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Xue W, Fan X, Hui Y, Yu J. Active compounds of licorice ameliorate microplastics-induced intestinal damage by targeting FADD. Food Chem Toxicol 2025:115570. [PMID: 40412644 DOI: 10.1016/j.fct.2025.115570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/15/2025] [Accepted: 05/20/2025] [Indexed: 05/27/2025]
Abstract
Microplastics (MPs), as a novel type of environmental pollutant, have the potential to impact human health. This study aims to investigate the protective efficacy of active compounds in licorice on microplastics-injured rats and reveal the underlying mechanisms. The MPs-injured rat model was established by orally administrated with MPs. After the treatment with different doses of a combination of liquiritigenin, isoliquiritigenin and glycyrrhetinic acid, the tissue injury, oxidative stress, inflammation and expressions of tight junction proteins in colon and liver were evaluated. Our data showed that active compounds of licorice significantly ameliorate colonic and liver damage caused by MPs, improving function colonic barrier and liver function, reducing oxidative stress and systemic inflammatory factors. Then, a total of 29 differentially expressed proteins were identified by label-free proteomics analysis, among which the down-regulated Fas-associating protein with a novel death domain (FADD) was found to be the most related with the protective effects of licorice. What's more, this protein target also interacts directly with active compounds of licorice, through hydrogen bounds and hydrophobic interactions involving 11 residues. This study suggested that licorice exerts protective effects against MPs on rats, through down-regulating as well as directly interacting with FADD.
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Affiliation(s)
- Wen Xue
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry/State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation)/Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, Xianyang 712046, China.
| | - Xiuhe Fan
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry/State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation)/Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, Xianyang 712046, China.
| | - Yujing Hui
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry/State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation)/Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, Xianyang 712046, China.
| | - Jingao Yu
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry/State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation)/Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, Xianyang 712046, China.
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Lin CH, Jiang WP, Itokazu N, Huang GJ. Chlorogenic acid attenuates 5-fluorouracil-induced intestinal mucositis in mice through SIRT1 signaling-mediated oxidative stress and inflammatory pathways. Biomed Pharmacother 2025; 186:117982. [PMID: 40106967 DOI: 10.1016/j.biopha.2025.117982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/17/2025] [Accepted: 03/10/2025] [Indexed: 03/22/2025] Open
Abstract
Mucositis, a common side effect of the chemotherapeutic drug 5-Fluorouracil (5-FU), causes severe and aggravating effects on mucosal cells in the oral cavity and intestine. This study in mice aimed to assess the antioxidant, anti-inflammatory, and mucosal protective properties of chlorogenic acid in mitigating 5-FU-induced intestinal mucositis. To investigate these potential protective effects, we developed a mouse model by administering an initial intraperitoneal (i.p.) injection of 5-FU, followed by daily i.p. injections of chlorogenic acid (10 and 20 mg/kg) for 10 consecutive days. Chlorogenic acid mitigated intestinal histopathological damage, reduced proinflammatory mediators and malondialdehyde (MDA) levels, and increased the glutathione (GSH) level by 5-FU. Chlorogenic acid treatment led to a significant reduction in the expression of inflammation-related proteins decreased oxidative stress-related proteins and, attenuated the expression of apoptosis and autophagy-related proteins in small intestinal tissues. Additional investigations are necessary to verify our findings and enhance our comprehension of how SIRT1 inhibition (EX-527) counteracts the anti-inflammatory effects of chlorogenic acid in intestinal tissues. In conclusion, our mice study has shown that chlorogenic acid exerts its protective effects on 5-FU-induced intestinal tissue damage, by reducing oxidative stress and inflammation through the modulation of multiple signaling pathways, including the TLR4/NF-κB/MAPK, AMPK/ SIRT1, and PI3K/AKT axis. These findings highlight the potential of chlorogenic acid as a therapeutic agent for mucositis, given its anti-inflammatory and antioxidant properties.
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Affiliation(s)
- Che-Hsuan Lin
- Department of Otolaryngology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Department of Otolaryngology, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
| | - Wen-Ping Jiang
- School of Pharmacy, College of Pharmacy, China Medical University, Taichung 404, Taiwan
| | - Nanae Itokazu
- Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, Saitama 3620806, Japan
| | - Guan-Jhong Huang
- Department of Food Nutrition and Healthy Biotechnology, Asia University, Asia University, Taichung 413, Taiwan; Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan.
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Lin JG, Sun YW, Wu WL, Jiang WP, Zhung FY, Huang GJ. Multi-Target Protective Effects of Sanghuangporus sanghuang Against 5-Fluorouracil-Induced Intestinal Injury Through Suppression of Inflammation, Oxidative Stress, Epitheli-Al-Mesenchymal Transition, and Tight Junction. Int J Mol Sci 2025; 26:3444. [PMID: 40244381 PMCID: PMC11989720 DOI: 10.3390/ijms26073444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/28/2025] [Accepted: 04/03/2025] [Indexed: 04/18/2025] Open
Abstract
Sanghuang (Sanghuangporus sanghuang, SS) is a medicinal fungus with multiple pharmacological effects, including antioxidant, anti-inflammatory, immune-boosting, and anti-cancer activities. 5-fluorouracil (5-FU) is a commonly used chemotherapeutic agent for the treatment of colorectal cancer. It primarily exerts its antitumor effect by inhibiting DNA and RNA synthesis, leading to cell apoptosis. However, it frequently induces adverse effects These issues limit the clinical application of 5-FU. This research aims to determine the potential of SS as a therapeutic agent in reducing 5-FU-induced intestinal mucositis in a mouse model. The results indicated that 5-FU administration significantly increased diarrhea severity, reduced colon length, caused small intestinal villus atrophy, disrupted intestinal architecture, led to insufficient crypt cell proliferation, and resulted in weight loss. It also significantly upregulated inflammatory responses, apoptosis, oxidative stress, and epithelial-mesenchymal transition (EMT) pathways, and disrupted the integrity of intestinal mucosal tight junction, while elevating pro-inflammatory cytokines and reducing antioxidant capacity. However, SS significantly ameliorating alleviating the adverse impacts of the chemotherapeutic agent on the intestinal mucosa. In conclusion, this investigation provides the first evidence of the protective effects of SS on 5-FU-induced mucositis. These findings suggest SS as a potential therapeutic application, offering a promising strategy for reducing the adverse effects of 5-FU chemotherapy and improving the treatment and quality of life for colorectal cancer patients.
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Affiliation(s)
- Jaung-Geng Lin
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan; (J.-G.L.); (W.-L.W.)
- Chinese Medicine Research Center, China Medical University, Taichung 404, Taiwan
| | - Yu-Wen Sun
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan
| | - Wen-Liang Wu
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan; (J.-G.L.); (W.-L.W.)
| | - Wen-Ping Jiang
- Department of Pharmacy, China Medical University, Taichung 404, Taiwan;
| | - Fang-Yu Zhung
- Department of Nutrition, China Medical University, Taichung 404, Taiwan
| | - Guan-Jhong Huang
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan
- Department of Food Nutrition and Healthy Biotechnology, Asia University, Taichung 413, Taiwan
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4
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Nie LJ, Cheng Z, He YX, Yan QH, Sun YH, Yang XY, Tian J, Zhu PF, Yu JY, Zhou HP, Zhou XQ. Role of duodenal mucosal resurfacing in controlling diabetes in rats. World J Diabetes 2025; 16:102277. [PMID: 40093272 PMCID: PMC11885968 DOI: 10.4239/wjd.v16.i3.102277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 12/09/2024] [Accepted: 01/03/2025] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND The duodenum plays a significant role in metabolic regulation, and thickened mucous membranes are associated with insulin resistance. Duodenal mucosal resurfacing (DMR), a new-style endoscopic procedure using hydrothermal energy to ablate this thickened layer, shows promise for enhancing glucose and lipid metabolism in type 2 diabetes (T2D) patients. However, the mechanisms driving these improvements remain largely unexplored. AIM To investigate the mechanisms by which DMR improves metabolic disorders using a rat model. METHODS Rats with T2D underwent a revised DMR procedure via a gastric incision using a specialized catheter to abrade the duodenal mucosa. The duodenum was evaluated using histology, immunofluorescence, and western blotting. Serum assays measured glucose, lipid profiles, lipopolysaccharide, and intestinal hormones, while the gut microbiota and metabolomics profiles were analyzed through 16S rRNA gene sequencing and ultra performance liquid chromatography-mass spectrum/mass spectrum, severally. RESULTS DMR significantly improved glucose and lipid metabolic disorders in T2D rats. It increased the serum levels of cholecystokinin, gastric inhibitory peptide, and glucagon-like peptide 1, and reduced the length and depth of duodenal villi and crypts. DMR also enhanced the intestinal barrier integrity and reduced lipopolysaccharide translocation. Additionally, DMR modified the gut microbiome and metabolome, particularly affecting the Blautia genus. Correlation analysis revealed significant links between the gut microbiota, metabolites, and T2D phenotypes. CONCLUSION This study illustrates that DMR addresses metabolic dysfunctions in T2D through multifaceted mechanisms, highlighting the potential role of the Blautia genus on T2D pathogenesis and DMR's therapeutic impact.
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Affiliation(s)
- Li-Juan Nie
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Zhe Cheng
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Yi-Xian He
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Qian-Hua Yan
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Yao-Huan Sun
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Xin-Yi Yang
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Jie Tian
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Peng-Fei Zhu
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Jiang-Yi Yu
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Hui-Ping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23284, United States
| | - Xi-Qiao Zhou
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
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El-Samad LM, Maklad AM, Elkady AI, Hassan MA. Unveiling the mechanism of sericin and hydroxychloroquine in suppressing lung oxidative impairment and early carcinogenesis in diethylnitrosamine-induced mice by modulating PI3K/Akt/Nrf2/NF-κB signaling pathway. Biomed Pharmacother 2025; 182:117730. [PMID: 39671723 DOI: 10.1016/j.biopha.2024.117730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 11/24/2024] [Accepted: 12/03/2024] [Indexed: 12/15/2024] Open
Abstract
This study sheds light on the ameliorative influence of combined sericin and hydroxychloroquine (HQ) on mitigating diethylnitrosamine (DEN)-induced lung oxidative impairment and inflammation, thereby precluding early carcinogenic episodes in mice. Besides, the pivotal role of sericin and HQ in controlling the PI3K/Akt/Nrf2/NF-κB signaling pathway was probed. Therefore, male Swiss albino mice were assigned to different groups and treated with different drugs. Oxidative stress and inflammatory biomarkers, in addition to the expression of PI3K and Akt genes were evaluated in lung tissues. Treatment with DEN disturbed the redox homeostasis associated with inflammation in the lungs. Conversely, sericin combined with HQ remarkably upregulated Nrf2 expression in the lungs associated with significant ameliorations of antioxidant factors, including SOD, GST, GSH, and MDA. Furthermore, sericin and HQ abated inflammation instigated by DEN through downregulating NF-κB and inflammatory biomarkers, including TNF-α and IL-6, with an increase in IL-10. Importantly, sericin and HQ treatment significantly downregulated PI3K and Akt expression. Immunohistochemical investigations demonstrated marked diminutions in Ki-67 and p53 expressions in animals cotreated with sericin and HQ compared to the DEN-treated group, inhibiting lung cancer progression. Histopathological and ultrastructural anomalies were detected in lung tissues from the DEN group, while significant enhancements were perceived in lung tissues treated with sericin and HQ. Our findings emphasized that the combinatorial therapy of sericin and HQ could orchestrate the PI3K/Akt/Nrf2/NF-κB signaling pathway in the lungs, counteracting oxidative stress, inflammation, and uncontrolled cellular proliferation and sustaining lung structures. Furthermore, they could serve as anticancer agents, hindering lung cancer progression.
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Affiliation(s)
- Lamia M El-Samad
- Department of Zoology, Faculty of Science, Alexandria University, Egypt
| | - Alaa M Maklad
- Department of Zoology, Faculty of Science, Alexandria University, Egypt
| | - Ayman I Elkady
- Department of Zoology, Faculty of Science, Alexandria University, Egypt; Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
| | - Mohamed A Hassan
- Protein Research Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City, Alexandria 21934, Egypt.
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Xu L, Zhao X, Tang F, Zhang J, Peng C, Ao H. Ameliorative Effect of Ginsenoside Rc on 5-Fluorouracil-Induced Chemotherapeutic Intestinal Mucositis via the PI3K-AKT/NF-κB Signaling Pathway: In Vivo and In Vitro Evaluations. Int J Mol Sci 2024; 25:13085. [PMID: 39684797 DOI: 10.3390/ijms252313085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 11/26/2024] [Accepted: 12/01/2024] [Indexed: 12/18/2024] Open
Abstract
5-Fluorouracil (5-Fu) is a chemotherapeutic agent widely used to treat various cancers, which causes intestinal mucositis as a common side effect. Ginsenoside Rc, an active compound with anti-inflammatory, antioxidant, immunomodulatory, and antitumor properties, has protective effects against chemotherapy-induced mucositis caused by 5-Fu. This study aims to evaluate the protective effects of Rc on 5-Fu-induced chemotherapy-related mucositis and to elucidate its underlying mechanisms. In vivo experiments were conducted to measure intestinal permeability and assess the effects of Rc on body weight loss, diarrhea, and intestinal pathology induced by 5-Fu. Network pharmacology was also employed to explore potential mechanisms. In vitro, IEC-6 cell models were used to validate the cytoprotective effects of Rc, including assessments of cell viability, apoptosis, lactate dehydrogenase (LDH) release, and changes in inflammatory cytokine levels. The results indicate that Rc significantly ameliorated body weight reduction, diarrhea, and intestinal damage in mice treated by 5-Fu. Rc significantly mitigated 5-Fu-induced cellular damage by reducing levels of inflammatory cytokines such as IL-1β, IL-6, and TNF-α and decreasing apoptosis and cell permeability. Western blot analysis revealed that Rc upregulated the expression of Bcl-2 and tight junction proteins and downregulated the expression of Bax. Furthermore, Rc exerts anti-inflammatory and anti-apoptotic effects through PI3K-AKT and NF-κB signaling pathways. In conclusion, ginsenoside Rc demonstrated significant protective effects against 5-Fu-induced intestinal mucositis via the PI3K-AKT/NF-κB signaling pathway, suggesting its potential as a therapeutic agent for chemotherapy-related mucositis.
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Affiliation(s)
- Liyue Xu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xiaolan Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Fei Tang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jingnan Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Hui Ao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu, University of Traditional Chinese Medicine, Chengdu 611137, China
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Mrwad AA, El-Shafey SE, Said NM. Chitosan-encapsulated selenium nanoparticles alleviate CCl 4 induced hepatotoxicity through synergistically modulating NF-κB and Nrf2 signaling pathways and regulating Bcl-2 and Caspase-3 expression: A comprehensive study with multiple regression analysis. J Trace Elem Med Biol 2024; 86:127563. [PMID: 39547053 DOI: 10.1016/j.jtemb.2024.127563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 10/24/2024] [Accepted: 11/08/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND The delivery of selenium in a nano-form (Se-NPs) is a promising modality of treatment for various oxidative stress-induced diseases. OBJECTIVE This study aims to investigate the conceivable effects of selenium nanoparticles either alone (Se-NPs) or encapsulated with chitosan (Se-CS-NPs) on toxicity induced by CCl4 in rats. METHODS Eighty albino rats were divided equally into eight groups. The first group was the placebo. The second group was a positive control, while the third and the fourth groups got orally (Se-NPs 5 mg/Kg) and (Se-CS-NPs 225 mg/Kg) respectively. The fifth and sixth groups were protective groups in which Se-NPs or Se-CS-NPs were given simultaneously. The seventh and eighth groups were therapeutic as they received either Se-NPs or Se-CS-NPs after stopping the CCl4 injection for 4 weeks more. RESULTS Our results showed that the protective and therapeutic groups showed an increase in caspase-3 gene expression with a decline in the expression of Bcl-2, Nrf2, and AFP genes. Histopathological and immunohistochemical investigations showed the role of selenium nanoparticles either alone or coated with chitosan in decreasing fibrotic marker collagen I positive reaction CONCLUSION: Selenium nanoparticles showed an excellent effect in counteracting the toxic effect of carbon tetrachloride on liver functions, inflammation reactions, and apoptosis process. Moreover, using selenium nanoparticles has a strong role in preserving the liver architecture with its normal constituents. No additional benefit was observed when the selenium nanoparticles were encapsulated with chitosan.
