The unfolded protein response pathway is an evolutionarily conserved cytoprotective signaling cascade,essential for cell function and survival.Unfolded protein response signaling is tightly integrated with bone cell d...The unfolded protein response pathway is an evolutionarily conserved cytoprotective signaling cascade,essential for cell function and survival.Unfolded protein response signaling is tightly integrated with bone cell differentiation and function,and chronic unfolded protein response activation has been identified in bone disease.The unfolded protein response has been found to promote oncogenesis and drug resistance,raising the possibility that unfolded protein response modulators may have activity as anti-cancer agents.Cancer-associated bone disease remains a major cause of morbidity for patients with multiple myeloma or bone-metastatic disease.Understanding the critical role of unfolded protein response signaling in cancer development and metastasis,as well as its role in bone homeostasis,may lead to novel mechanisms by which to target cancer-associated bone disease.In this review,we summarize the current research delineating the roles of the unfolded protein response in bone biology and pathophysiology,and furthermore,review unfolded protein response modulating agents in the contexts of cancer and cancer-associated bone disease.展开更多
Rheumatoid arthritis(RA)is one of the most common refractory diseases in the world,and traditional Chinese medicine Notopterygium(NE)has been used in the treatment of upper limb pain for a long time.NE can significant...Rheumatoid arthritis(RA)is one of the most common refractory diseases in the world,and traditional Chinese medicine Notopterygium(NE)has been used in the treatment of upper limb pain for a long time.NE can significantly reduce the expression of inflammatory pain target P2X3 receptor in rats with upper-limb arthritis.To verify the relationship between the mechanism of NE for“upper limb paralysis”and the P2X3 receptor-mediated PKC inflammatory response pathway,UPLC was taken to measure the exact medicinal substance of ethyl acetate from NE.Sprague Dawley rats were randomly divided into a blank group,a model group,a live-action group,and a positive group.The joint cavity was removed after 21 d.Moreover,a model group,a live group,and a positive group were also set up with RA-FLS cells in our in vitro study.The expressions of P2X3 and PKC inflammation pathway indicators were detected by Western blotting analysis.A P2X3 inhibitor(A-317491)acted on RA-FLS cells,and a model group and a positive group were set.Then the protein expression of PKC was detected.NE reduced the expressions of P2X3,Rab7,PKC,and NF-κB at the protein level in both systems.NE and P2X3 receptor antagonists reduced the expressions of key proteins in the PKC pathway in RA-FLS cells to similar extents,and their effects were not additive.NE could effectively improve the“forelimb pain”of RA rats,with a mechanism closely related to the P2X3/Rab7/PKC/NF-κB pathway.展开更多
In the Research Article“A New Insight into the Mechanism of Atrazine-Induced Neurotoxicity:Triggering Neural Stem Cell Senescence by Activating the Integrated Stress Response Pathway,”an error needs to be corrected ...In the Research Article“A New Insight into the Mechanism of Atrazine-Induced Neurotoxicity:Triggering Neural Stem Cell Senescence by Activating the Integrated Stress Response Pathway,”an error needs to be corrected in Figure 5[1].展开更多
Alzheimer＇s disease（AD） is characterized by amyloid-b（Ab） toxicity,tau pathology,insulin resistance,neuroinflammation,and dysregulation of cholesterol homeostasis,all of which play roles in neurodegeneration.Insu...Alzheimer＇s disease（AD） is characterized by amyloid-b（Ab） toxicity,tau pathology,insulin resistance,neuroinflammation,and dysregulation of cholesterol homeostasis,all of which play roles in neurodegeneration.Insulin has polytrophic effects on neurons and may be at the center of these pathophysiological changes.In this study,we investigated possible relationships among insulin signaling and cholesterol biosynthesis,along with the effects of Ab42 on these pathways in vitro.We found that neuroblastoma 2a（N2a） cells transfected with the human gene encoding amyloid-b protein precursor（Ab PP）（N2aAb PP） produced Ab and exhibited insulin resistance by reduced p-Akt and a suppressed cholesterol-synthesis pathway following insulin treatment,and by increased phosphorylation of insulin receptor subunit-1 at serine 612（p-IRS-S612） as compared to parental