Cisplatin-induced Damage Research Articles

Human umbilical cord mesenchymal stem cells restore chemotherapy-induced premature ovarian failure by inhibiting ferroptosis in vitro ovarian culture system

BackgroundMesenchymal stem cells (MSCs) have shown potential in repairing chemotherapy-induced premature ovarian failure (POF). However, challenges such as stem cell loss and immune phagocytosis post-transplantation hinder their application. Due to easy and safe handling, in vitro ovarian culture is widely available for drug screening, pathophysiological research, and in vitro fertilization. MSCs could exhibit therapeutic capacity for ovarian injury, and avoid stem cell loss and immune phagocytosis in vitro tissue culture system. Therefore, this study utilizes an in vitro ovarian culture system to investigate the reparative potential of human umbilical cord mesenchymal stem cells (hUCMSCs) and their mechanism.MethodsIn this study, a chemotherapy-induced POF model was established by introducing cisplatin in vitro ovarian culture system. The reparative effects of hUCMSCs on damaged ovarian tissue were validated through Transwell chambers. Tissue histology examination, immunohistochemical staining, Western blotting, and RT-PCR were employed to evaluate the expression effects of hUCMSCs on ferroptosis and fibrosis-related genes during the process of repairing cisplatin-induced POF.ResultsCisplatin was found to activate ovarian follicles in vitro POF model. Transcriptomic sequencing analysis revealed that cisplatin could activate genes associated with ferroptosis. hUCMSCs alleviated cisplatin-induced POF by suppressing the expression of ferroptosis. Moreover, inhibiting ferroptosis by hUCMSCs also ameliorated ovarian hormone levels and reduced the expression of fibrosis-related factors α-SMA and COL-I in the ovaries.ConclusionsThis study confirms that cisplatin-induced ovarian damage via ferroptosis in vitro POF model, and hUCMSCs repair ovarian injury by inhibiting the ferroptosis pathway and suppressing fibrosis. This research contributes to evaluating the effectiveness of hUCMSCs in treating chemotherapy-induced POF by inhibiting ferroptosis in an in vitro ovarian culture system and provides a potential therapeutic strategy for chemotherapy-induced POF.

Chiisanoside from the Leaves of Acanthopanax sessiliflorus Can Resist Cisplatin-Induced Ototoxicity by Maintaining Cytoskeletal Homeostasis and Inhibiting Ferroptosis.

Ototoxicity is a common side effect of cisplatin cancer treatment, potentially leading to hearing loss. This study demonstrated the significant protective activity of Acanthopanax sessiliflorus (A. sessiliflorus) leaves against cisplatin-induced ototoxicity (CIO), investigated the active compounds, and elucidated their mechanisms in countering CIO. UPLC-Q/TOF-MS analysis identified 79 compounds. Network pharmacology and activity screening determined that chiisanoside (CSS) plays a crucial role in combating CIO. Transcriptomics combined with network pharmacology analysis and experiments revealed that CSS activates the Dock1/PIP5K1A pathway to suppress the actin-severing protein gelsolin, protecting hair cells from cisplatin-induced cytoskeleton damage. CSS also activates the SLC7A11/GPX4 pathway via TGFBR2, reducing lipid peroxidation and intracellular iron accumulation to suppress cisplatin-induced ferroptosis. This study discovers that the major component CSS in A. sessiliflorus leaves reverses CIO by regulating actin homeostasis via Dock1 and inhibiting ferroptosis through TGFBR2, providing a theoretical basis for expanding CIO treatment targets and related drug development.

