The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane pr...The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins aremembers of the basic helix-loop-helix-leucine zipper (bHLHZip) family of transcription factors. They activate the expression of at least 30 genes involved in the synthesis of cholesterol and lipids. SREBPs are synthesized as precursor proteins in the endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP). The SCAP molecule contains a sterol sensory domain. In the presence of high cellular sterol concentrations SCAP confines SREBP to the ER. With low cellular concentrations, SCAP escorts SREBP to activation in the Golgi. There, SREBP undergoes two proteolytic cleavage steps to release the mature, biologically active transcription factor, nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds to sterol response elements (SRE) in the promoter/enhancer regions of target genes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs are known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced from a single gene by alternate splicing. SREBP-2 is encoded by a different gene and does not display any isoforms. It appears that SREBPs alone, in the sequence described above, can exert complete control over cholesterol synthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is expected to prove highly beneficial in the management of cholesterol-related disease.展开更多
Ischemic brain injury triggers an inflammatory response. tissue but can also exacerbate brain injury. Microglia are This response is necessary to clear damaged brain the innate immune cells of the brain that execute t...Ischemic brain injury triggers an inflammatory response. tissue but can also exacerbate brain injury. Microglia are This response is necessary to clear damaged brain the innate immune cells of the brain that execute this critical function. In healthy brain, microglia perform a housekeeping function, pruning unused syn- apses between neurons. However, microglia become activated to an inflammatory phenotype upon brain injury. Interferon regulatory factors modulate microglial activation and their production of inflammatory cytokines. This review briefly discusses recent findings pertaining to these regulatory mechanisms in the context of stroke recovery.展开更多
AIM: To investigate the molecular mechanism for regulation of cholesterol metabolism by hepatitis C virus(HCV) core protein in Hep G2 cells.METHODS: HCV genotype 1b core protein was cloned and expressed in Hep G2 cell...AIM: To investigate the molecular mechanism for regulation of cholesterol metabolism by hepatitis C virus(HCV) core protein in Hep G2 cells.METHODS: HCV genotype 1b core protein was cloned and expressed in Hep G2 cells. The cholesterol content was determined after transfection. The expression of sterol regulatory element binding protein 2(SREBP2) and the rate-limiting enzyme in cholesterol synthesis(HMGCR) was measured by quantitative real-time PCR and immunoblotting after transfection. The effects of core protein on the SREBP2 promoter and 3'-untranslated region were analyzed by luciferase assay. We used different target predictive algorithms, micro RNA(mi RNA) mimics/inhibitors, and site-directed mutation to identify a putative target of a particular mi RNA.RESULTS: HCV core protein expression in Hep G2 cells increased the total intracellular cholesterol level(4.05 ± 0.17 vs 6.47 ± 0.68, P = 0.001), and this increase corresponded to an increase in SREBP2 and HMGCR m RNA levels(P = 0.009 and 0.037, respectively) and protein expression. The molecular mechanism studyrevealed that the HCV core protein increased the expression of SREBP2 by enhancing its promoter activity(P = 0.004). In addition, mi R-185-5p expression was tightly regulated by the HCV core protein(P = 0.041). Moreover, overexpression of mi R-185-5p repressed the SREBP2 m RNA level(P = 0.022) and protein expression. In contrast, inhibition of mi R-185-5p caused upregulation of SREBP2 protein expression. mi R-185-5p was involved in the regulation of SREBP2 expression by HCV core protein. CONCLUSION: HCV core protein disturbs the cholesterol homeostasis in Hep G2 cells via the SREBP2 pathway; mi R-185-5p is involved in the regulation of SREBP2 by the core protein.展开更多
