Cisplatin-induced Oxidative Stress Research Articles

Erucic acid increases the potency of cisplatin-induced colorectal cancer cell death and oxidative stress by upregulating the TRPM2 channel.

Erucic acid (ErA) is a source of omega-9 monounsaturated fatty acids. ErA exhibited antitumor effects by causing apoptosis and oxidative stress in tumor cells, with the exception of the HT-29 human colorectal cancer cell line. The apoptotic and Ca2+ signaling pathways in tumor cells are triggered when mitochondrial Ca2+ and Zn2+ accumulation produce reactive free oxygen species (ROS), which in turn activate TRPM2. ErA-induced ROS and TRPM2 stimulation may augment the anticancer action of cisplatin (CSP). We aimed to study the effects of ErA and CSP incubations on ROS, apoptosis, and cell death in the HT-29 cells by activating TRPM2. The cells were divided into five groups: control, ErA (200 µM for 48 h), CSP (25 µM for 24 h), and ErA + CSP + TRPM2 antagonists (200 µM carvacrol and 25 µM N-(p-amylcinnamoyl)anthranilic acid for 24 h). The TRPM2 antagonists reduced ErA plus CSP-induced increases in H2O2-induced intracellular free Ca2+ concentration ([Ca2+]c) and adenosine diphosphate-ribose-caused TRPM2 currents. ErA and CSP were found to cause apoptosis and cell death by raising the intracellular free Zn2+ concentration (Zn2+]c), caspase-3, -8, and -9, mitochondrial membrane dysfunction, and ROS, while lowering reduced glutathione, cell viability, and cell number. The oxidative, apoptotic, and tumor cell death effects of CSP in the cells were enhanced by the increase of ErA-mediated [Ca2+]c and Zn2+]c entering mitochondria through the activation of TRPM2. In conclusion, we observed that the combination of ErA and CSP was synergistic via TRPM2 activation for the treatment of HT-29 tumor cells.

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.

Probucol-Ursodeoxycholic Acid Otic Formulations: Stability and In Vitro Assessments for Hearing Loss Treatment

Targeted drug delivery is an ongoing aspect of scientific research that is expanding through the design of micro- and nanoparticles. In this paper, we focus on spray dried microparticles as carriers for a repurposed lipophilic antioxidant (probucol). We characterise the microparticles and quantify probucol prior to assessing cytotoxicity on both control and cisplatin treated hair cells (known as House Ear Institute-Organ of Corti 1; HEI-OC1). The addition of water-soluble polymers to 2% β-cyclodextrin resulted in a stable probucol formulation. Ursodeoxycholic acid (UDCA) used as formulation excipient increases probucol miscibility and microparticle drug content. Formulation characterisations reveals spray drying results in spherical UDCA-drug microparticles with a mean size distribution of ∼5–12 μm. Probucol microparticles show stable short-term storage conditions accounting for only ∼10% loss over seven days. By mimicking cell culture conditions, both UDCA-probucol (67%) and probucol only (82%) microparticles show drug release in the initial two hours. Furthermore, probucol formulations with or without UDCA preserve cell viability and reduce cisplatin-induced oxidative stress. Mitochondrial bioenergetics results in lower basal respiration and non-mitochondrial respiration, with higher maximal respiration, spare capacity, ATP production and proton leak within cisplatin challenged UDCA-probucol groups. Overall, we present a facile method for incorporating lipophilic antioxidant carriers in polymer-based particles that are tolerated by HEI-OC1 cells and show stable drug release, sufficient in reducing cisplatin-induced reactive oxygen species accumulation.

Nobiletin alleviates cisplatin-induced ototoxicity via activating autophagy and inhibiting NRF2/GPX4-mediated ferroptosis