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Affiliation(s)
| | - Shaymaa E El-Shafey
- Physical Chemistry Department, Surface and Catalysis Lab., National Research Center, El-Bohouth St. 33, Dokki, Giza, Egypt
| | - Noha Mohamed Said
- Biochemistry Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt.
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Awais M, Zubair HM, Nadeem H, Hill JW, Ali J, Saleem A, Asghar R, Khan S, Maqbool T, Akhtar MF, Naveed M, Asif M. Benzimidazole Derivative (N-{4-[2-(4-Methoxyphenyl)-1H-Benzimidazole-1-Sulfonyl] Phenyl} Acetamide) Ameliorates Methotrexate-Induced Intestinal Mucositis by Suppressing Oxidative Stress and Inflammatory Markers in Mice. Inflammation 2024; 47:1185-1203. [PMID: 38289578 DOI: 10.1007/s10753-024-01969-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 01/05/2024] [Accepted: 01/05/2024] [Indexed: 08/24/2024]
Abstract
Methotrexate (MTX)-induced intestinal mucositis (IM) is a common side effect in cancer treatment that impairs the immune system and gut microbes, resulting in loss of mucosal integrity and gut barrier dysfunction. The quality of life and outcomes of treatment are compromised by IM. The present study was designed to investigate the mucoprotective potential of the benzimidazole derivative N-{4-[2-(4-methoxyphenyl)-1H-benzimidazole-1-sulfonyl] phenyl} acetamide (B8) on MTX-induced IM in mice. IM was induced by a single dose of MTX in mice and assessed by physical manifestations as well as biochemical, oxidative, histological, and inflammatory parameters. B8 (1, 3, 9 mg/kg) significantly reduced diarrhea score, mitigated weight loss, increased feed intake and, survival rate in a dose-dependent manner. Notably, B8 exhibited a mucoprotective effect evident through the mitigation of villus atrophy, crypt hypoplasia, diminished crypt mitotic figures, mucin depletion, and oxidative stress markers (GSH, SOD, MDA, and catalase concentration). Gene expression analysis revealed that B8 downregulated the mRNA expression of tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), IL-1β, and nuclear factor-κB (NF-κB) and concurrently upregulated IL-10 expression in contrast to the MTX group. Further, B8 significantly improved the luminal microflora profile by augmenting the growth of Lactobacillus spp. and reducing the number of pathogenic bacteria (E. coli). Additionally, the enzyme-linked immunoassay showed that B8 decreased the levels of pro-inflammatory cytokines. Our findings suggest that B8 had mucoprotective effects against MTX-induced IM and could be used as an adjunct in chemotherapy to deter this side effect.
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Affiliation(s)
- Muhammad Awais
- Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan
| | - Hafiz Muhammad Zubair
- Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan.
- Post-Graduate Medical College, Faculty of Medicine and Allied Health Sciences, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan.
| | - Humaira Nadeem
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Jennifer W Hill
- Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, 43614, USA
| | - Jawad Ali
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan
| | - Ammara Saleem
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, 38000, Pakistan
| | - Rabia Asghar
- Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan
| | - Samiullah Khan
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Tahir Maqbool
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Muhammad Furqan Akhtar
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Lahore, Pakistan
| | - Muhammad Naveed
- Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, 43614, USA
| | - Muhammad Asif
- Department of Pharmacology, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan
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Wu C, Yang J, Ye C, Wu H, Shu W, Li R, Wang S, Lu Y, Chen H, Zhang Z, Yao Q. Berberine attenuates 5-fluorouracil-induced intestinal mucosal injury by modulating the gut microbiota without compromising its anti-tumor efficacy. Heliyon 2024; 10:e34528. [PMID: 39114045 PMCID: PMC11305238 DOI: 10.1016/j.heliyon.2024.e34528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 07/10/2024] [Accepted: 07/10/2024] [Indexed: 08/10/2024] Open
Abstract
Background 5-Fluorouracil (5-Fu), a prominent chemotherapeutic agent for colorectal cancer (CRC) treatment, is often associated with gastrointestinal toxicities, particularly diarrhea. Our previous study demonstrated that berberine (BBR) ameliorates 5-Fu-induced intestinal mucosal injury by modulating the gut microbiota in rats. Nevertheless, the precise molecular mechanism underlying BBR's protective effect on intestinal mucosa remains elusive, and its impact on the anti-tumor efficacy of 5-Fu warrants further investigation. Methods The effect of BBR on 5-Fu-induced intestinal mucosal injury was investigated using a tumor-bearing murine model, employing H&E staining, 16 S rDNA sequencing, transcriptome sequencing, Western blot analysis, cell experiments and constructing a pseudo-germ-free tumor xenograft model. Result Our findings demonstrate that BBR alleviates intestinal mucosal damage, reduces the levels of inflammatory factors (IL-6, TNF-α, and IL-1β), and inhibits epithelial cell apoptosis in 5-Fu-treated mice without compromising 5-Fu's anti-tumor efficacy. Moreover, 16 S rDNA sequencing indicated that BBR significantly increases the abundance of Akkermansia and decreases the abundance of pathogenic bacteria Escherichia/Shigella at the genus level. Mechanistically, transcriptome sequencing and Western blot analysis confirmed that BBR upregulates PI3K/AKT/mTOR expression in the intestinal mucosa. However, this effect was not observed in tumor tissues. Notably, BBR did not demonstrate a direct protective effect on 5-Fu-treated CCD841 and SW480 cells. Additionally, BBR had no effect on the PI3K/AKT/mTOR pathway in the intestinal tissue of the 5-Fu-treated mouse model with a depleted gut microbiota. Conclusion This study indicates that BBR alleviates 5-Fu-induced intestinal mucosal injury by modulating the gut microbiota and regulating the PI3K/AKT/mTOR signaling pathway without compromising the anti-tumor efficacy of 5-Fu.
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Affiliation(s)
- Changhong Wu
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jie Yang
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Chenxiao Ye
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Hui Wu
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Wenxi Shu
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Rongrong Li
- The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310012, China
| | - Sihan Wang
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yi Lu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Department of Clinical Nutrition, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Haitao Chen
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
- Integrated Traditional Chinese and Western Medicine Oncology Laboratory, Key Laboratory of Traditional Chinese Medicine of Zhejiang Province, Hangzhou, Zhejiang, 310022, China
| | - Zewei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, 310022, China
| | - Qinghua Yao
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, Xinhua Hospital of Zhejiang Province, Hangzhou, Zhejiang, 310005, China
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10
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He S, Wang Z, Xia J, Jia H, Dai Q, Chen C, He F, Wang X, Zhou M. Dasabuvir alleviates 5-fluorouracil-induced intestinal injury through anti-senescence and anti-inflammatory. Sci Rep 2024; 14:15730. [PMID: 38977864 PMCID: PMC11231161 DOI: 10.1038/s41598-024-66771-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 07/03/2024] [Indexed: 07/10/2024] Open
Abstract
5-Fluorouracil (5-Fu) is a basic drug that is used to treat colorectal cancer. Patients who receive 5-Fu chemotherapy often experience side effects that affect the digestive system, such as intestinal injury and diarrhoea, which significantly affect patient compliance with anticancer treatment and quality of life. Therefore, identifying approaches to treat or prevent these side effects is urgent. Dasabuvir (DSV) is a hepatitis C virus inhibitor, but its impact on 5-Fu-induced intestinal injury remains unknown. Our study investigated the effects of DSV on 5-Fu-induced intestinal injury in HUVECs, HIECs and male BALB/c mice. We found that 5-Fu caused intestinal damage by inducing senescence, increasing inflammatory factor expression, and generating oxidative stress. Compared with 5-Fu treatment alone, DSV inhibited senescence by reducing senescence-β-galactosidase (SA-β-gal) activity, the senescence-associated secretory phenotype (SASP, including IL-1, IL-6, and TNF-α) and senescence marker expression levels (p16, p21, and p53). Moreover, the anti-senescence effect of DSV was achieved by inhibiting the mTOR signaling pathway. DSV increased antioxidant enzyme levels and alleviated intestinal tissue injury in mice. In addition, DSV suppressed the 5-Fu-induced increase the diarrhoea scores and ameliorated the weight loss, food intake and water intake of the mice. Overall, this study indicated that DSV could be used to treat chemotherapy-induced intestinal damage.
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Affiliation(s)
- Siyue He
- School of Basic Medicine, Dali University, Dali, 671000, Yunnan, China
| | - Zhiwei Wang
- School of Basic Medicine, Dali University, Dali, 671000, Yunnan, China
| | - Jing Xia
- School of Basic Medicine, Dali University, Dali, 671000, Yunnan, China
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610000, Sichuan, China
| | - Huijie Jia
- School of Basic Medicine, Dali University, Dali, 671000, Yunnan, China
| | - Qianlong Dai
- School of Basic Medicine, Dali University, Dali, 671000, Yunnan, China
| | - Cui Chen
- School of Basic Medicine, Dali University, Dali, 671000, Yunnan, China
- Qujing Medical College, Qujing, 655011, Yunnan, China
| | - Fei He
- School of Basic Medicine, Dali University, Dali, 671000, Yunnan, China.
| | - Xiaobo Wang
- School of Basic Medicine, Dali University, Dali, 671000, Yunnan, China.
| | - Min Zhou
- School of Basic Medicine, Dali University, Dali, 671000, Yunnan, China.
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11
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Guan Y, Wu D, Wang H, Liu N. Microbiome-driven anticancer therapy: A step forward from natural products. MLIFE 2024; 3:219-230. [PMID: 38948147 PMCID: PMC11211674 DOI: 10.1002/mlf2.12118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 12/25/2023] [Accepted: 01/25/2024] [Indexed: 07/02/2024]
Abstract
Human microbiomes, considered as a new emerging and enabling cancer hallmark, are increasingly recognized as critical effectors in cancer development and progression. Manipulation of microbiome revitalizing anticancer therapy from natural products shows promise toward improving cancer outcomes. Herein, we summarize our current understanding of the human microbiome-driven molecular mechanisms impacting cancer progression and anticancer therapy. We highlight the potential translational and clinical implications of natural products for cancer prevention and treatment by developing targeted therapeutic strategies as adjuvants for chemotherapy and immunotherapy against tumorigenesis. The challenges and opportunities for future investigations using modulation of the microbiome for cancer treatment are further discussed in this review.
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Affiliation(s)
- Yunxuan Guan
- State Key Laboratory of Systems Medicine for Cancer, Center for Single‐Cell Omics, School of Public HealthShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Di Wu
- State Key Laboratory of Systems Medicine for Cancer, Center for Single‐Cell Omics, School of Public HealthShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Hui Wang
- State Key Laboratory of Systems Medicine for Cancer, Center for Single‐Cell Omics, School of Public HealthShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ning‐Ning Liu
- State Key Laboratory of Systems Medicine for Cancer, Center for Single‐Cell Omics, School of Public HealthShanghai Jiao Tong University School of MedicineShanghaiChina
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12
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Kassab RB, Elhenawy AA, AbdulrahmanTheyab, Hawsawi YM, Al-Amer OM, Oyouni AAA, Habotta OA, Althagafi HA, Alharthi F, Lokman MS, Alsharif KF, Albrakati A, Al-Ghamdy AO, Elmahallawy EK, Elhefny MA, Hassan KE, Albarakati AJA, Abdel Moneim AE, Moustafa AA. Modulation of inflammatory, oxidative, and apoptotic stresses mediates the renoprotective effect of daidzein against glycerol-induced acute kidney injury in rats. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:119016-119033. [PMID: 37919499 DOI: 10.1007/s11356-023-30461-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 10/10/2023] [Indexed: 11/04/2023]
Abstract
Acute kidney injury (AKI) is a life-threatening complication that accompanies rhabdomyolysis. Daidzein is a dietary isoflavone that has various biological activities. This study examined the therapeutic potential of daidzein and the underlying mechanisms against AKI induced by glycerol in male rats. Animals were injected once with glycerol (50%, 10 ml/kg, intramuscular) for induction of AKI and pre-treated orally with daidzein (25, 50, and 100 mg/kg) for 2 weeks. Biochemical, histopathological, immunohistopathological, and molecular parameters were assessed to evaluate the effect of daidzein. The results revealed that the model group displayed remarkable functional, molecular, and structural changes in the kidney. However, pre-administration of daidzein markedly decreased the kidney relative weight as well as the levels of urea, creatinine, K, P, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and cystatin C. Further, daidzein lessened the rhabdomyolysis-related markers [lactate dehydrogenase (LDH) and creatine kinase (CK)]. Notably, the enhancement of the antioxidant biomarkers [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and reduced glutathione (GSH) is accompanied by a decrease in malondialdehyde (MDA) and nitric oxide (NO) levels. Moreover, upregulated gene expression levels of nuclear factor erythroid 2-related factor 2 (Nfe212) and hemeoxygenase-1 (Hmox1) were exerted by daidzein administration. Rats who received daidzein displayed markedly lower interleukin-1β (IL-1β), tumor nuclear factor-α (TNF-α), myleoperoxidase (MPO), and nuclear factor kappa B (NF-κB) levels together with higher interleukin-10 (IL-10) related to the model group. Remarkably, significant declines were noticed in the pro-apoptotic (Bax and caspase-3) and rises in antiapoptotic (Bcl-2) levels in the group that received daidzein. The renal histological screening validated the aforementioned biochemical and molecular alterations. Our findings support daidzein as a potential therapeutic approach against AKI-induced renal injury via suppression of muscle degradation, oxidative damage, cytokine release, and apoptosis.
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Affiliation(s)
- Rami B Kassab
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Ain Helwan, 11795, Egypt
- Department of Biology, Faculty of Science and Arts, Al-Baha University, Almakhwah, Al-Baha, Saudi Arabia
| | - Ahmed A Elhenawy
- Chemistry Department, Faculty of Science, Al-Azhar University (Boys' Branch), Nasr City, Cairo, Egypt
| | - AbdulrahmanTheyab
- Department of Laboratory Medicine, Security Forces Hospital, Mecca, Saudi Arabia
| | - Yousef M Hawsawi
- Research Center, King Faisal Specialist Hospital and Research Center, MBC-J04, P.O. Box 40047, Jeddah, 21499, Saudi Arabia
| | - Osama M Al-Amer
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Atif Abdulwahab A Oyouni
- Department of Biology, Genome and Biotechnology Unit, Faculty of Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Ola A Habotta
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Hussam A Althagafi
- Department of Biology, Faculty of Science and Arts, Al-Baha University, Almakhwah, Al-Baha, Saudi Arabia
| | - Fahad Alharthi
- Department of Biology, College of Science, Taif University, Taif, Saudi Arabia
| | - Maha S Lokman
- Biology Department, College of Science and Humanities, Prince Sattam bin Abdul Aziz University, Alkharj, Saudi Arabia
| | - Khalaf F Alsharif
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia
| | - Ashraf Albrakati
- Department of Human Anatomy, College of Medicine, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia
| | - Ali O Al-Ghamdy
- Department of Biology, Faculty of Science and Arts, Al-Baha University, Almakhwah, Al-Baha, Saudi Arabia
| | - Ehab Kotb Elmahallawy
- Department of Zoonoses, Faculty of Veterinary Medicine, Sohag University, Sohag, 82524, Egypt.