N2 a cells.Treatment of human neuroblastoma SH-SY5 Y cells with Ab42 also increased p-IRS-S612,suggesting that Ab42 is responsible for insulin resistance.The insulin resistance was alleviated when N2a-Ab PP cells were treated with higher insulin concentrations.Insulin increased Ab release from N2 aAb PP cells,by which it may promote Ab clearance.Insulin increased cholesterol-synthesis gene expression in SHSY5 Y and N2 a cells,including 24-dehydrocholesterol reductase（DHCR24） and 3-hydroxy-3-methyl-glutaryl-Co A reductase（HMGCR） through sterol-regulatory element-binding protein-2（SREBP2）.While Ab42-treated SH-SY5 Y cells exhibited increased HMGCR expression and c-Jun phosphorylation as pro-inflammatory responses,they also showed down-regulation of neuro-protective/antiinflammatory DHCR24.These results suggest that Ab42 may cause insulin resistance,activate JNK for c-Jun phosphorylation,and lead to dysregulation of cholesterol homeostasis,and that enhancing insulin signaling may relieve the insulin-resistant phenotype and the dysregulated cholesterol-synthesis pathway to promote Ab release for clearance from neural cells.展开更多
We report stochastic simulations of the yeast mating signal transduction pathway. The effects of intrinsic and external noise, the influence of cell-to-cell difference in the pathway capacity, and noise propagation in...We report stochastic simulations of the yeast mating signal transduction pathway. The effects of intrinsic and external noise, the influence of cell-to-cell difference in the pathway capacity, and noise propagation in the pathway have been examined. The stochastic temporal behaviour of the pathway is found to be robust to the influence of inherent fluctuations, and intrinsic noise propagates in the pathway in a uniform pattern when the yeasts are treated with pheromones of different stimulus strengths and of varied fluctuations. In agreement with recent experimental findings, extrinsic noise is found to play a more prominent role than intrinsic noise in the variability of proteins. The occurrence frequency for the reactions in the pathway are also examined and a more compact network is obtained by dropping most of the reactions of least occurrence.展开更多
Background:According to our previous studies,Shenling Baizhu powder has an excellent preventive and therapeutic effect on nonalcoholic fatty liver disease,but the prevention mechanism is still not clear.In this study,...Background:According to our previous studies,Shenling Baizhu powder has an excellent preventive and therapeutic effect on nonalcoholic fatty liver disease,but the prevention mechanism is still not clear.In this study,we intended to explore the effects of Shenling Baizhu powder on the endoplasmic reticulum stress related signaling pathway in nonalcoholic fatty liver disease rats’liver tissues.Methods:After 16 weeks,the levels of serum total cholesterol,triglyceride,high-density lipoprotein cholesterol,low-density lipoprotein cholesterol,alanine transaminase and aspartate transaminase were evaluated by an automatic biochemical analyzer,and the levels of serum free fatty acid and hepatic total cholesterol and triglyceride were evaluated by commercial kits.Then,histological changes of the liver were observed by hematoxylin and eosin and oil red-O staining.Protein expression related to the liver unfolded protein response signalling pathway was assessed using Western blot analysis.Results:The results showed that Shenling Baizhu powder supplementation reduced serum total cholesterol,triglyceride,free fatty acid,alanine transaminase,and aspartate transaminase(P<0.05 or P<0.01),as well as the levels of hepatic total cholesterol and triglyceride(P<0.01).Pathological examination showed that Shenling Baizhu powder improved hepatic steatosis and lipid accumulation.The results of biochemical parameters and histological changes indicated that Shenling Baizhu powder administration exerted protective effects against nonalcoholic fatty liver disease.In addition,Shenling Baizhu powder decreased the protein expression levels of binding immunoglobulin protein,activating transcription factor 6,phosphorylation of eukaryotic initiation factor 2 alpha,protein kinase RNA-like endoplasmic reticulum kinase and X-box binding protein 1s in the liver(P<0.05 or P<0.01).Conclusion:Shenling Baizhu powder can ameliorate high-fat diet-induced liver lipid metabolism disorder in nonalcoholic fatty liver disease rats.The mechanisms may be related to the inhibition of the expression of proteins related to unfolded protein response signaling pathways in endoplasmic reticulum stress.展开更多
