PPARγis a peroxisome proliferator-activated receptor(PPAR)family protein and is a target for type 2 diabetes(T2D).In this paper,we have performed a molecular docking analysis between ligand molecules(CID9816265,CID11...PPARγis a peroxisome proliferator-activated receptor(PPAR)family protein and is a target for type 2 diabetes(T2D).In this paper,we have performed a molecular docking analysis between ligand molecules(CID9816265,CID11608015,CID20251380,CID20251343,CID20556263,CID624491,CID42609928,and CID86287562)and PPARγto determine the ligand specificity.It also helps to understand the ligand-binding domain(LBD)activity of PPARγduring the binding of the ligand.Further,a molecular dynamics simulation study was performed to determine the ligand biding stability in the PPARγLBD.Its ligand specificity informed us about the potentiality of selecting a partial agonist.The study also shows the binding conformation of Ceramicine B having hydrogen bonding affinity with a tricyclic polar head and stabilized theβ-sheet region.On the other hand,the tricyclic polar head of nimbolide also formed hydrogen bonding(Ser342),but it shows a lesser degree of stabilization in theβ-sheet region.It shows the binding conformation of partial agonist(PPARγ)in the Pocket-II of PPARγLBD,which has a significant role in stabilizing theβ-sheet region.It might help to regulate ERK/Cdk5 mediated phosphorylation of Ser245.The study helps us understand the valid pose of a set of ligands confirmation and target protein conformation using docking and molecular dynamics study.This in silico study will also help to initiate a drug discovery process of T2D.展开更多
Background:Type 2 diabetes(T2D)is a polygenic metabolic disease,character-ized by high fasting blood glucose(FBG).The ability of cranberry(CRN)fruit to regulate glycemia in T2D patients is well known.Here,a cohort of ...Background:Type 2 diabetes(T2D)is a polygenic metabolic disease,character-ized by high fasting blood glucose(FBG).The ability of cranberry(CRN)fruit to regulate glycemia in T2D patients is well known.Here,a cohort of 13 lines of the genetically diverse Collaborative Cross(CC)mouse model was assessed for the effect of non-dialyzable material(NDM)of cranberry extract in lowering fasting blood glucose.Methods:Eight-week-old mice were maintained on either a standard chow diet(con-trol group)or a high-fat diet(HFD)for 12 weeks,followed by injections of intraperi-toneal(IP)NDM(50 mg/kg)per mouse,three times a week for the next 6 weeks.Absolute FBG(mg/dl)was measured bi-weekly and percentage changes in FBG(%FBG)between weeks 0 and 12 were calculated.Results:Statistical analysis showed a significant decrease in FBG between weeks 0 and 12 in male and female mice maintained on CHD.However,a non-significant in-crease in FBG values was observed in male and female mice maintained on HFD dur-ing the same period.Following administration of NDM during the following 6 weeks,the results show a variation in significant levels of FBG lowering between lines,male and female mice and under the different diets.Conclusion:The results suggest that the efficacy of NDM treatment in lowering FGB depends on host genetic background(pharmacogenetics),sex of the mouse(phar-macosex),and diet(pharmacodiet).All these results support the need for follow-up research to better understand and implement a personalized medicine approach/uti-lization of NDM for reducing FBG.展开更多
Background: Type 2 diabetes (T2D) remains a major global public health problem. This complex metabolic disorder can lead to various complications, including cardiovascular diseases (leading cause of death) in T2D. Amo...Background: Type 2 diabetes (T2D) remains a major global public health problem. This complex metabolic disorder can lead to various complications, including cardiovascular diseases (leading cause of death) in T2D. Among the biochemical markers associated with increased risk for cardiovascular disease, homocysteine is currently one of the predictive markers under evaluation. We investigate the link between hyperhomocysteinemia and diabetes complications in DT2 population in Brazzaville. Methodology: We conducted a cross-sectional analytical study, from October to December 2022. One hundred and fifty participants were included, 100 patients T2D (34 with complications, 33 with comorbidities, 33 without), and 50 patients controls. Sociodemographic and clinical characteristics were collected. Homocysteine (Hcy) serum levels were measured using Sandwich ELISA method. Results: Study population was composed of 50% males and 50% females with sex ratio of 1;mean age was 52.2 ± 10.8 years (30 - 83). The prevalence of hyperhomocysteinemia (HHcy) was 36% (20% moderate Hcy, 15% intermediate and 1% severe). Mean Hcy concentration was 31.9 μmol/l (18 - 103). Age, gender and physical inactivity were strongly correlated to Hcy (OR of 3.5;9.4 and 3 respectively). Multivariate analysis showed that HHcy was a risk accelerator for degenerative complications (stroke: OR = 6.2;ischemic heart disease: 4.9;neuropathy: 9.2;retinopathy: 4.5 and peripheral arterial disease: 4.9). Conclusion: These findings suggest that hyperhomocysteinemia can be considered as a predictive marker to be taken into account in targeting cardiovascular risk in Congolese subjects with T2D.展开更多