Nobiletin, a citrus polymethoxy flavonoid with antiapoptotic and antioxidative properties, could safeguard against cisplatin-induced nephrotoxicity and neurotoxicity. Cisplatin, as the pioneer of anti-cancer drug, the severe ototoxicity limits its clinical applications, while the effect of nobiletin on cisplatin-induced ototoxicity has not been identified. The current study investigated the alleviating effect of nobiletin on cisplatin-induced ototoxicity and the underlying mechanisms. Apoptosis and ROS formation were evaluated using the CCK-8 assay, Western blotting, and immunofluorescence, indicating that nobiletin attenuated cisplatin-induced apoptosis and oxidative stress. LC3B and SQSTM1/p62 were determined by Western blotting, qPCR, and immunofluorescence, indicating that nobiletin significantly activated autophagy. Nobiletin promoted the nuclear translocation of NRF2 and the transcription of its target genes, including Hmox1, Nqo1, and ferroptosis markers (Gpx4, Slc7a11, Fth, and Ftl), thereby inhibiting ferroptosis. Furthermore, RNA sequencing analysis verified that autophagy, ferroptosis, and the NRF2 signaling pathway served as crucial points for the protection of nobiletin against ototoxicity caused by cisplatin. Collectively, these results indicated, for the first time, that nobiletin alleviated cisplatin-elicited ototoxicity through suppressing apoptosis and oxidative stress, which were attributed to the activation of autophagy and the inhibition of NRF2/GPX4-mediated ferroptosis. Our study suggested that nobiletin could be a prospective agent for preventing cisplatin-induced hearing loss.

Olesoxime protects against cisplatin-induced acute kidney injury by attenuating mitochondrial dysfunction

BackgroundMitochondrial dysfunction is a critical factor in the pathogenesis of acute kidney injury (AKI). Agents that ameliorate mitochondrial dysfunction hold potential for AKI treatment. The objective of this study was to investigate the impact of olesoxime, a novel mitochondrial-targeted agent, on cisplatin-induced AKI. MethodsIn vivo, a cisplatin-induced AKI mouse model was established by administering a single intraperitoneal dose of cisplatin (25 mg/kg) to male C57BL/6 mice for 72 hours, followed by gavage of either olesoxime or a control solution. In vitro, human proximal tubular HK2 cells were cultured and subjected to treatments with cisplatin, either in the presence or absence of olesoxime. ResultsIn vivo, our findings demonstrated that olesoxime administration significantly mitigated the nephrotoxic effects of cisplatin in mice, as evidenced by reduced blood urea nitrogen (BUN) and serum creatinine (SCr) levels, improved renal histopathology, and decreased expression of renal tubular injury markers such as kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, olesoxime administration markedly reduced cisplatin-induced apoptosis, inflammation, and oxidative stress in the kidneys of AKI mice. Additionally, olesoxime treatment effectively restored mitochondrial function in the kidneys of AKI mice. In vitro, our results indicated that olesoxime treatment protected against cisplatin-induced apoptosis and mitochondrial dysfunction in cultured HK2 cells. Notably, cisplatin's anticancer effects were unaffected by olesoxime treatment in human cancer cells. ConclusionThe results of this study suggest that olesoxime is a viable and efficient therapeutic agent in the treatment of cisplatin-induced acute kidney injury presumably by alleviating mitochondrial dysfunction.

Propolis alleviated Cisplatin-induced hepatorenal oxidative stress and apoptosis

Propolis alleviated Cisplatin-induced hepatorenal oxidative stress and apoptosis

Abstract 443: Unsaturated fatty acids promote cell cycle progression and proliferation of platinum resistant ovarian cancer cells