Electroacupuncture improves depressive behavior faster and with fewer adverse effects than antidepressant medication. However, the antidepressant mechanism of electroacupuncture remains poorly understood. Here, we est...Electroacupuncture improves depressive behavior faster and with fewer adverse effects than antidepressant medication. However, the antidepressant mechanism of electroacupuncture remains poorly understood. Here, we established a rat model of chronic unpredicted mild stress, and then treated these rats with electroacupuncture at Yintang （EX-HN3） and Baihui （DU20） with sparse waves at 2 Hz and 0.6 mA for 30 minutes, once a day. We found increased horizontal and vertical activity, and decreased immobility time, at 2 and 4 weeks after treatment. Moreover, levels of neurotransmitters （5-hydroxytryptamine, glutamate, and y-aminobutyric acid） and protein levels of brain-derived neurotrophic factor and brain-derived neurotrophic factor-related proteins （TrkB, protein kinase A, and phosphorylation of cyclic adenosine monophosphate response element binding protein） were increased in the hippocampus. Similarly, protein kinase A and TrkB mRNA levels were increased, and calcium-calmodulin-dependent protein kinase lI levels decreased. These findings suggest that electroacupuncture increases phosphorylation of cyclic adenosine monophosphate response element binding protein and brain-derived neurotrophic factor levels by regulating multiple targets in the cyclic adenosine rnonophosphate response element binding protein signal- ing pathway, thereby promoting nerve regeneration, and exerting an antidepressive effect.展开更多
Objective To investigate whether exogenous hydrogen sulfide（H2S）protects high glucose（HG）-inducedH9c2 cardiomyocyte injury and inflammation response by inhibiting reactive oxygen species（ROS）-Toll-like receptor ...Objective To investigate whether exogenous hydrogen sulfide（H2S）protects high glucose（HG）-inducedH9c2 cardiomyocyte injury and inflammation response by inhibiting reactive oxygen species（ROS）-Toll-like receptor 4（TLR4）pathway.Methods Cell counter kit-8（CCK-8）assay was used to measure the cell viability,展开更多
Background： Amyloid β （Aβ） deposits and the endoplasmic reticulum stress （ERS） are both well established in the development and progression of Alzheimer＇s disease （AD）. However, the mechanism and role of Aβ...Background： Amyloid β （Aβ） deposits and the endoplasmic reticulum stress （ERS） are both well established in the development and progression of Alzheimer＇s disease （AD）. However, the mechanism and role of Aβ-induced ERS in AD-associated pathological progression remain to be elucidated. Methods： The five familial AD （5×FAD） mice and wild-type （WT） mice aged 2, 7, and 12 months were used in the present study. Monis water maze test was used to evaluate their cognitive performance, lmmunofluorescence and Western blot analyses were used to examine the dynamic changes of pro-apoptotic （CCAAT/enhancer-binding protein homologous protein [CHOP] and cleaved caspase-12） and anti-apoptotic factors （chaperone glucose-regulated protein [GRP] 78 and endoplasmic reticulum-associated protein degradation-associated ubiquitin ligase synovial apoptosis inhibitor 1 [SYVN 1]） in the ERS-associated unfolded protein response （UPR） pathway. Results： Compared with age-matched WT mice, 5 xFAD mice showed higher cleaved caspase-3, lower neuron-positive staining at the age of 12 months, but earlier cognitive deficit at the age of 7 months （all P 〈 0.05）. Interestingly, for 2-month-old 5×FAD mice, the related proteins involved in the ERS-associated UPR pathway, including CHOP, cleaved caspase-12, GRP 78, and SYVN 1, were significantly increased when compared with those in age-matched WT mice （all P 〈 0.05）. Moreover, ERS occurred mainly in neurons, not in astrocytes. Conclusions： These findings suggest that compared with those of age-matched WT mice, ERS-associated pro-apoptotic and anti-apoptotic proteins are upregulated in 2-month-old 5×FAD mice, consistent with intracellular Aβ aggregation in neurons.展开更多
