Background
Diphenyleneiodonium (DPI) chloride (DPIC), as a NADH/NADPH oxidase inhibitor, has possessing potent antimicrobial activity against Mtb and S. aureus[1].
In vitro efficacy test it shown that DPIC was equi-potently effective against drug-resistant clinical isolates of S. aureus with MIC of 0.5-1 mg/L as compared to S. aureus ATCC 29213. DPIC has no obvious potency against gram-negative bacteria with MIC ranging from 4-32 mg/L. DPIC also has potent antimicrobial activity against H37Rv with MIC of 0.39 μM or 0.12 mg/L[1]. In vitro, with 0.1 mM DPIC inhibits fungal spore germination and bacterial cell proliferation[2]. In vitro, treatment with 10 μM Diphenyleneiodonium chloride, DPI has strongest inhibition against neutrophil extracellular trap creation[3]. In vitro test it exhibited that treatment with 0.5-4 μM DPI in HCT116 cells decrease in G1 and increase in S phase cells. In addition, DPI treatment (0.5 μM DPI for 3 days) induces senescence of MCF-7 cells[4].
In vivo test it demonstrated that rat were administrated with 1 mg/kg DPI subcutaneously maybe protect against the functional and neurohistological damage of bupivacaine-blocked sciatic nerves in a high-fat diet/streptozotocin-induced DN model[5]. In vivo, treatment with 5 mg/kg DPI intraperitoneally in Sprague-Dawley rats, there was obvious reduction in the intracellular ROS, the number of inflammatory cells, and cytokines (TNF-α and IL-6) in BALF compared with LPS-treated rats[6].
参考文献:
[1] Pandey M, et al. Diphenyleneiodonium chloride (DPIC) displays broad-spectrum bactericidal activity. Sci Rep. 2017 Sep 14;7(1):11521.
[2] Jung B, et al. Efficacy of Diphenyleneiodonium Chloride (DPIC) Against Diverse Plant Pathogens. Mycobiology. 2019 Jan 14;47(1):105-111.
[3] Ostafin M, et al. Different procedures of diphenyleneiodonium chloride addition affect neutrophil extracellular trap formation. Anal Biochem. 2016 Sep 15;509:60-66.
[4] Piszczatowska K, et al. Inhibition of NADPH Oxidases Activity by Diphenyleneiodonium Chloride as a Mechanism of Senescence Induction in Human Cancer Cells. Antioxidants (Basel). 2020 Dec 8;9(12):1248.
[5] Ji ZH, et al. Diphenyleneiodonium Mitigates Bupivacaine-Induced Sciatic Nerve Damage in a Diabetic Neuropathy Rat Model by Attenuating Oxidative Stress. Anesth Analg. 2017 Aug;125(2):653-661.
[6] Kim SK, et al. Protective effects of diphenyleneiodonium, an NADPH oxidase inhibitor, on lipopolysaccharide-induced acute lung injury. Clin Exp Pharmacol Physiol. 2019 Feb;46(2):153-162.
二苯碘铵 (DPI) 氯化物 (DPIC) 作为 NADH/NADPH 氧化酶抑制剂，对 Mtb 和 S. aureus 具有有效的抗菌活性[1]。
体外药效试验表明，DPIC对金黄色葡萄球菌的耐药临床分离株具有同等效力，MIC为0.5-1 mg/L，与金黄色葡萄球菌ATCC 29213相比，DPIC对金黄色葡萄球菌无明显效力MIC 范围为 4-32 mg/L 的革兰氏阴性菌。 DPIC 还对 H37Rv 具有有效的抗菌活性，MIC 为 0.39 μM 或 0.12 mg/L[1]。在体外，0.1 mM DPIC 抑制真菌孢子萌发和细菌细胞增殖[2]。在体外，用 10 μM Diphenyleneiodonium chloride 处理后，DPI 对中性粒细胞胞外陷阱产生的抑制作用最强[3]。体外试验表明，在 HCT116 细胞中用 0.5-4 μM DPI 处理后，G1 期细胞减少，S 期细胞增加。此外，DPI 处理（0.5 μM DPI 处理 3 天）可诱导 MCF-7 细胞衰老[4]。
体内试验表明，在高脂肪饮食/链脲佐菌素诱导的 DN 模型中，皮下给予大鼠 1 mg/kg DPI 可能会防止布比卡因阻断坐骨神经的功能和神经组织学损伤[5 ]。在体内，用 5 mg/kg DPI 腹腔注射 Sprague-Dawley 大鼠，与 LPS 处理相比，BALF 中的细胞内 ROS、炎症细胞数量和细胞因子（TNF-α 和 IL-6）明显减少大鼠[6].
Protocol
| Cell experiment [1]: |
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Cell lines
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MG-63 cells
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Preparation Method
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Permeabilization of the cytoplasmic membrane of MG-63 cells was achieved by exposing the cells to 12 μM digitonin for 10 min. Permeabilized MG-63 cells were treated with different concentrations of DPI (0.625 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM, and 100 μM) and 0.5% dimethyl sulfoxide (DMSO) as the control.
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Reaction Conditions
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0.625 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM, and 100 μM; 30 min
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Applications
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After 30 min of treatment, mitochondrial respiration with glutamate/malate (substrates of complex I) decreased with increasing DPI concentrations (0.625-100 M), reaching its minimum at approx. 5 μM DPI.
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| Animal experiment [2]: |
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Animal models
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female BALB/c mice (18-20 gm)
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Preparation Method
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Mice were rendered neutropenic by a series of cyclophosphamide injections given intraperitoneally (IP) 1 day and 1 h before infection. This was followed by injection of S. aureus ATCC 29213 in the right thigh of mice to establish infection. After 3 h post infection, DPI chloride (DPIC) and vancomycin at 1 mg/Kg and 25 mg/Kg of body weight respectively, were injected IP into mice twice at an interval of 3 h between injections. Control animals were administered saline in the same volume and frequency as those receiving treatment. After 24 h, the mice were sacrificed, thigh tissue were collected from the animal and weighed.
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Dosage form
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1 mg/Kg; i.p.
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Applications
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Treatment with DPI chloride significantly reduced mean bacterial counts in thigh compared to control group, which is comparable to vancomycin. Vancomycin at 25 mg/Kg caused a reduction of ~1 log10 cfu while DPI chloride at 1 mg/Kg caused a reduction of ~1.2 log10 cfu in 24 h as compared to no-drug control.
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参考文献:
[1] Zavadskis S, et al. Effect of Diphenyleneiodonium Chloride on Intracellular Reactive Oxygen Species Metabolism with Emphasis on NADPH Oxidase and Mitochondria in Two Therapeutically Relevant Human Cell Types. Pharmaceutics. 2020 Dec 23;13(1):10.
[2] Pandey M, et al. Diphenyleneiodonium chloride (DPIC) displays broad-spectrum bactericidal activity. Sci Rep. 2017 Sep 14;7(1):11521.
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