- Departamento de Sanidad Animal, Grupo de Investigación en Sanidad Animal y Zoonosis (GISAZ), Facultad de Veterinaria, Universidad de Córdoba, Córdoba, Spain.
| | - Mohamed A Elhefny
- Department of Cancer and Molecular Biology, National Cancer Institute, Cairo University, Cairo, Egypt
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Alqunfudah, Saudi Arabia
| | - Kalid E Hassan
- Pathology Department, College of Medicine, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia
| | - Alaa Jameel A Albarakati
- Surgery Department, College of Medicine, Al-Qunfudah Branch, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Ahmed E Abdel Moneim
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Ain Helwan, 11795, Egypt
| | - Ahmed A Moustafa
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Ain Helwan, 11795, Egypt
- Urology Department, Tulane University, 1430 Tulane Avenue, New Orleans, LA, 70112, USA
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13
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Hammoodi HZ, Al-Shawi NN. Neuroprotective effects of daidzein against ifosfamide-induced neurotoxicity in male rats: role of selected inflammatory and apoptotic markers. J Med Life 2023; 16:1628-1632. [PMID: 38406792 PMCID: PMC10893576 DOI: 10.25122/jml-2023-0082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 05/13/2023] [Indexed: 02/27/2024] Open
Abstract
Ifosfamide (IFO), an alkylating chemotherapy agent, is known for its association with neurotoxicity and encephalopathy. This trial was designed to evaluate the protective action of daidzein (DZN) against IFO-induced neurotoxicity in male rats by determining the difference in certain inflammatory and apoptotic markers in the brain tissue of rats. Twenty-eight Wistar rats, weighing 120-150 g, were divided into four groups of seven rats: Group 1 (Control) received no treatment; Group 2 was orally administered DZN (100 mg/kg/day) for seven days; Group 3 received a single intraperitoneal (IP) dose of IFO (500 mg/kg); Group 4 received oral DZN (100 mg/kg/day) for one week prior to a single IP dose of IFO on the seventh day. Twenty-four hours post-treatment, serum and brain tissue samples were collected for analysis. The results indicated a significant increase in serum inflammatory markers (TNF-alpha, IL-6, and iNOS) and the anti-inflammatory marker (IL-10), along with elevated caspase-3 enzyme activity in the brain tissue of the IFO-treated group compared to the control group. Conversely, pre-treatment with DZN significantly reduced serum inflammatory markers and caspase-3 levels in tissue. The findings suggest that daidzein has anti-inflammatory and anti-apoptotic properties, potentially offering protection against IFO-induced neurotoxicity in rats.
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Affiliation(s)
- Hiba Zaki Hammoodi
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq
| | - Nada Naji Al-Shawi
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq
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14
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Mohamed EE, Ahmed OM, Zoheir KMA, El-Shahawy AAG, Tamur S, Shams A, Burcher JT, Bishayee A, Abdel-Moneim A. Naringin-Dextrin Nanocomposite Abates Diethylnitrosamine/Acetylaminofluorene-Induced Lung Carcinogenesis by Modulating Oxidative Stress, Inflammation, Apoptosis, and Cell Proliferation. Cancers (Basel) 2023; 15:5102. [PMID: 37894468 PMCID: PMC10605195 DOI: 10.3390/cancers15205102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 09/29/2023] [Accepted: 10/19/2023] [Indexed: 10/29/2023] Open
Abstract
Nanotechnology has proven advantageous in numerous scientific applications, one being to enhance the delivery of chemotherapeutic agents. This present study aims to evaluate the mechanisms underlying the chemopreventive action of naringin-dextrin nanocomposites (Nar-Dx-NCs) against diethylnitrosamine (DEN)/2-acetylaminofluorene (2AAF)-induced lung carcinogenesis in male Wistar rats. DEN was administered intraperitoneally (i.p.) (150 mg/kg/week) for two weeks, followed by the oral administration of 2AAF (20 mg/kg) four times a week for three weeks. Rats receiving DEN/2AAF were concurrently treated with naringin or Nar-Dx-NCs orally at a dose of 10 mg/kg every other day for 24 weeks. Naringin and Nar-Dx-NCs treatments prevented the formation of tumorigenic cells within the alveoli of rats exposed to DEN/2AAF. These findings were associated with a significant decrease in lipid peroxidation, upregulation of antioxidant enzyme (glutathione peroxidase and superoxide dismutase) activity, and enhanced glutathione and nuclear factor erythroid 2-related factor 2 expression in the lungs. Naringin and Nar-Dx-NCs exerted anti-inflammatory actions manifested by a decrease in lung protein expression of tumor necrosis factor-α and interleukin-1β and mRNA expression of interleukin-6, interferon-γ, nuclear factor-κB, and inducible nitric oxide synthase, with a concurrent increase in interleukin-10 expression. The anti-inflammatory effect of Nar-Dx-NCs was more potent than naringin. Regarding the effect on apoptosis, both naringin and Nar-Dx-NCs significantly reduced Bcl-2 and increased Bax and P53 expressions. Moreover, naringin or Nar-Dx-NCs induced a significant decrease in the expression of the proliferator marker, Ki-67, and the effect of Nar-Dx-NCs was more marked. In conclusion, Nar-Dx-NCs improved naringin's preventive action against DEN/2AAF-induced lung cancer and exerted anticarcinogenic effects by suppressing oxidative stress and inflammation and improving apoptotic signal induction and propagation.
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Affiliation(s)
- Eman E. Mohamed
- Physiology Division, Faculty of Science, Beni-Suef University, Beni-Suef 62521, Egypt; (E.E.M.)
| | - Osama M. Ahmed
- Physiology Division, Faculty of Science, Beni-Suef University, Beni-Suef 62521, Egypt; (E.E.M.)
| | - Khairy M. A. Zoheir
- Cell Biology Department, Biotechnology Research Institute, National Research Centre, Cairo 12622, Egypt;
| | - Ahmed A. G. El-Shahawy
- Materials Science and Nanotechnology Department, Faculty of Postgraduate Studies for Advanced Sciences, Beni-Suef University, Beni-Suef 62521, Egypt;
| | - Shadi Tamur
- Departement of Pediatrics, College of Medicine, Taif University, Taif 21944, Saudi Arabia;
| | - Anwar Shams
- Departement of Pharmacology, College of Medicine, Taif University, Taif 21944, Saudi Arabia
- Centre of Biomedical Sciences Research, Deanship of Scientific Research, Taif University, Taif 21974, Saudi Arabia
- High Altitude Research Center, Taif University, Taif 21944, Saudi Arabia
| | - Jack T. Burcher
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA; (J.T.B.); or (A.B.)
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA; (J.T.B.); or (A.B.)
| | - Adel Abdel-Moneim
- Physiology Division, Faculty of Science, Beni-Suef University, Beni-Suef 62521, Egypt; (E.E.M.)
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15
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He S, Xia J, Jia H, Dai Q, Chen C, Zhou Y, Wang XB. Peficitinib ameliorates 5-fluorouracil-induced intestinal damage by inhibiting aging, inflammatory factors and oxidative stress. Int Immunopharmacol 2023; 123:110753. [PMID: 37572505 DOI: 10.1016/j.intimp.2023.110753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 07/30/2023] [Accepted: 07/31/2023] [Indexed: 08/14/2023]
Abstract
5-Fluorouracil (5-FU) is a conventional and effective drug for colorectal cancer patients, and it is an important part of combined chemotherapy and adjuvant chemotherapy. Chemotherapy intestinal mucositis (CIM) is a severe side effect caused by 5-FU that, induces cancer treatment failure and affects patients' quality of life. The mechanism of 5-FU-induced CIM is related to normal cell senescence induced by 5-FU. Peficitinib, a Janus Kinase (JAK) inhibitor, treats inflammatory disorders, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. However, the therapeutic role and underlying mechanism of peficitinib in CIM remain unclear. The main objective of our research was to investigate the effects of peficitinib on 5-FU-induced senescence and intestinal damage in human umbilical vein endothelial (HUVEC) cells, human intestinal epithelial (HIEC) cells and BABL/C mice. The results showed that 5-FU caused intestinal damage by inducing aging and increasing inflammation and oxidative stress. Peficitinib alleviated aging by reducing senescence-beta-galactosidase (SA-β-gal) activity and the protein levels of aging indicators (p53, p21, p16). Moreover, peficitinib reversed the changes in senescence-associated secretory phenotype (SASP) expression caused by 5-FU. Besides, 5-FU induced release of inflammatory factors and oxidative stress indicators was reversed by peficitinib. Additionally, the combination of peficitinib and 5-FU reinforced the anticancer curative intent of 5-FU in two colorectal cancer cell lines (HCT116 cells and SW620 cells). In conclusion, peficitinib alleviates mucositis by alleviating aging, reducing inflammatory accumulation and oxidative stress and enhancing the antitumor activity of 5-FU.
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Affiliation(s)
- Siyue He
- School of Basic Medicine, Dali University, Dali, Yunnan Province 671000, China; Key Laboratory of University Cell Biology Yunnan Province, Dali, Yunnan Province 671000, China
| | - Jing Xia
- School of Basic Medicine, Dali University, Dali, Yunnan Province 671000, China; Key Laboratory of University Cell Biology Yunnan Province, Dali, Yunnan Province 671000, China
| | - Huijie Jia
- School of Basic Medicine, Dali University, Dali, Yunnan Province 671000, China; Key Laboratory of University Cell Biology Yunnan Province, Dali, Yunnan Province 671000, China
| | - Qianlong Dai
- School of Basic Medicine, Dali University, Dali, Yunnan Province 671000, China; Key Laboratory of University Cell Biology Yunnan Province, Dali, Yunnan Province 671000, China
| | - Cui Chen
- School of Basic Medicine, Dali University, Dali, Yunnan Province 671000, China; Qujing Medical College, Qujing, Yunnan Province 655011, China
| | - Yue Zhou
- School of Basic Medicine, Dali University, Dali, Yunnan Province 671000, China.
| | - Xiao Bo Wang
- School of Basic Medicine, Dali University, Dali, Yunnan Province 671000, China; Key Laboratory of University Cell Biology Yunnan Province, Dali, Yunnan Province 671000, China.
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16
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Akram MW, Mazhar D, Afzal I, Zeb A, Ain QU, Khan S, Ali H. Design and Evaluation of Continentalic Acid Encapsulated Transfersomal Gel and Profiling of its Anti-arthritis Activity. AAPS PharmSciTech 2023; 24:192. [PMID: 37726536 DOI: 10.1208/s12249-023-02648-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 08/29/2023] [Indexed: 09/21/2023] Open
Abstract
Rheumatoid arthritis restricts the physical ability of patients and increases the disease burden; therefore, research has always been focused on evaluating better therapeutic options. The present research aimed to design Continentalic acid (CA)-loaded transfersomes (CA-TF) embedded in Carbopol gel containing permeation enhancer (PE) for the treatment of rheumatoid arthritis. CA-TF was developed via a modified thin film hydration method and incorporated into Carbopol 934 gel containing Eucalyptus oil (EO) as PE. The fabricated CA-TF showed particle size of < 140 nm with spherical geometry, optimal encapsulation efficiency (EE), and sustained drug release pattern. CA-TF-gel along with PE (CA-TF-PE-gel) showed better ex vivo skin penetration than plain CA gel and CA-TF-gel without PE. In vivo evaluation supported improved therapeutic outcomes of CA-TF-PE-gel in terms of behavioral findings, arthritic index, and histological findings whereas biochemical assays and pro-inflammatory cytokines (TNF-α and IL-1β) showed a significant decrease in their levels. Furthermore, immunohistochemistry assay for Nrf2 and HO-1 signaling pathways showed significant improvement in the expression of the Nrf2, and HO-1 proteins to depict improvement in arthritic condition in the animal model. CA-TF-PE-gel significantly delivered CA to the diseased target site via a topical route with promising therapeutic outcomes displayed in the CFA-induced arthritic model.
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Affiliation(s)
| | - Danish Mazhar
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Iqra Afzal
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Ahmad Zeb
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Qurat Ul Ain
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Salman Khan
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Hussain Ali
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan.
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17
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Tambe PK, Qsee HS, Bharati S. Mito-TEMPO mitigates 5-fluorouracil-induced intestinal injury via attenuating mitochondrial oxidative stress, inflammation, and apoptosis: an in vivo study. Inflammopharmacology 2023:10.1007/s10787-023-01261-6. [PMID: 37338659 DOI: 10.1007/s10787-023-01261-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 05/31/2023] [Indexed: 06/21/2023]
Abstract
BACKGROUND Recent evidences highlight role of mitochondria in the development of 5-fluorouracil (5-FU)-induced intestinal toxicity. Mitochondria-targeted antioxidants are well-known for their protective effects in mitochondrial oxidative stress- mediated diseases. In the present study, we investigated protective effect of Mito-TEMPO in 5-FU-induced intestinal toxicity. METHODS Mito-TEMPO (0.1 mg/kg b.w.) was administered intraperitoneally to male BALB/c mice for 7 days, followed by co-administration of 5-FU for next 4 days (intraperitoneal 12 mg/kg b.w.). Protective effect of Mito-TEMPO on intestinal toxicity was assessed in terms of histopathological alterations, modulation in inflammatory markers, apoptotic cell death, expression of 8-OhDG, mitochondrial functional status and oxidative stress. RESULTS 5-FU administered animals showed altered intestinal histoarchitecture wherein a shortening and atrophy of the villi was observed. The crypts were disorganized and inflammatory cell infiltration was noted. Mito-TEMPO pre-protected animals demonstrated improved histoarchitecture with normalization of villus height, better organized crypts and reduced inflammatory cell infiltration. The inflammatory markers and myeloperoxidase activity were normalized in mito-TEMPO protected group. A significant reduction in intestinal apoptotic cell death and expression of 8-OhDG was also observed in mito-TEMPO group as compared to 5-FU group. Further, mtROS, mtLPO and mitochondrial antioxidant defense status were improved by mito-TEMPO. CONCLUSION Mito-TEMPO exerted significant protective effect against 5-FU-induced intestinal toxicity. Therefore, it may be used as an adjuvant in 5-FU chemotherapy.
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Affiliation(s)
- Prasad Kisan Tambe
- Department of Nuclear Medicine, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - H S Qsee
- Department of Nuclear Medicine, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Sanjay Bharati
- Department of Nuclear Medicine, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India.
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Luisa Valerio de Mello Braga L, Simão G, Silva Schiebel C, Caroline Dos Santos Maia A, Mulinari Turin de Oliveira N, Barbosa da Luz B, Rita Corso C, Soares Fernandes E, Maria Ferreira D. Rodent models for anticancer toxicity studies: contributions to drug development and future perspectives. Drug Discov Today 2023:103626. [PMID: 37224998 DOI: 10.1016/j.drudis.2023.103626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 05/08/2023] [Accepted: 05/17/2023] [Indexed: 05/26/2023]
Abstract
Antineoplastic treatment induces a type of gastrointestinal toxicity known as mucositis. Findings in animal models are usually easily reproducible, and standardized treatment regimens are often used, thus supporting translational science. Essential characteristics of mucositis, including intestinal permeability, inflammation, immune and oxidative responses, and tissue repair mechanisms, can be easily investigated in these models. Given the effects of mucositis on the quality of life of patients with cancer, and the importance of experimental models in the development of more effective new therapeutic alternatives, this review discusses progress and current challenges in using experimental models of mucositis in translational pharmacology research. Teaser Experimental models for studying gastrointestinal mucositis have provided a wealth of information improving the understanding of antineoplastic toxicity.
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Affiliation(s)
- Lara Luisa Valerio de Mello Braga
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Gisele Simão
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Carolina Silva Schiebel
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Andressa Caroline Dos Santos Maia
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Natalia Mulinari Turin de Oliveira
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Bruna Barbosa da Luz
- Departamento de Farmacologia, Universidade Federal do Paraná, Curitiba, PR, Brazil
| | - Claudia Rita Corso
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Elizabeth Soares Fernandes
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Daniele Maria Ferreira
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil.
