over the combination of LBP and SBP in evaluating the activity of compounds and avoiding the inconsistent prediction of LBP and SBP,which would be beneficial to guide drug design and optimization.
基金Supported by Coordena??o de Aperfei?oamento de Pessoal de Nível Superior–Brasil,No. CAPES–Finance Code 001Funda??o Carlos Chagas Filho de Amparo à Pesquisa do Rio de Janeiro (FAPERJ) to Souza-Mello V,No. E-26/202.657/2018 and No. E-26/010.002136/2019supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq),No. 303785/2020-9
文摘BACKGROUND Obesity and comorbidities onset encompass gut dysbiosis,altered intestinal permeability,and endotoxemia.Treatments that target gut dysbiosis can cope with obesity and nonalcoholic fatty liver disease(NAFLD)management.Peroxisome proliferator-activated receptor(PPAR)-alpha activation and dipeptidyl-peptidase-4(DPP-4)inhibition alleviate NAFLD,but the mechanism may involve gut microbiota modulation and merits further investigation.AIM To address the effects of PPAR-alpha activation and DPP-4 inhibition(isolated or combined)upon the gut-liver axis,emphasizing inflammatory pathways in NAFLD management in high-fat-fed C57BL/6J mice.METHODS Male C57BL/6J mice were fed a control diet(C,10%of energy as lipids)or a highfat diet(HFD,50%of energy as lipids)for 12 wk,when treatments started,forming the groups:C,HF,HFA(HFD+PPAR-alpha agonist WY14643,2.5 mg/kg body mass),HFL(HFD+DPP-4 inhibitor linagliptin,15 mg/kg body mass),and HFC(HFD+the combination of WY14643 and linagliptin).RESULTS The HFD was obesogenic compared to the C diet.All treatments elicited significant body mass loss,and the HFC group showed similar body mass to the C group.All treatments tackled oral glucose intolerance and raised plasma glucagon-like peptide-1 concentrations.These metabolic benefits restored Bacteroidetes/Firmicutes ratio,resulting in increased goblet cells per area of the large intestine and reduced lipopolysaccharides concentrations in treated groups.At the gene level,treated groups showed higher intestinal Mucin 2,Occludin,and Zo-1 expression than the HFD group.The reduced endotoxemia suppressed inflammasome and macrophage gene expression in the liver of treated animals.These observations complied with the mitigation of liver steatosis and reduced hepatic triacylglycerol,reassuring the role of the proposed treatments on NAFLD mitigation.CONCLUSION PPAR alpha activation and DPP-4 inhibition(isolated or combined)tackled NAFLD in dietinduced obese mice by restoration of gut-liver axis.The reestablishment of the intestinal barrier and the rescued phylogenetic gut bacteria distribution mitigated liver steatosis through antiinflammatory signals.These results can cope with NAFLD management by providing pre-clinical evidence that drugs used to treat obesity comorbidities can help to alleviate this silent and harmful liver disease.
文摘Background: Cytokines are mediators of diseases. Expression levels in the blood could be of clinical relevance. Objective: sIL-2Rα is used as a marker for different malignancies in human medicine. The aim of this study was to show if sIL-2Rα is detectable and if there is any correlation to different diseases in dogs. Methods: For this purposes sIL-2Rα concentrations in the blood were measured in healthy dogs, in dogs with different non-neoplastic diseases and benign tumors and in dogs with malignant tumors. Serum levels of sIL-2Rα were measured by using a human specific enzyme linked immunosorbent assay (ELISA). Results: Measurement of sIL-2Rα was successful in most of the samples. Dogs with diseases have significantly increased serum levels of sIL-2Rα compared to healthy controls. sIL-2Rα serum levels are higher in patients with non-neoplastic diseases and benign tumors than in those with malignant neoplasia. There is a strong correlation between sIL-2Rα and leukocyte count. Conclusion: Measurements of sIL-2Rα in serum may be helpful in detecting stages and grades of inflammation in the progression of disease. sIL-2Rα could actually not be used as an indicator for malignant diseases in dogs like in humans. The strong correlation between sIL-2Rα and the leukocyte count indicates the inflammatory response to the disease. This could be helpful in giving a prognosis in some cases, because the inflammatory reaction is of prognostic relevance in different diseases including malignant and non-malignant neoplasia. Although the results of our research studies were very promising, further studies should be performed with a canine ELISA.
基金the grant from the National Natural Science Foundation of China
文摘Background： Systemic lupus eiLythenaatosus （SLE） is a prototypic autoimmune disease wida complex genetic inheritance. This study was conducted to examine whether the association ofa proliferation-inducing ligand （APRIL）, spermatogenesis associated 8 （SPATA8）, platelet-derived growth lhctor receptor-alpha （PDGFRA）, and DNA polymerase beta （POLB） with SLE can be replicated in a Chinese Han population. Methods： Chinese SLE patients （n = 1247） and ethnically and geographically matched healthy controls （n 1440） were genotyped for the APRI L, SPATAS. PDGFRA, and POLB single-nucleotide polymorphisms （SN Ps）, rs3803800 rs8023715, rs1364089 and rsl2678588 using the Sequenom MassARRAY System. Results： The Chinese Hart SLE patients and controls had statistically similar liequencies of alleles and genotypes of four gene polynlorphisms. Moreover, no association signal was detected on different genetic models （additive, dominant, and recessive, all, P〉 0.05） or in SLE subgroups stratified by various clinical nlanifestations （all, P 〉 0.05）. Conclusions： Different genetic backgrounds from different ancestries and various populations may result in different genetic risk litctors for SLE. We did not detect any significant association with SNPs of APRIL SPATAS, PDGFRA, and POLB.
基金This work was supported by a grant from the National Natural Science Foundation of China （No. 30600588）.
文摘Background Estrogen receptor （ER）-negative breast cancer cells are more aggressive than ER-positive cells. Elevated levels of cyclooxygenase-2 （COX-2） and vascular endothelial growth factor-C （VEGF-C） expression have been detected in cultured human breast cancer cells and are associated with negative hormone receptor status. In this study, we created ERα stable transfectants in MDA-MB-231 cells to explore the effect of ERα on cell growth and COX-2 and VEGF-C expression.Methods The green fluorescent protein （GFP）-ERα plasmids were stably transfected into ER-negative MDA-MB-231 cells. The proliferation and migration of untransfected MDA-MB-231 cells, ERα-transfected MDA-MB-231 cells and ER-positive MCF-7 cells were determined. The expression of COX-2, and the levels of VEGF-C mRNA and the VEGF-C secretion concentration were assayed in these cell lines.Results The proliferation and migration capacities of ERα-tranfected MDA-MB-231 cells were significantly decreased （P 〈0.05）. The expression of COX-2 was significantly lower in ERa-tranfected MDA-MB-231 cells than in untranfected MDA-MB-231 cells. The mRNA and protein levels of VEGF-C were lower in ERa-tranfected MDA-MB-231 cells than in untransfected MDA-MB-231 cells （P〈0.05）.Conclusions ERα stable transfection inhibits proliferation and migration capacities of MDA-MB-231 cells and decreases expression of COX-2 and VEGF-C. The decreases of proliferation and migration capacities may be related to suppression of COX-2 and VEGF-C expression.