人类疾病的产生是遗传和环境相互作用的结果,科学家已经定位了许多与疾病相关的突变区域,其中FTO(fat mass and obesity associate)基因是近期发现与肥胖显著相关的基因。研究发现FTO基因单核苷酸多态性(single nucleotide polymorphism...人类疾病的产生是遗传和环境相互作用的结果,科学家已经定位了许多与疾病相关的突变区域,其中FTO(fat mass and obesity associate)基因是近期发现与肥胖显著相关的基因。研究发现FTO基因单核苷酸多态性(single nucleotide polymorphism,SNP)与二型糖尿病(T2D)、肥胖、癌症、阿尔茨海默症、神经元功能等多种健康问题有关,然而针对不同人群的研究结果存在差异,本文通过查阅国内外关于FTO基因的最新文章,论述FTO基因SNPs与疾病的关系,为进一步研究FTO基因功能提供参考。展开更多
Background:Multimorbidity of intestinal cancer(IC),type 2 diabetes(T2D)and obesity is a complex set of diseases,affected by environmental and genetic risk factors.High-fat diet(HFD)and oral bacterial infection play im...Background:Multimorbidity of intestinal cancer(IC),type 2 diabetes(T2D)and obesity is a complex set of diseases,affected by environmental and genetic risk factors.High-fat diet(HFD)and oral bacterial infection play important roles in the etiology of these diseases through inflammation and various biological mechanisms.Methods:To study the complexity of this multimorbidity,we used the collaborative cross(CC)mouse genetics reference population.We aimed to study the multimorbidity of IC,T2D,and obesity using CC lines,measuring their responses to HFD and oral bacterial infection.The study used 63 mice of both sexes generated from two CC lines(IL557 and IL711).For 12 weeks,experimental mice were maintained on specific dietary regimes combined with co-infection with oral bacteria Porphyromonas gingivalis and Fusobacterium nucleatum,while control groups were not infected.Body weight(BW)and results of a intraperitoneal glucose tolerance test(IPGTT)were recorded at the end of 12 weeks,after which length and size of the intestines were assessed for polyp counts.Results:Polyp counts ranged between 2 and 10 per CC line.The combination of HFD and infection significantly reduced(P<.01)the colon polyp size of IL557 females to 2.5 cm 2,compared to the other groups.Comparing BW gain,IL557 males on HFD gained 18 g,while the females gained 10 g under the same conditions and showed the highest area under curve(AUC)values of 40000-45000(min mg/dL)in the IPGTT.Conclusion:The results show that mice from different genetic backgrounds respond differently to a high fat diet and oral infection in terms of polyp development and glucose tolerance,and this effect is gender related.展开更多
Background: Host genetic background and sex, play central roles in defining the pathogenesis of type 2 diabetes(T2 D), obesity and infectious diseases. Our previous studies demonstrated the utilization of genetically ...Background: Host genetic background and sex, play central roles in defining the pathogenesis of type 2 diabetes(T2 D), obesity and infectious diseases. Our previous studies demonstrated the utilization of genetically highly diverse inbred mouse lines, namely collaborative cross(CC), for dissecting host susceptibility for the development of T2 D and obesity, showing significant variations following high-fat(42% fat) diet(HFD). Here, we aimed to assessing the host genetic background and sex effects on T2 D and obesity development in response to oral-mixed bacterial infection and HFD using the CC lines.Materials and Methods: Study cohort consists of 97 mice from 2 CC lines(both sexes), maintained on either HFD or Standard diet(CHD) for 12 weeks. At week 5 a group of mice from each diet were infected with Porphyromonas gingivalis(Pg) and Fusobacterium nucleatum(Fn) bacteria(control groups without infection). Body weight(BW) and glucose tolerance ability were assessed at the end time point of the experiment.Results: The CC lines varied(P <.05) at their BW gain and glucose tolerance ability(with sex effect) in response to diets and/or infection, showing opposite responses despite sharing the same environmental conditions. The combination of diet and infection enhances BW accumulation for IL1912, while restraints it for IL72. As for glucose tolerance ability, only females(both lines) were deteriorated in response to infection.Conclusions: This study emphasizes the power of the CC mouse population for the characterization of host genetic makeup for defining the susceptibility of the individual to development of obesity and/or impaired glucose tolerance.展开更多
基金supported by Hallym University Research Fund and by Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(NRF-2020R1C1C1008694&NRF-2020R1I1A3074575).