Integrated global proteomic and phosphoproteomic analysis of cisplatin-induced apoptosis in A549 cells

Protein phosphorylation, a widely occurring and significant post-translational modification, is integral to various biological processes. We previously utilized a protein affinity probe to identify genes damaged by cisplatin, revealing that it inflicts substantial damage on protein kinase and protein phosphatase genes. In this study, we investigated cisplatin-induced alterations in the global proteome and phosphoproteome of A549 cells. Employing Fe-IMAC beads and tyrosine phosphorylation enrichment antibodies, we identified 6944 protein groups and 18,274 phosphorylation sites on 4,915 proteins across three biological replicates of both cisplatin-treated A549 cells and control cells. Among these, 730 tyrosine phosphorylation sites were identified—marking the most substantial discovery of such sites in A549 cells following cisplatin treatment. Bioinformatics analysis indicated that the proteins exhibiting significant phosphorylation level changes predominantly involved in RNA processing, modification, transcription, translation, and the spliceosome. This suggests that cisplatin-induced damage to protein kinases and phosphatases may disrupt the normal function of these proteins, consequently impairing DNA replication, RNA translation, and shearing, ultimately culminating in tumor cell death. Moreover, we cross-referenced our proteomic data with our previously obtained cisplatin-damaged genes, observing that the majority of down-regulated proteins derived from cisplatin-induced gene damage. The data are available on ProteomeXchange under the identifier PXD053902.

Apigenin attenuates cisplatin-induced hair cell damage in the zebrafish lateral line

Cisplatin, a widely used chemotherapy drug, is notorious for causing ototoxicity, which leads to irreversible sensorineural hearing loss by damaging cochlear sensory hair cells (HCs), spiral ganglion neurons (SGNs), and the stria vascularis (SV). Mechanisms include DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammation, ultimately triggering cell death pathways like apoptosis, necroptosis, pyroptosis, or ferroptosis. Apigenin, a natural flavonoid found in various foods and beverages, possesses antioxidant, anti-inflammatory, and anti-tumor properties. Despite these benefits, its potential to mitigate cisplatin-induced ototoxicity remains unexplored. To investigate, we administered varying concentrations of apigenin (1 μM, 20 μM, 100 μM, and 250 μM) alongside cisplatin (200 μM) to zebrafish larvae at 5 days post fertilization. Cisplatin significantly reduced lateral line HCs, impacting auditory function as shown in startle response tests. However, co-administration with apigenin preserved lateral line HCs and mitigated cisplatin-induced hearing loss. In larvae exposed to cisplatin, TUNEL assay confirmed significant HCs apoptosis, which apigenin effectively countered by suppressing reactive oxygen species accumulation in lateral line HCs. RNA-seq analysis highlighted apigenin's role in modulating apoptosis-related pathways, supporting its protective effects against cisplatin-induced ototoxicity. These findings underscore apigenin's potential as a crucial protective agent against cisplatin-induced ototoxicity, meriting further investigation for clinical applications.

TNFRSF10D expression as a potential biomarker for cisplatin-induced damage and ovarian tumor relapse prediction

Among gynecological malignancies, ovarian cancer (OC) presents the most challenging diagnostic scenario. Despite exhaustive efforts, up to 90% of patients treated with taxane/platinum-based chemotherapy experience relapse, leading to poor survival rates. Identifying new molecular markers that can characterize disease aggressiveness, chemoresistance, recurrence risk, and metastasis is crucial. This study aimed to assess the susceptibility of three ovarian tumor cell lines (TOV-21G, SKOV-3, and OV-90) to cisplatin and paclitaxel, and to investigate the influence of these treatments on the mRNA expression of TANK, RIPK1, NFKB1, TNFRSF10D, and TRAF2. Among the cell lines, SKOV-3 ovarian adenocarcinoma cells demonstrated the highest resistance to cisplatin treatment (0.125mg/mL), followed by TOV-21G (0.076mg/mL) and OV-90 cells (0.028mg/mL). Regarding paclitaxel treatment, the SKOV-3 cell line exhibited the highest resistance (1.4µg/mL), followed by OV-90 (1.3µg/mL) and TOV-21G cells (0.9µg/mL). Gene expression analysis after paclitaxel treatment remained unchanged; however, after cisplatin treatment, TNFRSF10D was observed to be upregulated nearly 100-fold in SKOV-3 compared to all other cell lines studied. SKOV-3 is described as cisplatin and tumor necrosis factor-resistant. Despite the defective signaling of the TNFRSF10D receptor for apoptosis, it can activate the NFKB transcription factor through non-canonical TRAIL signaling, contributing to a pro-inflammatory immune response. In light of this, damage associated with cisplatin increases TNFRSF10D expression and may promote cell survival through non-canonical NFKB pathway activation. This suggests that resistance to TRAIL-induced apoptosis in these cells could serve as a promising chemoresistance biomarker in OC.

