Parkinson’s disease(PD)is a common neurodegenerative disorder with no cure.Astragalus membranaceus is used in Chinese culture as a food supplement to boost immunity.The present study aimed to explore the neuroprotect...Parkinson’s disease(PD)is a common neurodegenerative disorder with no cure.Astragalus membranaceus is used in Chinese culture as a food supplement to boost immunity.The present study aimed to explore the neuroprotective effects of total flavonoids extracted from A.membranaceus(TFA)and their protective mechanisms.TFA offered neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)in the mouse model of Parkinsonism,by improving behavior performance in the gait analysis and pole test,and inhibiting the decline of tyrosine hydroxylase(TH)positive neurons and TH protein expression in substantia nigra of mice.TFA also prevented 1-methyl-4-phenylpyridinium(MPP+)induced neurotoxicity in SHSY5Y cells,by increasing GSH and GSH/GSSG ratio,and reducing reactive oxygen species.In addition,the neuroprotective effects of TFA were associated with its ability to restore MPTP/MPP+induced downregulation of SLC7A11 and glutathione peroxidase 4(GPX-4).In conclusion,we demonstrated that TFA exerted significant neuroprotection against MPTP/MPP+induced neurodegeneration by inhibiting ferroptosis through the regulation of SLC7A11/GPX-4 axis,suggesting the use of TFA as a possible food supplement in the prevention of PD.展开更多
BACKGROUND Peutz-Jeghers syndrome(PJS)is a rare hereditary neoplastic disorder mainly associated with serine/threonine kinase 11(STK11/LKB1)gene mutations.Preimplantation genetic testing can protect a patient’s offsp...BACKGROUND Peutz-Jeghers syndrome(PJS)is a rare hereditary neoplastic disorder mainly associated with serine/threonine kinase 11(STK11/LKB1)gene mutations.Preimplantation genetic testing can protect a patient’s offspring from mutated genes;however,some variations in this gene have been interpreted as variants of uncertain significance(VUS),which complicate reproductive decision-making in genetic counseling.AIM To identify the pathogenicity of two missense variants and provide clinical guidance.METHODS Whole exome gene sequencing and Sanger sequencing were performed on the peripheral blood of patients with PJS treated at the Reproductive and Genetic Hospital of Citic-Xiangya.Software was employed to predict the protein structure,conservation,and pathogenicity of the two missense variation sites in patients with PJS.Additionally,plasmids were constructed and transfected into HeLa cells to observe cell growth.The differences in signal pathway expression between the variant group and the wild-type group were compared using western blot and immunohistochemistry.Statistical analysis was performed using one-way analysis of variance.P<0.05 was considered statistically significant.RESULTS We identified two missense STK11 gene VUS[c.889A>G(p.Arg297Gly)and c.733C>T(p.Leu245Phe)]in 9 unrelated PJS families who were seeking reproductive assistance.The two missense VUS were located in the catalytic domain of serine/threonine kinase,which is a key structure of the liver kinase B1(LKB1)protein.In vitro experiments showed that the phosphorylation levels of adenosine monophosphate-activated protein kinase(AMPK)at Thr172 and LKB1 at Ser428 were significantly higher in transfected variation-type cells than