Abstract Introduction: Ovarian cancer (OC) depends on fat as fuel for metastasis and growth. We have previously demonstrated that cisplatin resistant (Pt-R) OC cells uptake higher amounts of fatty acids (FAs) compared to sensitive (Pt-S) cells- a process which facilitates cancer cell survival under cisplatin-induced oxidative stress. Here we aimed to determine which class of FAs promotes the Pt-R phenotype and to identify the mechanism through which FAs support cancer survival. Materials and methods: We used two isogenic OC cell lines pairs, sensitive and resistant to cisplatin: OVCAR5 Pt-S (IC50 = 2.881μM) vs Pt-R (IC50 = 6.831 μM) and PEO1 (IC50 = 4.901 μM) vs PEO4 (IC50 = 8.285 μM). Cells were cultured under low serum conditions, supplemented with 50 µM oleic (OA) or 50 µM palmitic acid (PA), and used for viability assays, RNA-Seq, and cell cycle analysis. Quantitative RT-PCR measured expression of key FAs transporters in Pt-S and Pt-R cells. Results: A viability assay showed that Pt-R cells were less viable under serum depletion compared to Pt-S OC cells. OA (unsaturated), but not PA (saturated), promoted proliferation of both OC cell lines, and rescued Pt-R vs Pt-S cells; 268.4% vs 91.6% for OVCAR-5 and 38.1% for PEO4 vs 12.1% for PEO1, suggesting that Pt-R cells depend more on unsaturated FAs compared to Pt-S cells. Quantification of key FAs transporters demonstrated that Pt-R cell expressed higher levels of FABP4, FABP5 and CD36 compared to Pt-S cells. Treatment with an FABP inhibitor reduced the Pt IC50 in Pt-R cells (from 11.893 μM to 5.0415 μM in OVCAR5 and from 8.285 μM to 6.968 μM in PEO4). RNA-Seq analysis analysed transcriptomic changes induced by 24 hour treatment with OA in OVCAR5 cells. There were 923 differentially expressed protein-coding genes, with 300 upregulated and 623 downregulated transcripts (FDR<0.05). Pathway analysis revealed cell cycle related pathways like: cell cycle mitotic, cell cycle checkpoints, G2/M checkpoints among the top 10 most significantly upregulated pathways and E2F1 was identified as the main effector. Cell cycle analysis confirmed that OA induced increased percentages of cells in S- and G2/M phases - from 6.95% to 11.6% (p<0.05), and 13.6 to 17.6% (P<0.05), respectively. Treatment with an E2F1 inhibitor significantly reduced the OA-induced cell proliferation. Conclusion: Pt-R OC cells are dependent on unsaturated FAs compared to Pt-S cells and upregulate key transporters to allow increased uptake of FAs. OA supports proliferation of Pt-R cells and cell cycle progression from G1 to S- and G2/M phases. Ongoing experiments focus on key mechanisms activated by unsaturated FAs in Pt-R cells. Citation Format: Ana Maria Isac, Guangyuan Zhao, Horacio Cardenas, Daniela Matei. Unsaturated fatty acids promote cell cycle progression and proliferation of platinum resistant ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 443.

The copper transporter, SLC31A1, transcriptionally activated by ELF3, imbalances copper homeostasis to exacerbate cisplatin-induced acute kidney injury through mitochondrial dysfunction

Acute kidney injury (AKI) is a common complication of cisplatin chemotherapy, which greatly limits its clinical effect and application. This study explored the function of solute Carrier Family 31 Member 1 (SLC31A1) in cisplatin-induced AKI and its possible mechanism. Mice and HK-2 cells were exposed to cisplatin to establish the in vivo and in vitro AKI models. Cell viability was detected by CCK-8. Mitochondrial and oxidative damage was determined by Mito-Tracker Green staining, mtROS level, ATP production, mitochondrial membrane potential, MDA content and CAT activity. AKI was evaluated by renal function and histopathological changes. Apoptosis was detected by TUNEL and caspase-3 expression. Molecule expression was measured by RT-qPCR, Western blotting, and immunohistochemistry. Molecular mechanism was studied by luciferase reporter assay and ChIP. SLC31A1 level was predominantly increased by cisplatin exposure in AKI models. Notably, copper ion (Cu+) level was enhanced by cisplatin challenge. Moreover, Cu+ supplementation intensified cisplatin-induced cell death, mitochondrial dysfunction, and oxidative stress in HK-2 cells, indicating the involvement of cuproptosis in cisplatin-induced AKI, whereas these changes were partially counteracted by SLC31A1 knockdown. E74 like ETS transcription factor 3 (ELF3) could directly bind to SLC31A1 promoter and promote its transcription. ELF3 was up-regulated and positively correlated with SLC31A1 expression upon cisplatin-induced AKI. SLC31A1 silencing restored renal function, alleviated mitochondrial dysfunction, and apoptosis in cisplatin-induced AKI mice. ELF3 transcriptionally activated SLC31A1 to trigger cuproptosis that drove cisplatin-induced AKI through mitochondrial dysfunction, indicating that SLC31A1 might be a promising therapeutic target to mitigate AKI during cisplatin chemotherapy.