Metal ions play critical roles in the interaction between deoxyribonucleic acid(DNA) and protein.The experimental research has demonstrated that the Mg^2+ ion can affect the binding between transcription factor and DN...Metal ions play critical roles in the interaction between deoxyribonucleic acid(DNA) and protein.The experimental research has demonstrated that the Mg^2+ ion can affect the binding between transcription factor and DNA.In our work,by full-atom molecular dynamic simulation, the effects of the Mg^2+ ion on the cyclic adenosine monophosphate(cAMP)response element binding protein(CREB)/cAMP response elements(CRE) complex are investigated.It is illustrated that the number of hydrogen bonds formed at the interface between protein and DNA is significantly increased when the Mg^2+ ion is added.Hence, an obvious change in the structure of the DNA is observed.Then the DNA base groove and base pair parameters are analyzed.We find that, due to the introduction of the Mg2+ ion, the DNA base major groove becomes narrower.A potential mechanism for this observation is proposed.It is confirmed that the Mg^2+ ion can enhance the stability of the DNA–protein complex.展开更多
目的:探讨血清固醇调节元件结合蛋白2(sterol regulatory element binding protein-2,SREBP-2)与急性脑梗死的相关性。方法:纳入2020年10月至2021年3月入住的134名急性脑梗死患者和34名健康体检者。通过酶联免疫吸附实验法(enzyme-linke...目的:探讨血清固醇调节元件结合蛋白2(sterol regulatory element binding protein-2,SREBP-2)与急性脑梗死的相关性。方法:纳入2020年10月至2021年3月入住的134名急性脑梗死患者和34名健康体检者。通过酶联免疫吸附实验法(enzyme-linked immunosorbent assay,ELISA)检测血清SERBP-2浓度,并依据急性卒中Org 10172治疗试验(trial of Org 10172 in acute stroke treatment,TOAST)分型和是否合并糖尿病进行亚组分析。使用美国国立卫生研究院卒中量表(National Institutes of Health Stroke Scale,NIHSS)评分评估患者的病情严重程度,并分析血清SREBP-2与病情严重程度的相关性。使用改良Rankin量表评估患者的90 d功能预后,并将患者分为预后良好组和预后不良组,比较2组的血清SREBP-2浓度差异,并通过logistic回归分析血清SREBP-2是否与脑梗死预后相关。结果:脑梗死组的血清SREBP-2浓度明显低于对照组[72.60(57.50,83.35)ng/mL vs.86.80(77.20,97.90)ng/mL,P=0.000]。血清SREBP-2浓度识别急性脑梗死患者和健康人群的曲线下面积为0.782(P=0.000)。大动脉粥样硬化型、心源性栓塞型、小动脉闭塞型脑梗死血清SREBP-2浓度均明显低于对照组(P=0.000,P=0.003,P=0.000)。合并糖尿病患者的血清SREBP-2高于不合并糖尿病的患者(P=0.021)。血清SREBP-2浓度与入院NIHSS评分无相关性(P>0.05)。脑梗死患者预后良好组血清SREBP-2浓度较预后不良组低,但差异无统计学意义(P>0.05),logistic回归分析显示血清SREBP-2浓度与脑梗死90 d功能预后无关(OR=1.016,95%CI=0.991~1.042,P=0.205)。结论:血清SREBP-2浓度在急性脑梗死患者中明显下降。血清SREBP-2对识别脑梗死患者与健康人群具有一定的效能。然而,血清SREBP-2浓度与患者病情严重程度和预后无关。展开更多
Objective Schizophrenia(SZ)is associated with cognitive impairment,and it is known that the activity of cAMP response element binding protein(CREB)decreases in the brain of SZ patients.The previous study conducted by ...Objective Schizophrenia(SZ)is associated with cognitive impairment,and it is known that the activity of cAMP response element binding protein(CREB)decreases in the brain of SZ patients.The previous study conducted by the investigators revealed that the upregulation of CREB improves the MK801-related SZ cognitive deficit.The present study further investigates the mechanism on how CREB deficiency is associated with SZ-related cognitive impairment.Methods MK-801 was used to induce SZ in rats.Western blotting and immunofluorescence were performed to investigate CREB and the CREB-related pathway implicated in MK801 rats.The long-term potentiation and behavioral tests were performed to assess the synaptic plasticity and cognitive impairment,respectively.Results The phosphorylation of CREB at Ser133 decreased in the hippocampus of SZ rats.Interestingly,among the upstream kinases of