Abdelhamid Amir Mohamed, Youssef Mahmoud E, Cavalu Simona, Mostafa-Hedeab Gomaa, Youssef Amal, Elazab Sara T, Ibrahim Samar, Allam Shady, Elgharabawy Rehab Mohamed, El-Ahwany Eman, Amin Noha A, Shata Ahmed, Mohammed Osama A, Ibrahim Abdeldaiem Mahmoud Said, Alhowail Ahmed, El-Saber Batiha Gaber, El-Mahmoudy Engy A, Attia Maram, Allam Alaa, Zaater Mona Y, Osman Mona M, Nader Manar, Taha Aya, Makarem Nada Abul, Saber Sameh
Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania.
Front Pharmacol. 2022 Jun 8;13:887233. doi: 10.3389/fphar.2022.887233. eCollection 2022.
Ulcerative colitis (UC), an inflammatory bowel disease, is a chronic condition of a multifaceted pathophysiology. The incidence of UC is increasing internationally. The current therapies for UC lack relative effectiveness and are associated with adverse effects. Therefore, novel therapeutic options should be developed. It has been well documented that modulating the Nrf2/NFκB is a promising therapeutic target in inflammation. Carbocisteine is a mucoregulatory medication and its efficacy in COPD was found to be more closely related to its antioxidant and anti-inflammatory properties. Carbocisteine has not yet been examined for the management of UC. Hence, our approach was to investigate the potential coloprotective role of carbocisteine in acetic acid-induced colitis in rats. Our results revealed that carbocisteine improved colon histology and macroscopic features and subdued the disease activity as well. Additionally, carbocisteine attenuated colon shortening and augmented colon antioxidant defense mechanisms via upregulating catalase and HO-1 enzymes. The myeloperoxidase activity was suppressed indicating inhibition of the neutrophil infiltration and activation. Consistent with these findings, carbocisteine boosted Nrf2 expression along with NFκB inactivation. Consequently, carbocisteine downregulated the proinflammatory cytokines IL-6 and TNF-α and upregulated the anti-inflammatory cytokine IL-10. Concomitant to these protective roles, carbocisteine displayed anti-apoptotic properties as revealed by the reduction in the Bax: BCL-2 ratio. In conclusion, carbocisteine inhibited oxidative stress, inflammatory response, and apoptosis in acetic acid-induced UC by modulating the Nrf2/HO-1 and NFκB interplay in rats. Therefore, the current study provides a potential basis for repurposing a safe and a commonly used mucoregulator for the treatment of UC.
溃疡性结肠炎（UC）是一种炎症性肠病，是一种具有多方面病理生理学特征的慢性疾病。UC在国际上的发病率正在上升。目前用于治疗UC的疗法缺乏相对有效性，且伴有不良反应。因此，应开发新的治疗方案。有充分的文献记载，调节Nrf2/NFκB是炎症治疗中一个有前景的靶点。羧甲司坦是一种黏液调节剂，其在慢性阻塞性肺疾病（COPD）中的疗效被发现与其抗氧化和抗炎特性更为密切相关。羧甲司坦尚未用于UC的治疗研究。因此，我们的方法是研究羧甲司坦在大鼠乙酸诱导的结肠炎中潜在的结肠保护作用。我们的结果显示，羧甲司坦改善了结肠组织学和大体特征，并减轻了疾病活动度。此外，羧甲司坦通过上调过氧化氢酶和血红素氧合酶-1（HO-1）酶减轻了结肠缩短，并增强了结肠抗氧化防御机制。髓过氧化物酶活性受到抑制，表明中性粒细胞浸润和活化受到抑制。与这些发现一致，羧甲司坦增强了Nrf2表达并使NFκB失活。因此，羧甲司坦下调了促炎细胞因子白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α），并上调了抗炎细胞因子白细胞介素-10（IL-10）。与这些保护作用相伴的是，羧甲司坦表现出抗凋亡特性，这通过Bax与BCL-2比值的降低得以体现。总之，羧甲司坦通过调节大鼠体内Nrf2/HO-1和NFκB的相互作用，抑制了乙酸诱导的UC中的氧化应激、炎症反应和细胞凋亡。因此，本研究为将一种安全且常用的黏液调节剂重新用于治疗UC提供了潜在依据。
