Metals-triggered compound CDPDP exhibits anti-arthritic behavior by downregulating the inflammatory cytokines, and modulating the oxidative storm in mice models with extensive ADMET, docking and simulation studies.
Metals-triggered compound CDPDP exhibits anti-arthritic behavior by downregulating the inflammatory cytokines, and modulating the oxidative storm in mice models with extensive ADMET, docking and simulation studies.
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DOI：
10.3389/fphar.2022.1053744
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发表时间：
2022
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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通过非生物胁迫触发，包括重金属等化学触发物，是药物发现的新技术。本研究首次研究了重金属镍对放线菌Streptomyces sp. SH-1327产生胁迫衍生物的影响。以放线菌SH-1327为出发菌株，加入1 mM的镍离子，可引发一个新的化合物cyclo-（D）-Pro-（D）-Phe（CDPDP）。通过在白化病小鼠中的体外和体内测定，进一步评价应激化合物对类风湿性关节炎的抗氧化、镇痛和抗炎活性。CDPDP具有明显的体外抗氧化能力，其对DPPH的IC_（50）为30.06 ± 5.11 μg/ml，对NO自由基的IC_（50）为18.98 ± 2.91，对清除自由基的IC_（50）为27.15 ± 3.12，对铁螯合的IC_（50）为28.40 ± 3.14 μg/ml。通过下调促炎介质（NO和MDA），抑制促炎细胞因子（TNF-α、IL-6、IL-1 β）的水平，上调抗氧化酶（GSH、CAT和GST）的表达，揭示了其抗炎作用。在人软骨细胞系CHON-001中分析CDPDP，结果表明CDPDP显著增加细胞存活，并抑制IL-1β处理的软骨细胞的凋亡和IL-1β诱导的基质降解标志物。此外，为了评估CHON-001细胞的线粒体适应性，CDPDP显著上调pgc 1-α（线粒体生物合成的主要调节因子），表明CDPDP在CHON-001细胞中具有保护作用。CDPDP的吸收、分布、代谢、排泄和毒性（ADMET）特征表明，CDPDP在肝毒性、心脏毒性和细胞色素抑制情况下是安全的。对接结果表明CDPDP与IL-6有较好的结合，结合强度为17.4 kcal/mol，模拟结果证明了CDPDP与IL-6的稳定性。因此，本研究的结果前景CDPDP作为一种有效的抗氧化剂和一种合理的抗关节炎剂，具有很强的药代动力学和药理学特征。
Triggering through abiotic stress, including chemical triggers like heavy metals, is a new technique for drug discovery. In this research, the effect of heavy metal Nickel on actinobacteria Streptomyces sp. SH-1327 to obtain a stress-derived compound was firstly investigated. A new compound cyclo-(D)-Pro-(D)-Phe (CDPDP) was triggered from the actinobacteria strain SH-1327 with the addition of nickel ions 1 mM. The stress compound was further evaluated for its anti-oxidant, analgesic, and anti-inflammatory activity against rheumatoid arthritis through in-vitro and in-vivo assays in albino mice. A remarkable in-vitro anti-oxidant potential of CDPDP was recorded with the IC50 value of 30.06 ± 5.11 μg/ml in DPPH, IC50 of 18.98 ± 2.91 against NO free radicals, the IC50 value of 27.15 ± 3.12 against scavenging ability and IC50 value of 28.40 ± 3.14 μg/ml for iron chelation capacity. Downregulation of pro-inflammatory mediators (NO and MDA), suppressed levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-Iβ) and upregulation of expressions of anti-oxidant enzymes (GSH, catalase, and GST) unveiled its anti-inflammatory potential. CDPDP was analyzed in human chondrocyte cell line CHON-001 and the results demonstrated that CDPDP significantly increased cell survival, and inhibited apoptosis of IL-1β treated chondrocytes and IL-1β induced matrix degrading markers. In addition, to evaluate the mitochondrial fitness of CHON-001 cells, CDPDP significantly upregulated pgc1-α, the master regulator of mitochondrial biogenesis, indicating that CDPDP provides protective effects in CHON-001 cells. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile of the CDPDP showed that CDPDP is safe in cases of hepatotoxicity, cardiotoxicity, and cytochrome inhibition. Furthermore, docking results showed good binding of CDPDP with IL-6–17.4 kcal/mol, and the simulation studies proved the stability between ligand and protein. Therefore, the findings of the current study prospect CDPDP as a potent anti-oxidant and a plausible anti-arthritic agent with a strong pharmacokinetic and pharmacological profile.
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影响因子：
3.6
作者：
Braga RC;Alves VM;Silva MF;Muratov E;Fourches D;Lião LM;Tropsha A;Andrade CH
通讯作者：
Andrade CH
DOI：
10.3390/molecules21020234
发表时间：
2016-02-18
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
González-Menéndez V;Pérez-Bonilla M;Pérez-Victoria I;Martín J;Muñoz F;Reyes F;Tormo JR;Genilloud O
通讯作者：
Genilloud O
DOI：
10.1016/s0006-291x(02)00824-0
发表时间：
2002-08-09
影响因子：
3.1
作者：
Kim, SJ;Im, DS;Chun, JS
通讯作者：
Chun, JS
影响因子：
4.6
作者：
Daina A;Michielin O;Zoete V
通讯作者：
Zoete V
来自热液通风口真菌曲霉属的不寻常应激代谢物。
DOI：
10.3390/molecules21010105
发表时间：
2016-01-16
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Ding C;Wu X;Auckloo BN;Chen CT;Ye Y;Wang K;Wu B
通讯作者：
Wu B