CREB,merely ERK1/2 was downregulated,while CaMKII and PKA remained unchanged in the brain of MK801-related SZ rats.The inhibition of ERK1/2 by PD98059 reduced the phosphorylation of CREB-Ser133,and induced synaptic dysfunction in primary hippocampal neurons.Conversely,the activation of CREB attenuated the ERK1/2 inhibitor-induced synaptic and cognitive impairment.Conclusion These present findings partially suggest that the deficiency of the ERK1/2-CREB pathway is involved in MK801-related SZ cognitive impairment.The activation of the ERK1/2-CREB pathway may be therapeutically useful for treating SZ cognitive deficits.展开更多
The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding pla...The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding plays a role in ALS pathogenesis in two ways: non-ATG translation of the repeat can lead to aggregates of the known C9orf72 specific dipeptide polymer, whereas the repeat also can form neurotoxic RNA inclusions that dose-responsively kill motor neurons. We report the presence of a homology in the 5’untranslated region (UTR) of the messenger RNA encoding C9orf72 with the iron responsive elements (IRE) that control expression of iron-associated transcripts and predict that this RNA structure may iron-dependently regulate C9orf72 translation. We previously report altered serum ferritin levels track with severity of ALS in patients. Here, we conduct bioinformatics analyses to determine the secondary structure of the 5’UTR in C9orf72 mRNA and find it aligned with IREs in the human mitochondrial cis-aconitase and L and H-ferritin transcripts. Comparison of the role of RNA repeats in Friedriech’s ataxia and fragile X mental retardation suggests the utility of RNA based therapies for treatment of ALS. Antisense oligonucleotides (ASO) have been reported to therapeutically target these GGGGCC repeats. At the same time, because the function of C9orf72 is unknown, knockdown strategies carry some risk of inducing or compounding haploinsufficiency. We propose, for consideration, an approach that may enhance its therapeutic dynamic range by increasing the 5’UTR driven translation of C9orf72 protein to compensate for any potential ALS-specific or ASO-induced haploinsufficieny.展开更多
Background Sterol regulatory element binding protein （SREBP）-2 plays a key role in lipid homeostasis by stimulating gene expression of cholesterol biosynthetic pathways. The insulin-like growth factor binding prote...Background Sterol regulatory element binding protein （SREBP）-2 plays a key role in lipid homeostasis by stimulating gene expression of cholesterol biosynthetic pathways. The insulin-like growth factor binding protein （IGFBP） family regulates growth and metabolism, especially bone cell metabolism, and correlates with osteonecrosis. However, association of their gene polymorphisms with risk of avascular necrosis of the femoral head （ANFH） has rarely been reported. We determined whether SREBP-2 and IGFBP-3 gene polymorphisms were associated with increased ANFH risk in the Chinese population. Methods Two single nucleotide polymorphisms of SREBP2 gene, rs2267439 and rs2267443, and one of IGFBP-3 gene, rs2453839, were selected and genotyped in 49 ANFH patients and 42 control individuals by direct sequencing assay. Results The frequencies of rs2267439 TT and rs2267443 GA of SREBP2 and rs2453839 TT and CT of IGFBP-3 in the ANFH group showed increased and decreased tendencies （against normal control group）, respectively. Interaction analysis of genes revealed that the frequency of carrying rs2267439 TT and rs2267443 GA genotypes of SREBF-2 in ANFH patients was significantly higher than in the control group （P 〈0.05）. Association analysis between polymorphisms and clinical phenotype demonstrated that the disease course in ANFH patients with the rs2453839 TT genotype of