Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia.While multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid po...Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia.While multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes mellitus.Islet amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are unclear.In this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of dementia.We discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced cytotoxicity.There are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at best.Therefore,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating dementia.As such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.展开更多
Europium-doped gadolinium oxide （Gd2O3：Eu） nanoparticles have been synthesized, and then their surfaces have been conjugated with nucleolin- targeted AS1411 aptamer to form functionalized target-specific Gd2OB：EU ...Europium-doped gadolinium oxide （Gd2O3：Eu） nanoparticles have been synthesized, and then their surfaces have been conjugated with nucleolin- targeted AS1411 aptamer to form functionalized target-specific Gd2OB：EU nanoparticles （A-GdO：Eu nanoparticles）. The A-GdO：Eu nanoparticles present strong fluorescence in the visible range, high magnetic susceptibility, X-ray attenuation and good biocompatibility. The A-GdO：Eu nanoparticles have been applied to test molecular expression of nucleolin highly expressed CL1-5 lung cancer cells under a confocal microscope. Fluorescence imaging clearly reveals that the nanoparticles can be applied as fluorescent tags for cancer-targeting molecular imaging. Furthermore, taking together their excellent T1 contrast and strong computed tomography （CT） signal, the A-GdO：Eu nanoparticles demonstrate a great capability for use as a dual modality contrast agent for CT and magnetic resonance （MR） molecular imaging. Animal experiments also show that the A-GdO：Eu nanoparticles are able to contrast the tissues of BALB/c mice using CT modality. Moreover, the obvious red fluorescence of A-GdO：Eu nanoparticles can be visualized in a tumor by the naked eye. Overall, our results demonstrate that the A-GdO：Eu nanoparticles can not only serve as new medical contrast agents but also as intraoperative fluorescence imaging probes for guided surgery in the near future.展开更多
How tumor-associated macrophages transit from a predominant antitumor M1-like phenotype to a protumoral M2-like phenotype during the development of pancreatic ductal adenocarcinoma (PDA) remains to be elucidated. We t...How tumor-associated macrophages transit from a predominant antitumor M1-like phenotype to a protumoral M2-like phenotype during the development of pancreatic ductal adenocarcinoma (PDA) remains to be elucidated. We thus conducted a study by employing a PDA-macrophage co-culture system, an “orthotopic” PDA syngeneic mouse model, and human PDA specimens, together with macrophages derived from GARP knockout mice and multiple analytic tools including whole-genome RNA sequencing, DNA methylation arrays, multiplex immunohistochemistry, metabolism measurement, and invasion/metastasis assessment. Our study showed that PDA tumor cells, through direct cell–cell contact, induce DNA methylation and downregulation of a panel of glucose metabolism and OXPHOS genes selectively in M1-like macrophages, leading to a suppressed glucose metabolic status in M1-like but not in M2-like macrophages. Following the interaction with PDA tumor cells, M1-like macrophages are reprogrammed phenotypically to M2-like macrophages. The interaction between M1-like macrophages and PDA cells is mediated by GARP and integrin αV/β8, respectively. Blocking either GARP or integrin would suppress tumor-induced DNA methylation in Nqo-1 gene and the reprogramming of M1-like macrophages. Glucose-response genes such as Il-10 are subsequently activated in tumor-educated M1-like macrophages. Partly through Il-10 and its receptor Il-10R on tumor cells, M1-like macrophages functionally acquire a pro-cancerous capability. Both exogenous M1-like and M2-like macrophages promote metastasis in a mouse model of PDA while such a role of M1-like macrophages is dependent on DNA methylation. Our results suggest that PDA cells are able to reprogram M1-like macrophages metabolically and functionally through a GARP-dependent and DNA methylation-mediated mechanism to adopt a pro-cancerous fate.展开更多
The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeos...The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size,and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as farnesoid X nuclear receptor(FXR)and the G-protein-coupled bile acid receptor(TGR5).展开更多