Phytochemical profiling and nephroprotective potential of ethanolic leaf extract of Polyalthia longifolia against cisplatin-induced oxidative stress in rat model

Ethnopharmacological relevanceKidney problems are becoming more common globally and are considered a major health issue in the modern world with high mortality rate. Polyalthia longifolia (Sonn.) Thwaites is a tropical ethnomedicinal plant used to treat various diseases like diabetes, hypertension and urinary disorders and possess antioxidant and anti-inflammatory properties. Aim of the studyThis study aimed to investigate the phytochemical composition of 70% ethanolic leaf extract of Polyalthia longifolia (Sonn.) Thwaites (PL) and evaluates its nephroprotective effects against cisplatin-induced nephrotoxicity in Wistar rats. Materials and methodsThe leaves of PL were extracted with 70% ethanol and performed the phytochemical profiling using Liquid Chromatography–Mass Spectrometry (LC-MS). The nephroprotective effect of PL leaf extract was evaluated at three doses (150, 300 and 600 mg/kg, p.o.) for 14 days against cisplatin toxicity (16 mg/kg, i.p., once) in male Wistar rats. Body and kidney weight indices, kidney function markers and lipid profile markers in serum, and oxidative stress markers in kidney tissue were performed along with the histopathological analysis of kidney. ResultsThe LC-MS chromatograph confirmed the presence of various phytocompounds include N-Methylhernagine (aporphine alkaloid), 4-Acetamidobutanoic acid (gamma amino acid) and choline, etc. in the PL leaf extract. Exposure of cisplatin (16 mg/kg, i.p., once only) to the animals significantly elevated the levels of kidney functional markers (i.e. serum urea, uric acid, creatinine) and the lipid markers (triglyceride and total cholesterol) in blood circulation with depletion of serum albumin which were reversed by the therapy of PL leaf extract (150, 300 and 600 mg/kg) in dose-dependent manner. The altered level of body and kidney weight in cisplatin treated group was also restored by the therapy. PL leaf extract effectively improved the antioxidant defense system of kidney at all doses by restoring the levels of tissue glutathione, superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase with the dose-dependent reduction of lipid peroxidation against cisplatin-induced renal oxidative stress. The histopathological observations also showed the significant recovery in cellular morphology after PL treatment when compared to the cisplatin toxicity group. The highest dose 600 mg/kg of PL leaf extract showed more pronounced renal recovery (p < 0.001) followed by other two doses, which was similar to the silymarin treatment group (a reference drug) against nephrotoxicity. ConclusionThe results of this study revealed the nephroprotective effects of PL leaves against cisplatin-induced nephrotoxicity by reversing the level of biochemical markers and mitigating oxidative stress as well as improving the architecture of renal tissues. This renal protection by PL might be due to the synergistic effect of its phytoconstituents and antioxidant efficacy.

Drug screening identifies aldose reductase as a novel target for treating cisplatin-induced hearing loss

Cisplatin is a frequently used chemotherapeutic medicine for cancer treatment. Permanent hearing loss is one of the most serious side effects of cisplatin, but there are few FDA-approved medicines to prevent it. We applied high-through screening and target fishing and identified aldose reductase, a key enzyme of the polyol pathway, as a novel target for treating cisplatin ototoxicity. Cisplatin treatment significantly increased the expression level and enzyme activity of aldose reductase in the cochlear sensory epithelium. Genetic knockdown or pharmacological inhibition of aldose reductase showed a significant protective effect on cochlear hair cells. Cisplatin-induced overactivation of aldose reductase led to the decrease of NADPH/NADP+ and GSH/GSSG ratios, as well as the increase of oxidative stress, and contributed to hair cell death. Results of target prediction, molecular docking, and enzyme activity detection further identified that Tiliroside was an effective inhibitor of aldose reductase. Tiliroside was proven to inhibit the enzymatic activity of aldose reductase via competitively interfering with the substrate-binding region. Both Tiliroside and another clinically approved aldose reductase inhibitor, Epalrestat, inhibited cisplatin-induced oxidative stress and subsequent cell death and thus protected hearing function. These findings discovered the role of aldose reductase in the pathogenesis of cisplatin-induced deafness and identified aldose reductase as a new target for the prevention and treatment of hearing loss.

Protective effect of Galantamine on attenuating Cisplatin-induced Neurotoxicity: An In-vitro and In-vivo approach

