Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA.
Kizhner Research Center, Tomsk Polytechnic University, Tomsk 634050, Russia.
Molecules. 2019 May 10;24(9):1809. doi: 10.3390/molecules24091809.
Organosulfur compounds are bioactive components of garlic essential oil (EO), mustard oil, EOs, asafoetida, and other plant and food extracts. Traditionally, garlic () is used to boost the immune system; however, the mechanisms involved in the putative immunomodulatory effects of garlic are unknown. We investigated the effects of garlic EO and 22 organosulfur compounds on human neutrophil responses. Garlic EO, allyl propyl disulfide, dipropyl disulfide, diallyl disulfide, and allyl isothiocyanate (AITC) directly activated Ca flux in neutrophils, with the most potent being AITC. Although 1,3-dithiane did not activate neutrophil Ca flux, this minor constituent of garlic EO stimulated neutrophil reactive oxygen species (ROS) production. In contrast, a close analog (1,4-dithiane) was unable to activate neutrophil ROS production. Although 1,3-dithiane-1-oxide also stimulated neutrophil ROS production, only traces of this oxidation product were generated after a 5 h treatment of HL60 cells with 1,3-dithiane. Evaluation of several phosphatidylinositol-3 kinase (PI3K) inhibitors with different subtype specificities (A-66, TGX 221, AS605240, and PI 3065) showed that the PI3K p110δ inhibitor PI 3065 was the most potent inhibitor of 1,3-dithiane-induced neutrophil ROS production. Furthermore, 1,3-dithiane enhanced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), glycogen synthase kinase 3 α/β (GSK-3α/β), and cAMP response element binding (CREB) protein in differentiated neutrophil-like HL60 cells. Density functional theory (DFT) calculations confirmed the reactivity of 1,3-dithiane vs. 1,4-dithiane, based on the frontier molecular orbital analysis. Our results demonstrate that certain organosulfur compounds can activate neutrophil functional activity and may serve as biological response modifiers by augmenting phagocyte functions.
有机硫化合物是大蒜精油 (EO)、芥末油、EO、阿魏胶和其他植物及食品提取物中的生物活性成分。传统上，大蒜 () 用于增强免疫系统；然而，大蒜中假定的免疫调节作用的机制尚不清楚。我们研究了大蒜 EO 和 22 种有机硫化合物对人中性粒细胞反应的影响。大蒜 EO、烯丙基丙基二硫化物、二丙基二硫化物、二烯丙基二硫化物和烯丙基异硫氰酸酯 (AITC) 直接激活中性粒细胞中的钙通量，其中最有效的是 AITC。虽然 1,3-二噻烷不能激活中性粒细胞钙通量，但大蒜 EO 的这种少量成分刺激了中性粒细胞活性氧物质 (ROS) 的产生。相比之下，其密切类似物 (1,4-二噻烷) 则不能激活中性粒细胞 ROS 的产生。虽然 1,3-二噻烷-1-氧化物也刺激了中性粒细胞 ROS 的产生，但只有在 HL60 细胞用 1,3-二噻烷处理 5 小时后才会产生这种氧化产物的微量。用不同亚型特异性 (A-66、TGX 221、AS605240 和 PI 3065) 的几种磷脂酰肌醇-3 激酶 (PI3K) 抑制剂进行评估表明，PI3K p110δ 抑制剂 PI 3065 是抑制 1,3-二噻烷诱导的中性粒细胞 ROS 产生的最有效抑制剂。此外，1,3-二噻烷增强了分化的中性粒细胞样 HL60 细胞中细胞外信号调节激酶 1/2 (ERK1/2)、糖原合酶激酶 3α/β (GSK-3α/β) 和 cAMP 反应元件结合蛋白 (CREB) 的磷酸化。基于前沿分子轨道分析的密度泛函理论 (DFT) 计算证实了 1,3-二噻烷与 1,4-二噻烷的反应性。我们的结果表明，某些有机硫化合物可以激活中性粒细胞的功能活性，并通过增强吞噬细胞的功能作为生物反应调节剂。