Weight loss from an overweight state is associated with a disproportionate decrease in whole-body energy expenditure that may contribute to the heightened risk for weight regain.Evidence suggests that this energetic m...Weight loss from an overweight state is associated with a disproportionate decrease in whole-body energy expenditure that may contribute to the heightened risk for weight regain.Evidence suggests that this energetic mismatch originates from lean tissue.Although this phenomenon is well documented,the mechanisms have remained elusive.We hypothesized that increased mitochondrial energy efficiency in skeletal muscle is associated with reduced expenditure under weight loss.Wildtype(WT)male C57BL6/N mice were fed with high-fat diet for 10 weeks,followed by a subset of mice that were maintained on the obesogenic diet(OB)or switched to standard chow to promote weight loss(WL)for additional 6 weeks.Mitochondrial energy efficiency was evaluated using high-resolution respirometry and fluorometry.Mass spectrometric analyses were employed to describe the mitochondrial proteome and lipidome.Weight loss promoted~50%increase in the efficiency of oxidative phosphorylation(ATP produced per O_(2) consumed,or P/O)in skeletal muscle.However,Weight loss did not appear to induce significant changes in mitochondrial proteome,nor any changes in respiratory supercomplex formation.Instead,it accelerated the remodeling of mitochondrial cardiolipin(CL)acyl-chains to increase tetralinoleoyl CL(TLCL)content,a species of lipids thought to be functionally critical for the respiratory enzymes.We further show that lowering TLCL by deleting the CL transacylase tafazzin was sufficient to reduce skeletal muscle P/O and protect mice from diet-induced weight gain.These findings implicate skeletal muscle mitochondrial efficiency as a novel mechanism by which weight loss reduces energy expenditure in obesity.展开更多
SP100 is an antiviral protein that restricts the productive stage of human papillomavirus(HPV)and multiple other viruses,and viruses in turn block sUMO-1-mediated stabilization of SP100 and promotes its degradation(Ta...SP100 is an antiviral protein that restricts the productive stage of human papillomavirus(HPV)and multiple other viruses,and viruses in turn block sUMO-1-mediated stabilization of SP100 and promotes its degradation(Table S1).Interferon(IFN)signaling could still produce more SP100 through transcription to counteract viruses.1 Viruses also disable the transcriptional up-regulation of SP100 to achieve persistent infection in hosts.展开更多
基金supported by The Mike Hogg FundBaylor College of Medicine Medical Scientist Training Program,NICHD R01HD099252(to RJP)and R01HD098131(to RJP)the NHLBI T32 HL092332(to ASB)。
文摘Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia.While multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes mellitus.Islet amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are unclear.In this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of dementia.We discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced cytotoxicity.There are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at best.Therefore,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating dementia.As such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.
文摘Europium-doped gadolinium oxide （Gd2O3：Eu） nanoparticles have been synthesized, and then their surfaces have been conjugated with nucleolin- targeted AS1411 aptamer to form functionalized target-specific Gd2OB：EU nanoparticles （A-GdO：Eu nanoparticles）. The A-GdO：Eu nanoparticles present strong fluorescence in the visible range, high magnetic susceptibility, X-ray attenuation and good biocompatibility. The A-GdO：Eu nanoparticles have been applied to test molecular expression of nucleolin highly expressed CL1-5 lung cancer cells under a confocal microscope. Fluorescence imaging clearly reveals that the nanoparticles can be applied as fluorescent tags for cancer-targeting molecular imaging. Furthermore, taking together their excellent T1 contrast and strong computed tomography （CT） signal, the A-GdO：Eu nanoparticles demonstrate a great capability for use as a dual modality contrast agent for CT and magnetic resonance （MR） molecular imaging. Animal experiments also show that the A-GdO：Eu nanoparticles are able to contrast the tissues of BALB/c mice using CT modality. Moreover, the obvious red fluorescence of A-GdO：Eu nanoparticles can be visualized in a tumor by the naked eye. Overall, our results demonstrate that the A-GdO：Eu nanoparticles can not only serve as new medical contrast agents but also as intraoperative fluorescence imaging probes for guided surgery in the near future.
基金L.Z.was supported by NIH grant R01 CA169702NIH grant R01 CA197296+1 种基金the Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins,Sidney Kimmel Comprehensive Cancer Center Grant P30 CA006973K.F.was supported by a JSPS Overseas Research Fellowship from the Japan Society for the Promotion of Science.Z.L.is supported by multiple NIH grants(R01 AI077283,P01 CA186866,R01 CA199419,and R01 CA213290).