IGFBP-3 was significantly shorter than that of CT＋CC carriers （P 〈0.01）. CT＋CC genotype frequency in patients with stage Ill/IV bilateral hip lesions was significantly higher than in those with stage Ill/IV unilateral lesions and stage II/111 bilateral lesions （P 〈0.05-0.02）. Conclusions Our results suggested that interaction of SREBP-2 gene polymorphisms and the relationship between the polymorphisms and clinical phenotype of IGFBP-3 were closely related to increased ANFH risk in the Chinese population. The most significant finding was that the CT＋CC genotype carriers of IGFBP-3 rs2453839 were highly associated with the development of ANFH.展开更多
目的：研究胆固醇调节元件结合蛋白2基因（sterol regulatory element binding protein 2 gene，SREBP2） rs2228314多态性与儿童青少年肥胖和血脂水平的关系。方法：研究对象来自前期工作中收集的两批样本，共2030名7岁至18岁中小学生...目的：研究胆固醇调节元件结合蛋白2基因（sterol regulatory element binding protein 2 gene，SREBP2） rs2228314多态性与儿童青少年肥胖和血脂水平的关系。方法：研究对象来自前期工作中收集的两批样本，共2030名7岁至18岁中小学生，对这些学生进行身体测量和血清总胆固醇（total cholesterol，TC）、三酰甘油（triacylgly-ceride，TG）、高密度脂蛋白胆固醇（low density lipoprotein-cholesterol，HDL-C）、低密度脂蛋白胆固醇（low density lipo-protein-cholesterol ，LDL-C）的检测。采用基质支持的激光释放/电离飞行时间质谱分析检测rs2228314多态性基因型。在显性模型下进行统计学分析，采用t检验比较不同基因型组间血脂水平（计量资料）的差异，采用Logistic回归分析rs2228314多态性与血脂水平的异常（分类资料）和肥胖的关系。结果：rs2228314多态性GC/CC基因型组的HDL-C水平低于GG纯合子，差异有统计学意义（0．10＆#177;0．35 vs．0．14＆#177;0．36，P＝0．020），在显性模型下，调整研究样本、性别和年龄后，rs2228314多态性与 HDL-C 水平的异常相关（ OR ＝1．400，95％ CI：1．027～1．907， P ＝0．033）。调整研究样本、性别、年龄和HDL-C 水平后，rs2228314多态性与肥胖的相关性无统计学意义（OR ＝1．178，95％CI：0．971～1．430， P＝0．096）。结论：携带SREBP2基因rs2228314多态性GC/CC基因型的儿童青少年发生HDL-C水平异常的风险高于GG基因型携带者。展开更多
文摘The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins aremembers of the basic helix-loop-helix-leucine zipper (bHLHZip) family of transcription factors. They activate the expression of at least 30 genes involved in the synthesis of cholesterol and lipids. SREBPs are synthesized as precursor proteins in the endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP). The SCAP molecule contains a sterol sensory domain. In the presence of high cellular sterol concentrations SCAP confines SREBP to the ER. With low cellular concentrations, SCAP escorts SREBP to activation in the Golgi. There, SREBP undergoes two proteolytic cleavage steps to release the mature, biologically active transcription factor, nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds to sterol response elements (SRE) in the promoter/enhancer regions of target genes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs are known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced from a single gene by alternate splicing. SREBP-2 is encoded by a different gene and does not display any isoforms. It appears that SREBPs alone, in the sequence described above, can exert complete control over cholesterol synthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is expected to prove highly beneficial in the management of cholesterol-related disease.
基金supported by a grant from the Heart and Stroke Foundation of Canada(HHC,AFRS)a grant from the Natural Science&Engineering Research Council of Canada(HHC,AFRS)a Mid-Career Investigator Award from the Heart and Stroke Foundation of Ontario,Canada(HHC)
文摘Ischemic brain injury triggers an inflammatory response. tissue but can also exacerbate brain injury. Microglia are This response is necessary to clear damaged brain the innate immune cells of the brain that execute this critical function. In healthy brain, microglia perform a housekeeping function, pruning unused syn- apses between neurons. However, microglia become activated to an inflammatory phenotype upon brain injury. Interferon regulatory factors modulate microglial activation and their production of inflammatory cytokines. This review briefly discusses recent findings pertaining to these regulatory mechanisms in the context of stroke recovery.