Background Prediabetes is an early stage of β-cell dysfunction presenting as insulin resistance.Evidences suggest that endoplasmic reticulum （ER） stress is involved in the pathogenesis of type 2 diabetes mellitus a...Background Prediabetes is an early stage of β-cell dysfunction presenting as insulin resistance.Evidences suggest that endoplasmic reticulum （ER） stress is involved in the pathogenesis of type 2 diabetes mellitus and prediabetes.In a Chinese population with prediabetes,we investigated single nucleotide polymorphisms （SNPs） in the genes of PERK,JNK,XBP1,BIP and CHOP which encode molecular proteins involved in ER stress pathways.Methods Nine SNPs at the PERK,JNK,XBP1,BIP and CHOP loci were genotyped by mass spectrometry in 1 448 unrelated individuals.By using a 75 g oral glucose tolerance test （OGTT）,828 subjects were diagnosed as prediabetes and 620 subjects aged 55 years and over as normal controls based on WHO diagnostic criteria （1999） for diabetes mellitus.Results The allele C of SNP rs867529 at PERK locus was a risk factor for prediabetes,with the carriers of C allele genotype at a higher risk of prediabetes compared to non-carriers （OR=1.279,95％ CI：1.013-1.614,P=0.039,after adjustment for age,sex and body mass index （BMI）.The SNPs rs6750998 at PERK locus was associated with homeostasis model assessments of insulin resistance （HOMA-IR） （P=0.019）,and rs17037621 with BMI （P=0.044）.The allele G of SNP rs10986663 in BIP gene was associated with a decreased risk of prediabetes （OR=0.699,95％ CI：0.539-0.907,P=0.007）.The SNP rs2076431 in JNK gene was associated with fasting plasma glucose levels （P=0.006） and waist-hip ratios （P=0.019）.The SNP rs2239815 in XBP1 gene was associated with 2-hour plasma glucose levels after 75 g oral glucose load （P=0.048） in the observed population.Conclusion Common variants at PERK and BIP loci contributed to the risk of prediabetes,and the genetic variations in JNK and XBP1 genes are associated with diabetes-related clinical parameters in this Chinese population.展开更多
基金supported by the National Institutes of Health(Grants P30 CA036727 and R01 CA258621)and funding from the University of Nebraska Medical Center Graduate Studies Assistantship.
文摘The unfolded protein response pathway is an evolutionarily conserved cytoprotective signaling cascade,essential for cell function and survival.Unfolded protein response signaling is tightly integrated with bone cell differentiation and function,and chronic unfolded protein response activation has been identified in bone disease.The unfolded protein response has been found to promote oncogenesis and drug resistance,raising the possibility that unfolded protein response modulators may have activity as anti-cancer agents.Cancer-associated bone disease remains a major cause of morbidity for patients with multiple myeloma or bone-metastatic disease.Understanding the critical role of unfolded protein response signaling in cancer development and metastasis,as well as its role in bone homeostasis,may lead to novel mechanisms by which to target cancer-associated bone disease.In this review,we summarize the current research delineating the roles of the unfolded protein response in bone biology and pathophysiology,and furthermore,review unfolded protein response modulating agents in the contexts of cancer and cancer-associated bone disease.
基金The Department of Science&Technology of Fujian Province(Grant No.2017J01539 and 2020J01729)the Education Department Of Fujian Province(Grant No.JAT190239).
文摘Rheumatoid arthritis(RA)is one of the most common refractory diseases in the world,and traditional Chinese medicine Notopterygium(NE)has been used in the treatment of upper limb pain for a long time.NE can significantly reduce the expression of inflammatory pain target P2X3 receptor in rats with upper-limb arthritis.To verify the relationship between the mechanism of NE for“upper limb paralysis”and the P2X3 receptor-mediated PKC inflammatory response pathway,UPLC was taken to measure the exact medicinal substance of ethyl acetate from NE.Sprague Dawley rats were randomly divided into a blank group,a model group,a live-action group,and a positive group.The joint cavity was removed after 21 d.Moreover,a model group,a live group,and a positive group were also set up with RA-FLS cells in our in vitro study.The expressions of P2X3 and PKC inflammation pathway indicators were detected by Western blotting analysis.A P2X3 inhibitor(A-317491)acted on RA-FLS cells,and a model group and a positive group were set.Then the protein expression of PKC was detected.NE reduced the expressions of P2X3,Rab7,PKC,and NF-κB at the protein level in both systems.NE and P2X3 receptor antagonists reduced the expressions of key proteins in the PKC pathway in RA-FLS cells to similar extents,and their effects were not additive.NE could effectively improve the“forelimb pain”of RA rats,with a mechanism closely related to the P2X3/Rab7/PKC/NF-κB pathway.
