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. 2022 Jun 8:13:887233.
doi: 10.3389/fphar.2022.887233. eCollection 2022.

Carbocisteine as a Modulator of Nrf2/HO-1 and NFκB Interplay in Rats: New Inspiration for the Revival of an Old Drug for Treating Ulcerative Colitis

Amir Mohamed Abdelhamid  1 , Mahmoud E Youssef  1 , Simona Cavalu  2 , Gomaa Mostafa-Hedeab  3   4 , Amal Youssef  5 , Sara T Elazab  6 , Samar Ibrahim  7 , Shady Allam  8 , Rehab Mohamed Elgharabawy  9 , Eman El-Ahwany  10 , Noha A Amin  11 , Ahmed Shata  12   13 , Osama A Mohammed  14   15 , Mahmoud Said Ibrahim Abdeldaiem  16   17 , Ahmed Alhowail  18 , Gaber El-Saber Batiha  19 , Engy A El-Mahmoudy  20 , Maram Attia  20 , Alaa Allam  20 , Mona Y Zaater  20 , Mona M Osman  20 , Manar Nader  20 , Aya Taha  20 , Nada Abul Makarem  20 , Sameh Saber  1
Affiliations

Carbocisteine as a Modulator of Nrf2/HO-1 and NFκB Interplay in Rats: New Inspiration for the Revival of an Old Drug for Treating Ulcerative Colitis

Amir Mohamed Abdelhamid et al. Front Pharmacol. .

Abstract

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.

Keywords: NFκB; Nrf2/HO-1; acetic acid; carbocisteine; colitis; repositioning.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Effect of CRBST 250 and 500 mg/kg on colon weight/length ratio (A); DAI (B); MDI (C); and the colon pictures (D) in rats with AA-induced UC. Results in figure (A) are shown as the mean ± SD and in figure (B,C) are shown as the median ± interquartile range (n = 6). ∗p < 0.05, ∗∗p < 0.01, ∗∗∗∗p < 0.0001. Normal, normal control rats administered the vehicle; CRBST 500, normal rats administered carbocisteine (500 mg/kg); UC, AA-induced UC rats administered the vehicle; UC/CRBST 250, AA-induced UC rats treated with carbocisteine (250 mg/kg); UC/CRBST 500, AA-induced UC rats treated with carbocisteine (500 mg/kg).
FIGURE 2
FIGURE 2
Effect of CRBST 250 and 500 mg/kg on histopathological characteristics and histopathological score in rats with AA-induced UC. Representative histological appearance of colon tissue specimens stained with H&E from Normal (A) and CRBST 500 (B) control groups showing normal epithelium (red arrow), normal colonic mucosa (M) and submucosa (SM), crypts and glands (blue arrow); Colonic sections from UC group (C) showing deepithelialization (red arrow), erosions (green arrow), disrupted mucosa (M) and submucosa (SM), inflammatory cell infiltration (blue diamond), edema (orange double arrow), congestion (brown arrow) and complete necrosis of the crypts (blue arrow); Colonic sections from UC/CRBST 250 (D) and UC/CRBST 500 (E) showing a moderate restoration of architecture, with decreased superficial ulceration of the intestinal mucosa (green arrow) and is associated with a marked decrease of interstitial inflammatory cell infiltration in (blue diamond), lower degree of glands damage (blue arrow), lower degree of edema (orange double arrow), normal muscularis propria (MP), congestion still apparent (brown arrow). Results in (F) are shown as the median ± interquartile range (n = 6). ***p < 0.001. Normal, normal control rats administered the vehicle; CRBST 500, normal rats administered carbocisteine (500 mg/kg); UC, AA-induced UC rats administered the vehicle; UC/CRBST 250, AA-induced UC rats treated with carbocisteine (250 mg/kg); UC/CRBST 500, AA-induced UC rats treated with carbocisteine (500 mg/kg). H&E stain, X 100, bar = 200 µm.
FIGURE 3
FIGURE 3
Effect of CRBST 250 and 500 mg/kg on catalase (A); TAC (B); MPO activity (C); HO-1 mRNA (D); and HO-1 (E) in rats with AA-induced UC. Results are shown as the mean ± SD (n = 6). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Normal, normal control rats administered the vehicle; CRBST 500, normal rats administered carbocisteine (500 mg/kg); UC, AA-induced UC rats administered the vehicle; UC/CRBST 250, AA-induced UC rats treated with carbocisteine (250 mg/kg); UC/CRBST 500, AA-induced UC rats treated with carbocisteine (500 mg/kg).
FIGURE 4
FIGURE 4
Effect of CRBST 250 and 500 mg/kg on IL-6 (A); TNF-α (B); TLR4 (C) and IL-10 (D) in rats with AA-induced UC. Results are shown as the mean ± SD (n = 6). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Normal, normal control rats administered the vehicle; CRBST 500, normal rats administered carbocisteine (500 mg/kg); UC, AA-induced UC rats administered the vehicle; UC/CRBST 250, AA-induced UC rats treated with carbocisteine (250 mg/kg); UC/CRBST 500, AA-induced UC rats treated with carbocisteine (500 mg/kg).
FIGURE 5
FIGURE 5
Effect of CRBST 250 and 500 mg/kg on Bax (A); BCL-2 (B); Bax: BCL-2 ratio (C) and A-caspase-3 (D) in rats with AA-induced UC. Results are shown as the mean ± SD (n = 6). **p < 0.01, ***p < 0.001, ****p < 0.0001. Normal, normal control rats administered the vehicle; CRBST 500, normal rats administered carbocisteine (500 mg/kg); UC, AA-induced UC rats administered the vehicle; UC/CRBST 250, AA-induced UC rats treated with carbocisteine (250 mg/kg); UC/CRBST 500, AA-induced UC rats treated with carbocisteine (500 mg/kg).
FIGURE 6
FIGURE 6
Effect of CRBST 250 and 500 mg/kg on NF-κB p-65 mRNA (A); Phosphorylated NF-κB p-65/p65 ratio (B); IκBα mRNA (C); IκBα (D); Nrf2 (E) and NFκB DNA binding activity (F) in rats with AA-induced UC. Results are shown as the mean ± SD (n = 6). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Normal, normal control rats administered the vehicle; CRBST 500, normal rats administered carbocisteine (500 mg/kg); UC, AA-induced UC rats administered the vehicle; UC/CRBST 250, AA-induced UC rats treated with carbocisteine (250 mg/kg); UC/CRBST 500, AA-induced UC rats treated with carbocisteine (500 mg/kg).
FIGURE 7
FIGURE 7
The proposed mechanism of action of carbocisteine.
See this image and copyright information in PMC