基金Supported by Medical Specialty Development Projects of Beijing Municipal Administration of Hospitals,No.ZYLX201402Ministry of Education of The People’s Republic of China,No.20121107110012+1 种基金Beijing Municipal Commission of Education,No.11320016Collaborative Innovation Center of Infectious Diseases and Beijing Key Laboratory of Emerging Infectious Diseases,Beijing,China
文摘AIM: To investigate the molecular mechanism for regulation of cholesterol metabolism by hepatitis C virus(HCV) core protein in Hep G2 cells.METHODS: HCV genotype 1b core protein was cloned and expressed in Hep G2 cells. The cholesterol content was determined after transfection. The expression of sterol regulatory element binding protein 2(SREBP2) and the rate-limiting enzyme in cholesterol synthesis(HMGCR) was measured by quantitative real-time PCR and immunoblotting after transfection. The effects of core protein on the SREBP2 promoter and 3'-untranslated region were analyzed by luciferase assay. We used different target predictive algorithms, micro RNA(mi RNA) mimics/inhibitors, and site-directed mutation to identify a putative target of a particular mi RNA.RESULTS: HCV core protein expression in Hep G2 cells increased the total intracellular cholesterol level(4.05 ± 0.17 vs 6.47 ± 0.68, P = 0.001), and this increase corresponded to an increase in SREBP2 and HMGCR m RNA levels(P = 0.009 and 0.037, respectively) and protein expression. The molecular mechanism studyrevealed that the HCV core protein increased the expression of SREBP2 by enhancing its promoter activity(P = 0.004). In addition, mi R-185-5p expression was tightly regulated by the HCV core protein(P = 0.041). Moreover, overexpression of mi R-185-5p repressed the SREBP2 m RNA level(P = 0.022) and protein expression. In contrast, inhibition of mi R-185-5p caused upregulation of SREBP2 protein expression. mi R-185-5p was involved in the regulation of SREBP2 expression by HCV core protein. CONCLUSION: HCV core protein disturbs the cholesterol homeostasis in Hep G2 cells via the SREBP2 pathway; mi R-185-5p is involved in the regulation of SREBP2 by the core protein.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.11705064,11675060,and 91730301)the Fundamental Research Funds for the Central Universities,China(Grant Nos.2662016QD005 and 26622018JC017)the Huazhong Agricultural University Scientific and Technological Self-Innovation Foundation Program,China(Grant No.2015RC021)
文摘Metal ions play critical roles in the interaction between deoxyribonucleic acid(DNA) and protein.The experimental research has demonstrated that the Mg^2+ ion can affect the binding between transcription factor and DNA.In our work,by full-atom molecular dynamic simulation, the effects of the Mg^2+ ion on the cyclic adenosine monophosphate(cAMP)response element binding protein(CREB)/cAMP response elements(CRE) complex are investigated.It is illustrated that the number of hydrogen bonds formed at the interface between protein and DNA is significantly increased when the Mg^2+ ion is added.Hence, an obvious change in the structure of the DNA is observed.Then the DNA base groove and base pair parameters are analyzed.We find that, due to the introduction of the Mg2+ ion, the DNA base major groove becomes narrower.A potential mechanism for this observation is proposed.It is confirmed that the Mg^2+ ion can enhance the stability of the DNA–protein complex.