Mitigation of Cisplatin-Induced Nephrotoxicity and Augmentation of Anticancer Potency via Tea Polyphenol Nanoparticles' Codelivery of siRNA from CRISPR/Cas9 Screened Targets.

Cisplatin, a frontline chemotherapeutic agent against cancer, faces challenges in clinical application due to significant toxicities and suboptimal efficacy. Renal toxicity, a dose-limiting factor of cisplatin, results from multifactorial processes including cisplatin-induced cellular pyroptosis, oxidative damage, and inflammatory responses. Our findings reveal that Tea Polyphenols Nanoparticles (TPNs) derived from Epigallocatechin gallate (EGCG) effectively could address these diverse mechanisms, comprehensively alleviating cisplatin-induced nephrotoxicity. Leveraging TPNs as carriers, chemical conjugation enables the encapsulation of tetravalent cisplatin prodrug, extending its systemic half-life, enhancing tumor tissue accumulation, while simultaneously mitigating renal toxicity. Concurrently, employing a CRISPR/Cas9 kinase library, we identified CSNK2A1 as a target sensitizing tumor cells to cisplatin, enabling specific siRNA sequences to augment cisplatin susceptibility, thereby minimizing the dosage requirement. Benefiting from the versatile carrier properties of TPNs to codeliver cisplatin prodrug and anti-CSNK2A1 siRNA, we developed a codelivery system, Pt-TPNs/siRNA. Pt-TPNs/siRNA not only enhances the anticancer effects but also mitigates cisplatin-induced renal toxicity, achieving efficacy while reducing toxicity. Mechanistic and safety assessments of these nanoparticles were conducted at both cellular and animal levels, opening new avenues for improved clinical utilization of cisplatin.

Notoginsenoside R1 Attenuates Cisplatin-Induced Ototoxicity by Inducing Heme Oxygenase-1 Expression and Suppressing Oxidative Stress.

Cisplatin-induced ototoxicity occurs in approximately half of patients treated with cisplatin, and pediatric patients are more likely to be affected than adults. The oxidative stress elicited by cisplatin is a key contributor to the pathogenesis of ototoxicity. Notoginsenoside R1 (NGR1), the main bioactive compound of Panax notoginseng saponins, has antioxidant and antiapoptotic effects. This study investigated the ability of NGR1 to protect against cisplatin-induced damage in auditory HEI-OC1 cells and neonatal murine cochlear explants. The viability of HEI-OC1 cells treated with NGR1 and cisplatin was greater than that of cells treated with cisplatin alone. The results of Western blots and immunostaining for cleaved caspase-3 revealed that the level of cleaved caspase-3 in the cells treated with cisplatin was repressed by NGR1. NGR1 attenuated cisplatin-induced cytotoxicity in HEI-OC1 cells. Intracellular reactive oxygen species (ROS) were detected with a DCFDA assay and immunostaining for 4-HNE. The result revealed that its expression was induced by cisplatin and was significantly reduced by NGR1. Moreover, NGR1 can promote heme oxygenase-1 (HO-1) expression at both the mRNA and protein levels. ZNPPIX, an HO-1 inhibitor, was administered to cisplatin-treated cells to investigate the role of HO-1 in the protective effect of NGR1. The suppression of HO-1 activity by ZNPPIX markedly abolished the protective effect of NGR1 on cisplatin-treated cells. Therefore, NGR1 protects cells from cisplatin-induced damage by activating HO-1 and its antioxidative activity. In cochlear explants, NGR1 protects cochlear hair cells and attenuates cisplatin-induced ototoxicity by inhibiting ROS generation. In the group treated with cisplatin alone, prominent loss of outer hair cells and severe damage to the structure of the stereociliary bundles of inner and outer hair cells were observed. Compared with the group treated with cisplatin alone, less loss of outer hair cells (p = 0.009) and better preservation of the stereociliary bundles of hair cells were observed in the group treated with cisplatin and NGR1. In conclusion, these findings indicate that NGR1 can protect against cisplatin-induced ototoxicity by inducing HO-1 expression and suppressing oxidative stress.

