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Testicular damage has been described as a common side effect of cisplatin (CDDP), which limits its clinical uses. Since oxidative injury and inflammatory response are the most pathological impact, estimation of natural antioxidant and anti-inflammatory agents like trans-ferulic acid (TFA) could protect against CDDP-induced testicular damage. In the current investigation, rats were assigned into four groups: normal, TFA (50 mg/kg/day, P.O), CDDP (10 mg/kg) as single intraperitoneal (I.P) injection at the end of the 5th day, and TFA+CDDP where TFA was administered 5 days before CDDP injection and 5 days after. Interestingly, TFA significantly restored testosterone levels and abrogated oxidative stress injury. Additionally, TFA effectively suppressed inflammatory cytokines. It also counteracted the inflammation via downregulation of TLR4 and IRF3, P38-MAPK, NF-κB-p65, JAK1, STAT3, ERK1, and ERK2. Besides, TFA can modulate AKT and p-AKT protein expressions. In parallel, TFA mitigated the histopathological aberration of the testis and prevented spermatogenesis disruption. On the other hand, TFA augmented the in vitro CDDP cytotoxicity on Caco-2 and MCF-7 cells. Interestingly, TFA enhanced the cytotoxic effect of CDDP via apoptosis induction in both the early and late stages of apoptosis. Collectively, TFA exhibited a potential protective effect against CDDP-induced testicular injury by inhibiting oxidative stress as well as TLR4/IRF3/INF-γ, P38-MAPK/NF-κB-p65/TNF-α, and JAK1/STAT-3/ERK1/2 inflammatory signaling pathways with enhancing its in vitro cytotoxic activity., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cisplatin (CIS)-induced testicular injury is a major obstacle in its application as antineoplastic agent. In this study, we investigated the protective effect and mechanism of roflumilast (ROF), a PDE4 inhibitor, against CIS-induced testicular toxicity in rats. Besides, the cytotoxic effect of CIS, with and without ROF, was evaluated on PC3 cell line. ROF reversed CIS-induced abnormalities in sperm characteristics, normalized serum testosterone level, and ameliorated CIS-induced alterations in testicular and epidydimal weights and restored normal testicular structure. Moreover, ROF increased intracellular cAMP level, PKA and HO-1 activities and Nrf2, NQO-1 and HO-1 gene expression, improved testicular oxidative stress parameters (TBARS, NO, GSH levels, and CAT activity) and inflammatory mediators (IL-1β and TNF-α, and NF-κβ p65gene expression) and reduced the proapoptotic proteins, caspase-3, Bax and increased Bcl-2. Lastly, in vitro analyses showed that ROF augmented the anticancer efficacy of CIS and enhanced the increase in gene expression of Nrf2, HO-1, and NQO-1 and the inhibition of gene expression of NF-κβ p65 induced by CIS and enhanced its apoptotic effect in PC3 cells. Conclusively, PDE4 inhibition with induction of Nrf2/HO-1, NQO-1 is a potential therapeutic approach to protect male reproductive system from the detrimental effects with augmenting, the antineoplastic effect of CIS., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Cisplatin (Cis) is one of the most potent and effective broad-spectrum antitumor drugs, but its use is limited due to nephrotoxicity. The current study investigated the renoprotective effect of umbelliferone (UMB) on Cis-induced nephrotoxicity in rats. Renal injury was induced by a single injection of Cis (7 mg/kg, ip). Our results exhibited that the injection of Cis significantly disrupted renal function biomarkers as well as KIM-1 expression. The expressions of TNF-α, IL-1β, NF-kB-p65, and IKKβ were elevated along with downregulation of IkBα expression. Also, Cis disrupted cellular oxidant/antioxidant balance through the reduction of glutathione (GSH), glutathione-S-transferase (GST), and superoxide dismutase (SOD) levels and elevation of malondialdehyde (MDA) content. On the contrary, the levels of renal function biomarkers, cytokines, NF-kB-p65, IkBα, IKKβ, and oxidant/antioxidant status have been improved after UMB treatment. Mechanistically, rats administered Cis only exhibited a significant decrease in NRF2 and cytoglobin expressions as well as the CREB, SIRT1, FOXO-3, and PPAR-γ genes. Treatment with UMB significantly upregulated NRF2 and cytoglobin proteins, as well as effectively increased the expression of CREB, SIRT1, FOXO-3, PPAR-γ, and NRF2 genes. Histopathological findings strongly supported our biochemical results, as evidenced by attenuation of renal hemorrhage, cast diffusion, and inflammatory cell infiltration. Interestingly, UMB significantly enhanced Cis cytotoxicity in both HL-60 and HeLa cells in a dose-dependent manner. Together, our results demonstrated that UMB can protect against Cis-induced nephrotoxicity in normal rats along with the enhancement of its in vitro antitumor activity. These findings suggested that UMB could be used as a potential adjuvant therapy in Cis chemotherapeutic protocols., (© 2021 Wiley Periodicals LLC.)

Male reproductive toxicity is a well-known adverse effect of cisplatin (CIS), an important antineoplastic agent used to control several types of cancers. Tadalafil (TDF), is a long-acting phosphodiesterase-5 (PDE5) inhibitor commonly used as treatment for erectile dysfunction. The aim of this work was to study the possible protective effect of TDF against CIS-induced testicular toxicity in rats and the possible involvement of Nrf2/HO-1 pathway, which demonstrates antioxidant and inflammatory activities utilizing zinc protoporphyrin-IX (ZnPP) as HO-1 inhibitor. Results revealed that TDF attenuated the CIS-induced disturbances in sperm count and activities, normalized the serum testosterone level, improved the CIS-induced changes in epididymal and testicular weights and restored the normal structure of testicular tissues. In addition, TDF upregulated the gene expression levels of Nrf2 and HO-1 and the activity of HO-1 whereas, it reduced the CIS-induced changes in testicular oxidative stress markers and the levels of inflammatory mediators (TNF-α and iNOS). Furthermore, TDF antagonized the CIS-induced increase in testicular gene expression of apoptotic markers caspase-3 and Bax, and the decrease in Bcl-2. However, ZnPP co-administration significantly attenuated all TDF-mediated improvements in CIS-induced testicular toxicity, biochemical changes, and apoptosis. In conclusion, TDF exerts a protective effect against CIS-induced reproductive toxicity in males, through different mechanisms, besides its inhibitory action to PDE5, possibly mediated by the upregulation of Nrf2/HO-1, along with its antioxidant, anti-inflammatory, and anti-apoptotic effects. Hence, the use of TDF represents a promising therapeutic approach to protect the male reproductive system from the harmful toxic effects of CIS., (Copyright © 2020 Elsevier Inc. All rights reserved.)