文摘目的:探讨血清固醇调节元件结合蛋白2(sterol regulatory element binding protein-2,SREBP-2)与急性脑梗死的相关性。方法:纳入2020年10月至2021年3月入住的134名急性脑梗死患者和34名健康体检者。通过酶联免疫吸附实验法(enzyme-linked immunosorbent assay,ELISA)检测血清SERBP-2浓度,并依据急性卒中Org 10172治疗试验(trial of Org 10172 in acute stroke treatment,TOAST)分型和是否合并糖尿病进行亚组分析。使用美国国立卫生研究院卒中量表(National Institutes of Health Stroke Scale,NIHSS)评分评估患者的病情严重程度,并分析血清SREBP-2与病情严重程度的相关性。使用改良Rankin量表评估患者的90 d功能预后,并将患者分为预后良好组和预后不良组,比较2组的血清SREBP-2浓度差异,并通过logistic回归分析血清SREBP-2是否与脑梗死预后相关。结果:脑梗死组的血清SREBP-2浓度明显低于对照组[72.60(57.50,83.35)ng/mL vs.86.80(77.20,97.90)ng/mL,P=0.000]。血清SREBP-2浓度识别急性脑梗死患者和健康人群的曲线下面积为0.782(P=0.000)。大动脉粥样硬化型、心源性栓塞型、小动脉闭塞型脑梗死血清SREBP-2浓度均明显低于对照组(P=0.000,P=0.003,P=0.000)。合并糖尿病患者的血清SREBP-2高于不合并糖尿病的患者(P=0.021)。血清SREBP-2浓度与入院NIHSS评分无相关性(P>0.05)。脑梗死患者预后良好组血清SREBP-2浓度较预后不良组低,但差异无统计学意义(P>0.05),logistic回归分析显示血清SREBP-2浓度与脑梗死90 d功能预后无关(OR=1.016,95%CI=0.991~1.042,P=0.205)。结论:血清SREBP-2浓度在急性脑梗死患者中明显下降。血清SREBP-2对识别脑梗死患者与健康人群具有一定的效能。然而,血清SREBP-2浓度与患者病情严重程度和预后无关。
基金supported in part by grants from National Natural Science Foundation of China(No.31929002,No.82201326 No.82071440 and No.92049107)Science,Technology and Innovation Commission of Shenzhen Municipality(No.JCYJ20210324141405014)+1 种基金Guangdong Basic and Applied Basic Research Foundation(No.2020B1515120017)the Academic Frontier Youth Team Project to Xiao-chuan WANG from Huazhong University of Science and Technology.
文摘Objective Schizophrenia(SZ)is associated with cognitive impairment,and it is known that the activity of cAMP response element binding protein(CREB)decreases in the brain of SZ patients.The previous study conducted by the investigators revealed that the upregulation of CREB improves the MK801-related SZ cognitive deficit.The present study further investigates the mechanism on how CREB deficiency is associated with SZ-related cognitive impairment.Methods MK-801 was used to induce SZ in rats.Western blotting and immunofluorescence were performed to investigate CREB and the CREB-related pathway implicated in MK801 rats.The long-term potentiation and behavioral tests were performed to assess the synaptic plasticity and cognitive impairment,respectively.Results The phosphorylation of CREB at Ser133 decreased in the hippocampus of SZ rats.Interestingly,among the upstream kinases of CREB,merely ERK1/2 was downregulated,while CaMKII and PKA remained unchanged in the brain of MK801-related SZ rats.The inhibition of ERK1/2 by PD98059 reduced the phosphorylation of CREB-Ser133,and induced synaptic dysfunction in primary hippocampal neurons.Conversely,the activation of CREB attenuated the ERK1/2 inhibitor-induced synaptic and cognitive impairment.Conclusion These present findings partially suggest that the deficiency of the ERK1/2-CREB pathway is involved in MK801-related SZ cognitive impairment.The activation of the ERK1/2-CREB pathway may be therapeutically useful for treating SZ cognitive deficits.
文摘The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding plays a role in ALS pathogenesis in two ways: non-ATG translation of the repeat can lead to aggregates of the known C9orf72 specific dipeptide polymer, whereas the repeat also can form neurotoxic RNA inclusions that dose-responsively kill motor neurons. We report the presence of a homology in the 5’untranslated region (UTR) of the messenger RNA encoding C9orf72 with the iron responsive elements (IRE) that control expression of iron-associated transcripts and predict that this RNA structure may iron-dependently regulate C9orf72 translation. We previously report altered serum ferritin levels track with severity of ALS in patients. Here, we conduct bioinformatics analyses to determine the secondary structure of the 5’UTR in C9orf72 mRNA and find it aligned with IREs in the human mitochondrial cis-aconitase and L and H-ferritin transcripts. Comparison of the role of RNA repeats in Friedriech’s ataxia and fragile X mental retardation suggests the utility of RNA based therapies for treatment of ALS. Antisense oligonucleotides (ASO) have been reported to therapeutically target these GGGGCC repeats. At the same time, because the function of C9orf72 is unknown, knockdown strategies carry some risk of inducing or compounding haploinsufficiency. We propose, for consideration, an approach that may enhance its therapeutic dynamic range by increasing the 5’UTR driven translation of C9orf72 protein to compensate for any potential ALS-specific or ASO-induced haploinsufficieny.
