PMID- 37559381 OWN - NLM STAT- MEDLINE DCOM- 20230811 LR - 20240320 IS - 1521-0464 (Electronic) IS - 1071-7544 (Print) IS - 1071-7544 (Linking) VI - 30 IP - 1 DP - 2023 Dec TI - Oral delivery of nerolidol alleviates cyclophosphamide-induced renal inflammation, apoptosis, and fibrosis via modulation of NF-kappaB/cleaved caspase-3/TGF-beta signaling molecules. PG - 2241661 LID - 10.1080/10717544.2023.2241661 [doi] LID - 2241661 AB - Cyclophosphamide (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 microM + 30 microM 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-alpha, IL-1beta (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-beta-1 (p < 0.001), when treated with NERO 50 microM whereas NERO 25 microM only reduced the level of cleaved caspase-3 (p < 0.05) when compared with 30 microM. 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-beta1, 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. FAU - Iqubal, Ashif AU - Iqubal A AD - Department of Pharmacology, School of Pharmaceutical Education and Research, New Delhi, India. FAU - Najmi, Abul Kalam AU - Najmi AK AD - Department of Pharmacology, School of Pharmaceutical Education and Research, New Delhi, India. FAU - Md, Shadab AU - Md S AD - Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia. FAU - Alkreathy, Huda Mohammed AU - Alkreathy HM AD - Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. FAU - Ali, Javed AU - Ali J AD - Department of Pharmaceutics, School of Pharmaceutical Education and Research, New Delhi, India. FAU - Syed, Mansoor Ali AU - Syed MA AD - Department of Biotechnology, Jamia Millia Islamia, New Delhi, India. FAU - Haque, Syed Ehtaishamul AU - Haque SE AD - Department of Pharmacology, School of Pharmaceutical Education and Research, New Delhi, India. LA - eng PT - Journal Article PL - England TA - Drug Deliv JT - Drug delivery JID - 9417471 RN - EC 3.4.22.- (Caspase 3) RN - 8N3DW7272P (Cyclophosphamide) RN - QR6IP857S6 (nerolidol) RN - 0 (NF-kappa B) RN - 8W8T17847W (Urea) SB - IM MH - Animals MH - Mice MH - Apoptosis MH - Caspase 3/metabolism MH - Cyclophosphamide/adverse effects MH - Fibrosis MH - Inflammation/chemically induced/drug therapy/metabolism MH - *Kidney/metabolism MH - *NF-kappa B/metabolism MH - Oxidative Stress MH - Urea/metabolism PMC - PMC10946274 OTO - NOTNLM OT - Nephrotoxicity OT - oxidative stress OT - renal fibrosis and inflammation COIS- No potential conflict of interest was reported by the authors. EDAT- 2023/08/10 06:43 MHDA- 2023/08/11 06:43 PMCR- 2023/08/09 CRDT- 2023/08/10 02:11 PHST- 2023/08/11 06:43 [medline] PHST- 2023/08/10 06:43 [pubmed] PHST- 2023/08/10 02:11 [entrez] PHST- 2023/08/09 00:00 [pmc-release] AID - 2241661 [pii] AID - 10.1080/10717544.2023.2241661 [doi] PST - ppublish SO - Drug Deliv. 2023 Dec;30(1):2241661. doi: 10.1080/10717544.2023.2241661.