文摘In the Research Article“A New Insight into the Mechanism of Atrazine-Induced Neurotoxicity:Triggering Neural Stem Cell Senescence by Activating the Integrated Stress Response Pathway,”an error needs to be corrected in Figure 5[1].
基金supported by CIHR Grants (109606,106886,and TAD 125698)an Ontario Graduate Scholarship,an Admission Scholarship,and an Excellence Scholarship from the University of Ottawa
文摘Alzheimer＇s disease（AD） is characterized by amyloid-b（Ab） toxicity,tau pathology,insulin resistance,neuroinflammation,and dysregulation of cholesterol homeostasis,all of which play roles in neurodegeneration.Insulin has polytrophic effects on neurons and may be at the center of these pathophysiological changes.In this study,we investigated possible relationships among insulin signaling and cholesterol biosynthesis,along with the effects of Ab42 on these pathways in vitro.We found that neuroblastoma 2a（N2a） cells transfected with the human gene encoding amyloid-b protein precursor（Ab PP）（N2aAb PP） produced Ab and exhibited insulin resistance by reduced p-Akt and a suppressed cholesterol-synthesis pathway following insulin treatment,and by increased phosphorylation of insulin receptor subunit-1 at serine 612（p-IRS-S612） as compared to parental N2 a cells.Treatment of human neuroblastoma SH-SY5 Y cells with Ab42 also increased p-IRS-S612,suggesting that Ab42 is responsible for insulin resistance.The insulin resistance was alleviated when N2a-Ab PP cells were treated with higher insulin concentrations.Insulin increased Ab release from N2 aAb PP cells,by which it may promote Ab clearance.Insulin increased cholesterol-synthesis gene expression in SHSY5 Y and N2 a cells,including 24-dehydrocholesterol reductase（DHCR24） and 3-hydroxy-3-methyl-glutaryl-Co A reductase（HMGCR） through sterol-regulatory element-binding protein-2（SREBP2）.While Ab42-treated SH-SY5 Y cells exhibited increased HMGCR expression and c-Jun phosphorylation as pro-inflammatory responses,they also showed down-regulation of neuro-protective/antiinflammatory DHCR24.These results suggest that Ab42 may cause insulin resistance,activate JNK for c-Jun phosphorylation,and lead to dysregulation of cholesterol homeostasis,and that enhancing insulin signaling may relieve the insulin-resistant phenotype and the dysregulated cholesterol-synthesis pathway to promote Ab release for clearance from neural cells.
基金supported by the National Natural Science Foundation of China(Grant No 10774008)National Key Basic Research Program of China(Grant Nos 2007CB814800 and 2006CB910706)the support of the National Funds for Fostering Talents in Basic Science of China(Grant No J0630311)
文摘We report stochastic simulations of the yeast mating signal transduction pathway. The effects of intrinsic and external noise, the influence of cell-to-cell difference in the pathway capacity, and noise propagation in the pathway have been examined. The stochastic temporal behaviour of the pathway is found to be robust to the influence of inherent fluctuations, and intrinsic noise propagates in the pathway in a uniform pattern when the yeasts are treated with pheromones of different stimulus strengths and of varied fluctuations. In agreement with recent experimental findings, extrinsic noise is found to play a more prominent role than intrinsic noise in the variability of proteins. The occurrence frequency for the reactions in the pathway are also examined and a more compact network is obtained by dropping most of the reactions of least occurrence.