文摘How tumor-associated macrophages transit from a predominant antitumor M1-like phenotype to a protumoral M2-like phenotype during the development of pancreatic ductal adenocarcinoma (PDA) remains to be elucidated. We thus conducted a study by employing a PDA-macrophage co-culture system, an “orthotopic” PDA syngeneic mouse model, and human PDA specimens, together with macrophages derived from GARP knockout mice and multiple analytic tools including whole-genome RNA sequencing, DNA methylation arrays, multiplex immunohistochemistry, metabolism measurement, and invasion/metastasis assessment. Our study showed that PDA tumor cells, through direct cell–cell contact, induce DNA methylation and downregulation of a panel of glucose metabolism and OXPHOS genes selectively in M1-like macrophages, leading to a suppressed glucose metabolic status in M1-like but not in M2-like macrophages. Following the interaction with PDA tumor cells, M1-like macrophages are reprogrammed phenotypically to M2-like macrophages. The interaction between M1-like macrophages and PDA cells is mediated by GARP and integrin αV/β8, respectively. Blocking either GARP or integrin would suppress tumor-induced DNA methylation in Nqo-1 gene and the reprogramming of M1-like macrophages. Glucose-response genes such as Il-10 are subsequently activated in tumor-educated M1-like macrophages. Partly through Il-10 and its receptor Il-10R on tumor cells, M1-like macrophages functionally acquire a pro-cancerous capability. Both exogenous M1-like and M2-like macrophages promote metastasis in a mouse model of PDA while such a role of M1-like macrophages is dependent on DNA methylation. Our results suggest that PDA cells are able to reprogram M1-like macrophages metabolically and functionally through a GARP-dependent and DNA methylation-mediated mechanism to adopt a pro-cancerous fate.
基金supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH,No.R01DK047987)supported by a Research Supplement to Promote Diversity in Health Related Research from the NIH
文摘The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size,and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as farnesoid X nuclear receptor(FXR)and the G-protein-coupled bile acid receptor(TGR5).
基金This research is supported by NIH DK107397,DK127979,GM144613,AG074535,AG067186(to K.F.),AG065993(to A.C.),DK091317(to M.J.L.)Department of Defense W81XWH-19-1-0213(to K.H.F-W)+2 种基金American Heart Association 18PRE33960491(to A.R.P.V.),19PRE34380991(to J.M.J.),and 915674(P.S.)Larry H.&Gail Miller Family Foundation(to P.J.F.)University of Utah Metabolomics Core Facility is supported by S10 OD016232,S10 OD021505,and U54 DK110858.
文摘Weight loss from an overweight state is associated with a disproportionate decrease in whole-body energy expenditure that may contribute to the heightened risk for weight regain.Evidence suggests that this energetic mismatch originates from lean tissue.Although this phenomenon is well documented,the mechanisms have remained elusive.We hypothesized that increased mitochondrial energy efficiency in skeletal muscle is associated with reduced expenditure under weight loss.Wildtype(WT)male C57BL6/N mice were fed with high-fat diet for 10 weeks,followed by a subset of mice that were maintained on the obesogenic diet(OB)or switched to standard chow to promote weight loss(WL)for additional 6 weeks.Mitochondrial energy efficiency was evaluated using high-resolution respirometry and fluorometry.Mass spectrometric analyses were employed to describe the mitochondrial proteome and lipidome.Weight loss promoted~50%increase in the efficiency of oxidative phosphorylation(ATP produced per O_(2) consumed,or P/O)in skeletal muscle.However,Weight loss did not appear to induce significant changes in mitochondrial proteome,nor any changes in respiratory supercomplex formation.Instead,it accelerated the remodeling of mitochondrial cardiolipin(CL)acyl-chains to increase tetralinoleoyl CL(TLCL)content,a species of lipids thought to be functionally critical for the respiratory enzymes.We further show that lowering TLCL by deleting the CL transacylase tafazzin was sufficient to reduce skeletal muscle P/O and protect mice from diet-induced weight gain.These findings implicate skeletal muscle mitochondrial efficiency as a novel mechanism by which weight loss reduces energy expenditure in obesity.
基金supported in part by the National Institutes of Health under award number K08CA255933.
文摘SP100 is an antiviral protein that restricts the productive stage of human papillomavirus(HPV)and multiple other viruses,and viruses in turn block sUMO-1-mediated stabilization of SP100 and promotes its degradation(Table S1).Interferon(IFN)signaling could still produce more SP100 through transcription to counteract viruses.1 Viruses also disable the transcriptional up-regulation of SP100 to achieve persistent infection in hosts.