Galantamine is a drug of choice for the treatment of Alzheimer's disease and possesses antioxidant, anti-inflammatory and cholinomimetic as non-FDA-approved indications. This study designed to explore the impact of Galantamine to attenuate cisplatin-induced neurotoxicity and oxidative stress. Experimental animals were segregated into five groups viz-a-viz group I as normal control, II as cisplatin control, and III-V as galantamine at varying doses, low (2.5mg/kg), medium (5mg/kg) and higher (10mg/kg). All the samples were orally administered, daily for 14 days. Cisplatin was injected intraperitoneally on day 8 to all groups except normal control. Assessment of neurotoxicity was done by measurement of a balance of antioxidant (GSH, SOD) and pro-oxidant (MDA), histopathological investigations. Dose-dependent significant (p&lt;0.05) reduction in neurotoxicityhas been found by galantamine with reduction (p&lt;0.01) in oxidant stress markers. Pronouncedreduction in apoptosis and elevation of disturbed hematological, and biochemical alterations were also observed with significance of p&lt;0.001 in galantamine groups. We have observed that galantaminedose-dependentlyattenuates neurotoxicity, and oxidative stress, reversed the histopathological alterations and inhibits activated pro-inflammatory mediators (TNF-α). The research work provides drug repurposing of galantamine and providespreliminary ground for the treatment and management of cisplatin-induced neurotoxicity towards the clinical domain.

ALKBH5-mediated CHAC1 depletion promotes malignant progression and decreases cisplatin-induced oxidative stress in gastric cancer

The m6a demethyltransferase ALKBH5 dynamically modulates gene expression and intracellular metabolic molecules by modifying RNA m6a in cancer cells. However, ALKBH5’s function in gastric cancer (GC) has remained controversial. This study demonstrates that ALKBH5 is highly expressed in GC. Silencing ALKBH5 hampers proliferation, and metastatic potential, and induces cell death in GC cells. Through a comprehensive analysis of the transcriptome and m6A sequencing, alterations in certain ALKBH5 target genes, including CHAC1, were identified. ALKBH5’s demethylation effect regulates CHAC1 RNA stability, leading to reduced CHAC1 expression. Moreover, CHAC1 modulates intracellular ROS levels, influencing the chemotherapy sensitivity of gastric cancer. In summary, our study unveils the pivotal role of the ALKBH5-CHAC1-ROS axis and highlights the significance of m6A methylation in gastric cancer.

Baicalin Exhibits a Protective Effect against Cisplatin-Induced Cytotoxic Damage in Canine Renal Tubular Epithelial Cells.

Renal failure is a common chronic disease in dogs that substantially affects both their quality of life and longevity. The objective of this study was to assess the protective mechanisms of baicalin in cisplatin-induced Madin-Darby canine kidney (MDCK) epithelial cells' apoptosis model and explore the impacts of baicalin at varying doses on various indexes, such as cisplatin-induced MDCK cell apoptosis, oxidation and antioxidation, and inflammatory factors. (Methods) MDCK cells in the logarithmic growth phase were randomly divided into a control group, a model group (20 μmol/L cisplatin), and a baicalin-protection group (20 μmol/L cisplatin + 50, 25 μmol/L baicalin) and received the corresponding treatments for 24 h. The effects of cisplatin on MDCK cell apoptosis, oxidation and antioxidation, inflammatory factors, and other indicators were studied, and the relieving effect of baicalin on cisplatin-induced MDCK cell damage was explored. Calcein/PI staining and Annexin V-FITC/PI staining showed that cisplatin induced the apoptosis of MDCK cells, while baicalin effectively reduced the damage caused by cisplatin. The ELISA results demonstrated a significant elevation in the nitric oxide (NO) and malondialdehyde (MDA) levels within the MDCK cells following treatment with cisplatin (p < 0.01). In addition, superoxide dismutase (SOD), glutathione peroxidase (GSH), and catalase (CAT) activities remarkably declined (p < 0.01), while tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) expression within the MDCK cells were apparently elevated (p < 0.01). However, baicalin treatment resulted in opposite changes in these factors. The findings suggested that baicalin exhibits potential in mitigating cisplatin-induced oxidative stress and inflammation in MDCK cells. As revealed with the Western blot results, cisplatin promoted P62, P53, and BAX protein levels, increased mTOR phosphorylation, inhibited AMPK phosphorylation, and reduced Beclin1 and BCL-2 protein levels. However, a contrasting trend was observed following baicalin treatment. Cisplatin can inhibit the activity of MDCK cells, lead to abnormalities in oxidation and antioxidation functions and cell inflammatory factors, and accelerate cell apoptosis. Moreover, baicalin can significantly alleviate the damage of cisplatin to MDCK cells.

ALDH2 dysfunction and alcohol cooperate in cancer stem cell enrichment.