文摘PPARγis a peroxisome proliferator-activated receptor(PPAR)family protein and is a target for type 2 diabetes(T2D).In this paper,we have performed a molecular docking analysis between ligand molecules(CID9816265,CID11608015,CID20251380,CID20251343,CID20556263,CID624491,CID42609928,and CID86287562)and PPARγto determine the ligand specificity.It also helps to understand the ligand-binding domain(LBD)activity of PPARγduring the binding of the ligand.Further,a molecular dynamics simulation study was performed to determine the ligand biding stability in the PPARγLBD.Its ligand specificity informed us about the potentiality of selecting a partial agonist.The study also shows the binding conformation of Ceramicine B having hydrogen bonding affinity with a tricyclic polar head and stabilized theβ-sheet region.On the other hand,the tricyclic polar head of nimbolide also formed hydrogen bonding(Ser342),but it shows a lesser degree of stabilization in theβ-sheet region.It shows the binding conformation of partial agonist(PPARγ)in the Pocket-II of PPARγLBD,which has a significant role in stabilizing theβ-sheet region.It might help to regulate ERK/Cdk5 mediated phosphorylation of Ser245.The study helps us understand the valid pose of a set of ligands confirmation and target protein conformation using docking and molecular dynamics study.This in silico study will also help to initiate a drug discovery process of T2D.
基金supported by a core fund from Tel-Aviv University.
文摘Background:Type 2 diabetes(T2D)is a polygenic metabolic disease,character-ized by high fasting blood glucose(FBG).The ability of cranberry(CRN)fruit to regulate glycemia in T2D patients is well known.Here,a cohort of 13 lines of the genetically diverse Collaborative Cross(CC)mouse model was assessed for the effect of non-dialyzable material(NDM)of cranberry extract in lowering fasting blood glucose.Methods:Eight-week-old mice were maintained on either a standard chow diet(con-trol group)or a high-fat diet(HFD)for 12 weeks,followed by injections of intraperi-toneal(IP)NDM(50 mg/kg)per mouse,three times a week for the next 6 weeks.Absolute FBG(mg/dl)was measured bi-weekly and percentage changes in FBG(%FBG)between weeks 0 and 12 were calculated.Results:Statistical analysis showed a significant decrease in FBG between weeks 0 and 12 in male and female mice maintained on CHD.However,a non-significant in-crease in FBG values was observed in male and female mice maintained on HFD dur-ing the same period.Following administration of NDM during the following 6 weeks,the results show a variation in significant levels of FBG lowering between lines,male and female mice and under the different diets.Conclusion:The results suggest that the efficacy of NDM treatment in lowering FGB depends on host genetic background(pharmacogenetics),sex of the mouse(phar-macosex),and diet(pharmacodiet).All these results support the need for follow-up research to better understand and implement a personalized medicine approach/uti-lization of NDM for reducing FBG.
文摘Background: Type 2 diabetes (T2D) remains a major global public health problem. This complex metabolic disorder can lead to various complications, including cardiovascular diseases (leading cause of death) in T2D. Among the biochemical markers associated with increased risk for cardiovascular disease, homocysteine is currently one of the predictive markers under evaluation. We investigate the link between hyperhomocysteinemia and diabetes complications in DT2 population in Brazzaville. Methodology: We conducted a cross-sectional analytical study, from October to December 2022. One hundred and fifty participants were included, 100 patients T2D (34 with complications, 33 with comorbidities, 33 without), and 50 patients controls. Sociodemographic and clinical characteristics were collected. Homocysteine (Hcy) serum levels were measured using Sandwich ELISA method. Results: Study population was composed of 50% males and 50% females with sex ratio of 1;mean age was 52.2 ± 10.8 years (30 - 83). The prevalence of hyperhomocysteinemia (HHcy) was 36% (20% moderate Hcy, 15% intermediate and 1% severe). Mean Hcy concentration was 31.9 μmol/l (18 - 103). Age, gender and physical inactivity were strongly correlated to Hcy (OR of 3.5;9.4 and 3 respectively). Multivariate analysis showed that HHcy was a risk accelerator for degenerative complications (stroke: OR = 6.2;ischemic heart disease: 4.9;neuropathy: 9.2;retinopathy: 4.5 and peripheral arterial disease: 4.9). Conclusion: These findings suggest that hyperhomocysteinemia can be considered as a predictive marker to be taken into account in targeting cardiovascular risk in Congolese subjects with T2D.
