Aug 2026· Toxicology and Applied Pharmacology· Vol 515, pp.
117983
· 0 citations· 48 references
Medicine
Abstract
Cyclophosphamide is a currently used antineoplastic drug to manage a number of malignant tumors. Hepatotoxicity is one of the most significant complications of cyclophosphamide therapy, which restricts its clinical application. Protodioscin, as a natural saponin, possesses multiple striking biological properties. This preclinical research was conducted to assess the ameliorative influences of protodioscin against cyclophosphamide-triggered hepatotoxicity. Forty male mice were apportioned into five distinct groups: control (normal saline) group, cyclophosphamide (200 mg/kg, i.p.) group, protodioscin (12.5, 25, and 50 mg/kg, i.p.) + cyclophosphamide groups. The mice received protodioscin for 10 days and cyclophosphamide was administrated on day 5. The results exhibited that protodioscin significantly attenuated the activities of ALT, AST, and ALP as well as the serum level of total bilirubin. Protodioscin remarkably inhibited ROS generation and upregulated the protein expression of NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) to suppress hepatic oxidative stress as documented by an increase in SOD level and a reduction in MDA level. Furthermore, protodioscin remarkably diminished the protein expression of nuclear factor κB (NF-κB) and NLRP3 as well as the mRNA expression of tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) to inhibit hepatic inflammation. Protodioscin markedly downregulated the mRNA expression of Bax and caspase-3 and upregulated the mRNA expression of Bcl-2 to block hepatic apoptosis. Notably, protodioscin treatment effectively improved the cyclophosphamide-induced pathological alterations in liver tissue. These data accentuate that protodioscin can serve as a promising hepatoprotective compound to considerably prevent liver damage caused by cyclophosphamide.
Background/Objectives: The clinical efficacy of cyclophosphamide, a commonly used chemotherapeutic drug, is often restricted by off-target neurotoxicity, which is primarily caused by oxidative stress, neuroinflammation, and apoptosis. With the aim of finding natural neuroprotective agents, pterostilbene was investigated in this study, either in conventional form or when solubilized as a nanoemulsion, for its neuroprotective potential against cyclophosphamide-induced neurotoxicity. Methods: Female Wistar rats were orally administered pterostilbene, either in its conventional form (50 mg/kg p.o) or nanoemulsion form (25 and 50 mg/kg p.o), for 15 days. Cyclophosphamide was injected once on day 14 (200 mg/kg ip). Results: Our findings revealed that administering pterostilbene as a nanoemulsion or in its conventional powder form managed to counteract the cyclophosphamide-induced intoxication features via disrupting the oxidative stress–inflammasome–cytokine axis; by upregulating cortical and hippocampal PPAR-γ, Nrf2, HO-1, BCL2 levels and the BCL2/Bax ratio; and downregulating NLRP3, IL-1β, COX-2, Bax and GFAP levels. Further histopathological and immunohistochemical evaluation confirmed the improved neuronal morphology, reduced degeneration and apoptosis, restoration of cortical and hippocampal architecture, and normalization of GFAP expression levels, approaching those of the control group upon treatment with either conventional or nanoformulated pterostilbene. Conclusions: The promising nature of the nanoemulsion formulation, particularly when administered at the high dose level, was evidenced, hence emphasizing the important role of proper formulation of natural bioactives such as pterostilbene in maximizing their therapeutic potential.