The alcohol metabolite acetaldehyde is a potent human carcinogen linked to esophageal squamous cell carcinoma (ESCC) initiation and development. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme that detoxifies acetaldehyde in the mitochondria. Acetaldehyde accumulation causes genotoxic stress in cells expressing the dysfunctional ALDH2E487K dominant negative mutant protein linked to ALDH2*2, the single nucleotide polymorphism highly prevalent among East Asians. Heterozygous ALDH2*2 increases the risk for the development of ESCC and other alcohol-related cancers. Despite its prevalence and link to malignant transformation, how ALDH2 dysfunction influences ESCC pathobiology is incompletely understood. Herein, we characterize how ESCC and preneoplastic cells respond to alcohol exposure using cell lines, three-dimensional organoids and xenograft models. We find that alcohol exposure and ALDH2*2 cooperate to increase putative ESCC cancer stem cells with high CD44 expression (CD44H cells) linked to tumor initiation, repopulation and therapy resistance. Concurrently, ALHD2*2 augmented alcohol-induced reactive oxygen species and DNA damage to promote apoptosis in the non-CD44H cell population. Pharmacological activation of ALDH2 by Alda-1 inhibits this phenotype, suggesting that acetaldehyde is the primary driver of these changes. Additionally, we find that Aldh2 dysfunction affects the response to cisplatin, a chemotherapeutic commonly used for the treatment of ESCC. Aldh2 dysfunction facilitated enrichment of CD44H cells following cisplatin-induced oxidative stress and cell death in murine organoids, highlighting a potential mechanism driving cisplatin resistance. Together, these data provide evidence that ALDH2 dysfunction accelerates ESCC pathogenesis through enrichment of CD44H cells in response to genotoxic stressors such as environmental carcinogens and chemotherapeutic agents.

CTRP3 attenuates inflammation, oxidative and cell death in cisplatin induced HK-2 cells.

Cisplatin has been widely studied and found to be a highly effective anti-tumor drug. It has several side effects, including acute kidney injury (AKI). Cisplatin-induced AKI can be primarily attributed to oxidative stress, inflammation, and apoptosis. The CTRP3 adipokine is a new adipokine that exhibits antioxidant, anti-inflammatory, and antiapoptotic properties. Despite this, the role of CTRP3 in AKI remain unclear. In cisplatin-induced AKI models, our findings demonstrated that CTRP3 expression was decreased in human proximal tubule epithelial cells (HK-2). In the in vitro experiments, HK-2 cells were first transfected with an overexpression plasmid of CTRP3 (pcDNA-CTRP3) or a small interfering RNA for CTRP3 (si-CTRP3) and induced by cisplatin; and cell oxidative stress, inflammation, proliferation, and apoptosis were found to be present. Overexpressing CTRP3 inhibited oxidative stress through decreasing malondialdehyde (MDA) levels and increasing the activity of SOD and CAT. The mRNA levels of SOD1 and SOD2 were increased in response to CTRP3 overexpression. Additionally, CTRP3 decreased TNF-α and MCP-1 levels. Moreover, CTRP3 overexpression increased cisplatin-induced cell activity and decreased cell apoptosis, as indicated by the elevated numbers of EdU positive cells and decreased numbers of apoptotic cells. Consistent with these results, the overexpression of CTRP3 effectively elevated the mRNA levels of Bcl-2 and reduced the mRNA levels of Bax. In contrast, inhibition of CTRP3 expression by si-CTRP3 reversed the cisplatin-induced indices. Mechanistically, we found that the overexpression of CTRP3 can increase expression of Nrf2 and inhibit the activation of MAPK phosphorylation (ERK, JNK, and p38). Furthermore, inhibition of ERK, JNK and p38 activity eliminated aggravation of cisplatin-induced inflammation and apoptosis caused by CTRP3 knockdown. Additionally, the cisplatin-induced oxidative stress and activation of MAPK phosphorylation (ERK, JNK, and p38) in HK-2 cells were reversed by Nrf2 suppression by siRNA. Collectively, these results indicated that CTRP3 may identify as a novel target for AKI treatment and protect against cisplatin-induced AKI through the Nrf2/MAPK pathway.

Antioxidant Nanoparticles Restore Cisplatin-Induced Male Fertility Defects by Promoting MDC1-53bp1-Associated Non-Homologous DNA Repair Mechanism and Sperm Intracellular Calcium Influx.