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19
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Jiang H, Zuo J, Li B, Chen R, Luo K, Xiang X, Lu S, Huang C, Liu L, Tang J, Gao F. Drug-induced oxidative stress in cancer treatments: Angel or devil? Redox Biol 2023; 63:102754. [PMID: 37224697 DOI: 10.1016/j.redox.2023.102754] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/03/2023] [Accepted: 05/17/2023] [Indexed: 05/26/2023] Open
Abstract
Oxidative stress (OS), defined as redox imbalance in favor of oxidant burden, is one of the most significant biological events in cancer progression. Cancer cells generally represent a higher oxidant level, which suggests a dual therapeutic strategy by regulating redox status (i.e., pro-oxidant therapy and/or antioxidant therapy). Indeed, pro-oxidant therapy exhibits a great anti-cancer capability, attributing to a higher oxidant accumulation within cancer cells, whereas antioxidant therapy to restore redox homeostasis has been claimed to fail in several clinical practices. Targeting the redox vulnerability of cancer cells by pro-oxidants capable of generating excessive reactive oxygen species (ROS) has surfaced as an important anti-cancer strategy. However, multiple adverse effects caused by the indiscriminate attacks of uncontrolled drug-induced OS on normal tissues and the drug-tolerant capacity of some certain cancer cells greatly limit their further applications. Herein, we review several representative oxidative anti-cancer drugs and summarize their side effects on normal tissues and organs, emphasizing that seeking a balance between pro-oxidant therapy and oxidative damage is of great value in exploiting next-generation OS-based anti-cancer chemotherapeutics.
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Affiliation(s)
- Hao Jiang
- The First Hospital of Ningbo University, Ningbo, 315020, China
| | - Jing Zuo
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bowen Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Rui Chen
- The First Hospital of Ningbo University, Ningbo, 315020, China
| | - Kangjia Luo
- The First Hospital of Ningbo University, Ningbo, 315020, China
| | - Xionghua Xiang
- The First Hospital of Ningbo University, Ningbo, 315020, China
| | - Shuaijun Lu
- The First Hospital of Ningbo University, Ningbo, 315020, China
| | - Canhua Huang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lin Liu
- Ningbo Women & Children's Hospital, Ningbo, 315012, China.
| | - Jing Tang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China.
| | - Feng Gao
- The First Hospital of Ningbo University, Ningbo, 315020, China.
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20
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Zafar S, Luo Y, Zhang L, Li CH, Khan A, Khan MI, Shah K, Seo EK, Wang F, Khan S. Daidzein attenuated paclitaxel-induced neuropathic pain via the down-regulation of TRPV1/P2Y and up-regulation of Nrf2/HO-1 signaling. Inflammopharmacology 2023:10.1007/s10787-023-01225-w. [PMID: 37145202 DOI: 10.1007/s10787-023-01225-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 03/27/2023] [Indexed: 05/06/2023]
Abstract
Paclitaxel (PTX) is an anti-microtubule agent, used for the treatment of various types of cancers; however, it produces painful neuropathy which limits its use. Many neuroprotective agents have been introduced to mitigate PTX-induced neuropathic pain (PINP), but they pose many adverse effects. The purpose of this study was to evaluate the pharmacological characteristics of soy isoflavone, and daidzein (DZ) in attenuating PINP. At the beginning of the investigation, the effect of DZ was confirmed through behavioral analysis, as it reduced pain hypersensitivity. Moreover, changes in the histological parameters were reversed by DZ administration along with vascular permeability. PTX administration upregulated transient receptor potential vanilloid 1 (TRPV1) channels and purinergic receptors (P2Y), contributing to hyperalgesia; but administration of DZ downregulated the TRPV1 and P2Y, thus reducing hyperalgesia. DZ increased nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), playing a pivotal role in the activation of the antioxidant pathway. DZ also decreased neuronal apoptosis by decreasing caspase-3 and Bcl2-associated X-protein (Bax), while simultaneously, increasing Bcl-2. PTX administration produced severe DNA damage, which was mitigated by DZ. Similarly, DZ administration resulted in inhibition of neuroinflammation by increasing antioxidant enzymes and reducing oxidative stress markers. PTX caused increased in production of pro-inflammatory mediators such as the cytokines production, while DZ inhibited the pro-inflammatory mediators. Additionally, in silico pharmacokinetic and toxicodynamic study of DZ was also conducted. In summary, DZ demonstrated significant neuroprotective activity against PTX induced neuropathic pain.
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Affiliation(s)
- Sana Zafar
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Yong Luo
- Department of Head and Neck Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Li Zhang
- Department of Medical Oncology, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan, People's Republic of China
| | - Chang Hu Li
- Division of Radiation Physics, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Adnan Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
- DHQ Teaching Hospital Timergara, Lower Dir, Timergara, KPK, Pakistan
| | - Muhammad Ibrar Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Kifayatullah Shah
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Eun Kyoung Seo
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, South Korea
| | - Feng Wang
- Department of Medical Oncology, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan, People's Republic of China.
| | - Salman Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
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21
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Khan A, Shal B, Ullah Khan A, Ullah Shah K, Saniya Zahra S, ul Haq I, ud Din F, Ali H, Khan S. Neuroprotective mechanism of Ajugarin-I against Vincristine-Induced neuropathic pain via regulation of Nrf2/NF-κB and Bcl2 signalling. Int Immunopharmacol 2023; 118:110046. [PMID: 36989890 DOI: 10.1016/j.intimp.2023.110046] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 02/13/2023] [Accepted: 03/13/2023] [Indexed: 03/29/2023]
Abstract
Vincristine (VCR) is a well-known chemotherapeutic agent that frequently triggers neuropathic pain. Ajugarin-I (Aju-I) isolated from Ajuga bracteosa exerts antioxidant, anti-inflammatory, and neuroprotective properties. The present study was designed to investigate the ameliorative potential of Aju-I against VCR-induced neuropathic pain and explored the underlying mechanism involved. The neuroprotective potential of Aju-I was first confirmed against hydrogen peroxide (H2O2)-induced cytotoxicity and oxidative stress in PC12 cells. For neuropathic pain induction, vincristine was given intraperitoneally (i.p.) into adult male albino mice (BALB/c) of the same age (8-12 weeks old) for 10 days (days 1-10). Aju-I (1 and 5 mg/kg) doses were administered from day 11 to 21 intraperitoneally (i.p.) after the neuropathic induction. Initially, behavioral tests such as thermal hyperalgesia, mechanical allodynia, and cold allodynia were performed to investigate the antinociceptive potential of Ajugarin-I (1 and 5 mg/kg, b.w). The nuclear factor-erythroid factor 2-related factor 2(Nrf2), nuclear factor-κB (NF-κB), BCL2-associated × protein (Bax), and B-cell-lymphoma-2 (Bcl-2) signaling proteins were determined by immunohistochemistry and western blot. Additionally, inflammatory cytokines, antioxidant, and oxidative stress parameters were also measured in the spinal cord and sciatic nerve. The behavioral results demonstrated that Aju-I (5 mg/kg) markedly alleviated VCR-induced neuropathic pain behaviors including hyperalgesia and allodynia. It reversed the histological alterations caused by VCR in the sciatic nerve, spinal cord, and brain. It significantly alleviated oxidative stress and inflammation by regulating the immunoreactivity of Nrf2/NF-κB signaling. It suppressed apoptosis by regulating the immunoreactivity of Bcl-2/Bax and Caspase-3. The flow cytometry and comet analysis also confirmed its anti-apoptotic potential. It considerably improved the antioxidant status and mitigated VCR-induced inflammatory cytokines. High-performance liquid chromatography (HPLC) analysis indicated that Aju-I crosses the blood-brain barrier (BBB) and penetrated the brain tissue. These findings suggest that Aju-I treatment inhibited vincristine-induced neuropathy via regulation of Nrf2/NF-κB and Bcl2 signaling.
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22
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AL-hoshary DM, Zalzala MH. Mucoprotective effect of ellagic acid in 5 fluorouracil-induced intestinal mucositis model. J Med Life 2023; 16:712-718. [PMID: 37520490 PMCID: PMC10375349 DOI: 10.25122/jml-2023-0052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 03/23/2023] [Indexed: 08/01/2023] Open
Abstract
Intestinal mucositis (IM) is a common side effect of several anticancer medications, including 5-fluorouracil (5-FU), and can lead to treatment disruptions and compromised outcomes. IM has severe clinical effects such as diarrhea, erythematous mucosal lesions, and the development of ulcers accompanied by excruciating pain. This study aimed to evaluate the mucoprotective effects of ellagic acid on 5-FU-induced IM in mice. Mice were administered normal saline intraperitoneally for six days, followed by intraperitoneal injection of 5-FU for four days at a dose of 50 mg per kilogram. Ellagic acid was orally administered to the mice in groups III and IV in two doses (5 mg and 10 mg), with a one-hour time separation from 5-FU for ten days. At the end of the experiment, small intestine tissue was collected to measure the levels of antioxidant enzymes superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and inflammatory cytokines (IL-6, IL-B, TNF) using ELISA assay. Pre-treatment with ellagic acid led to a significant decrease in pro-inflammatory cytokines and improved antioxidant enzyme levels compared to the 5-FU group. Histopathological analysis demonstrated the mucoprotective effect of ellagic acid against 5-FU-induced intestinal changes, including villi atrophy, damage to stem cells, infiltration of inflammatory cells in the mucosal layer, edema, damage to muscular mucosa, and decreased oxidative stress production, such as MDA. These results suggest that ellagic acid may be a potential candidate for treating IM induced by antineoplastic drugs.
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Affiliation(s)
- Dareen Mahmood AL-hoshary
- Al-Kut Hospital for Gynecology Obstetrics and Pediatrics, Ministry of Health, Baghdad, Iraq
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq
| | - Munaf Hashim Zalzala
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq
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23
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Gui Y, Famurewa AC, Olatunji OJ. Naringin ameliorates 5-fluorouracil induced cardiotoxicity: An insight into its modulatory impact on oxidative stress, inflammatory and apoptotic parameters. Tissue Cell 2023; 81:102035. [PMID: 36753813 DOI: 10.1016/j.tice.2023.102035] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 02/03/2023] [Accepted: 02/03/2023] [Indexed: 02/07/2023]
Abstract
5-fluorouracil (5-FU) is an efficacious fluoropyrimidine antimetabolite anticancer drug, however, its clinical utility is constrained due to side effect toxicity on delicate organs, including the heart. This study thus aimed at exploring the cardioprotective potentials of naringin (NRG) against 5-FU-induced cardiotoxicity in rats. We divided Wistar rats into four experimental groups (n = 6) for the administration of NRG (100 mg/kg bw, orally) and/or 5-FU (150 mg/kg bw, intraperitoneal). NRG was administered for 10 days, while 5-FU was injected on the 8th day only. Serum troponin-I (cTn-I) and creatine kinase (CK) were estimated. Cardiac activities/level of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), reduced glutathione (GSH), malondialdehyde (MDA), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) and nuclear factor-ĸB (NF-κB) and caspase-3 were determined. 5-FU markedly increased cTn-I, CK, cardiac inflammatory mediators and caspase-3 expressions, whereas antioxidant mediators decreased appreciably when compared to the control groups. Interestingly, the prophylactic administration of NRG prominently inhibited the 5-FU-provoked oxidative stress, pro-inflammation and apoptosis in the heart of rats. Histopathology confirmed the biochemical results of the heart. Therefore, NRG is a potential natural flavonoid for mitigation of 5-FU cardiotoxicity in rats.
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Affiliation(s)
- Yang Gui
- Department of General Surgery, The Second Peoples Hospital of Wuhu, Wuhu 241001, Anhui, China
| | - Ademola C Famurewa
- Department of Medical Biochemistry, Faculty of Basic Medical Sciences, College of Medical Sciences, Alex-Ekwueme Federal University, Ndufu-Alike, Ikwo, Ebonyi, Nigeria; Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal University, Karnataka State, India
| | - Opeyemi Joshua Olatunji
- Traditional Thai Medical Research and Innovation Center, Faculty of Traditional Thai Medicine, Prince of Songkla University, Hat Yai 90110, Thailand; African Genome Center, Mohammed VI Polytechnic University, Ben Guerir 43150, Morocco.
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24
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Khan A, Shal B, Khan AU, Bibi T, Zeeshan S, Zahra SS, Crews P, Haq IU, Din FU, Ali H, Khan S. Suppression of MAPK/NF-kB and activation of Nrf2 signaling by Ajugarin-I in EAE model of multiple sclerosis. Phytother Res 2023. [PMID: 36789832 DOI: 10.1002/ptr.7751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 12/13/2022] [Accepted: 01/21/2023] [Indexed: 02/16/2023]
Abstract
Multiple sclerosis (MS) is a debilitating neurodegenerative autoimmune disease of the central nervous system (CNS). The current study aimed to investigate the neuroprotective properties of Ajugarin-I (Aju-I) against the experimental autoimmune encephalomyelitis (EAE) model of MS and explored the underlying mechanism involved. The protective potential of Aju-I was first confirmed against glutamate-induced HT22 cells and hydrogen peroxide (H2 O2 )-induced BV2 cells. Next, an EAE model has been established to investigate the mechanisms of MS and identify potential candidates for MS treatment. The behavioral results demonstrated that Aju-I post-immunization treatment markedly reduced the EAE-associated clinical score, motor impairment, and neuropathic pain. Evans blue and fluorescein isothiocyanate extravasation in the brain were markedly reduced by Aju-I. It effectively restored the EAE-associated histopathological changes in the brain and spinal cord. It markedly attenuated EAE-induced inflammation in the CNS by reducing the expression levels of p-38/JNK/NF-κB but increased the expression of IkB-α. It suppressed oxidative stress by increasing the expression of Nrf2 but decreasing the expression of keap-1. It suppressed EAE-induced apoptosis in the CNS by regulating Bax/Bcl-2 and Caspase-3 expression. Taken together, this study suggests that Aju-I treatment exhibits neuroprotective properties in the EAE model of MS via regulation of MAPK/NF-κB, Nrf2/Keap-1, and Bcl2/Bax signaling.
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Affiliation(s)
- Adnan Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,DHQ Teaching Hospital Timergara, Lower Dir, Timergara, Pakistan
| | - Bushra Shal
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Department of Pharmaceutical Sciences, Pak-Austria Fachhochschule Institute of Applied Sciences and Technology, Haripur, Pakistan
| | - Ashraf Ullah Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Faculty of Pharmaceutical Sciences, Abasyn University, Peshawar, Pakistan
| | - Tehmina Bibi
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Sara Zeeshan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Syeda Saniya Zahra
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Phillip Crews
- Division of Physical Sciences, Department of Chemistry and Biochemistry, University of California, Santa Cruz, California, USA
| | - Ihsan Ul Haq
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Fakhar Ud Din
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Hussain Ali
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Salman Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
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25
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Singh S, Grewal S, Sharma N, Behl T, Gupta S, Anwer MK, Vargas-De-La-Cruz C, Mohan S, Bungau SG, Bumbu A. Unveiling the Pharmacological and Nanotechnological Facets of Daidzein: Present State-of-the-Art and Future Perspectives. Molecules 2023; 28:1765. [PMID: 36838751 PMCID: PMC9958968 DOI: 10.3390/molecules28041765] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/02/2023] [Accepted: 02/10/2023] [Indexed: 02/17/2023] Open
Abstract
Herbal drugs have been attracting much scientific interest in the last few decades and nowadays, phytoconstituents-based research is in progress to disclose their unidentified medicinal potential. Daidzein (DAI) is the natural phytoestrogen isoflavone derived primarily from leguminous plants, such as the soybean and mung bean, and its IUPAC name is 4',7-dihydroxyisoflavone. This compound has received great attention as a fascinating pharmacophore with remarkable potential for the therapeutic management of several diseases. Certain pharmacokinetic properties of DAI such as less aqueous solubility, low permeability, and poor bioavailability are major obstacles restricting the therapeutic applications. In this review, distinctive physicochemical characteristics and pharmacokinetics of DAI has been elucidated. The pharmacological applications in treatment of several disorders like oxidative stress, cancer, obesity, cardiovascular, neuroprotective, diabetes, ovariectomy, anxiety, and inflammation with their mechanism of action are explained. Furthermore, this review article comprehensively focuses to provide up-to-date information about nanotechnology-based formulations which have been investigated for DAI in preceding years which includes polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carrier, polymer-lipid nanoparticles, nanocomplexes, polymeric micelles, nanoemulsion, nanosuspension, liposomes, and self-microemulsifying drug delivery systems.