R. Ahmed, Hadir Farouk, Y. A. Hussien et al.· Biomedicines· 0 citations
Cyclophosphamide (Cyclo) is an effective chemotherapeutic agent, but its clinical use is limited by severe cardiotoxicity driven by oxidative stress, inflammation, and apoptosis. Natural antioxidants such as carnosic acid (CA) may offer protection. This study aimed to investigate the protective effects of CA against Cyclo-induced cardiotoxicity in rats and to elucidate the underlying molecular mechanisms. Forty male Wistar rats were divided into four groups: control, CA alone, Cyclo alone, and Cyclo + CA. CA was administered orally at 100 mg/kg for 14 days, while Cyclo was injected intraperitoneally at 100 mg/kg on day 14. Cardiac injury was assessed using serum biomarkers, histology, immunohistochemistry (NF-κB, TNF-α, IL-1β, caspase-3), RT-PCR (Keap-1, Nrf2, HO-1, Bax, Bcl-2), and oxidative stress markers. Cyclo significantly elevated serum cardiac injury markers (CK, troponin, and LDH), as well as hepatic injury markers (ALT and AST), and induced severe histopathological damage, including leukocytic infiltration, congestion, edema, and fibrosis. Mechanistically, Cyclo suppressed the Keap1/Nrf2/HO-1 pathway by downregulating Nrf2 and HO-1 while upregulating Keap-1. Cyclo also depleted antioxidant enzyme activities (SOD, GPx, CAT), increased lipid peroxidation (MDA), activated NF-κB-driven pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and promoted apoptosis via upregulation of Bax and caspase-3 alongside downregulation of Bcl-2. Co-treatment with CA markedly reversed all these pathological changes, restoring antioxidant and Nrf2/HO-1 signaling, reducing inflammatory markers, inhibiting apoptosis, and improving cardiac histology. CA effectively attenuates Cyclo-induced cardiotoxicity through its antioxidant, anti-inflammatory, and anti-apoptotic properties. These protective effects are likely associated with modulation of the Keap-1/Nrf2/HO-1 and NF-κB signaling pathways, highlighting CA’s therapeutic potential as a natural cardioprotective agent in chemotherapy-associated cardiac injury. Proposed schematic representation of the cardioprotective mechanism of CA against Cyclo-induced cardiotoxicity based on the present findings and previously published literature. Cyclophosphamide exposure leads to cardiac damage through the induction of oxidative stress, inflammation (NF-κB-mediated), and disorganization of cardiac histology, ultimately resulting in cardiotoxicity. Carnosic Acid mitigates this damage by activating the KEAP-1/NRF2/HO-1 pathway. This activation inhibits cytosolic Nrf2 degradation, allowing it to translocate to the nucleus and activate the Antioxidant Response Element (ARE). Concurrently, CA inhibits the NF-κB cascade, reducing the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). The combined effect is a reduction in oxidative stress (↓ROS, ↓MDA), inflammation, and apoptosis (as indicated by modulated Bax, Bcl-2, and Caspase-3), leading to decreased serum injury markers (CK, LDH, Troponin, AST, ALT, MDA), improved cardiac histology, and mitigation of cardiotoxicity.
Basma Salah, A. Abdelmonsef, Medhat Taha et al.· Bratislava Medical Journal· 0 citations
RUPA counteracts hepatotoxicity evoked by CISP in rats via its anti‐oxidative as well as anti‐inflammatory properties via repression of hepatic HMGB1/TLR4/NF‐κB and thus restricts the activation of NLRP3/caspase‐1 signaling cascade.
Shaimaa Mohamed Abdelrahman, A. Bekhit, Olivia N. Beshay· Journal of biochemical and m...· 0 citations
Background
Although microRNAs have been investigated, the reno-protective role of microRNA-205 (miR-205) in cyclophosphamide (CPA)-induced nephrotoxicity has not yet been explored. Therefore, this study evaluated the influence of buspirone on miR-205 and its downstream target EGLN2, focusing on oxidative and ER stress as key drivers of renal injury. This represents a significant gap in nephrotoxicology and epigenetic Toxicology research.
Methods
Animals were randomly allocated among four groups (n = 8), including the normal control group and the CPA group that received one intraperitoneal injection of CPA at 200 mg/kg on day 7. Buspirone at 5 or 10 mg/kg per day was administered by oral gavage for ten consecutive days, whereas CPA injected on the seventh day. At experimental completion, blood samples and renal tissues were subjected to analysis using biochemical, histopathological, immunohistochemical, Western blotting, and qRT-PCR techniques.