基金supported by the Natural Science Foundation of Guangdong Province(No.2018A030310597)the Traditional Chinese Medicine Bureau Foundation of Guangdong Province(No.20201104,20182022)+3 种基金the Scientific Research and Cultivation Fund of the First Affiliated Hospital of Jinan University(No.2017107)the Fundamental Research Funds for the Central Universities(No.21616331)the National Natural Science Foundation of China(No.81873206,82104947)the Sixth Batch of National Traditional Chinese Medicine Experts’Academic Experience Inheritance Project.
文摘Background:According to our previous studies,Shenling Baizhu powder has an excellent preventive and therapeutic effect on nonalcoholic fatty liver disease,but the prevention mechanism is still not clear.In this study,we intended to explore the effects of Shenling Baizhu powder on the endoplasmic reticulum stress related signaling pathway in nonalcoholic fatty liver disease rats’liver tissues.Methods:After 16 weeks,the levels of serum total cholesterol,triglyceride,high-density lipoprotein cholesterol,low-density lipoprotein cholesterol,alanine transaminase and aspartate transaminase were evaluated by an automatic biochemical analyzer,and the levels of serum free fatty acid and hepatic total cholesterol and triglyceride were evaluated by commercial kits.Then,histological changes of the liver were observed by hematoxylin and eosin and oil red-O staining.Protein expression related to the liver unfolded protein response signalling pathway was assessed using Western blot analysis.Results:The results showed that Shenling Baizhu powder supplementation reduced serum total cholesterol,triglyceride,free fatty acid,alanine transaminase,and aspartate transaminase(P<0.05 or P<0.01),as well as the levels of hepatic total cholesterol and triglyceride(P<0.01).Pathological examination showed that Shenling Baizhu powder improved hepatic steatosis and lipid accumulation.The results of biochemical parameters and histological changes indicated that Shenling Baizhu powder administration exerted protective effects against nonalcoholic fatty liver disease.In addition,Shenling Baizhu powder decreased the protein expression levels of binding immunoglobulin protein,activating transcription factor 6,phosphorylation of eukaryotic initiation factor 2 alpha,protein kinase RNA-like endoplasmic reticulum kinase and X-box binding protein 1s in the liver(P<0.05 or P<0.01).Conclusion:Shenling Baizhu powder can ameliorate high-fat diet-induced liver lipid metabolism disorder in nonalcoholic fatty liver disease rats.The mechanisms may be related to the inhibition of the expression of proteins related to unfolded protein response signaling pathways in endoplasmic reticulum stress.
基金supported by the General Program of the National Natural Science Foundation of China,No.81273847
文摘Electroacupuncture improves depressive behavior faster and with fewer adverse effects than antidepressant medication. However, the antidepressant mechanism of electroacupuncture remains poorly understood. Here, we established a rat model of chronic unpredicted mild stress, and then treated these rats with electroacupuncture at Yintang （EX-HN3） and Baihui （DU20） with sparse waves at 2 Hz and 0.6 mA for 30 minutes, once a day. We found increased horizontal and vertical activity, and decreased immobility time, at 2 and 4 weeks after treatment. Moreover, levels of neurotransmitters （5-hydroxytryptamine, glutamate, and y-aminobutyric acid） and protein levels of brain-derived neurotrophic factor and brain-derived neurotrophic factor-related proteins （TrkB, protein kinase A, and phosphorylation of cyclic adenosine monophosphate response element binding protein） were increased in the hippocampus. Similarly, protein kinase A and TrkB mRNA levels were increased, and calcium-calmodulin-dependent protein kinase lI levels decreased. These findings suggest that electroacupuncture increases phosphorylation of cyclic adenosine monophosphate response element binding protein and brain-derived neurotrophic factor levels by regulating multiple targets in the cyclic adenosine rnonophosphate response element binding protein signal- ing pathway, thereby promoting nerve regeneration, and exerting an antidepressive effect.
