Catalytic Longevity, United States; Departamento de Ciencias Quimico Biologicas, Universidad de Sonora, Mexico; Department of Preventive Cardiology, Saint Luke's Mid America Heart Institute, KS, United States.
Catalytic Longevity, United States; Departamento de Ciencias Quimico Biologicas, Universidad de Sonora, Mexico; Department of Preventive Cardiology, Saint Luke's Mid America Heart Institute, KS, United States.
Med Hypotheses. 2019 Feb;123:125-129. doi: 10.1016/j.mehy.2019.01.012. Epub 2019 Jan 16.
Receptor-mediated activation of NADPH oxidase complexes commonly occurs in endosomes; the hydrogen peroxide produced by the dismutation of superoxide generated within the endosomes often functions to boost receptor function by reversibly inhibiting protein tyrosine phosphatases or by promoting formation of signaling complexes. NADPH oxidase-mediated formation of superoxide entails transfer of two electrons (provided by NADPH) from the cytosol to the endosomal lumen, where two molecules of superoxide are generated. This charge transfer must be balanced if NADPH oxidase activity is to be sustained. In many cells, this balance is achieved by ClC-3, a chloride-proton antiporter which can extrude two chlorides from the endosome to balance the importation of two electrons. The efficiency of this chloride extrusion will evidently be contingent on the cytosolic chloride level. Pro-inflammatory hormones which stimulate NADPH oxidase activity in endosomes have been shown to promote chloride extrusion from the cell, thereby expediting endosomal chloride export. Conversely, high cytosolic chloride could potentially slow endosomal NADPH oxidase activity by impeding ClC-3-mediated chloride export. Glycine-activated, strychnine-inhibitable chloride channels, which boost intracellular chloride in cells which maintain intracellular chloride levels lower than that of plasma, have shown anti-inflammatory and anti-angiogenic activity in cell culture and rodent studies. It is proposed that many of these effects may be attributable to glycine-mediated suppression of endosomal NADPH oxidase activity. This model suggests that supplemental glycine may have utility for prevention and control of atherosclerosis, heart failure, angiogenesis associated with cancer or retinal disorders, and a range of inflammation-driven syndromes - including metabolic syndrome; and it might complement the suppression of NADPH oxidase activity achievable with phycocyanobilin-enriched spirulina extracts.
NADPH 氧化酶复合物的受体介导激活通常发生在内体中；在内体中产生的超氧化物歧化产生的过氧化氢通常通过可逆抑制蛋白酪氨酸磷酸酶或通过促进信号复合物的形成来增强受体功能。NADPH 氧化酶介导的超氧化物形成需要将来自细胞质的两个电子（由 NADPH 提供）转移到内体腔中，在那里生成两个超氧化物分子。如果要维持 NADPH 氧化酶活性，则必须平衡这种电荷转移。在许多细胞中，这种平衡是通过 ClC-3 实现的，ClC-3 是一种氯离子-质子反向转运蛋白，它可以将两个氯离子从内体中排出，以平衡两个电子的导入。这种氯离子外排的效率显然取决于细胞质中的氯离子水平。已显示刺激内体中 NADPH 氧化酶活性的促炎激素可促进氯离子从细胞中排出，从而加速内体氯离子的输出。相反，高细胞质氯离子可能通过阻碍 ClC-3 介导的氯离子外排而潜在地减慢内体 NADPH 氧化酶活性。甘氨酸激活、士的宁抑制的氯离子通道可增加细胞内氯离子浓度，而细胞内氯离子浓度低于血浆中的氯离子浓度，在细胞培养和啮齿动物研究中表现出抗炎和抗血管生成活性。据推测，这些作用中的许多可能归因于甘氨酸介导的对内体 NADPH 氧化酶活性的抑制。该模型表明，补充甘氨酸可能对预防和控制动脉粥样硬化、心力衰竭、与癌症或视网膜疾病相关的血管生成以及一系列炎症驱动的综合征（包括代谢综合征）有用；并且它可能补充藻蓝蛋白富集螺旋藻提取物抑制 NADPH 氧化酶活性的作用。