文摘Background Sterol regulatory element binding protein （SREBP）-2 plays a key role in lipid homeostasis by stimulating gene expression of cholesterol biosynthetic pathways. The insulin-like growth factor binding protein （IGFBP） family regulates growth and metabolism, especially bone cell metabolism, and correlates with osteonecrosis. However, association of their gene polymorphisms with risk of avascular necrosis of the femoral head （ANFH） has rarely been reported. We determined whether SREBP-2 and IGFBP-3 gene polymorphisms were associated with increased ANFH risk in the Chinese population. Methods Two single nucleotide polymorphisms of SREBP2 gene, rs2267439 and rs2267443, and one of IGFBP-3 gene, rs2453839, were selected and genotyped in 49 ANFH patients and 42 control individuals by direct sequencing assay. Results The frequencies of rs2267439 TT and rs2267443 GA of SREBP2 and rs2453839 TT and CT of IGFBP-3 in the ANFH group showed increased and decreased tendencies （against normal control group）, respectively. Interaction analysis of genes revealed that the frequency of carrying rs2267439 TT and rs2267443 GA genotypes of SREBF-2 in ANFH patients was significantly higher than in the control group （P 〈0.05）. Association analysis between polymorphisms and clinical phenotype demonstrated that the disease course in ANFH patients with the rs2453839 TT genotype of IGFBP-3 was significantly shorter than that of CT＋CC carriers （P 〈0.01）. CT＋CC genotype frequency in patients with stage Ill/IV bilateral hip lesions was significantly higher than in those with stage Ill/IV unilateral lesions and stage II/111 bilateral lesions （P 〈0.05-0.02）. Conclusions Our results suggested that interaction of SREBP-2 gene polymorphisms and the relationship between the polymorphisms and clinical phenotype of IGFBP-3 were closely related to increased ANFH risk in the Chinese population. The most significant finding was that the CT＋CC genotype carriers of IGFBP-3 rs2453839 were highly associated with the development of ANFH.
文摘目的：研究胆固醇调节元件结合蛋白2基因（sterol regulatory element binding protein 2 gene，SREBP2） rs2228314多态性与儿童青少年肥胖和血脂水平的关系。方法：研究对象来自前期工作中收集的两批样本，共2030名7岁至18岁中小学生，对这些学生进行身体测量和血清总胆固醇（total cholesterol，TC）、三酰甘油（triacylgly-ceride，TG）、高密度脂蛋白胆固醇（low density lipoprotein-cholesterol，HDL-C）、低密度脂蛋白胆固醇（low density lipo-protein-cholesterol ，LDL-C）的检测。采用基质支持的激光释放/电离飞行时间质谱分析检测rs2228314多态性基因型。在显性模型下进行统计学分析，采用t检验比较不同基因型组间血脂水平（计量资料）的差异，采用Logistic回归分析rs2228314多态性与血脂水平的异常（分类资料）和肥胖的关系。结果：rs2228314多态性GC/CC基因型组的HDL-C水平低于GG纯合子，差异有统计学意义（0．10＆#177;0．35 vs．0．14＆#177;0．36，P＝0．020），在显性模型下，调整研究样本、性别和年龄后，rs2228314多态性与 HDL-C 水平的异常相关（ OR ＝1．400，95％ CI：1．027～1．907， P ＝0．033）。调整研究样本、性别、年龄和HDL-C 水平后，rs2228314多态性与肥胖的相关性无统计学意义（OR ＝1．178，95％CI：0．971～1．430， P＝0．096）。结论：携带SREBP2基因rs2228314多态性GC/CC基因型的儿童青少年发生HDL-C水平异常的风险高于GG基因型携带者。