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Affiliation(s)
- Sukhbir Singh
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to Be University), Ambala 133207, India
| | - Sonam Grewal
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to Be University), Ambala 133207, India
| | - Neelam Sharma
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to Be University), Ambala 133207, India
| | - Tapan Behl
- School of Health Sciences & Technology, University of Petroleum and Energy Studies, Bidholi, Dehradun 248007, India
| | - Sumeet Gupta
- Department of Pharmacology, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to Be University), Ambala 133207, India
| | - Md. Khalid Anwer
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia
| | - Celia Vargas-De-La-Cruz
- Department of Pharmacology, Bromatology and Toxicology, Faculty of Pharmacy and Biochemistry, Universidad Nacional Mayor de San Marcos, Lima 15081, Peru
- E-Health Research Center, Universidad de Ciencias y Humanidades, Lima 15081, Peru
| | - Syam Mohan
- School of Health Sciences & Technology, University of Petroleum and Energy Studies, Bidholi, Dehradun 248007, India
- Substance Abuse and Toxicology Research Centre, Jazan University, Jazan 45142, Saudi Arabia
- Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai 602117, India
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
| | - Adrian Bumbu
- Department of Surgery, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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26
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Lokman MS, Althagafi HA, Alharthi F, Habotta OA, Hassan AA, Elhefny MA, Al Sberi H, Theyab A, Mufti AH, Alhazmi A, Hawsawi YM, Khafaga AF, Gewaily MS, Alsharif KF, Albrakati A, Kassab RB. Protective effect of quercetin against 5-fluorouracil-induced cardiac impairments through activating Nrf2 and inhibiting NF-κB and caspase-3 activities. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:17657-17669. [PMID: 36197616 DOI: 10.1007/s11356-022-23314-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 09/24/2022] [Indexed: 06/16/2023]
Abstract
5-Fluorouracil (5-FU) is a chemotherapy used to treat many types of cancer. Cardiotoxicity is one of the common drawbacks of 5-FU therapy. Quercetin (Qu) is a bioflavonoid with striking biological activities. This research aimed to assess the ameliorative effect of Qu against 5-FU-mediated cardiotoxicity. Thirty-five rats were allocated into five groups: control group (normal saline), 5-FU group (30 mg/kg, intraperitoneally), Qu group (50 mg/kg, oral), 25 mg/kg Qu+5-FU group, and 50 mg/kg Qu+5-FU. The experimental animals were received the above-mentioned drugs for 21 days. Results showed that 5-FU significantly elevated creatine kinase, lactate dehydrogenase, serum cholesterol and triglyceride, and upregulated troponin and renin mRNA expression. Additionally, cardiac oxidant/antioxidant imbalance was evident in elevated oxidants (malondialdehyde and nitric oxide) and depleted antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione). 5-FU also downregulated the gene expression of nuclear factor erythroid 2-related factor 2. Furthermore, 5-FU significantly increased cardiac pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta) and upregulated gene expression of nuclear factor kappa-B. 5-FU significantly enhanced cardiac apoptosis through upregulating caspase-3 expression and downregulating B-cell lymphoma 2. Immunohistochemical and histopathological examinations verified the above-mentioned findings. However, all these changes were significantly ameliorated in Qu pre-administered rats. Conclusively, Qu counteracted 5-FU-mediated cardiotoxicity through potent antioxidant, anti-inflammatory, and anti-apoptotic effects.
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Affiliation(s)
- Maha S Lokman
- Department of Biology, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-kharj, 11942, Saudi Arabia.
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, 11795, Egypt.
| | - Hussam A Althagafi
- Department of Biology, Faculty of Science and Arts, Al-Baha University, Almakhwah, Al-Baha, Saudi Arabia
| | - Fahad Alharthi
- Department of Biology, College of Science, Taif University, Taif, Saudi Arabia
| | - Ola A Habotta
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Arwa A Hassan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy and Pharmaceutical Industries, Sinai University, El Arish, Egypt
| | - Mohamed A Elhefny
- Department of Cancer and Molecular Biology, National Cancer Institute, Cairo University, Cairo, Egypt
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Alqunfudah, Saudi Arabia
| | - Hassan Al Sberi
- Basic Medical Science, Histopathology Department, National Organization for Drug Control and Research, Giza, Egypt
- Department of Biology, Faculty of Science, Taif University, Taif, Saudi Arabia
| | - Abdulrahman Theyab
- Department of Laboratory & Blood Bank, Security Forces Hospital, P.O. Box 14799, Mecca, 21955, Saudi Arabia
- College of Medicine, Al-Faisal University, P.O. Box 50927, Riyadh, 11533, Saudi Arabia
| | - Ahmad Hasan Mufti
- Medical Genetics Department, Faculty of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia
| | - Alaa Alhazmi
- Medical Laboratory Technology Department, Jazan University, Jazan, Saudi Arabia
- SMIRES for Consultation in Specialized Medical Laboratories, Jazan University, Jazan, Saudi Arabia
| | - Yousef M Hawsawi
- Research Center, King Faisal Specialist Hospital and Research Center, MBC-J04, PO Box 40047, Jeddah, 21499, Saudi Arabia
| | - Asmaa F Khafaga
- Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Edfina, 22758, Egypt
| | - Mahmoud S Gewaily
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt
| | - Khalaf F Alsharif
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, PO Box 11099, Taif, 21944, Saudi Arabia
| | - Ashraf Albrakati
- Department of Human Anatomy, College of Medicine, Taif University, PO Box 11099, Taif, 21944, Saudi Arabia
| | - Rami B Kassab
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, 11795, Egypt
- Department of Biology, Faculty of Science and Arts, Al-Baha University, Almakhwah, Al-Baha, Saudi Arabia
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Zheng X, Mai L, Xu Y, Wu M, Chen L, Chen B, Su Z, Chen J, Chen H, Lai Z, Xie Y. Brucea javanica oil alleviates intestinal mucosal injury induced by chemotherapeutic agent 5-fluorouracil in mice. Front Pharmacol 2023; 14:1136076. [PMID: 36895947 PMCID: PMC9990700 DOI: 10.3389/fphar.2023.1136076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 02/06/2023] [Indexed: 02/22/2023] Open
Abstract
Background: Brucea javanica (L.) Merr, has a long history to be an anti-dysentery medicine for thousand of years, which is commonly called "Ya-Dan-Zi" in Chinese. The common liquid preparation of its seed, B. javanica oil (BJO) exerts anti-inflammatory action in gastrointestinal diseases and is popularly used as an antitumor adjuvant in Asia. However, there is no report that BJO has the potential to treat 5-Fluorouracil (5-FU)-induced chemotherapeutic intestinal mucosal injury (CIM). Aim of the study: To test the hypothesis that BJO has potential intestinal protection on intestinal mucosal injury caused by 5-FU in mice and to explore the mechanisms. Materials and methods: Kunming mice (half male and female), were randomly divided into six groups: normal group, 5-FU group (5-FU, 60 mg/kg), LO group (loperamide, 4.0 mg/kg), BJO group (0.125, 0.25, 0.50 g/kg). CIM was induced by intraperitoneal injection of 5-FU at a dose of 60 mg/kg/day for 5 days (from day 1 to day 5). BJO and LO were given orally 30 min prior to 5-FU administration for 7 days (from day 1 to day 7). The ameliorative effects of BJO were assessed by body weight, diarrhea assessment, and H&E staining of the intestine. Furthermore, the changes in oxidative stress level, inflammatory level, intestinal epithelial cell apoptosis, and proliferation, as well as the amount of intestinal tight junction proteins were evaluated. Finally, the involvements of the Nrf2/HO-1 pathway were tested by western blot. Results: BJO effectively alleviated 5-FU-induced CIM, as represented by the improvement of body weight, diarrhea syndrome, and histopathological changes in the ileum. BJO not only attenuated oxidative stress by upregulating SOD and downregulating MDA in the serum, but also reduced the intestinal level of COX-2 and inflammatory cytokines, and repressed CXCL1/2 and NLRP3 inflammasome activation. Moreover, BJO ameliorated 5-FU-induced epithelial apoptosis as evidenced by the downregulation of Bax and caspase-3 and the upregulation of Bcl-2, but enhanced mucosal epithelial cell proliferation as implied by the increase of crypt-localized proliferating cell nuclear antigen (PCNA) level. Furthermore, BJO contributed to the mucosal barrier by raising the level of tight junction proteins (ZO-1, occludin, and claudin-1). Mechanistically, these anti-intestinal mucositis pharmacological effects of BJO were relevant for the activation of Nrf2/HO-1 in the intestinal tissues. Conclusion: The present study provides new insights into the protective effects of BJO against CIM and suggests that BJO deserves to be applied as a potential therapeutic agent for the prevention of CIM.
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Affiliation(s)
- Xinghan Zheng
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Pharmacy, Shenzhen University General Hospital/Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, Guangdong, China.,Pharmacy Department, Quanzhou Hospital of Traditional Chinese Medicine, Quanzhou, China
| | - Liting Mai
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Medical Insurance Office, Zhaoqing Hospital, Sun Yat-sen University, Zhaoqing, China.,Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, China
| | - Ying Xu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, China
| | - Minghui Wu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, China
| | - Li Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, China
| | - Baoyi Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, China
| | - Ziren Su
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, China
| | - Jiannan Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, China
| | - Hongying Chen
- Guangzhou Baiyunshan Mingxing Pharmaceutical Co. Ltd, Guangzhou, China
| | - Zhengquan Lai
- Department of Pharmacy, Shenzhen University General Hospital/Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, Guangdong, China
| | - Youliang Xie
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.,Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, China
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Shal B, Amanat S, Khan AU, Lee YJ, Ali H, Din FU, Park Y, Khan S. Potential applications of PEGylated green gold nanoparticles in cyclophosphamide-induced cystitis. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2022; 50:130-146. [PMID: 35620802 DOI: 10.1080/21691401.2022.2078340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
We investigated the effect of green tea extract PEGylated gold nanoparticles (P-AuNPs) making use of its targeted and sustained drug delivery against cyclophosphamide (CYP)-induced cystitis. AuNPs were synthesized by reduction reaction of gold salts with green tea extract following the concept of green synthesis. Mostly spherical-shaped P-AuNPs were synthesized with an average size of 14.3 ± 3.3 nm. Pre-treatment with P-AuNPs (1, 10 mg/kg, i.p.) before CYP (150 mg/kg, i.p.) challenge suggested its uroprotective properties. P-AuNPs significantly reversed all pain-like behaviours and toxicities produced by CYP resulting in a decreased aspartate aminotransferase, alanine aminotransferase, C-reactive protein, and creatinine level. P-AuNPs increased anti-oxidant system by increasing the level of reduced glutathione, glutathione-S-transferase, catalase and superoxide dismutase, and reduced nitric oxide production in bladder tissue. Additionally, it attenuated hypokalaemia and hyponatremia, along with a decrease in Evans blue content in bladder tissue and peritoneal cavity. CYP-induced bladder tissue damage observed by macroscopic and histological findings were remarkably attenuated by P-AuNPs, along with reduced fibrosis of collagen fibre in bladder smooth muscles shown by Masson's trichrome staining. Additionally, alterations in hematological parameters and clinical scoring were also prevented by P-AuNPs suggesting its uroprotective effect.
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Affiliation(s)
- Bushra Shal
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Faculty of Health Sciences, IQRA University, Islamabad Campus, (Chak Shahzad), Islamabad, Pakistan
| | - Safa Amanat
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Ashraf Ullah Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Department of Pharmacy, Abasyn University, Peshawar, Pakistan
| | - You Jeong Lee
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam, Republic of Korea
| | - Hussain Ali
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Fakhar Ud Din
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Youmie Park
- College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam, Republic of Korea
| | - Salman Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.,Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
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29
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Anti-nociceptive effects of magnolol via inhibition of TRPV1/P2Y and TLR4/NF-κB signaling in a postoperative pain model. Life Sci 2022; 312:121202. [PMID: 36414090 DOI: 10.1016/j.lfs.2022.121202] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 11/04/2022] [Accepted: 11/13/2022] [Indexed: 11/21/2022]
Abstract
AIMS The current study explored the anti-nociceptive activity of magnolol in post-incisional inflammatory nociceptive pain. MAIN METHODS Preliminary, the anti-inflammatory, antioxidant, and cytoprotective potential of magnolol were confirmed against hydrogen peroxide (H2O2)-induced PC12 cells. Next, an in-vivo model of planter incision surgery was established in BALB/c mice. Tramadol 50 mg/kg intraperitoneal (i.p.) and magnolol (0.1, 1, 10 mg/kg i.p. + 10 mg/kg intra planter) were administered after plantar incision surgery and behavior parameters were measured. KEY FINDINGS The results indicate that magnolol significantly suppressed post-incision-induced mechanical allodynia, thermal hyperalgesia, and paw edema. Magnolol promisingly inhibited post-incision induces nitric oxide (NO), malondialdehyde (MDA), eosinophil peroxidase (EPO), and neutrophil infiltration. Magnolol strongly attenuated post-incision inducing the release of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and inhibited deoxyribonucleic acid (DNA) fragmentation. Magnolol markedly reverses post-incisional histopathological changes and biochemical composition of the incised paw. Magnolol markedly down-regulated post-incisional increase expression of transient receptor potential vanilloid 1 (TRPV1), purinergic (P2Y) nociceptors as well as toll-like receptor 4 (TLR4), nuclear factor kappa light chain enhancer of activated B cell (NF-κB), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) while upregulating the expression of inhibitor of nuclear kappa B alpha (IκB-α). SIGNIFICANCE The present study strongly suggests that magnolol significantly suppressed post-incisional inflammatory nociceptive pain by targeting TRPV1/P2Y and TLR4/NF-κB signaling.
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Liao YF, Luo FL, Tang SS, Huang JW, Yang Y, Wang S, Jiang TY, Man Q, Liu S, Wu YY. Network analysis and experimental pharmacology study explore the protective effects of Isoliquiritigenin on 5-fluorouracil-Induced intestinal mucositis. Front Pharmacol 2022; 13:1014160. [PMID: 36278232 PMCID: PMC9582754 DOI: 10.3389/fphar.2022.1014160] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/20/2022] [Indexed: 11/21/2022] Open
Abstract
5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs for malignant tumors. However, intestinal mucositis caused by 5-FU is a severe dose-limiting toxic effect and even leads to treatment interruption. Isoliquiritigenin (ISL) is one of the main active compounds of licorice, which is a traditional Chinese herbal medicine commonly used in inflammation and gastrointestinal diseases. It is speculated that ISL have protective effects on intestinal mucositis. However, no such studies have been reported. Therefore, to investigate the impact of ISL on 5-Fu-induced intestinal mucositis, a strategy based on network prediction and pharmacological experimental validation was proposed in this study. Firstly, the targets and mechanism of ISL in alleviating 5-Fu-induced gastrointestinal toxicity were predicted by network analysis. And the results were further confirmed by molecular docking. Then, a mouse model of intestinal mucositis was established by intraperitoneal injection of 5-FU (384 μmol/kg) to verify the prediction of network analysis. The network analysis results suggested that PTGS2 (Prostaglandin G/H synthase 2) and NOS2 (Nitric oxide synthase, inducible) might be the critical targets of ISL for reducing the intestinal toxicity of 5-FU. In addition, KEGG and GO enrichment analysis revealed that the HIF-1, TNF, MAPK, IL-17, PI3K-Akt, Ras, NF-kappa B signaling pathway, and biological processes of the inflammatory response, apoptosis regulation, NO production and NF-kappa B transcription factor activity might be involved in the mechanism of ISL against intestinal mucositis. Subsequent animal experiments showed that ISL could reduce the weight loss, leukopenia and mucosal damage caused by 5-FU. Compared with the intestinal mucositis model, the protein expressions of PTGS2, NOS2, TNFα (Tumor necrosis factor-alpha) and NF-κB p65 (nuclear factor kappa-B P65) were decreased after ISL treatment. In conclusion, this study is the fist time to find that ISL can attenuate 5-FU-induced intestinal mucositis in mice. Its anti-mucositis effect may be through regulating TNF/NF-κB pathway and inhibiting inflammatory mediators PTGS2 and NOS2. It will provide a potential candidate for the prevention and treatment of chemotherapy-induced intestinal mucositis.