Cisplatin vestibulotoxicity: a current review.

Cisplatin, a commonly used chemotherapy drug, is well-established for its ototoxic effects, primarily attributed to the damage it inflicts on cochlear hair cells. However, its impact on the vestibular system remains inadequately understood. Here, we provide a comprehensive review of existing literature concerning cisplatin-induced vestibulotoxicity. Animal studies have shown that cisplatin induces a vestibular hair cell loss that is dose-dependent, with the severity of damage also varying according to the route of administration. Notably, intratympanic and systemic injections in animal models have manifested significant damage primarily to utricular hair cells, with a lesser degree of damage observed for the other vestibular end organs. The underlying mechanisms of cisplatin induced vestibular hair cell loss include apoptosis, oxidative stress, and inflammatory cytokines. Several protective agents, such as Pifithrin-α, DAPT, Ginkgolide B, and heat shock proteins, have demonstrated efficacy in inhibiting cisplatin-induced vestibular damage in preclinical studies. Human clinical findings indicate that cisplatin treatment can cause vestibular dysfunction, characterized by symptoms ranging from transient dizziness to persistent vertigo. Challenges in diagnosis, including the limited utilization of comprehensive vestibular testing for many patients, contribute to the variability in reported outcomes. Cisplatin-induced vestibulotoxicity is a significant complication of chemotherapy, necessitating further research to understand its mechanisms and to improve diagnosis and management, ultimately aiming to enhance the quality of life for cancer patients undergoing cisplatin therapy.

Thymoquinone Effects on the Expression of p62 Gene in Cisplatin-Induced Testicular Damage in Mice

Background: Cisplatin (CPN) is widely used for the management of various malignant tumors. Objectives: This study investigated the effects of Thymoquinone (TQN) on the expression of the p62 gene in CPN-induced testicular damage in mice. Methods: Histomorphometry, testis injury scores, expression of p62, and protein levels of LC3-II were assessed. Results: Cisplatin induced histological changes, increased p62 expression (P < 0.01), and reduced LC3-II levels (P < 0.001). Thymoquinone pretreatment decreased p62 expression while increasing LC3-II protein levels. Thymoquinone significantly reversed the testicular injury scores and improved histomorphometric parameters. Conclusions: The results indicate that TQN enhances autophagy and improves testicular tissue in CPN-intoxicated mice.

DEWNA: dynamic entropy weight network analysis and its application to the DNA-binding proteome in A549 cells with cisplatin-induced damage.