in wild-type cells.In addition,the two missense STK11 variants promoted the proliferation of HeLa cells.Subsequent immunohistochemical analysis showed that phosphorylated-AMPK(Thr172)expression was significantly lower in gastric,colonic,and uterine polyps from PJS patients with missense variations than in non-PJS patients.Our findings indicate that these two missense STK11 variants are likely pathogenic and inactivate the STK11 gene,causing it to lose its function of regulating downstream phosphorylated-AMPK(Thr172),which may lead to the development of PJS.The identification of the pathogenic mutations in these two clinically characterized PJS patients has been helpful in guiding them toward the most appropriate mode of pregnancy assistance.CONCLUSION These two missense variants can be interpreted as likely pathogenic variants that mediated the onset of PJS in the two patients.These findings not only offer insights for clinical decision-making,but also serve as a foundation for further research and reanalysis of missense VUS in rare diseases.展开更多
目的探讨血清IL-11在急性脑梗死诊断和预后评估中的价值及其与血清脑源性神经营养因子(BDNF)的相关性。方法收集102例急性脑梗死患者(脑梗死组)和64名正常对照者(正常对照组)的一般临床资料。根据90 d mRS评分将脑梗死组分为预后良好亚...目的探讨血清IL-11在急性脑梗死诊断和预后评估中的价值及其与血清脑源性神经营养因子(BDNF)的相关性。方法收集102例急性脑梗死患者(脑梗死组)和64名正常对照者(正常对照组)的一般临床资料。根据90 d mRS评分将脑梗死组分为预后良好亚组和预后不良亚组。采用Pearson相关性分析血清IL-11和NIHSS评分、脑梗死体积、血清BDNF的相关性,Logistics回归分析脑梗死预后的影响因素,并绘制IL-11在脑梗死诊断和预后预测中的ROC曲线。结果脑梗死组高血压比率及糖化血红蛋白、低密度脂蛋白水平显著高于正常对照组(均P<0.05)。预后不良亚组的年龄、糖尿病比率、糖化血红蛋白水平、入院时NIHSS评分、脑梗死体积显著高于预后良好亚组(均P<0.05)。脑梗死组血清IL-11水平显著低于正常对照组(t=10.123,P<0.001)。脑梗死预后不良亚组血清IL-11水平显著低于预后良好亚组(t=7.438,P<0.001)。脑梗死患者血清IL-11表达与NIHSS评分(r=-0.603,P<0.001)及脑梗死体积(r=-0.681,P<0.001)呈负相关关系。Logistics回归分析显示,IL-11为影响脑梗死患者预后的保护性因素(OR=0.814,P=0.009),脑梗死体积(OR=2.262,P<0.001)和NIHSS评分(OR=2.107,P=0.006)为影响脑梗死预后的危险因素。当IL-11应用于脑梗死的诊断时,ROC曲线下面积为0.841,灵敏性为91.18%,特异性为72.42%,截断值为378.47;当IL-11应用于脑梗死预后预测时,ROC曲线下面积为0.786,灵敏性为67.09%,特异性为87.93%,截断值为310.94。脑梗死患者血清IL-11水平与血清BDNF水平的相关系数为r=0.711、P<0.01。结论脑梗死患者血清IL-11水平显著降低,且预后不良患者的IL-11水平显著低于预后良好亚组。同时,IL-11水平与血清BDNF水平呈负相关,可能可以用于脑梗死的辅助诊断和预后评估。展开更多
文摘Parkinson’s disease(PD)is a common neurodegenerative disorder with no cure.Astragalus membranaceus is used in Chinese culture as a food supplement to boost immunity.The present study aimed to explore the neuroprotective effects of total flavonoids extracted from A.membranaceus(TFA)and their protective mechanisms.TFA offered neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)in the mouse model of Parkinsonism,by improving behavior performance in the gait analysis and pole test,and inhibiting the decline of tyrosine hydroxylase(TH)positive neurons and TH protein expression in substantia nigra of mice.TFA also prevented 1-methyl-4-phenylpyridinium(MPP+)induced neurotoxicity in SHSY5Y cells,by increasing GSH and GSH/GSSG ratio,and reducing reactive oxygen species.In addition,the neuroprotective effects of TFA were associated with its ability to restore MPTP/MPP+induced downregulation of SLC7A11 and glutathione peroxidase 4(GPX-4).In conclusion,we demonstrated that TFA exerted significant neuroprotection against MPTP/MPP+induced neurodegeneration by inhibiting ferroptosis through the regulation of SLC7A11/GPX-4 axis,suggesting the use of TFA as a possible food supplement in the prevention of PD.
基金Supported by the Natural Science Foundation of Hunan Province,China,No.2023JJ30422.