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Affiliation(s)
- Yi-fan Liao
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Feng-lin Luo
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Shan-shan Tang
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Jing-wei Huang
- Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Sichuan Engineering & Technology Research Center of Coarse Cereal Industralization, Chengdu University, Chengdu, Sichuan, China
| | - Ying Yang
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Shuang Wang
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Tang-yu Jiang
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Qiong Man
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
- *Correspondence: Yi-ying Wu, ; Qiong Man, ; Sha Liu,
| | - Sha Liu
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
- *Correspondence: Yi-ying Wu, ; Qiong Man, ; Sha Liu,
| | - Yi-ying Wu
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
- *Correspondence: Yi-ying Wu, ; Qiong Man, ; Sha Liu,
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Malik S, Miana G, Ata A, Kanwal M, Maqsood S, Malik I, Kazmi Z. SYNTHESIS, CHARACTERIZATION, IN-SILICO, AND PHARMACOLOGICAL EVALUATION OF NEW 2-AMINO-6-TRIFLUOROMETHOXY BENZOTHIAZOLE DERIVATIVES. Bioorg Chem 2022; 130:106175. [PMID: 36410112 DOI: 10.1016/j.bioorg.2022.106175] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 09/18/2022] [Accepted: 09/21/2022] [Indexed: 11/28/2022]
Abstract
Alzheimer's disease (AD), a relentless neurodegenerative disorder, is still waiting for safer profile drugs, risk factors affecting AD's pathogenesis include aβ accumulation, tau protein hyperphosphorylation, and neuroinflammation. This research aimed to synthesize 2-amino-6‑trifluoromethoxy benzothiazole schiff bases. Synthesis was straightforward, combining the riluzole skeleton with compounds containing the azomethine group. Schiff bases synthesized were characterized spectroscopically using proton NMR (1H NMR), and FTIR. In-vivo biological evaluation against scopolamine-induced neuronal damage revealed that these newly synthesized schiff bases were effective in protecting neurons against neuroinflammatory mediators. In-vitro results revealed that these compounds had remarkable potential in improving the anti-oxidant levels. It downregulated glutathione (GSH), glutathione S-transferase (GST), catalase levels, and upregulated lipid peroxidation (LPO) levels. Immunohistochemical studies revealed that groups treated with the newly synthesized schiff bases had reduced expression of inflammatory mediators such as cyclooxygenase 2 (COX-2), JNK, tumor necrosis factor (TNF-α), nuclear factor kappa B (NF-kB) in contrast to the disease group. Moreover, molecular docking studies on these compounds also showed that they possessed a better binding affinity for above mentioned inflammatory mediators. The results of these studies showed that 2-amino-6-trifluoromethoxy benzothiazole schiff bases are remarkably effective against oxidative stress-mediated neuroinflammation.
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Khan A, Khan A, Shal B, Aziz A, Ahmad S, Amin MU, Ahmed MN, Zia-Ur-Rehman, Khan S. Ameliorative effect of two structurally divergent hydrazide derivatives against DSS-induced colitis by targeting Nrf2 and NF-κB signaling in mice. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2022; 395:1167-1188. [PMID: 35851927 DOI: 10.1007/s00210-022-02272-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 07/08/2022] [Indexed: 11/27/2022]
Abstract
The environmental factors and genetic vulnerability trigger the inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn's disease. Furthermore, the oxidative stress and inflammatory cytokines have been implicated in the aggravation of the IBDs. The aim of the present study was to investigate the effect of N-(benzylidene)-2-((2-hydroxynaphthalen-1-yl)diazenyl)benzohydrazides (NCHDH and NTHDH) compounds against the DSS-induced colitis in mice. The colitis was induced by 5% dextran sulfate sodium (DSS) dissolved in normal saline for 5 days. The effect of the NCHDH and NTHDH on the behavioral, biochemical, histological, and immunohistological parameters was assessed. The NCHDH and NTHDH treatment improved the behavioral parameters such as food intake, disease activity index, and diarrhea score significantly compared to DSS control. The NCHDH and NTHDH treatments significantly increased the antioxidant enzymes, whereas oxidative stress markers were markedly reduced. Similarly, the NCHDH and NTHDH treatments significantly suppressed the activity of nitric oxide (NO), myeloperoxidase (MPO), and eosinophil peroxidase (EPO). The histological studies showed a significant reduction in inflammation, immune cell infiltration, and fibrosis in the NCHDH- and NTHDH-treated groups. The immunohistochemical results demonstrated that NCHDH and NTHDH treatments markedly increase the expression level of Nrf2, HO-1 (hemeoxygenase-1), TRX (thioredoxin reductase), and IκB compared to the DSS-induced group. In the same way, the NCHDH and NTHDH significantly reduced the NF-κB and COX-2 (cyclooxygenase-2) expression levels. The NCHDH and NTHDH treatment significantly improved the symptoms associated with colitis via inducing antioxidants and attenuating oxidative stress markers.
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Affiliation(s)
- Ashrafullah Khan
- Pharmacological Sciences Research Laboratory, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, 45320, Pakistan
- Faculty of Pharmaceutical Sciences, Abasyn University, Peshawar, 25000, KPK, Pakistan
| | - Adnan Khan
- Pharmacological Sciences Research Laboratory, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Bushra Shal
- Pharmacological Sciences Research Laboratory, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Abdul Aziz
- Department of Chemistry, The University of Azad Jammu and Kashmir, Muzaffarabad, 13100, Pakistan
| | - Sajjad Ahmad
- Department of Health and Biological Sciences, Abasyn University, Peshawar, 25000, Pakistan
| | - Muhammad Usman Amin
- Faculty of Pharmaceutical Sciences, Abasyn University, Peshawar, 25000, KPK, Pakistan
| | - Muhammad Naeem Ahmed
- Department of Chemistry, The University of Azad Jammu and Kashmir, Muzaffarabad, 13100, Pakistan
| | - Zia-Ur-Rehman
- Department of Chemistry, Quaid-I-Azam University, Islamabad, Pakistan
| | - Salman Khan
- Pharmacological Sciences Research Laboratory, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, 45320, Pakistan.
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Li C, Xie J, Wang J, Cao Y, Pu M, Gong Q, Lu Q. Therapeutic effects and mechanisms of plant-derived natural compounds against intestinal mucositis. Front Pharmacol 2022; 13:969550. [PMID: 36210837 PMCID: PMC9533105 DOI: 10.3389/fphar.2022.969550] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 09/05/2022] [Indexed: 01/26/2023] Open
Abstract
Intestinal mucositis is a clinically related adverse reaction of antitumor treatment. Majority of patients receiving high-dose chemical therapy, radiotherapy, and bone-marrow transplant suffer from intestinal mucositis. Clinical manifestations of intestinal mucositis mainly include pain, body-weight reduction, inflammatory symptom, diarrhea, hemoproctia, and infection, which all affect regular nutritional input and enteric function. Intestinal mucositis often influences adherence to antitumor treatment because it frequently restricts the sufferer’s capacity to tolerate treatment, thus resulting in schedule delay, interruption, or premature suspension. In certain circumstances, partial and general secondary infections are found, increasing the expenditures on medical care and hospitalization. Current methods of treating intestinal mucositis are provided, which do not always counteract this disorder. Against this background, novel therapeutical measures are extremely required to prevent and treat intestinal mucositis. Plant-derived natural compounds have lately become potential candidates against enteric injury ascribed to the capacity to facilitate mucosal healing and anti-inflammatory effects. These roles are associated with the improvement of intestinal mucosal barrier, suppression of inflammatory response and oxidant stress, and modulation of gut microflora and immune system. The present article aims at systematically discussing the recent progress of plant-derived natural compounds as promising treatments for intestinal mucositis.
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Affiliation(s)
- Cailan Li
- Department of Pharmacology, Zunyi Medical University, Zhuhai Campus, Zhuhai, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
- Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Jianhui Xie
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiahao Wang
- Department of Pharmacology, Zunyi Medical University, Zhuhai Campus, Zhuhai, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
- Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Ying Cao
- Department of Pharmaceutical Sciences, Zunyi Medical University, Zhuhai Campus, Zhuhai, China
| | - Min Pu
- Department of Pharmaceutical Sciences, Zunyi Medical University, Zhuhai Campus, Zhuhai, China
| | - Qihai Gong
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
- Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi, China
- *Correspondence: Qihai Gong, ; Qiang Lu,
| | - Qiang Lu
- Department of Pharmaceutical Sciences, Zunyi Medical University, Zhuhai Campus, Zhuhai, China
- *Correspondence: Qihai Gong, ; Qiang Lu,
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Lu L, Dong J, Liu Y, Qian Y, Zhang G, Zhou W, Zhao A, Ji G, Xu H. New insights into natural products that target the gut microbiota: Effects on the prevention and treatment of colorectal cancer. Front Pharmacol 2022; 13:964793. [PMID: 36046819 PMCID: PMC9420899 DOI: 10.3389/fphar.2022.964793] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant carcinomas. CRC is characterized by asymptomatic onset, and most patients are already in the middle and advanced stages of disease when they are diagnosed. Inflammatory bowel disease (IBD) and the inflammatory-cancer transformation of advanced colorectal adenoma are the main causes of CRC. There is an urgent need for effective prevention and intervention strategies for CRC. In recent years, rapid research progress has increased our understanding of gut microbiota. Meanwhile, with the deepening of research on the pathogenesis of colorectal cancer, gut microbiota has been confirmed to play a direct role in the occurrence and treatment of colorectal cancer. Strategies to regulate the gut microbiota have potential value for application in the prevention and treatment of CRC. Regulation of gut microbiota is one of the important ways for natural products to exert pharmacological effects, especially in the treatment of metabolic diseases and tumours. This review summarizes the role of gut microbiota in colorectal tumorigenesis and the mechanism by which natural products reduce tumorigenesis and improve therapeutic response. We point out that the regulation of gut microbiota by natural products may serve as a potential means of treatment and prevention of CRC.
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Affiliation(s)
- Lu Lu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiahuan Dong
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yujing Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yufan Qian
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guangtao Zhang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenjun Zhou
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Aiguang Zhao
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hanchen Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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khan A, Wang F, Shal B, Khan AU, Zahra SS, Haq IU, Khan S, Rengasamy KRR. Anti-neuropathic pain activity of Ajugarin-I via activation of Nrf2 signaling and inhibition of TRPV1/TRPM8 nociceptors in STZ-induced diabetic neuropathy. Pharmacol Res 2022; 183:106392. [DOI: 10.1016/j.phrs.2022.106392] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/04/2022] [Accepted: 08/04/2022] [Indexed: 12/26/2022]
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Zhang Q, Zhou S, Lim PE, Wei B, Xue C, Xue Y, Tang Q. Kappaphycus Alvarezii Compound Powder Prevents Chemotherapy-Induced Intestinal Mucositis in BALB/c Mice. Nutr Cancer 2022; 74:3735-3746. [PMID: 35758096 DOI: 10.1080/01635581.2022.2089699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
This study aimed to formulate Kappaphycus alvarezii compound powder containing Kappaphycus alvarezii powder (KP), cooked sorghum powder (SP), and longan powder (LP); which was evaluated for its therapeutic effects against chemotherapy-induced intestinal mucosal injury (CIMI). Based on rheological properties, sensory evaluation, and antioxidant activity and using single factor and response surface methodology, the optimal formula to develop the compound powder was determined to be 35% KP, 30% SP, 5% LP, and 30% xylitol. Thereafter, the efficacy of the compound powder was tested by feeding BALB/c mice with diets supplemented with the Kappaphycus alvarezii compound powder (3% and 5%) for 14 consecutive days. The chemotherapeutic drug 5-fluorouracil was intraperitoneally injected (50 mg/kg) in the mice to induce CIMI for the last three consecutive days. Compared to the CIMI mice, those fed 5% Kappaphycus alvarezii compound powder (HC) showed significantly improved the intestinal injury, increased mucin-2 secretion, and reduced TNF-α, IL-1β, IL-6, LT, and COX-2 levels. Furthermore, HC intake significantly reduced the Firmicutes-to-Bacteroidetes ratio, promoted the growth of beneficial bacteria, such as Alloprevotella, and inhibited the growth of harmful bacteria, such as Clostridium. In conclusion, HC has a protective effect against CIMI and provides a novel dietary strategy for patients undergoing chemotherapy.
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Affiliation(s)
- Qing Zhang
- College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Sainan Zhou
- College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Phaik Eem Lim
- Institute of Ocean and Earth Sciences, University of Malaya, Kuala Lumpur, Malaysia
| | - Biqian Wei
- College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Changhu Xue
- College of Food Science and Engineering, Ocean University of China, Qingdao, China.,Pilot National Laboratory for Marine Science and Technology, Laboratory for Marine Drugs and Bioproducts, Qingdao, China
| | - Yong Xue
- College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Qingjuan Tang
- College of Food Science and Engineering, Ocean University of China, Qingdao, China
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Khan A, Zhang L, Li CH, Khan AU, Shal B, Khan A, Ahmad S, Din FU, Rehman ZU, Wang F, Khan S. Suppression of NF-κB signaling by ECN in an arthritic model of inflammation. BMC Complement Med Ther 2022; 22:158. [PMID: 35698107 PMCID: PMC9195475 DOI: 10.1186/s12906-022-03629-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 05/19/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The 7β-(3-ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), a sesquiterpenoid isolated from the Tussilago farfara Linneaus (Asteraceae), was evaluated against acute Carrageenan and chronic complete Freund's adjuvant (CFA)-induced arthritis in mice. METHODS Acute and chronic arthritis were induced by administering Carrageenan and CFA to the intraplantar surface of the mouse paw. Edema, mechanical allodynia, mechanical hyperalgesia, and thermal hyperalgesia were assessed in the paw. Similarly, histological and immunohistological parameters were assessed following arthritis induced by CFA. Antioxidants, inflammatory cytokines, and oxidative stress markers were also studied in all the treated groups. RESULTS The ECN treatment significantly attenuated edema in the paw and elevated the nocifensive threshold following induction of this inflammatory model. Furthermore, ECN treatment markedly improved the arthritis index and distress symptoms, while attenuating the CFA-induced edema in the paw. ECN treatment also improved the histological parameters in the paw tissue compared to the control. At the same time, there was a significant reduction in edema and erosion in the ECN-treated group, as measured by radiographic analysis. Using the Comet's assay, we showed that ECN treatment protected the DNA from chronic CFA-induced arthritis. Immunohistochemistry analysis showed a marked decrease in the expression level of p-JNK (phosphorylated C-Jun N-terminal kinase), NF-κB (Nuclear factor-kappa B), COX-2 (Cyclooxygenase-2), and TNF-α (Tumour necrosis factor-alpha) compared to the CFA-treated group. Biophysical analysis involving molecular docking, molecular dynamics simulations, and binding free energies of ECN were performed to explore the underlying mechanism. CONCLUSION ECN exhibited significant anti-inflammatory and anti-arthritic activity against Carrageenan and CFA-induced models.
