Oral delivery of nerolidol alleviates cyclophosphamide-induced renal inflammation, apoptosis, and fibrosis via modulation of NF-κB/cleaved caspase-3/TGF-β signaling molecules
AbstractCyclophosphamide (CP) is one of the most extensively used antineoplastic drug, but the nephrotoxicity caused by this drug is a major limiting factor for its use. Nerolidol (NERO) is a natural bioactive compound with diverse pharmacological actions. In Vitro and in vivo study was performed us...
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| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Drug Delivery |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/10717544.2023.2241661 |
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| author | Ashif Iqubal Abul Kalam Najmi Shadab Md Huda Mohammed Alkreathy Javed Ali Mansoor Ali Syed Syed Ehtaishamul Haque |
| author_facet | Ashif Iqubal Abul Kalam Najmi Shadab Md Huda Mohammed Alkreathy Javed Ali Mansoor Ali Syed Syed Ehtaishamul Haque |
| author_sort | Ashif Iqubal |
| collection | DOAJ |
| description | AbstractCyclophosphamide (CP) is one of the most extensively used antineoplastic drug, but the nephrotoxicity caused by this drug is a major limiting factor for its use. Nerolidol (NERO) is a natural bioactive compound with diverse pharmacological actions. In Vitro and in vivo study was performed using HK-2 renal cells and Swiss Albino mice. Cell lines and animals were treated with NERO 25 and 50 µM + 30 µM CP (in vitro), 200 and 400 mg/kg, p.o. NERO from day 1 to day 15 + 200 mg/kg, i.p. CP on day 17 as single intraperitoneal injection (in vivo). The makers of oxidative stress, renal-specific injury markers, inflammation, apoptosis, fibrosis, and histopathological changes were studied. The study’s outcome showed a significant reduction in the level of malonaldehyde and interleukin-6 (p < 0.01), tumor necrosis factor-α, IL-1β (p < 0.001), and an increase in the superoxide dismutase, catalase, glutathione and interleukin-10 level (p < 0.01), in the in vivo study when treated with NERO 400 and compared with CP 200. In Vitro study showed reduced expression of nuclear factor kappa light chain enhancer of activated B cells, cleaved caspase-3, kidney injury molecule-1 and transforming growth factor-β-1 (p < 0.001), when treated with NERO 50 µM whereas NERO 25 µM only reduced the level of cleaved caspase-3 (p < 0.05) when compared with 30 µM. NERO 400 also reduced uric acid (p < 0.05), urea (p < 0.01), blood urea nitrogen, and serum creatinine levels (p < 0.001) and increased the level of blood-urea-nitrogen/creatinine ratio (p < 0.001). Additionally, the level of fibrosis-specific markers such as transforming growth factor-β1, hyaluronic acid (p < 0.01), 4-hydroxyproline, a collagen-rich area in Masson’s’ trichome stain, and Smad3 expression was also significantly reduced (p < 0.001). Furthermore, the outcome of multiple renal staining showed structural reversal aberrations, reduction of the thick basement membrane, and glycogen level toward normal when treated with NERO 400. Thus, the study showed a novel mechanistic modality of NERO against cyclophosphamide-induced renal toxicity. The outcome of this study can be considered a step closer to the development of an adjuvant to mitigate cyclophosphamide-induced renal toxicity among patients treated with cyclophosphamide. |
| first_indexed | 2024-03-08T23:31:18Z |
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| issn | 1071-7544 1521-0464 |
| language | English |
| last_indexed | 2024-04-24T23:33:51Z |
| publishDate | 2023-12-01 |
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| spelling | doaj.art-fe41a575306b4d4a8ec6fa2660d389bf2024-03-15T14:22:17ZengTaylor & Francis GroupDrug Delivery1071-75441521-04642023-12-0130110.1080/10717544.2023.2241661Oral delivery of nerolidol alleviates cyclophosphamide-induced renal inflammation, apoptosis, and fibrosis via modulation of NF-κB/cleaved caspase-3/TGF-β signaling moleculesAshif Iqubal0Abul Kalam Najmi1Shadab Md2Huda Mohammed Alkreathy3Javed Ali4Mansoor Ali Syed5Syed Ehtaishamul Haque6Department of Pharmacology, School of Pharmaceutical Education and Research, New Delhi, IndiaDepartment of Pharmacology, School of Pharmaceutical Education and Research, New Delhi, IndiaDepartment of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi ArabiaDepartment of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi ArabiaDepartment of Pharmaceutics, School of Pharmaceutical Education and Research, New Delhi, IndiaDepartment of Biotechnology, Jamia Millia Islamia, New Delhi, IndiaDepartment of Pharmacology, School of Pharmaceutical Education and Research, New Delhi, IndiaAbstractCyclophosphamide (CP) is one of the most extensively used antineoplastic drug, but the nephrotoxicity caused by this drug is a major limiting factor for its use. Nerolidol (NERO) is a natural bioactive compound with diverse pharmacological actions. In Vitro and in vivo study was performed using HK-2 renal cells and Swiss Albino mice. Cell lines and animals were treated with NERO 25 and 50 µM + 30 µM CP (in vitro), 200 and 400 mg/kg, p.o. NERO from day 1 to day 15 + 200 mg/kg, i.p. CP on day 17 as single intraperitoneal injection (in vivo). The makers of oxidative stress, renal-specific injury markers, inflammation, apoptosis, fibrosis, and histopathological changes were studied. The study’s outcome showed a significant reduction in the level of malonaldehyde and interleukin-6 (p < 0.01), tumor necrosis factor-α, IL-1β (p < 0.001), and an increase in the superoxide dismutase, catalase, glutathione and interleukin-10 level (p < 0.01), in the in vivo study when treated with NERO 400 and compared with CP 200. In Vitro study showed reduced expression of nuclear factor kappa light chain enhancer of activated B cells, cleaved caspase-3, kidney injury molecule-1 and transforming growth factor-β-1 (p < 0.001), when treated with NERO 50 µM whereas NERO 25 µM only reduced the level of cleaved caspase-3 (p < 0.05) when compared with 30 µM. NERO 400 also reduced uric acid (p < 0.05), urea (p < 0.01), blood urea nitrogen, and serum creatinine levels (p < 0.001) and increased the level of blood-urea-nitrogen/creatinine ratio (p < 0.001). Additionally, the level of fibrosis-specific markers such as transforming growth factor-β1, hyaluronic acid (p < 0.01), 4-hydroxyproline, a collagen-rich area in Masson’s’ trichome stain, and Smad3 expression was also significantly reduced (p < 0.001). Furthermore, the outcome of multiple renal staining showed structural reversal aberrations, reduction of the thick basement membrane, and glycogen level toward normal when treated with NERO 400. Thus, the study showed a novel mechanistic modality of NERO against cyclophosphamide-induced renal toxicity. The outcome of this study can be considered a step closer to the development of an adjuvant to mitigate cyclophosphamide-induced renal toxicity among patients treated with cyclophosphamide.https://www.tandfonline.com/doi/10.1080/10717544.2023.2241661Nephrotoxicityoxidative stressrenal fibrosis and inflammation |
| spellingShingle | Ashif Iqubal Abul Kalam Najmi Shadab Md Huda Mohammed Alkreathy Javed Ali Mansoor Ali Syed Syed Ehtaishamul Haque Oral delivery of nerolidol alleviates cyclophosphamide-induced renal inflammation, apoptosis, and fibrosis via modulation of NF-κB/cleaved caspase-3/TGF-β signaling molecules Drug Delivery Nephrotoxicity oxidative stress renal fibrosis and inflammation |
| title | Oral delivery of nerolidol alleviates cyclophosphamide-induced renal inflammation, apoptosis, and fibrosis via modulation of NF-κB/cleaved caspase-3/TGF-β signaling molecules |
| title_full | Oral delivery of nerolidol alleviates cyclophosphamide-induced renal inflammation, apoptosis, and fibrosis via modulation of NF-κB/cleaved caspase-3/TGF-β signaling molecules |
| title_fullStr | Oral delivery of nerolidol alleviates cyclophosphamide-induced renal inflammation, apoptosis, and fibrosis via modulation of NF-κB/cleaved caspase-3/TGF-β signaling molecules |
| title_full_unstemmed | Oral delivery of nerolidol alleviates cyclophosphamide-induced renal inflammation, apoptosis, and fibrosis via modulation of NF-κB/cleaved caspase-3/TGF-β signaling molecules |
| title_short | Oral delivery of nerolidol alleviates cyclophosphamide-induced renal inflammation, apoptosis, and fibrosis via modulation of NF-κB/cleaved caspase-3/TGF-β signaling molecules |
| title_sort | oral delivery of nerolidol alleviates cyclophosphamide induced renal inflammation apoptosis and fibrosis via modulation of nf κb cleaved caspase 3 tgf β signaling molecules |
| topic | Nephrotoxicity oxidative stress renal fibrosis and inflammation |
| url | https://www.tandfonline.com/doi/10.1080/10717544.2023.2241661 |
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