According to a genome-wide association study,intronic SNPs within the human sterile 20/SPS1-related proline/alanine-rich kinase(SPAK) gene was linked to 20% of the general population and may be associated with elevate...According to a genome-wide association study,intronic SNPs within the human sterile 20/SPS1-related proline/alanine-rich kinase(SPAK) gene was linked to 20% of the general population and may be associated with elevated blood pressure. As cell volume changes,mammalian SPAK kinases respond to phosphorylate and regulate cation-coupled chloride co-transporter activity. To our knowledge,phosphorylation of upstream with-no-lysine(K)(WNK) kinases would activate SPAK kinases. The activation of WNK-OSR1/SPAK cascade on the kidneys and aortic tissue is related to the development of hypertension. Several regulators of the WNK pathway such as the Kelch kinase protein 3-Cullin 3 E3 ligase,hyperinsulinemia,and low potassium intake to mediate hypertension have been identified. In addition,the SPAK kinases may affect the action of renin-angiotensin-aldosterone system on blood pressure as well. In 2010,two SPAK knock-in and knock-out mouse models have clarified the pathogenesis of lowering blood pressure by influencing the receptors on the kidneys and aortic smooth muscle. More recently,two novel SPAK inhibitors for mice,Stock 1S-14279 and Closantel were discovered in 2014. Targeting of SPAK seems to be promising for future antihypertensive therapy. Therefore we raised some viewpoints for the issue for the antihypertensive therapy on the SPAK(gene or kinase).展开更多
We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation r...We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation remains unclear.In this study,we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine,a H2S precursor,attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionineβsynthase(a major H2S synthetase in the brain)in the prefrontal cortex.We also found that an miR-9-5p inhibitor blocked the expression of cystathionineβsynthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia.Furthermore,miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury.L-cysteine decreased the expression of CXCL11,an miR-9-5p target gene,in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3,FSTL1,SOCS2 and SOCS5,while treatment with an miR-9-5p inhibitor reversed these changes.These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoringβ-synthase expression,thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.展开更多
【目的】观察扶正化瘀通络方治疗高血压脑出血恢复期气虚血瘀证患者的临床疗效及对血清基质金属蛋白酶9(matrix metalloproteinase-9,MMP-9)、S100-β蛋白(S100-βprotein,S100-β)、苏氨酸蛋白激酶(threonine protein kinase,AKT)和Th1...【目的】观察扶正化瘀通络方治疗高血压脑出血恢复期气虚血瘀证患者的临床疗效及对血清基质金属蛋白酶9(matrix metalloproteinase-9,MMP-9)、S100-β蛋白(S100-βprotein,S100-β)、苏氨酸蛋白激酶(threonine protein kinase,AKT)和Th1/Th2平衡的影响。【方法】将130例高血压脑出血恢复期气虚血瘀证患者随机分为对照组和观察组,每组各65例。对照组给予西医常规治疗,观察组在对照组的基础上联合扶正化瘀通络方治疗,疗程为4周。观察2组患者治疗前后美国国立卫生研究院卒中量表(NIHSS)评分、健康状况调查简表(SF-36)评分、中医证候积分(主要症状包括乏力、偏瘫、口眼歪斜,次要症状包括头部刺痛、气短)及血清MMP-9、S100-β、AKT和白细胞介素10(IL-10)、超敏C反应蛋白(Hs-CRP)、同型半胱氨酸(Hcy)、白细胞介素6(IL-6)水平的变化情况,并评价2组患者的临床疗效。【结果】(1)治疗4周后,观察组的总有效率为95.38%(62/65),对照组为78.46%(51/65),组间比较,观察组的疗效明显优于对照组(P<0.05)。(2)治疗后,2组患者的NIHSS评分和中医证候积分均较治疗前明显降低(P<0.05),SF-36评分均较治疗前明显升高(P<0.05),且观察组对NIHSS评分和中医证候积分的降低幅度及对SF-36评分的升高幅度均明显优于对照组(P<0.05)。(3)治疗后,2组患者的血清MMP-9、S100-β、AKT水平均较治疗前明显降低(P<0.05),且观察组对血清MMP-9、S100-β、AKT水平的降低幅度均明显优于对照组(P<0.05)。(4)治疗后,2组患者血清Hs-CRP、Hcy、IL-6水平均较治疗前明显降低(P<0.05),血清IL-10水平均较治疗前明显升高(P<0.05),且观察组对血清Hs-CRP、Hcy、IL-6水平的降低幅度及对血清IL-10水平的升高幅度均明显优于对照组,差异均有统计学意义(P<0.05)。【结论】对于高血压脑出血恢复期气虚血瘀证患者而言,在西医常规治疗基础上联合扶正化瘀通络方治疗,可有效促进Th1/Th2平衡恢复,减轻氧化应激失衡,提高临床疗效。展开更多