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Affiliation(s)
- Amna Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Li Zhang
- Department of Medical Oncology, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan, People's Republic of China
| | - Chang Hu Li
- Division of Radiation Physics, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Ashraf Ullah Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
- Faculty of Pharmaceutical Sciences, Abasyn University, Peshawar, KPK, Pakistan
| | - Bushra Shal
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Adnan Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Sajjad Ahmad
- Department of Health and Biological Sciences, Abasyn University, Peshawar, 25000, Pakistan
| | - Fakhar Ud Din
- Department of Pharmacy, Faculty of Biological Sciences, Quad-i-Azam University, Islamabad, Pakistan
| | - Zia Ur Rehman
- Department of Chemistry, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Feng Wang
- Department of Medical Oncology, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan, People's Republic of China.
| | - Salman Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
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Pharmacological mechanism of xanthoangelol underlying Nrf-2/TRPV1 and anti-apoptotic pathway against scopolamine-induced amnesia in mice. Biomed Pharmacother 2022; 150:113073. [PMID: 35658216 DOI: 10.1016/j.biopha.2022.113073] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/26/2022] [Accepted: 04/29/2022] [Indexed: 11/23/2022] Open
Abstract
Alzheimer's disease (AD) is a well-known type of age-related dementia. The present study was conducted to investigate the effect of xanthoangelol against memory deficit and neurodegeneration associated with AD. Preliminarily, xanthoangelol produced neuroprotective effect against H2O2-induced HT-22 cells. Furthermore, effect of xanthoangelol against scopolamine-induced amnesia in mice was determined by intraperitoneally (i.p.) administering xanthoangelol (1, 10 and 20 mg/kg), 30 min prior to induction. Mice were administered scopolamine at a concentration of 1 mg/kg; i.p. for the induction of amnesia associated with AD. Xanthoangelol dose dependently reduced the symptoms of Alzheimer's disease as observed by the results obtained from the behavioral analysis performed using Morris water maze and Y-maze test. The immunohistochemical analysis suggested that xanthoangelol significantly improved Keap-1/Nrf-2 signaling pathway. It greatly reduced the effects of oxidative stress and showed improvement in the anti-oxidant enzyme such as GSH, GST, SOD and catalase. Additionally, xanthoangelol decreased the expression of transient receptor potential vanilloid 1 (TRPV-1), a nonselective cation channel, involved in synaptic plasticity and memory. It activated the anti-oxidants and attenuated the apoptotic (Bax/Bcl-2) pathway. Xanthoangelol also significantly attenuated the scopolamine-induced neuroinflammation by the inhibition of interleukin-1 beta (IL-1β), and tumor necrosis factor-α (TNF-α) levels. The histological analysis, showed a significant reduction in amyloid plaques by xanthoangelol. Therefore, the present study indicated that xanthoangelol has the ability to ameliorate the AD symptoms by attenuating neuroinflammation and neurodegeneration induced by scopolamine.
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Bibi T, Khan A, Khan AU, Shal B, Ali H, Seo EK, Khan S. Magnolol prevented brain injury through the modulation of Nrf2-dependent oxidative stress and apoptosis in PLP-induced mouse model of multiple sclerosis. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2022; 395:717-733. [PMID: 35348816 DOI: 10.1007/s00210-022-02230-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 03/11/2022] [Indexed: 01/07/2023]
Abstract
Multiple sclerosis (MS) is an immune-mediated chronic inflammatory demyelinating disease of the central nervous system (CNS). The aim of the current study was to investigate the effects of magnolol in an experimental autoimmune encephalomyelitis (EAE) model of MS in female mice. Magnolol (0.1, 1, and 10 mg/kg) was administered once daily for 21 days after immunization of mice. Magnolol post-immunization treatment significantly reversed clinical scoring, EAE-associated pain parameters, and motor dysfunction in a dose-dependent manner. Magnolol treatment significantly inhibited oxidative stress by reducing malondialdehyde (MDA), nitric oxide (NO) production, and myeloperoxidase (MPO) activity while enhancing the level of antioxidants such as reduced glutathione (GSH), glutathione-S-transferase (GST), catalase, and superoxide dismutase (SOD) in the brain and spinal cord. It reduced cytokine levels in the brain and spinal cord. It suppressed CD8+ T cells frequency in the spleen tissue. Magnolol remarkably reversed the EAE-associated histopathology of the brain and spinal cord tissue. Magnolol significantly intensifies the antioxidant defense system by enhancing the expression level of nuclear factor erythroid 2-related factor (Nrf2) while decreasing the expression of inducible nitric oxide synthase (iNOS) and cleaved-caspase-3 in the brain. Molecular docking results showed that magnolol possesses a better binding affinity for Nrf2, iNOS, and caspase-3 proteins. Taken together, the present study demonstrated that magnolol has significant neuroprotective properties in EAE via inhibition of oxidative stress.
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Affiliation(s)
- Tehmina Bibi
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Adnan Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Ashraf Ullah Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
- Faculty of Pharmaceutical Sciences, Abasyn University, Peshawar, Pakistan
| | - Bushra Shal
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
- Faculty of Health Sciences, IQRA University, Islamabad Campus, (Chak Shahzad), Islamabad, Pakistan
| | - Hussain Ali
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Eun Kyoung Seo
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, South Korea.
| | - Salman Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
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Yu QQ, Zhang H, Guo Y, Han B, Jiang P. The Intestinal Redox System and Its Significance in Chemotherapy-Induced Intestinal Mucositis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7255497. [PMID: 35585883 PMCID: PMC9110227 DOI: 10.1155/2022/7255497] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/04/2022] [Accepted: 04/09/2022] [Indexed: 12/12/2022]
Abstract
Chemotherapy-induced intestinal mucositis (CIM) is a significant dose-limiting adverse reaction brought on by the cancer treatment. Multiple studies reported that reactive oxygen species (ROS) is rapidly produced during the initial stages of chemotherapy, when the drugs elicit direct damage to intestinal mucosal cells, which, in turn, results in necrosis, mitochondrial dysfunction, and ROS production. However, the mechanism behind the intestinal redox system-based induction of intestinal mucosal injury and necrosis of CIM is still undetermined. In this article, we summarized relevant information regarding the intestinal redox system, including the composition and regulation of redox enzymes, ROS generation, and its regulation in the intestine. We innovatively proposed the intestinal redox "Tai Chi" theory and revealed its significance in the pathogenesis of CIM. We also conducted an extensive review of the English language-based literatures involving oxidative stress (OS) and its involvement in the pathological mechanisms of CIM. From the date of inception till July 31, 2021, 51 related articles were selected. Based on our analysis of these articles, only five chemotherapeutic drugs, namely, MTX, 5-FU, cisplatin, CPT-11, and oxaliplatin were shown to trigger the ROS-based pathological mechanisms of CIM. We also discussed the redox system-mediated modulation of CIM pathogenesis via elaboration of the relationship between chemotherapeutic drugs and the redox system. It is our belief that this overview of the intestinal redox system and its role in CIM pathogenesis will greatly enhance research direction and improve CIM management in the future.
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Affiliation(s)
- Qing-Qing Yu
- Laboratory of Biochemistry and Biomedical Materials, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China
- Jining First People's Hospital, Jining Medical College, Jining 272000, China
| | - Heng Zhang
- Department of Laboratory, Shandong Daizhuang Hospital, Jining 272051, China
| | - Yujin Guo
- Jining First People's Hospital, Jining Medical College, Jining 272000, China
| | - Baoqin Han
- Laboratory of Biochemistry and Biomedical Materials, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China
| | - Pei Jiang
- Jining First People's Hospital, Jining Medical College, Jining 272000, China
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Amanat S, Shal B, Kyoung Seo E, Ali H, Khan S. Icariin attenuates cyclophosphamide-induced cystitis via down-regulation of NF-кB and up-regulation of Nrf-2/HO-1 signaling pathways in mice model. Int Immunopharmacol 2022; 106:108604. [PMID: 35149295 DOI: 10.1016/j.intimp.2022.108604] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 01/27/2022] [Accepted: 01/30/2022] [Indexed: 02/08/2023]
Abstract
Cystitis is a chronic bladder pain associated with frequency and nocturia. In the present study, Icariin a prenylated flavonoid extracted from Epimedium koreanum, was investigated against cyclophosphamide (CYP)-induced cystitis pain in mice model. Preliminarily in an acute model, single dose of CYP (150 mg/kg; i.p) was administered followed by Icariin (5, 25 and 50 mg/kg, i.p.). The visceral sensitivity and nociceptive behaviors were significantly ameliorated by pretreatment with Icariin (25, 50 mg/kg) that were assessed by spontaneous pain scoring, von Frey test and clinical scoring. Further, in chronic model Icariin (25 mg/kg, i.p.) was administered for 10 consecutive days prior to CYP (75 mg/kg; i.p) challenged every 3rd day for the duration of 10 days. Icariin not only had a protective effect on edema including bladder wet weight and hemorrhage but also had a potential to reduce vascular permeability, mast cells infiltration and tissue fibrosis. Evidently, Icariin prevented the neutrophilia/lymphopenia caused by CYP, and markedly improved the antioxidant enzymes level including superoxide dismutase, glutathione sulfo-transferase, catalase, glutathione level and reduced Malondialdehyde level, myeloperoxidase activity and nitric oxide, and also decreased the production of tumor necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1β) in bladder. Icariin markedly enhanced the Nrf-2, heme oxygenase (HO-1) and IкB-α expression, while attenuated the expression level of Keap1, TLR-4, NF-кB, i-NOS, COX-2 and TRPV1 as compared to negative group. This research illustrated the anti-inflammatory properties of Icariin and effectively improved CYP-induced cystitis pain.
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Affiliation(s)
- Safa Amanat
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan; Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Bushra Shal
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan; Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan; Faculty of Health Sciences, IQRA University, Islamabad Campus, (Chak Shahzad), Islamabad, Pakistan
| | - Eun Kyoung Seo
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea
| | - Hussain Ali
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Salman Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan; Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
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Arafah A, Rehman MU, Ahmad A, AlKharfy KM, Alqahtani S, Jan BL, Almatroudi NM. Myricetin (3,3',4',5,5',7-Hexahydroxyflavone) Prevents 5-Fluorouracil-Induced Cardiotoxicity. ACS OMEGA 2022; 7:4514-4524. [PMID: 35155943 PMCID: PMC8829927 DOI: 10.1021/acsomega.1c06475] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/12/2022] [Indexed: 05/05/2023]
Abstract
5-Fluorouracil (5-FU) is a strong anti-cancer drug used to manage numerous cancers. Cardiotoxicity, renal toxicity, and liver toxicity are some of the adverse effects which confine its clinical use to some extent. 5-FU-induced organ injuries are associated with redox imbalance, inflammation, and damage to heart functioning, particularly in the present study. Myricetin is an abundant flavonoid, commonly extracted from berries and herbs having anti-oxidative and anti-cancer activities. We planned the current work to explore the beneficial effects of myricetin against 5-FU-induced cardiac injury in Wistar rats through a biochemical and histological approach. Prophylactic myricetin treatment at two doses (25 and 50 mg/kg) was given to rats orally for 21 days against cardiac injury induced by a single injection of 5-FU (150 mg/kg b.wt.) given on the 20th day intraperitoneally. The 5-FU injection induced oxidative stress, inflammation, and extensive cardiac damage. Nevertheless, myricetin alleviated markers of inflammation, apoptosis, cardiac toxicity, oxidative stress, and upregulated anti-oxidative machinery. The histology of heart further supports our biochemical findings mitigated by the prophylactic treatment of myricetin. Henceforth, myricetin mitigates 5-FU-induced cardiac damage by modulating oxidative stress, inflammation, and cardiac-specific markers, as found in the present study.
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Affiliation(s)
- Azher Arafah
- Department
of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Muneeb U. Rehman
- Department
of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
- ,
| | - Ajaz Ahmad
- Department
of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Khalid M. AlKharfy
- Department
of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Saeed Alqahtani
- Department
of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Basit L. Jan
- Department
of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Nada M. Almatroudi
- Department
of Clinical Pharmacy, College of Pharmacy (Girls Campus), King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
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Ullah H, Khan A, Bibi T, Ahmad S, Shehzad O, Ali H, Seo EK, Khan S. Comprehensive in vivo and in silico approaches to explore the hepatoprotective activity of poncirin against paracetamol toxicity. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2022; 395:195-215. [PMID: 34994820 DOI: 10.1007/s00210-021-02192-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 11/26/2021] [Indexed: 01/05/2023]
Abstract
In the present study, poncirin was evaluated against paracetamol-induced liver injury using in vivo and computational approaches. Paracetamol was administered intraperitoneally (i.p,) to establish liver injury in mice and, subsequently, to investigate the hepatoprotective effect of poncirin (administered intraperitoneally) on liver injury. The effect of poncirin was evaluated against the liver injury markers and inflammatory cytokines. Similarly, in the present study, the antioxidants and oxidative stress parameters were also assessed following paracetamol-induced liver injury. The histological studies following liver injury were also assessed using H and E staining, Masson's trichrome staining, and periodic acid-Schiff staining. Similarly, the computational approach was used to assess the pharmacokinetic parameters of poncirin and its interaction with various protein targets. Poncirin markedly improved the antioxidant enzymes while attenuated the oxidative stress markers and inflammatory cytokines. Poncirin also markedly improved hematological parameters. Furthermore, poncirin treatment significantly improved the histological parameters using H and E staining, Masson's trichrome, and PAS staining compared to the control. Poncirin treatment also improved the liver function tests and liver synthetic activity compared to paracetamol treated group. The immunohistochemistry analysis revealed significant decrease in the inflammatory signaling protein such as nuclear factor kappa light chain enhancer of activated B cells (NF-κB), Jun N-terminal kinase (JNK), and cyclooxygenase-2 (COX-2) expression level compared to the paracetamol treated group. Computational analysis (molecular docking and molecular dynamic simulation) showed significant binding affinity of poncirin with the NF-κB, JNK, COX-2, IL-1β, IL-6, and TNF-α via multiple hydrophilic and hydrophobic binds. Similarly, the SwissADME software revealed that poncirin follows various drug-likeness rules and exhibited better pharmacokinetic parameters. Poncirin improved the sign and symptoms associated with liver injury using both in vivo and computational approaches.
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Affiliation(s)
- Hadayat Ullah
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan
| | - Ashrafullah Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan
- Faculty of Pharmacy, Abasyn University, Peshawar, 25000, Pakistan
| | - Tehmina Bibi
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan
| | - Sajjad Ahmad
- Department of Health and Biological Sciences, Abasyn University, Peshawar, 25000, Pakistan
| | - Omer Shehzad
- Department of Pharmacy, Abdul Wali Khan University, KPK, Mardan, Pakistan
| | - Hussain Ali
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan
| | - Eun Kyoung Seo
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Korea
| | - Salman Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
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Development of an intelligent, stimuli-responsive transdermal system for efficient delivery of Ibuprofen against rheumatoid arthritis. Int J Pharm 2021; 610:121242. [PMID: 34737113 DOI: 10.1016/j.ijpharm.2021.121242] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 10/23/2021] [Accepted: 10/25/2021] [Indexed: 12/26/2022]
Abstract
The present study aimed to fabricate and evaluate the therapeutic efficacy of pH-responsive Ibuprofen (IB) nanoparticles (NPs) loaded transdermal hydrogel against rheumatoid arthritis (RA). The IB loaded Eudragit® L 100 (EL 100) nanoparticles were formulated through a modified nanoprecipitation technique and optimized using central composite design software. The optimized NPs were loaded into Carbopol® 934-based hydrogel by solvent evaporation method and were analyzed for physicochemical characteristics. The mean particle size of the prepared NPs was 48 nm with an entrapment efficiency of 90%. The transdermal hydrogel showed a pH-responsive sustained drug release and high penetration through the skin. Moreover, the prepared nanocarrier system exhibited therapeutic efficacy at inflamed joints' sites both in acute and chronic RA mice model. The therapeutic efficacy of the prepared formulation was confirmed through the results of various behavioral, biochemical, and cytokines-based assays. Similarly, the assessment of histopathological and radiological images, as well as the skin irritation studies further strengthens the potential use of the prepared formulation through the transdermal route. The current findings suggested that IB loaded pH-responsive NPs based transdermal hydrogel can be used as an efficient agent to manage RA.
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Naveed M, Ullah R, Khan A, Shal B, Khan AU, Khan SZ, Rehman ZU, Khan S. Anti-neuropathic pain activity of a cationic palladium (II) dithiocarbamate by suppressing the inflammatory mediators in paclitaxel-induced neuropathic pain model. Mol Biol Rep 2021; 48:7647-7656. [PMID: 34734371 DOI: 10.1007/s11033-021-06754-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 09/10/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Neuropathic pain is a chronic pain state that negatively impacts the quality of life. Currently, available therapies for the treatment of neuropathic pain often lack efficacy and tolerability. Therefore, the search for novel drugs is crucial to obtain treatments that effectively suppress neuropathic pain. OBJECTIVES The present study was undertaken to investigate the antinociceptive properties of (1,4-bis-(diphenylphosphino) butane) palladium (II) chloride monohydrate (Compound 1) in a paclitaxel (PTX)-induced neuropathic pain model. METHODS Initially, behavioral tests such as mechanical and cold allodynia as well as thermal and tail immersion hyperalgesia were performed to investigate the antinociceptive potential of Compound 1 (5 and 10 mg/kg, b.w). RT-PCR was performed to determine the effect of Compound 1 on the mRNA expression level of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and proinflammatory cytokines such as tumor necrosis factor-alpha (TNF)-α, interleukin (IL)-1β, and IL-6. In addition, antioxidant protein, nitric oxide (NO), and malondialdehyde (MDA) levels were also determined. RESULTS The results demonstrated that once-daily dosing of Compound 1 significantly suppressed the PTX-induced behavioral pain responses dose-dependently. The mRNA gene expressions of iNOS, COX-2, and inflammatory cytokines were markedly reduced by Compound 1. Furthermore, it enhanced the level of antioxidant enzymes and lowered the level of MDA and NO production. CONCLUSION These findings suggest that the antinociceptive potential of Compound 1 in the PTX-induced neuropathic pain model is via suppression of oxidative stress and inflammation. Thus, Compound 1 might be a potential candidate for the therapeutic management of PTX induced neuropathic pain.