文摘人类疾病的产生是遗传和环境相互作用的结果,科学家已经定位了许多与疾病相关的突变区域,其中FTO(fat mass and obesity associate)基因是近期发现与肥胖显著相关的基因。研究发现FTO基因单核苷酸多态性(single nucleotide polymorphism,SNP)与二型糖尿病(T2D)、肥胖、癌症、阿尔茨海默症、神经元功能等多种健康问题有关,然而针对不同人群的研究结果存在差异,本文通过查阅国内外关于FTO基因的最新文章,论述FTO基因SNPs与疾病的关系,为进一步研究FTO基因功能提供参考。
文摘Background:Multimorbidity of intestinal cancer(IC),type 2 diabetes(T2D)and obesity is a complex set of diseases,affected by environmental and genetic risk factors.High-fat diet(HFD)and oral bacterial infection play important roles in the etiology of these diseases through inflammation and various biological mechanisms.Methods:To study the complexity of this multimorbidity,we used the collaborative cross(CC)mouse genetics reference population.We aimed to study the multimorbidity of IC,T2D,and obesity using CC lines,measuring their responses to HFD and oral bacterial infection.The study used 63 mice of both sexes generated from two CC lines(IL557 and IL711).For 12 weeks,experimental mice were maintained on specific dietary regimes combined with co-infection with oral bacteria Porphyromonas gingivalis and Fusobacterium nucleatum,while control groups were not infected.Body weight(BW)and results of a intraperitoneal glucose tolerance test(IPGTT)were recorded at the end of 12 weeks,after which length and size of the intestines were assessed for polyp counts.Results:Polyp counts ranged between 2 and 10 per CC line.The combination of HFD and infection significantly reduced(P<.01)the colon polyp size of IL557 females to 2.5 cm 2,compared to the other groups.Comparing BW gain,IL557 males on HFD gained 18 g,while the females gained 10 g under the same conditions and showed the highest area under curve(AUC)values of 40000-45000(min mg/dL)in the IPGTT.Conclusion:The results show that mice from different genetic backgrounds respond differently to a high fat diet and oral infection in terms of polyp development and glucose tolerance,and this effect is gender related.
基金Israeli Science Foundation (ISF),Grant/Award Number 1085/18German Israeli Science Foundation (GIF),Grant/Award Number I-63-410.20-2017+1 种基金Binational Science Foundation (BSF),Grant/Award Number 2015077Tel-Aviv University
文摘Background: Host genetic background and sex, play central roles in defining the pathogenesis of type 2 diabetes(T2 D), obesity and infectious diseases. Our previous studies demonstrated the utilization of genetically highly diverse inbred mouse lines, namely collaborative cross(CC), for dissecting host susceptibility for the development of T2 D and obesity, showing significant variations following high-fat(42% fat) diet(HFD). Here, we aimed to assessing the host genetic background and sex effects on T2 D and obesity development in response to oral-mixed bacterial infection and HFD using the CC lines.Materials and Methods: Study cohort consists of 97 mice from 2 CC lines(both sexes), maintained on either HFD or Standard diet(CHD) for 12 weeks. At week 5 a group of mice from each diet were infected with Porphyromonas gingivalis(Pg) and Fusobacterium nucleatum(Fn) bacteria(control groups without infection). Body weight(BW) and glucose tolerance ability were assessed at the end time point of the experiment.Results: The CC lines varied(P <.05) at their BW gain and glucose tolerance ability(with sex effect) in response to diets and/or infection, showing opposite responses despite sharing the same environmental conditions. The combination of diet and infection enhances BW accumulation for IL1912, while restraints it for IL72. As for glucose tolerance ability, only females(both lines) were deteriorated in response to infection.Conclusions: This study emphasizes the power of the CC mouse population for the characterization of host genetic makeup for defining the susceptibility of the individual to development of obesity and/or impaired glucose tolerance.
