Jul 2026· Journal of biochemical and molecular toxicology· Vol 40· 0 citations· 86 references
Medicine
TL;DR
Overall, RA‐loaded Chitosan nanoparticles provided superior protection against CFP‐induced testicular toxicity compared with crude RA, highlighting the potential of nanoformulation strategies to enhance RA's biological efficacy.
Abstract
Chlorfenapyr (CFP) is a widely used pesticide associated with significant toxicological effects, including reproductive toxicity. Rosmarinic acid (RA) possesses potent antioxidant and anti‐inflammatory properties; however, its therapeutic application may be limited by poor physicochemical characteristics. This study investigated the molecular mechanisms underlying CFP‐induced testicular toxicity and evaluated whether nano‐encapsulation of RA within Chitosan nanoparticles (RA‐CHNPs) improves its protective efficacy against CFP‐induced reproductive damage. A total of 60 adult male Wistar rats were allocated into six groups (n = 10/group): control, RA, RA‐CHNPs, CFP, CFP + RA, and CFP + RA‐CHNPs. Animals received oral CFP (180 mg/kg/day) and/or RA (75 mg/kg/day, crude or nano‐encapsulated) for 30 consecutive days. CFP exposure significantly reduced testicular weight, sperm count, sperm motility, luteinizing hormone, follicle‐stimulating hormone, and testosterone levels. These alterations were accompanied by oxidative stress, increased pro‐inflammatory cytokine production, apoptosis, and activation of NF‐κB/NLRP3 signaling. Immunohistochemical analysis revealed marked NF‐κB expression in spermatogenic and Leydig cells, together with strong NLRP3 expression within seminiferous tubules. Co‐administration of RA‐CHNPs was associated with a marked attenuation of these adverse effects, denoting greater protective efficacy than crude RA. RA‐CHNPs reduced NF‐κB and NLRP3 expression, which was accompanied by improved testicular architecture, restored spermatogenic activity, and normalized reproductive hormone levels. These protective effects were associated with activation of the NRF2/HO‐1 antioxidant pathway, suppression of inflammatory responses, and regulation of apoptosis‐related genes. Overall, RA‐loaded Chitosan nanoparticles provided superior protection against CFP‐induced testicular toxicity compared with crude RA, highlighting the potential of nanoformulation strategies to enhance RA's biological efficacy.
Chlorfenapyr (CFP) is a widely used pesticide associated with nephrotoxicity through oxidative stress, inflammation, and mitochondrial dysfunction. This study investigated the protective effects of limonene (LM) and its nano-liposomal formulation (LM-LNPs) against CFP-induced renal injury in rats. Animals were divided into six groups—control, LM, LM-LNPs, CFP, CFP + LM, and CFP + LM-LNPs—and treated orally for 30 days. CFP exposure resulted in marked renal dysfunction, histopathological and ultrastructural damage, suppression of the NRF2/HO-1/NQO1 antioxidant pathway, depletion of endogenous antioxidants excessive generation of reactive oxygen and nitrogen species, lipid peroxidation products, and DNA damage. These changes were accompanied by activation of NF-κB/COX-2-mediated inflammation, mitochondrial respiratory impairment, disrupted energy metabolism, and induction of apoptosis. Co-treatment with LM significantly ameliorated these alterations, whereas LM-LNPs produced greater improvements in renal function, tissue architecture, redox homeostasis, mitochondrial function, and inflammatory and apoptotic signaling. Immunohistochemical analyses further confirmed enhanced NRF2 expression and reduced NF-κB immunoreactivity in LM-LNP-treated kidneys. Overall, nano-liposomal delivery enhanced the renoprotective efficacy of limonene, highlighting its potential as a therapeutic strategy against pesticide-induced kidney injury.
E. Elmorsy, Amina A. Farag, Amal M. Abdel-Kareim et al.· Toxics· 0 citations
Background: Cisplatin is a widely used chemotherapeutic agent whose gonadotoxic effects, largely driven by oxidative stress and inflammation, pose a major threat to male reproductive health. This study evaluated whether hesperetin (HES) and hesperetin-loaded poly (lactic-co-glycolic acid) nanoparticles (HES-PLGA-NPs) can protect against cisplatin-induced testicular dysfunction in adult male Sprague Dawley rats. Methods: Sixty rats were randomly assigned to six groups: control, HES, HES-PLGA-NPs, cisplatin (CIS), CIS + HES, and CIS + HES-PLGA-NPs. CIS (7.5 mg/kg/week, i.p.) was given intraperitoneally for four weeks, while HES and nano-HES (50 mg/kg/day, p.o.) were orally administered concurrently. Reproductive hormones, testicular weight, sperm parameters, oxidative stress and antioxidant markers, NRF2/HO-1 and NF-κB signaling, apoptotic indices, ferroptosis-related markers, histopathology, and GPX4/ACSL4 immunoexpression were assessed. Results: CIS caused marked reproductive dysfunction, including reduced testosterone, FSH, and LH, decreased testicular weight, and impaired sperm quality. These changes were associated with severe oxidative and nitrosative stress (↑ MDA, NO, 8-OHdG), depletion of antioxidant defenses (↓ SOD, CAT, GSH), reduced NRF2/HO-1, elevated NF-κB activity and pro-inflammatory cytokines, apoptosis-related changes (↑ Bax, caspase-3; ↓ Bcl-2), and ferroptosis-associated alterations (↑ Fe2+, TFR1, lipid ROS, ACSL4, 4-HNE; ↓ GPX4, SLC7A11). Both HES and HES-PLGA-NPs were associated with significant amelioration of these alterations, but the nanoformulation showed more pronounced protection, normalizing several oxidative and ferroptosis-associated markers toward control levels and more effectively preserving seminiferous tubule architecture and spermatogenesis. Conclusions: HES-PLGA-NPs were associated with multi-mechanistic protection against cisplatin-induced oxidative, inflammatory, apoptotic, and ferroptosis-associated damage in the testes, and may represent a promising nanoantioxidant candidate warranting further investigation for preserving male reproductive function during chemotherapy.