Cisplatin is one of the most commonly used chemotherapy drugs for treating solid tumors. As a genotoxic agent, cisplatin binds to DNA and forms platinum-DNA adducts that cause DNA damage and activate a series of signaling pathways mediated by various DNA-binding proteins (DBPs), ultimately leading to cell death. Therefore, DBPs play crucial roles in the cellular response to cisplatin and in determining cell fate. However, systematic studies of DBPs responding to cisplatin damage and their temporal dynamics are still lacking. To address this, we developed a novel and user-friendly stand-alone software, DEWNA, designed for dynamic entropy weight network analysis to reveal the dynamic changes of DBPs and their functions. DEWNA utilizes the entropy weight method, multiscale embedded gene co-expression network analysis and generalized reporter score-based analysis to process time-course proteome expression data, helping scientists identify protein hubs and pathway entropy profiles during disease progression. We applied DEWNA to a dataset of DBPs from A549 cells responding to cisplatin-induced damage across 8 time points, with data generated by data-independent acquisition mass spectrometry (DIA-MS). The results demonstrate that DEWNA can effectively identify protein hubs and associated pathways that are significantly altered in response to cisplatin-induced DNA damage, and offer a comprehensive view of how different pathways interact and respond dynamically over time to cisplatin treatment. Notably, we observed the dynamic activation of distinct DNA repair pathways and cell death mechanisms during the drug treatment time course, providing new insights into the molecular mechanisms underlying the cellular response to DNA damage.

PARVB deficiency alleviates cisplatin-induced tubular injury by inhibiting TAK1 signaling

Cisplatin-induced renal tubular injury largely restricts the wide-spread usage of cisplatin in the treatment of malignancies. Identifying the key signaling pathways that regulate cisplatin-induced renal tubular injury is thus clinically important. PARVB, a focal adhesion protein, plays a crucial role in tumorigenesis. However, the function of PARVB in kidney disease is largely unknown. To investigate whether and how PARVB contributes to cisplatin-induced renal tubular injury, a mouse model (PARVB cKO) was generated in which PARVB gene was specifically deleted from proximal tubular epithelial cells using the Cre-LoxP system. In this study, we found depletion of PARVB in proximal tubular epithelial cells significantly attenuates cisplatin-induced renal tubular injury, including tubular cell death and inflammation. Mechanistically, PARVB associates with transforming growth factor-β-activated kinase 1 (TAK1), a central regulator of cell survival and inflammation that is critically involved in mediating cisplatin-induced renal tubular injury. Depletion of PARVB promotes cisplatin-induced TAK1 degradation, inhibits TAK1 downstream signaling, and ultimately alleviates cisplatin-induced tubular cell damage. Restoration of PARVB or TAK1 in PARVB-deficient cells aggravates cisplatin-induced tubular cell injury. Finally, we demonstrated that PARVB regulates TAK1 protein expression through an E3 ligase ITCH-dependent pathway. PARVB prevents ITCH association with TAK1 to block its ubiquitination. Our study reveals that PARVB deficiency protects against cisplatin-induced tubular injury through regulation of TAK1 signaling and indicates targeting this pathway may provide a novel therapeutic strategy to alleviate cisplatin-induced kidney damage.

Melatonin Mitigates Cisplatin-Induced Submandibular Gland Damage by Inhibiting Oxidative Stress, Inflammation, Apoptosis, and Fibrosis.

The study aims to examine the possible effect of melatonin against cisplatin-induced submandibular degeneration in experimental rats exploring its ameliorative mechanisms. Rats were classified into four experimental groups; control group; melatonin group; cisplatin group; and cisplatin+melatonin group. Submandibular tissues were collected. Biochemical, histopathological, and immunohistopathological examination and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis were performed. The results indicate that intraperitoneal administration of melatonin (30 mg/kg body weight) alongsidecisplatin significantly elevated submandibular glands (SMG) and reduced glutathione (GSH) and superoxide dismutase (SOD) levels (p < 0.001), while it reducedmalondialdehyde (MDA) levels, NF-κB gene expression, the protein level of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), immunoexpression of low-dose cyclooxygenase-2 (Cox-2), and CD68. Moreover, melatonin reduced immune and gene expression of alpha-smooth muscle actin (α-SMA), immunoexpression of caspase-3, and gene expression of Bax in comparison to the cisplatin group. Melatonin attenuated cisplatin-induced submandibular destruction alleviating SMG oxidative stress, inflammation, and fibrosis in addition to halting cellular apoptosis, sheds light on its usage in clinical application.