References

    1. Abd El-Fattah E. E., Saber S., Youssef M. E., Eissa H., El-Ahwany E., Amin N. A., et al. (2021b). AKT-AMPKα-mTOR-dependent HIF-1α Activation Is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma. Front. Pharmacol. 12, 720173. 10.3389/fphar.2021.720173 - DOI - PMC - PubMed
    1. Abd El-Fattah E. E., Saber S., Mourad A. A. E., El-Ahwany E., Amin N. A., Cavalu S., et al. (2022a). The Dynamic Interplay between AMPK/NFκB Signaling and NLRP3 Is a New Therapeutic Target in Inflammation: Emerging Role of Dapagliflozin in Overcoming Lipopolysaccharide-Mediated Lung Injury. Biomed. Pharmacother. 147, 112628. 10.1016/j.biopha.2022.112628 - DOI - PubMed
    1. Abdelhamid A. M., Abdelaziz R. R., Salem H. A. A. (2018). Vildagliptin/pioglitazone Combination Improved the Overall Glycemic Control in Type I Diabetic Rats. Can. J. Physiol. Pharmacol. 96, 710–718. 10.1139/cjpp-2017-0680 - DOI - PubMed
    1. Abdelhamid A. M., Elsheakh A. R., Suddek G. M., Abdelaziz R. R. (2021a). Telmisartan Alleviates Alcohol-Induced Liver Injury by Activation of PPAR-γ/Nrf-2 Crosstalk in Mice. Int. Immunopharmacol. 99, 107963. 10.1016/j.intimp.2021.107963 - DOI - PubMed
    1. Abdelhamid A. M., Youssef M. E., Abd El-Fattah E. E., Gobba N. A., Gaafar A. G. A., Girgis S., et al. (2021b). Blunting P38 MAPKα and ERK1/2 Activities by Empagliflozin Enhances the Antifibrotic Effect of Metformin and Augments its AMPK-Induced NF-κB Inactivation in Mice Intoxicated with Carbon Tetrachloride. Life Sci. 286, 120070. 10.1016/j.lfs.2021.120070 - DOI - PubMed