Mohammed A. Akeel, E. Elmorsy, Aly A. M. Shaalan et al.· Antioxidants· 0 citations
Despite cisplatin (CISP) is broadly employed in cancer therapy, its adverse effects, involving hepatotoxicity, restrict its clinical usage. Thus, this study was designed to explore the prospect of repurposing rupatadine (RUPA), a dual antagonist of histamine and platelet‐activating factor (PAF), against CISP‐evoked hepatotoxicity in rats. Rats were i.p. injected with CISP (6 mg/kg) for the induction of hepatotoxicity on the 8th day of the study in the presence and absence of RUPA in two dosages (3, 6 mg/kg) orally for 14 days. Different biochemical parameters and histopathological assessments, along with the mechanistic characterizations of the possible protective impact of the RUPA were conducted. Administration of CISP evoked hepatic histopathological modifications and raised serum liver enzyme levels and hepatic MDA content, PAF, and histamine levels, along with diminishing the serum albumin level, hepatic SOD activity, and GSH level. Moreover, CISP remarkably augmented the levels of HMGB1, TLR4, p‐NF‐κB p65, IL‐6, TNF‐α, IL‐18, IL‐1β, NLRP3, and cleaved caspase‐1 proteins with an evident decline in the level of IL‐10. On the contrary, pretreatment with either RUPA.3 or RUPA.6 dramatically ameliorated these alterations triggered by CISP injection. 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
Methotrexate (MTX) is a widely used chemotherapeutic and immunosuppressive agent; however, its clinical use is limited by severe testicular toxicity associated with oxidative stress, inflammation, apoptosis, and ferroptosis. Therefore, the present study investigated the protective effects of icariin-loaded nanoliposomal formulation (ICA-LNPs) against MTX-induced testicular injury in rats compared with crude icariin (ICA). Sixty adult male Sprague Dawley rats were randomly allocated into six groups: control, ICA, ICA-LNPs, MTX, MTX+ICA, and MTX+ICA-LNPs. MTX administration markedly impaired reproductive function, evidenced by significant reductions in testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), sperm count, motility, and viability, together with increased sperm abnormalities. MTX also disrupted the NRF2/HO-1/NQO1 signaling pathway, suppressed antioxidant defenses, and elevated oxidative stress markers. In addition, MTX significantly activated NF-κB-mediated inflammatory responses, enhanced apoptotic and ferroptotic pathways, increased iron accumulation and ACSL4 expression, and reduced GPX4 and SLC7A11 expression in testicular tissue. Histopathological examination further confirmed severe degeneration of seminiferous tubules and impaired spermatogenesis. Treatment with ICA-LNPs significantly ameliorated these alterations and demonstrated superior protective efficacy compared with crude ICA. ICA-LNPs restored reproductive hormones, improved semen quality, enhanced antioxidant status, suppressed inflammatory mediators, reduced apoptosis and ferroptosis-related markers, and preserved normal testicular histoarchitecture. Furthermore, GPX4 immunoreactivity was markedly increased, whereas ACSL4 expression was significantly reduced following ICA-LNPs treatment. In conclusion, ICA-loaded nanoliposomal formulation effectively attenuated MTX-induced testicular toxicity and was associated with reduced oxidative stress, inflammation, apoptosis, and ferroptosis, highlighting its potential as a promising therapeutic strategy for preserving male reproductive function.
Ahmed Al-Emam, Salim Jamil, Hesham M Hassan et al.· Reproductive Toxicology· 0 citations
Cardiotoxicity induced by doxorubicin (Dox) significantly contributes to increased mortality among cancer patients, yet available pharmacological interventions remain scarce. Recent studies suggest that ferroptosis is a key mechanism in the development of Dox‐induced cardiotoxicity (DIC). Morroniside (Mor), an active iridoid glycoside isolated from Cornus officinalis, exhibits multiple pharmacological properties such as antioxidant, anti‐ferroptotic, and anti‐inflammatory activities. Given this multi‐target profile, Mor shows potential as a treatment option for reducing DIC. This work was designed to examine the association between Mor and DIC. In vivo DIC model, C57BL/J mice received 5 mg/kg/d Mor via oral gavage for 5 weeks. In vitro DIC model, H9c2 cells were exposed to 10 μM Mor over a 48‐h period. Cardiac injury markers were quantified in serum and cell culture supernatants. Biochemical assays, western blotting, cellular immunofluorescence, and DHE/ROS staining were employed to evaluate ferroptosis and oxidative stress. Mor administration substantially reduced the levels of cardiac injury biomarkers while simultaneously attenuating ferroptosis and oxidative stress in vivo. In cellular models, Mor exhibited potent anti‐ferroptotic and antioxidant effects through Nrf2 pathway activation. Further mechanistic studies identified PI3K/AKT pathway as the upstream regulator of Nrf2 activation in response to Mor treatment. Our study provided the first evidence for Mor's cardioprotective effects against DIC. Mechanistically, Mor attenuated DIC by suppressing ferroptosis and reducing oxidative stress via activation of the PI3K/AKT/Nrf2/HO‐1 signaling pathway.
Zhi-Hui Lin, Xingyu Lin, Wen-Jie Lu et al.· Journal of biochemical and m...· 0 citations