Results
CPA induced marked renal dysfunction, reflected by elevated SCr, BUN, NGAL, and KIM-1, with evident histopathological damage. This was accompanied by miR-205 suppression, EGLN2 upregulation, impaired Nrf2 signaling, increased PC levels, and stimulation of PERK/eIF2α/ATF4/CHOP-linked ER stress signaling (p < 0.01). Concurrently, activation of JNK1, Fos, and NF-κB increased inflammatory cytokines, and initiated caspase-dependent apoptotic signaling (p < 0.01). Buspirone pretreatment mitigated these alterations, accompanied by increased miR-205 expression, reduced EGLN2 expression, enhanced Nrf2-associated antioxidant defenses, and attenuation of ER stress, inflammation, and apoptosis, thereby preserving renal function and tissue integrity.
Conclusion
These findings highlight the preventive renoprotective potential of buspirone against CPA-induced nephrotoxicity and underscore the relevance of miR-205/EGLN2 signaling in renal stress responses. Future toxicokinetic and toxicodynamic studies should evaluate buspirone's safety in tumor treatment.
Ahmed M. El-Dessouki, A. Alrashidi, Mohammad I Jumaa et al.· Frontiers in Pharmacology· 0 citations
Myelotoxicity is a common adverse effect of vincristine and other chemotherapeutic drugs. Hesperetin is a bioactive flavanone with anti-inflammatory activity. This study was planned to examine the hesperetin protecting effect against vincristine induced myelosuppression and splenic inflammation in mice and test whether this effect is mediated through the suppression of Toll-like receptor 4 (TLR4)/myeloid differentiation primary response-88 (MYD88)/nuclear factor-kappa B (NF-κB) signaling pathways.
Bioinformatics tools were used to establish the rationale of the study and molecular docking defined the potential binding of hesperetin to TLR4. Mice were allocated into different experimental groups: Group 1: was the saline mice, Group 2; mice were injected with vincristine (0.1 mg/kg, i. p) for 5 days per week, Group 3; mice received vincristine (as in Group 2) plus hesperetin (100 mg/kg, p. o.) and Group 4; mice received hesperetin (100 mg/kg, p. o.) only; the experiment continued for 2 weeks.
The mouse experiment showed that vincristine produced significant decreases in hematological parameters (mainly leukocytes dropped to 4.6 ± 0.32 and platelets dropped to 799.6 ± 25.46 versus 9.48 ± 0.19 and 1654 ± 273.26 × 10
˄
9/L in the saline group, p less than 0.05) and bone marrow hypocellularity (dropped to ∼30–40% compared to 95%–100% in the saline group). The spleens showed white pulp lymphoid depletion, red pulp mild hypocellularity, greater immunostaining for MYD88, and greater content for TLR4, NF-κB, MYD88, TNF-α and IL-1β proteins. Results of molecular docking showed that hesperetin is an interesting complementarity with the TLR4/MD2 interface which was a good rationale for the experimental validation. The mouse experiment showed that hesperetin prevented the decrease hematological parameters, enhanced the bone marrow cellularity to 80%–90%, and the splenic architecture. Hesperetin further inhibited the increases in the target proteins (TLR4, NF-κB, MYD88, TNF-α and IL-1β) significantly.
The present data documents the novel role of hesperetin in mitigating myelotoxicity of vincristine through modulation of TLR4/MYD88/NF-κB signaling and a direct binding to TLR4 was proposed by molecular docking. This highlights possible usefulness of this combination after adequate clinical studies.
Ghada A. Badawi, Asmaa K. K. AbdelMaogood, Nada H. Ahmed et al.· Frontiers in Pharmacology· 0 citations
Man could be considered as a potential protective agent against HgCl2-induced liver injury through controlling oxidative stress, inflammation, and apoptosis.
Hager E Hassan, Sara H. Hazem, M. Zaghloul· Naunyn-Schmiedeberg's Archiv...· 0 citations
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