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Celecoxib reduces Deoxynivalenol induced proliferation, inflammation and protein kinase C translocation via modulating downstream targets in mouse skin.
Chemico-Biological Interactions ( IF 5.1 ) Pub Date : 2020-05-13 , DOI: 10.1016/j.cbi.2020.109128 Sakshi Mishra 1 , Sonal Srivastava 1 , Aman Divakar 1 , Payal Mandal 2 , Jayant Dewangan 1 , Swati Chaturvedi 3 , Muhammad Wahajuddin 3 , Sadan Kumar 4 , Anurag Tripathi 2 , Srikanta Kumar Rath 1
Chemico-Biological Interactions ( IF 5.1 ) Pub Date : 2020-05-13 , DOI: 10.1016/j.cbi.2020.109128 Sakshi Mishra 1 , Sonal Srivastava 1 , Aman Divakar 1 , Payal Mandal 2 , Jayant Dewangan 1 , Swati Chaturvedi 3 , Muhammad Wahajuddin 3 , Sadan Kumar 4 , Anurag Tripathi 2 , Srikanta Kumar Rath 1
Affiliation
Exposure to mycotoxins is mostly by ingestion but also occurs by the dermal and inhalation routes. The present study for the first time demonstrated that mycotoxin Deoxynivalenol (DON), permeates through Swiss albino mice skin, which demands awareness of health risks in people who are dermally exposed to mycotoxins especially agricultural farmers. Despite the widespread contamination of DON in food commodities studies to alleviate DON's toxicity are sparsely reported. Thus effective measures to combat mycotoxins associated toxicity remains an imperative aspect to be considered from the angle of dermal exposure. Topical application of Celecoxib (1-2 mg), followed by DON (100 μμg) application on the dorsal side of mice, resulted in substantial decrease in DON-induced (i) edema, hyperplasia, cell proliferation (ii) inhibition of cytokine and prostaglandin-E2 levels (iii) phosphorylation of ERK1/2, JNK, p38, MAPKKs, CREB, P90-RSK (iv) downregulation of c-Jun, c- Fos, phospho-NF-kB and their downstream target proteins cyclin D1 and COX-2. Using Ro-31-8220 (Protein-Kinase-C inhibitor), it was observed PKC was responsible for DON induced upregulation of COX-2 and iNOS proteins. Treatment of Celecoxib decreased DON-induced translocation of Protein Kinase C isozymes (α,ε,γ), demonstrating the role of PKC in DON-mediated biochemical and molecular alterations responsible for its dermal toxicity. The present findings indicate that topical application of celecoxib is effective in the management of inflammatory skin disorders induced by foodborne fungal toxin DON. The skin permeation potential of Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor NSAID, was also assessed, and the results indicated that the permeation was relatively lower as compared to the oral mode of administration. Hence topical use of celecoxib may be preferred over oral dosing because of lower systemic absorption and to avoid the unwanted side effects. This study provides a prospect for exploring the clinical efficacy of topically applied COX-2 inhibitors for the management of inflammatory skin disorders induced by foodborne fungal toxins.
中文翻译:
塞来昔布通过调节小鼠皮肤中的下游靶标来减少脱氧雪腐酚诱导的增殖,炎症和蛋白激酶C易位。
真菌毒素的暴露主要是通过食入,但也可能通过皮肤和吸入途径发生。本研究首次表明,霉菌毒素脱氧雪腐酚(DON)会渗透到瑞士的白化病小鼠皮肤中,这就要求认识到皮肤上暴露于霉菌毒素的人们尤其是农业农民的健康风险。尽管在食品中广泛地污染了DON,但仍鲜有关于减轻DON毒性的研究。因此,从皮肤暴露的角度考虑,对抗真菌毒素相关毒性的有效措施仍然是必须考虑的方面。局部应用塞来昔布(1-2 mg),然后在小鼠背侧局部应用DON(100μg),导致DON引起的(i)水肿,增生,细胞增殖(ii)细胞因子和前列腺素E2水平的抑制(iii)ERK1 / 2,JNK,p38,MAPKKs,CREB,P90-RSK的磷酸化(iv)c-Jun,c-Fos,磷酸化NF-下调kB及其下游靶蛋白cyclin D1和COX-2。使用Ro-31-8220(蛋白激酶酶C抑制剂),观察到PKC负责DON诱导的COX-2和iNOS蛋白的上调。塞来昔布的治疗降低了DON诱导的蛋白激酶C同工酶(α,ε,γ)的易位,表明PKC在DON介导的生化和分子改变中起皮肤毒性作用。目前的发现表明,塞来昔布的局部应用可有效治疗由食源性真菌毒素DON引起的炎症性皮肤病。塞来昔布的皮肤渗透潜能,还评估了选择性环氧合酶-2(COX-2)抑制剂NSAID,结果表明与口服给药方式相比,其渗透性相对较低。因此,由于较低的全身吸收并避免了不良副作用,塞来昔布的局部使用可能比口服给药更可取。该研究为探索局部应用COX-2抑制剂治疗食源性真菌毒素引起的炎症性皮肤病的临床疗效提供了前景。
更新日期:2020-05-13
中文翻译:
塞来昔布通过调节小鼠皮肤中的下游靶标来减少脱氧雪腐酚诱导的增殖,炎症和蛋白激酶C易位。
真菌毒素的暴露主要是通过食入,但也可能通过皮肤和吸入途径发生。本研究首次表明,霉菌毒素脱氧雪腐酚(DON)会渗透到瑞士的白化病小鼠皮肤中,这就要求认识到皮肤上暴露于霉菌毒素的人们尤其是农业农民的健康风险。尽管在食品中广泛地污染了DON,但仍鲜有关于减轻DON毒性的研究。因此,从皮肤暴露的角度考虑,对抗真菌毒素相关毒性的有效措施仍然是必须考虑的方面。局部应用塞来昔布(1-2 mg),然后在小鼠背侧局部应用DON(100μg),导致DON引起的(i)水肿,增生,细胞增殖(ii)细胞因子和前列腺素E2水平的抑制(iii)ERK1 / 2,JNK,p38,MAPKKs,CREB,P90-RSK的磷酸化(iv)c-Jun,c-Fos,磷酸化NF-下调kB及其下游靶蛋白cyclin D1和COX-2。使用Ro-31-8220(蛋白激酶酶C抑制剂),观察到PKC负责DON诱导的COX-2和iNOS蛋白的上调。塞来昔布的治疗降低了DON诱导的蛋白激酶C同工酶(α,ε,γ)的易位,表明PKC在DON介导的生化和分子改变中起皮肤毒性作用。目前的发现表明,塞来昔布的局部应用可有效治疗由食源性真菌毒素DON引起的炎症性皮肤病。塞来昔布的皮肤渗透潜能,还评估了选择性环氧合酶-2(COX-2)抑制剂NSAID,结果表明与口服给药方式相比,其渗透性相对较低。因此,由于较低的全身吸收并避免了不良副作用,塞来昔布的局部使用可能比口服给药更可取。该研究为探索局部应用COX-2抑制剂治疗食源性真菌毒素引起的炎症性皮肤病的临床疗效提供了前景。