文摘Objective To investigate whether exogenous hydrogen sulfide（H2S）protects high glucose（HG）-inducedH9c2 cardiomyocyte injury and inflammation response by inhibiting reactive oxygen species（ROS）-Toll-like receptor 4（TLR4）pathway.Methods Cell counter kit-8（CCK-8）assay was used to measure the cell viability,
基金This work was supported by grants from the National Natural Science Foundation of China （No. 91232709, No. 811171216, and No. 81161120496 for Prof. Xiao-Chun Chen, and No. 81200991 for Prof. Xiao-Dong Pan） and the National and Fujian Province＇s Key Clinical Specialty Discipline Construction Programs.
文摘Background： Amyloid β （Aβ） deposits and the endoplasmic reticulum stress （ERS） are both well established in the development and progression of Alzheimer＇s disease （AD）. However, the mechanism and role of Aβ-induced ERS in AD-associated pathological progression remain to be elucidated. Methods： The five familial AD （5×FAD） mice and wild-type （WT） mice aged 2, 7, and 12 months were used in the present study. Monis water maze test was used to evaluate their cognitive performance, lmmunofluorescence and Western blot analyses were used to examine the dynamic changes of pro-apoptotic （CCAAT/enhancer-binding protein homologous protein [CHOP] and cleaved caspase-12） and anti-apoptotic factors （chaperone glucose-regulated protein [GRP] 78 and endoplasmic reticulum-associated protein degradation-associated ubiquitin ligase synovial apoptosis inhibitor 1 [SYVN 1]） in the ERS-associated unfolded protein response （UPR） pathway. Results： Compared with age-matched WT mice, 5 xFAD mice showed higher cleaved caspase-3, lower neuron-positive staining at the age of 12 months, but earlier cognitive deficit at the age of 7 months （all P 〈 0.05）. Interestingly, for 2-month-old 5×FAD mice, the related proteins involved in the ERS-associated UPR pathway, including CHOP, cleaved caspase-12, GRP 78, and SYVN 1, were significantly increased when compared with those in age-matched WT mice （all P 〈 0.05）. Moreover, ERS occurred mainly in neurons, not in astrocytes. Conclusions： These findings suggest that compared with those of age-matched WT mice, ERS-associated pro-apoptotic and anti-apoptotic proteins are upregulated in 2-month-old 5×FAD mice, consistent with intracellular Aβ aggregation in neurons.
基金The study was supported by a grant from the National Natural Science Foundation of China （No. 30771033）. No potential conflicts of interest relevant to this article were reported.
文摘Background Prediabetes is an early stage of β-cell dysfunction presenting as insulin resistance.Evidences suggest that endoplasmic reticulum （ER） stress is involved in the pathogenesis of type 2 diabetes mellitus and prediabetes.In a Chinese population with prediabetes,we investigated single nucleotide polymorphisms （SNPs） in the genes of PERK,JNK,XBP1,BIP and CHOP which encode molecular proteins involved in ER stress pathways.Methods Nine SNPs at the PERK,JNK,XBP1,BIP and CHOP loci were genotyped by mass spectrometry in 1 448 unrelated individuals.By using a 75 g oral glucose tolerance test （OGTT）,828 subjects were diagnosed as prediabetes and 620 subjects aged 55 years and over as normal controls based on WHO diagnostic criteria （1999） for diabetes mellitus.Results The allele C of SNP rs867529 at PERK locus was a risk factor for prediabetes,with the carriers of C allele genotype at a higher risk of prediabetes compared to non-carriers （OR=1.279,95％ CI：1.013-1.614,P=0.039,after adjustment for age,sex and body mass index （BMI）.The SNPs rs6750998 at PERK locus was associated with homeostasis model assessments of insulin resistance （HOMA-IR） （P=0.019）,and rs17037621 with BMI （P=0.044）.The allele G of SNP rs10986663 in BIP gene was associated with a decreased risk of prediabetes （OR=0.699,95％ CI：0.539-0.907,P=0.007）.The SNP rs2076431 in JNK gene was associated with fasting plasma glucose levels （P=0.006） and waist-hip ratios （P=0.019）.The SNP rs2239815 in XBP1 gene was associated with 2-hour plasma glucose levels after 75 g oral glucose load （P=0.048） in the observed population.Conclusion Common variants at PERK and BIP loci contributed to the risk of prediabetes,and the genetic variations in JNK and XBP1 genes are associated with diabetes-related clinical parameters in this Chinese population.