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Affiliation(s)
- Muhammad Naveed
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, Pakistan
| | - Rahim Ullah
- Department of Pharmacy, University of Peshawar, Peshawar, Pakistan
| | - Adnan Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, Pakistan
| | - Bushra Shal
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, Pakistan
| | - Ashraf Ullah Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, Pakistan
| | - Shahan Zeb Khan
- Department of Chemistry, Quaid-I-Azam University, Islamabad, 45320, Pakistan
- Department of Chemistry, University of Science and Technology, KPK, Bannu, 28100, Pakistan
| | - Zia Ur Rehman
- Department of Chemistry, Quaid-I-Azam University, Islamabad, 45320, Pakistan.
| | - Salman Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, Pakistan.
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Khan A, Shal B, Khan AU, Bibi T, Islam SU, Baig MW, Haq IU, Ali H, Ahmad S, Khan S. Withametelin, a novel phytosterol, alleviates neurological symptoms in EAE mouse model of multiple sclerosis via modulation of Nrf2/HO-1 and TLR4/NF-κB signaling. Neurochem Int 2021; 151:105211. [PMID: 34688804 DOI: 10.1016/j.neuint.2021.105211] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 09/11/2021] [Accepted: 10/10/2021] [Indexed: 02/07/2023]
Abstract
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS) that remains incurable. Withametelin (WMT), a phytosterol, showed diverse biological activities isolated from the leaves of Datura innoxa. In the present study, we used an in vitro model of HT22 and BV-2 cell lines and an in vivo murine model of MS, experimental autoimmune encephalomyelitis (EAE), to explore the antioxidant and anti neuroinflammatory potential of WMT. The results showed that pretreatment with WMT markedly inhibited H2O2-induced cytotoxicity and oxidative stress in a dose-dependent manner. Correspondingly, WMT post-immunization treatment significantly attenuated EAE-induced clinical score, weight loss, neuropathic pain behaviors, and motor dysfunction. It markedly lowers EAE-induced elevated circulating leucocytes, spinal deformity, and splenomegaly. It strikingly inhibited the Evans blue and FITC extravasation in the brain. It remarkably reversed the EAE-induced histopathological alteration of the brain, spinal cord, eye, and optic nerve. It significantly intensified the antioxidant defense mechanism by improving the expression level of nuclear factor-erythroid-related factor-2 (Nrf2), heme-oxygenase-1 (HO-1) but reducing the expression level of the Kelch-like-ECH-associated-protein-1 (keap-1), inducible-nitric-oxide-synthase (iNOS) in the CNS. Likewise, it markedly suppressed neuroinflammation by reducing the expression level of toll-like-receptor 4 (TLR4), nuclear-factor-kappa-B (NF-κB), activator-protein-1 (AP-1) but increased the expression level IkB-α in the CNS. Furthermore, molecular dynamics simulations and MMPBSA binding free energies were determined to validate the dynamic stability of complexes and shed light on the atomic level intermolecular interaction energies. Taken together, this study showed that WMT has significant neuroprotective potential in EAE via modulation of Nrf2 mediated-oxidative stress and NF-κB mediated inflammation.
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Affiliation(s)
- Adnan Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
| | - Bushra Shal
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
| | - Ashraf Ullah Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
| | - Tehmina Bibi
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
| | - Salman Ul Islam
- School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu, South Korea.
| | - Muhammad Waleed Baig
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
| | - Ihsan Ul Haq
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
| | - Hussain Ali
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
| | - Sajjad Ahmad
- Department of Health and Biological Sciences, Abasyn University, Peshawar, 25000, Pakistan.
| | - Salman Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
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Zeeshan M, Atiq A, Ain QU, Ali J, Khan S, Ali H. Evaluating the mucoprotective effects of glycyrrhizic acid-loaded polymeric nanoparticles in a murine model of 5-fluorouracil-induced intestinal mucositis via suppression of inflammatory mediators and oxidative stress. Inflammopharmacology 2021; 29:1539-1553. [PMID: 34420176 DOI: 10.1007/s10787-021-00866-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 08/13/2021] [Indexed: 01/04/2023]
Abstract
OBJECTIVES 5-Fluorouracil (5-FU), a chemotherapeutic drug, has severe deteriorating effects on the intestine, leading to mucositis. Glycyrrhizic acid is a compound derived from a common herbal plant Glycyrrhiza glabra, with mucoprotective, antioxidant and anti-inflammatory actions, however, associated with poor pharmacokinetics. Owing to the remarkable therapeutic action of glycyrrhizic acid-loaded polymeric nanocarriers in inflammatory bowel disease, we explored their activity against 5-FU-induced intestinal mucositis in mice. Polymeric nanocarriers have proven to be efficient drug delivery vehicles for the long-term treatment of inflammatory diseases, but have not yet been explored for 5-FU-induced mucositis. Therefore, this study aimed to produce glycyrrhizic acid-loaded polylactic-co-glycolic acid (GA-PLGA) nanoparticles to evaluate their protective and therapeutic effects in a 5-FU-induced mucositis model. METHODS GA-PLGA nanoparticles were prepared using a modified double emulsion method, physicochemically characterized, and tested for in vitro drug release. Thereafter, mucositis was induced by 5-FU (50 mg/kg; IP) administration to the mice for the first 3 days (day 0, 1, 2), and mice were treated orally with GA-PLGA nanoparticles for 7 days (day 0-6). RESULTS GA-PLGA nanoparticles significantly reduced mucositis severity measured by body weight, diarrhea score, distress, and anorexia. Further, 5-FU induced intestinal histopathological damage, altered villi-crypt length, reduced goblet cell count, elevated pro-inflammatory mediators, and suppressed antioxidant enzymes, all of which were reversed by GA-PLGA nanoparticles. CONCLUSION Morphological, behavioral, histological, and biochemical results suggested that GA-PLGA nanoparticles were efficient, biocompatible, targeted, and sustained release drug delivery nano-vehicle for enhanced mucoprotective, anti-inflammatory, and antioxidant effects in 5-FU-induced intestinal mucositis.
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Affiliation(s)
- Mahira Zeeshan
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Ayesha Atiq
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Qurat Ul Ain
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Jawad Ali
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Salman Khan
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Hussain Ali
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan.
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Wu Y, Cheng Y, Yang Y, Wang D, Yang X, Fu C, Zhang J, Hu Y. Mechanisms of Gegen Qinlian Pill to ameliorate irinotecan-induced diarrhea investigated by the combination of serum pharmacochemistry and network pharmacology. JOURNAL OF ETHNOPHARMACOLOGY 2021; 276:114200. [PMID: 33989737 DOI: 10.1016/j.jep.2021.114200] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 04/17/2021] [Accepted: 05/07/2021] [Indexed: 05/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Traditional Chinese medicine suggests the use of natural extracts and compounds is a promising strategy to prevent irinotecan (CPT-11)-induced gut toxicity and resulting diarrhea. Previous work from our lab indicated the protective effect of Gegen Qinlian decoction; given this, we further speculated that Gegen Qinlian Pill (GQP) would exhibit similar therapeutic effects. The effective material basis as well as potential mechanisms underlying the effect of GQP for the treatment of CPT-11-induced diarrhea have not been fully elucidated. AIM OF THE STUDY The application of natural extracts or compounds derived from Chinese medicine is deemed to a promising strategy to prevent irinotecan (CPT-11)-induced gut toxicity. The aim of this study was to investigated the beneficial effects of GQP on CPT-11-induced gut toxicity and further explored its anti-diarrheal mechanism. METHODS First, the beneficial effect of GQP in alleviating diarrhea in mice following CPT-11 administration was investigated. We also obtained the effective ingredients in GQP from murine serum samples using HPLC-Q-TOF-MS analysis. Based on these active components, we next established an interaction network linking "compound-target-pathway". Finally, a predicted mechanism of action was obtained using in vivo GQP validation based on Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. RESULTS A total of 19, GQP-derived chemical compounds were identified in murine serum samples. An interaction network linking "compound-target-pathway" was then established to illuminate the interaction between the components present in serum and their targets that mitigated diarrhea. These results indicated GQP exerted a curative effect on diarrhea and diarrhea-related diseases through different targets, which cumulatively regulated inflammation, oxidative stress, and proliferation processes. CONCLUSION Taken together, this study provides a feasible strategy to elucidate the effective constituents in traditional Chinese medicine formulations. More specifically, this work detailed the basic pharmacological effects and underlying mechanism behind GQP's effects in the treatment of CPT-11-induced gut toxicity.
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Affiliation(s)
- Yihan Wu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Yanfen Cheng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Yuhan Yang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
| | - Di Wang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Xiaoqin Yang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Chaomei Fu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Jinming Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Yichen Hu
- School of Medicine, Chengdu University, Chengdu, 610106, China.
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Hossain R, Islam MT, Mubarak MS, Jain D, Khan R, Saikat AS. Natural-Derived Molecules as a Potential Adjuvant in Chemotherapy: Normal Cell Protectors and Cancer Cell Sensitizers. Anticancer Agents Med Chem 2021; 22:836-850. [PMID: 34165416 DOI: 10.2174/1871520621666210623104227] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/18/2021] [Accepted: 04/18/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Cancer is a global threat to humans and a leading cause of death worldwide. Cancer treatment includes, among other things, the use of chemotherapeutic agents, compounds that are vital for treating and preventing cancer. However, chemotherapeutic agents produce oxidative stress along with other side effects that would affect the human body. OBJECTIVE To reduce the oxidative stress of chemotherapeutic agents in cancer and normal cells by naturally derived compounds with anti-cancer properties, and protect normal cells from the oxidation process. Therefore, the need to develop more potent chemotherapeutics with fewer side effects has become increasingly important. METHOD Recent literature dealing with the antioxidant and anticancer activities of the naturally naturally-derived compounds: morin, myricetin, malvidin, naringin, eriodictyol, isovitexin, daidzein, naringenin, chrysin, and fisetin has been surveyed and examined in this review. For this, data were gathered from different search engines, including Google Scholar, ScienceDirect, PubMed, Scopus, Web of Science, Scopus, and Scifinder, among others. Additionally, several patient offices such as WIPO, CIPO, and USPTO were consulted to obtain published articles related to these compounds. RESULT Numerous plants contain flavonoids and polyphenolic compounds such as morin, myricetin, malvidin, naringin, eriodictyol, isovitexin, daidzein, naringenin, chrysin, and fisetin, which exhibit antioxidant, anti-inflammatory, and anti-carcinogenic actions via several mechanisms. These compounds show sensitizers of cancer cells and protectors of healthy cells. Moreover, these compounds can reduce oxidative stress, which is accelerated by chemotherapeutics and exhibit a potent anticancer effect on cancer cells. CONCLUSIONS Based on these findings, more research is recommended to explore and evaluate such flavonoids and polyphenolic compounds.
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Affiliation(s)
- Rajib Hossain
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj-8100, Bangladesh
| | - Muhammad Torequl Islam
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj-8100, Bangladesh
| | | | - Divya Jain
- Department of Bioscience and Biotechnology, Banasthali Vidyapith, Rajasthan-304022, India
| | - Rasel Khan
- Pharmacy Discipline, Life Science School, Khulna University, Khulna-9280, Bangladesh
| | - Abu Saim Saikat
- Department of Biochemistry and Molecular Biology, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh
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Khan A, Shal B, Khan AU, Ullah R, Baig MW, ul Haq I, Seo EK, Khan S. Suppression of TRPV1/TRPM8/P2Y Nociceptors by Withametelin via Downregulating MAPK Signaling in Mouse Model of Vincristine-Induced Neuropathic Pain. Int J Mol Sci 2021; 22:ijms22116084. [PMID: 34199936 PMCID: PMC8200233 DOI: 10.3390/ijms22116084] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/27/2021] [Accepted: 05/30/2021] [Indexed: 02/06/2023] Open
Abstract
Vincristine (VCR) is a widely used chemotherapy drug that induced peripheral painful neuropathy. Yet, it still lacks an ideal therapeutic strategy. The transient receptor potential (TRP) channels, purinergic receptor (P2Y), and mitogen-activated protein kinase (MAPK) signaling play a crucial role in the pathogenesis of neuropathic pain. Withametelin (WMT), a potential Phytosteroid isolated from datura innoxa, exhibits remarkable neuroprotective properties. The present investigation was designed to explore the effect of withametelin on VCR-induced neuropathic pain and its underlying molecular mechanism. Initially, the neuroprotective potential of WMT was confirmed against hydrogen peroxide (H2O2)-induced PC12 cells. To develop potential candidates for neuropathic pain treatment, a VCR-induced neuropathic pain model was established. Vincristine (75 μg/kg) was administered intraperitoneally (i.p.) for 10 consecutive days (day 1-10) for the induction of neuropathic pain. Gabapentin (GBP) (60 mg/kg, i.p.) and withametelin (0.1 and 1 mg/kg i.p.) treatments were given after the completion of VCR injection on the 11th day up to 21 days. The results revealed that WMT significantly reduced VCR-induced pain hypersensitivity, including mechanical allodynia, cold allodynia, and thermal hyperalgesia. It reversed the VCR-induced histopathological changes in the brain, spinal cord, and sciatic nerve. It inhibited VCR-induced changes in the biochemical composition of the myelin sheath of the sciatic nerve. It markedly downregulated the expression levels of TRPV1 (transient receptor potential vanilloid 1); TRPM8 (Transient receptor potential melastatin 8); and P2Y nociceptors and MAPKs signaling, including ERK (Extracellular Signal-Regulated Kinase), JNK (c-Jun N-terminal kinase), and p-38 in the spinal cord. It suppressed apoptosis by regulating Bax (Bcl2-associated X-protein), Bcl-2 (B-cell-lymphoma-2), and Caspase-3 expression. It considerably attenuated inflammatory cytokines, oxidative stress, and genotoxicity. This study suggests that WMT treatment suppressed vincristine-induced neuropathic pain by targeting the TRPV1/TRPM8/P2Y nociceptors and MAPK signaling.
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Affiliation(s)
- Adnan Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan; (A.K.); (B.S.); (A.U.K.); (M.W.B.); (I.u.H.)
| | - Bushra Shal
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan; (A.K.); (B.S.); (A.U.K.); (M.W.B.); (I.u.H.)
| | - Ashraf Ullah Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan; (A.K.); (B.S.); (A.U.K.); (M.W.B.); (I.u.H.)
| | - Rahim Ullah
- Department of Pharmacy, University of Peshawar, Peshawar 25120, Pakistan;
| | - Muhammad Waleed Baig
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan; (A.K.); (B.S.); (A.U.K.); (M.W.B.); (I.u.H.)
| | - Ihsan ul Haq
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan; (A.K.); (B.S.); (A.U.K.); (M.W.B.); (I.u.H.)
| | - Eun Kyoung Seo
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Korea
- Correspondence: (E.K.S.); (S.K.); Tel.: +82-2-3277-3047 (E.K.S.); +92-51-9064-4056 (S.K.)
| | - Salman Khan
- Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan; (A.K.); (B.S.); (A.U.K.); (M.W.B.); (I.u.H.)
- Correspondence: (E.K.S.); (S.K.); Tel.: +82-2-3277-3047 (E.K.S.); +92-51-9064-4056 (S.K.)
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