Cisplatin induces acute liver injury by triggering caspase-3/GSDME-mediated cell pyroptosis

BackgroundCisplatin triggers Gasdermin E (GSDME) cleavage, causing membrane bubble formation, content release, and inflammation. Caspase-3 activation initiates GSDME cleavage, and thus inhibiting this pathway mitigates cisplatin-induced pyroptosis in hepatocytes. This study aimed to delve into how cisplatin induces liver injury via pyroptosis. MethodsFor animal experiments, C57BL/6J mice were divided into three groups: control, liver injury model group, and Ac-DMLD-CMK (caspase-3 inhibitor) intervention group. The liver histology was evaluated by hematoxylin and eosin staining, immunohistochemistry, immunofluorescence and TUNEL staining. The mRNA and protein levels were detected by real-time polymerase chain reaction (PCR) and Western blot analysis. For in vitro experiments, HL-7702 cells were treated with cisplatin or GSDME siRNA. Cell pyroptosis was determined via cellular morphology, cytotoxicity and viability detection, flow cytometric assay, and Western blot detection for the expression of pyroptosis-related proteins. ResultsCisplatin-induced distinct liver morphological changes, hepatocellular injury, and inflammation in mice, along with elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and increased pro-inflammatory cytokine expression. Heightened macrophage infiltration and hepatocellular death indicated cisplatin-induced hepatotoxicity. Cisplatin upregulated GSDME activation, along with Bax-mediated caspase-3 cleavage both in vivo and in vitro, implicating caspase-3/GSDME-dependent pyroptosis in liver injury. Treatment with Ac-DMLD-CMK ameliorated cisplatin-induced liver injury, reducing hepatocellular lesions, serum ALT and AST levels, cytokine expression, macrophage infiltration, and hepatocyte death. Ac-DMLD-CMK also attenuated GSDME-dependent pyroptosis post-cisplatin induction, as evidenced by decreased GSDME expression, Bax upregulation, and cleaved caspase-3 activation. For HL-7702 cells, GSDME siRNA transfection reduced GSDME expression, attenuated typical signs of cisplatin-induced pyroptosis, partially restored cell viability, and significantly inhibited cytotoxicity and a decrease in the proportion of propidium iodide-positive cells, indicating protection against cisplatin-induced hepatocyte pyroptosis. ConclusionOur study underscores the role of the caspase-3/GSDME signaling pathway in mediating cisplatin-induced hepatotoxicity, particularly in cases of excessive or cumulative cisplatin exposure. These findings suggest that targeting GSDME could represent a promising therapeutic approach to mitigate cisplatin-induced liver damage.

FOXO1-NCOA4 Axis Contributes to Cisplatin-Induced Cochlea Spiral Ganglion Neuron Ferroptosis via Ferritinophagy.

Mammalian cochlea spiral ganglion neurons (SGNs) are crucial for sound transmission, they can be damaged by chemotherapy drug cisplatin and lead to irreversible sensorineural hearing loss (SNHL), while such damage can also render cochlear implants ineffective. However, the mechanisms underlying cisplatin-induced SGNs damage and subsequent SNHL are still under debate and there is no currently effective clinical treatment. Here, this study demonstrates that ferroptosis is triggered in SGNs following exposure to cisplatin. Inhibiting ferroptosis protects against cisplatin-induced SGNs damage and hearing loss, while inducing ferroptosis intensifies these effects. Furthermore, cisplatin prompts nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in SGNs, while knocking down NCOA4 mitigates cisplatin-induced ferroptosis and hearing loss. Notably, the upstream regulator of NCOA4 is identified and transcription factor forkhead box O1 (FOXO1) is shown to directly suppress NCOA4 expression in SGNs. The knocking down of FOXO1 amplifies NCOA4-mediated ferritinophagy, increases ferroptosis and lipid peroxidation, while disrupting the interaction between FOXO1 and NCOA4 in NCOA4 knock out mice prevents the cisplatin-induced SGN ferroptosis and hearing loss. Collectively, this study highlights the critical role of the FOXO1-NCOA4 axis in regulating ferritinophagy and ferroptosis in cisplatin-induced SGNs damage, offering promising therapeutic targets for SNHL mitigation.