文摘According to a genome-wide association study,intronic SNPs within the human sterile 20/SPS1-related proline/alanine-rich kinase(SPAK) gene was linked to 20% of the general population and may be associated with elevated blood pressure. As cell volume changes,mammalian SPAK kinases respond to phosphorylate and regulate cation-coupled chloride co-transporter activity. To our knowledge,phosphorylation of upstream with-no-lysine(K)(WNK) kinases would activate SPAK kinases. The activation of WNK-OSR1/SPAK cascade on the kidneys and aortic tissue is related to the development of hypertension. Several regulators of the WNK pathway such as the Kelch kinase protein 3-Cullin 3 E3 ligase,hyperinsulinemia,and low potassium intake to mediate hypertension have been identified. In addition,the SPAK kinases may affect the action of renin-angiotensin-aldosterone system on blood pressure as well. In 2010,two SPAK knock-in and knock-out mouse models have clarified the pathogenesis of lowering blood pressure by influencing the receptors on the kidneys and aortic smooth muscle. More recently,two novel SPAK inhibitors for mice,Stock 1S-14279 and Closantel were discovered in 2014. Targeting of SPAK seems to be promising for future antihypertensive therapy. Therefore we raised some viewpoints for the issue for the antihypertensive therapy on the SPAK(gene or kinase).
基金supported by the National Natural Science Foundation of China,Nos.82271327(to ZW),82072535(to ZW),81873768(to ZW),and 82001253(to TL).
文摘We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation remains unclear.In this study,we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine,a H2S precursor,attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionineβsynthase(a major H2S synthetase in the brain)in the prefrontal cortex.We also found that an miR-9-5p inhibitor blocked the expression of cystathionineβsynthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia.Furthermore,miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury.L-cysteine decreased the expression of CXCL11,an miR-9-5p target gene,in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3,FSTL1,SOCS2 and SOCS5,while treatment with an miR-9-5p inhibitor reversed these changes.These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoringβ-synthase expression,thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.
文摘【目的】观察扶正化瘀通络方治疗高血压脑出血恢复期气虚血瘀证患者的临床疗效及对血清基质金属蛋白酶9(matrix metalloproteinase-9,MMP-9)、S100-β蛋白(S100-βprotein,S100-β)、苏氨酸蛋白激酶(threonine protein kinase,AKT)和Th1/Th2平衡的影响。【方法】将130例高血压脑出血恢复期气虚血瘀证患者随机分为对照组和观察组,每组各65例。对照组给予西医常规治疗,观察组在对照组的基础上联合扶正化瘀通络方治疗,疗程为4周。观察2组患者治疗前后美国国立卫生研究院卒中量表(NIHSS)评分、健康状况调查简表(SF-36)评分、中医证候积分(主要症状包括乏力、偏瘫、口眼歪斜,次要症状包括头部刺痛、气短)及血清MMP-9、S100-β、AKT和白细胞介素10(IL-10)、超敏C反应蛋白(Hs-CRP)、同型半胱氨酸(Hcy)、白细胞介素6(IL-6)水平的变化情况,并评价2组患者的临床疗效。【结果】(1)治疗4周后,观察组的总有效率为95.38%(62/65),对照组为78.46%(51/65),组间比较,观察组的疗效明显优于对照组(P<0.05)。(2)治疗后,2组患者的NIHSS评分和中医证候积分均较治疗前明显降低(P<0.05),SF-36评分均较治疗前明显升高(P<0.05),且观察组对NIHSS评分和中医证候积分的降低幅度及对SF-36评分的升高幅度均明显优于对照组(P<0.05)。(3)治疗后,2组患者的血清MMP-9、S100-β、AKT水平均较治疗前明显降低(P<0.05),且观察组对血清MMP-9、S100-β、AKT水平的降低幅度均明显优于对照组(P<0.05)。(4)治疗后,2组患者血清Hs-CRP、Hcy、IL-6水平均较治疗前明显降低(P<0.05),血清IL-10水平均较治疗前明显升高(P<0.05),且观察组对血清Hs-CRP、Hcy、IL-6水平的降低幅度及对血清IL-10水平的升高幅度均明显优于对照组,差异均有统计学意义(P<0.05)。【结论】对于高血压脑出血恢复期气虚血瘀证患者而言,在西医常规治疗基础上联合扶正化瘀通络方治疗,可有效促进Th1/Th2平衡恢复,减轻氧化应激失衡,提高临床疗效。