文摘BACKGROUND Peutz-Jeghers syndrome(PJS)is a rare hereditary neoplastic disorder mainly associated with serine/threonine kinase 11(STK11/LKB1)gene mutations.Preimplantation genetic testing can protect a patient’s offspring from mutated genes;however,some variations in this gene have been interpreted as variants of uncertain significance(VUS),which complicate reproductive decision-making in genetic counseling.AIM To identify the pathogenicity of two missense variants and provide clinical guidance.METHODS Whole exome gene sequencing and Sanger sequencing were performed on the peripheral blood of patients with PJS treated at the Reproductive and Genetic Hospital of Citic-Xiangya.Software was employed to predict the protein structure,conservation,and pathogenicity of the two missense variation sites in patients with PJS.Additionally,plasmids were constructed and transfected into HeLa cells to observe cell growth.The differences in signal pathway expression between the variant group and the wild-type group were compared using western blot and immunohistochemistry.Statistical analysis was performed using one-way analysis of variance.P<0.05 was considered statistically significant.RESULTS We identified two missense STK11 gene VUS[c.889A>G(p.Arg297Gly)and c.733C>T(p.Leu245Phe)]in 9 unrelated PJS families who were seeking reproductive assistance.The two missense VUS were located in the catalytic domain of serine/threonine kinase,which is a key structure of the liver kinase B1(LKB1)protein.In vitro experiments showed that the phosphorylation levels of adenosine monophosphate-activated protein kinase(AMPK)at Thr172 and LKB1 at Ser428 were significantly higher in transfected variation-type cells than in wild-type cells.In addition,the two missense STK11 variants promoted the proliferation of HeLa cells.Subsequent immunohistochemical analysis showed that phosphorylated-AMPK(Thr172)expression was significantly lower in gastric,colonic,and uterine polyps from PJS patients with missense variations than in non-PJS patients.Our findings indicate that these two missense STK11 variants are likely pathogenic and inactivate the STK11 gene,causing it to lose its function of regulating downstream phosphorylated-AMPK(Thr172),which may lead to the development of PJS.The identification of the pathogenic mutations in these two clinically characterized PJS patients has been helpful in guiding them toward the most appropriate mode of pregnancy assistance.CONCLUSION These two missense variants can be interpreted as likely pathogenic variants that mediated the onset of PJS in the two patients.These findings not only offer insights for clinical decision-making,but also serve as a foundation for further research and reanalysis of missense VUS in rare diseases.
文摘目的探讨血清IL-11在急性脑梗死诊断和预后评估中的价值及其与血清脑源性神经营养因子(BDNF)的相关性。方法收集102例急性脑梗死患者(脑梗死组)和64名正常对照者(正常对照组)的一般临床资料。根据90 d mRS评分将脑梗死组分为预后良好亚组和预后不良亚组。采用Pearson相关性分析血清IL-11和NIHSS评分、脑梗死体积、血清BDNF的相关性,Logistics回归分析脑梗死预后的影响因素,并绘制IL-11在脑梗死诊断和预后预测中的ROC曲线。结果脑梗死组高血压比率及糖化血红蛋白、低密度脂蛋白水平显著高于正常对照组(均P<0.05)。预后不良亚组的年龄、糖尿病比率、糖化血红蛋白水平、入院时NIHSS评分、脑梗死体积显著高于预后良好亚组(均P<0.05)。脑梗死组血清IL-11水平显著低于正常对照组(t=10.123,P<0.001)。脑梗死预后不良亚组血清IL-11水平显著低于预后良好亚组(t=7.438,P<0.001)。脑梗死患者血清IL-11表达与NIHSS评分(r=-0.603,P<0.001)及脑梗死体积(r=-0.681,P<0.001)呈负相关关系。Logistics回归分析显示,IL-11为影响脑梗死患者预后的保护性因素(OR=0.814,P=0.009),脑梗死体积(OR=2.262,P<0.001)和NIHSS评分(OR=2.107,P=0.006)为影响脑梗死预后的危险因素。当IL-11应用于脑梗死的诊断时,ROC曲线下面积为0.841,灵敏性为91.18%,特异性为72.42%,截断值为378.47;当IL-11应用于脑梗死预后预测时,ROC曲线下面积为0.786,灵敏性为67.09%,特异性为87.93%,截断值为310.94。脑梗死患者血清IL-11水平与血清BDNF水平的相关系数为r=0.711、P<0.01。结论脑梗死患者血清IL-11水平显著降低,且预后不良患者的IL-11水平显著低于预后良好亚组。同时,IL-11水平与血清BDNF水平呈负相关,可能可以用于脑梗死的辅助诊断和预后评估。