Dexamethasone reduces cisplatin-induced hair cell damage by inducing cisplatin resistance through metallothionein-2.

Hair cell damage is a common side effect caused by the anticancer drug cisplatin (CDDP), which reduces patient quality of life. One CDDP resistance mechanism that occurs in recurrent cancers is heavy metal detoxification by metallothionein-2 (mt2). Here, we show that in zebrafish larvae, dexamethasone (DEX) reduces CDDP-induced hair cell damage by enhancing mt2 expression. Transgenic zebrafish (cldn: gfp; atoh1: rfp) that express green and red fluorescent proteins in neuromasts and hair cells, respectively, were used. The zebrafish were pretreated with DEX at 52h post-fertilization (hpf) for 8h, followed by CDDP treatment for 12h. The lateral line hair cells of CDDP-treated zebrafish at 72hpf were observed by fluorescence microscopy. Reporting odds ratio (ROR) analysis using an adverse event database indicated an association between a decrease in CDDP-induced ototoxicity and DEX as an antiemetic treatment for cancer chemotherapy. Pretreatment with DEX protected 72hpf zebrafish hair cells from CDDP-induced damage. The expression of mt2 mRNA was significantly increased by the combination of 10µM DEX with CDDP. Gene editing of mt2 reversed the protective effect of DEX against CDDP-induced damage in hair cells. DEX protects hair cells from CDDP-induced damage through increased mt2 expression, which is a resistance mechanism for platinum-based anticancer drugs.

Icariin alleviates cisplatin-induced premature ovarian failure by inhibiting ferroptosis through activation of the Nrf2/ARE pathway

Cisplatin is a widely used chemotherapeutic drug that can induce ovarian damage. Icariin (ICA), a natural antioxidant derived from Epimedium brevicornum Maxim., has been found to protect against organ injury. The aim of the present study was to investigate whether ICA can exert an ovarian-protective effect on cisplatin induced premature ovarian failure (POF) and the underlying mechanism involved. The preventive effect of ICA was evaluated using body weight, the oestrous cycle, ovarian histological analysis, and follicle counting. ICA treatment increased body weight, ovarian weight, and the number of follicles and improved the oestrous cycle in POF mice. ICA reduced cisplatin-induced oxidative damage and upregulated the protein expression levels of Nrf2, GPX4 and HO-1. Moreover, ICA reduced the expression levels of Bax and γH2AX and inhibited ovarian apoptosis. In addition, ICA activated the Nrf2 pathway in vitro and reversed changes in the viability of cisplatin-induced KGN cells, reactive oxygen species (ROS) levels, lipid peroxidation, and apoptosis, and these effects were abrogated when Nrf2 was knocked down or inhibited. Molecular docking confirmed that ICA promotes the release of Nrf2 by competing with Nrf2 for binding to Keap1. The inhibitory effects of ICA on cisplatin-induced oxidative stress, ferroptosis, and apoptosis may be mediated by its modulatory effects on the Nrf2 pathway, providing a novel perspective on the potential mechanisms by which ICA prevents POF.

Taxifolin attenuates cisplatin-induced kidney damage in rats via suppressing p53 and iNOS

Cisplatin (CP) is a platinum-based anticancer drug used to treat many different solid tumors. Although CP has strong anticancer properties, its clinical use is limited due to side effects such as ototoxicity, neurotoxicity, myelosuppression and nephrotoxicity. Taxifolin (Tax) is reported to exhibit various possess effects such as anti-inflammatory, antioxidant, antimicrobial, antiviral and anticancer. In this study, we aimed to investigate the possible effects of Tax on CP-induced nephrotoxicity. This study consisted of Control (C), Taxifolin (Tax), Cisplatin (CP) and Cisplatin + Taxifolin (CP + Tax) groups, and there were 6 rats in each group. CP was administered to rats intraperitoneally (i.p.) in a single dose of 7 mg/kg, and Tax was administered orally at a dose of 50 mg/kg for 7 consecutive days. Histopathologically, significant changes such as tubular epithelial degeneration and necrosis, tubular dilatation, inflammatory cell infiltrates, hyaline cast, and glomerular atrophy were detected in the CP group. It was seen that the CP+Tax group significantly reduced histopathological changes (p

Effect of tangeretin on cisplatin-induced oxido-inflammatory brain damage in rats.

Cisplatin (CIS) is a platinum-derived chemotherapeutic agent commonly utilized in the treatment of various malignant tumours. However, anticancer doses of the drug cause serious damage to the brain. This study aimed to determine the potential protective effects of tangeretin, which has antioxidant and anti-inflammatory properties, in cisplatin-induced neurotoxicity on BALB/c mice brains. Male BALB/c mice were randomized and separated into four groups. Tangeretin was given for 10 days by gavage. CIS was injected as a single dose of 10 mg/kg intraperitoneally (ip) on the 10th day. Brain tissues, malondialdehyde (MDA), total glutathione (tGSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) and nitric oxide (NO) levels were measured to determine oxidative damage and myeloperoxidase, tumour necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), IL-6 and IL-10 were measured to determine inflammatory activity. In addition, 8-OHdG and caspase-3 were analysed by immunofluorescence methods. While CIS administration remarkably elevated reactive oxygen species, MDA, and NO levels in brain tissue compared to the control, tGSH, GPx, SOD and CAT levels were significantly decreased. Also, it has been detected that TNF-α, IL-1β and IL-6 obtained in CIS-treated groups increased as well as IL-10 decreased, thereby elevating the inflammatory response. In addition, 8-OHdG and caspase-3 immunoreactivity in neurons increased with CIS administration. Treatment with tangeretin ameliorated the deterioration in oxidant/antioxidant status, overpowered neuroinflammation and ameliorated neurotoxicity-induced apoptosis. This study shows that tangeretin has beneficial effects on CIS-induced neurodegeneration. Possible mechanisms underlying these beneficial effects include the antioxidant and anti-inflammatory properties of tangeretin.

Catechin hydrate prevents cisplatin-induced spermatogonia GC-1 spg cellular damage

Catechin hydrate prevents cisplatin-induced spermatogonia GC-1 spg cellular damage

Nuciferine Protects Cochlear Hair Cells from Ferroptosis through Inhibiting NCOA4-Mediated Ferritinophagy.

Cisplatin is a widely used antineoplastic drug for treating various types of cancers. However, it can cause severe side effects, such as bilateral and irreversible hearing loss, which significantly impacts quality of life. Ferroptosis, an iron-dependent form of programmed cell death, has been implicated in the pathogenesis of cisplatin-induced ototoxicity. Here, we investigated the effects of nuciferine, a natural active ingredient isolated from lotus species, on the ferroptosis of cochlear hair cells. Firstly, our results demonstrated that nuciferine can protect hair cells against RSL3-induced and cisplatin-induced damage. Secondly, nuciferine treatment reduced ferrous iron (Fe2+) overload in cochlear hair cells via inhibiting NCOA4-mediated ferritinophagy. Inhibition of ferritinophagy by knocking down Ncoa4 alleviated cisplatin-induced ototoxicity. Importantly, nuciferine treatment mitigated cochlear hair cell loss and damage to ribbon synapse, and improved mouse hearing function in an acute cisplatin-induced hearing loss model. Our findings highlight the role of NCOA4-mediated ferritinophagy in the pathogenesis of cisplatin-induced ototoxicity and provide evidence for nuciferine as a promising protective agent for treating cisplatin-induced hearing loss.