Cisplatin, a commonly used anticancer compound, exhibits severe off-target organ toxicity. Due to its wide application in cancer treatment, the reduction of its damage to normal tissue is an imminent clinical need. Cisplatin-induced testicular oxidative stress and damage lead to male sub- or infertility. Despite earlier studies showing that the natural polyphenol extracts honokiol serve as the free radical scavenger that reduces the accumulation of intracellular free radicals, whether honokiol exhibits direct effects on the testis and sperm is unclear. Thus, the aim of the current study is to investigate the direct effects of honokiol on testicular recovery and sperm physiology. We encapsulated this polyphenol antioxidation compound into liposome-based nanoparticles (nHNK) and gave intraperitoneally to mice at a dosage of 5 mg/kg body mass every other day for consecutive 6 weeks. We showed that nHNK promotes MDC1-53bp1-associated non-homologous DNA double-strand break repair signaling pathway that minimizes cisplatin-induced DNA damage. This positive effect restores spermatogenesis and allows the restructuring of the multi-spermatogenic layers in the testis. By reducing mitochondrial oxidative damage, nHNK also protects sperm mitochondrial structure and maintains both testicular and sperm ATP production. By a yet-to-identify mechanism, nHNK restores sperm calcium influx at the sperm midpiece and tail, which is essential for sperm hypermotility and their interaction with the oocyte. Taken together, the nanoparticulated antioxidant counteracts cisplatin-induced male fertility defects and benefits patients undertaking cisplatin-based chemotherapy. These data may allow the reintroduction of cisplatin for systemic applications in patients at clinics with reduced testicular toxicity.

Lansoprazole protects hepatic cells against cisplatin-induced oxidative stress through the p38 MAPK/ARE/Nrf2 pathway.

Lansoprazole, a proton pump inhibitor, can exert antioxidant effects through the induction of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, independently of the inhibition of acid secretion in the gastrointestinal tract. Lansoprazole has been reported to provide hepatoprotection in a drug-induced hepatitis animal model through the Nrf2/heme oxygenase-1 (HO1) pathway. We sought to investigate the molecular mechanism of cytoprotection by lansoprazole. An in vitro experimental model was conducted using cultured rat hepatic cells treated with lansoprazole to analyze the expression levels of Nrf2 and its downstream genes, the activity of Nrf2 using luciferase reporter assays, cisplatin-induced cytotoxicity, and signaling pathways involved in Nrf2 activation. Lansoprazole treatment of rat liver epithelial RL34 cells induced transactivation of Nrf2 and the expression of the Nrf2-dependent antioxidant genes encoding HO1, NAD(P)H quinone oxidoreductase-1, and glutathione S-transferase A2. Furthermore, cycloheximide chase experiments revealed that lansoprazole prolongs the half-life of the Nrf2 protein. Notably, cell viability was significantly increased by lansoprazole treatment in a cisplatin-induced cytotoxicity model. Moreover, the siRNA knockdown of Nrf2 fully abolished the cytoprotective effect of lansoprazole, whereas the inhibition of HO1 by tin-mesoporphyrin only partially abolished this. Finally, lansoprazole promoted the phosphorylation of p38 mitogen-activated protein kinase (MAPK) but not that of the extracellular signal-regulated kinase or the c-Jun N-terminal kinase. Using SB203580, a specific inhibitor for p38 MAPK, the lansoprazole-induced Nrf2/antioxidant response elements pathway activation and cytoprotective effects were shown to be exclusively p38 MAPK dependent. Lansoprazole was shown by these results to exert a cytoprotective effect on liver epithelial cells against the cisplatin-induced cytotoxicity through the p38 MAPK signaling pathway. This could have potential applications for the prevention and treatment of oxidative injury in the liver.

Dihydromyricetin attenuates cisplatin-induced acute kidney injury by reducing oxidative stress, inflammation and ferroptosis

BackgroundCisplatin is effective against various types of cancers. However, its clinical application is limited owing to its adverse effects, especially acute kidney injury (AKI). Dihydromyricetin (DHM), a flavonoid derived from Ampelopsis grossedentata, has varied pharmacological activities. This research aimed to determine the molecular mechanism for cisplatin-induced AKI. MethodsA murine model of cisplatin-induced AKI (22 mg/kg, I.P.) and a HK-2 cell model of cisplatin-induced damage (30 μM) were established to evaluate the protective function of DHM. Renal dysfunction markers, renal morphology and potential signaling pathways were investigated. ResultsDHM decreased the levels of renal function biomarkers (blood urea nitrogen and serum creatinine), mitigated renal morphological damage, and downregulated the protein levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. It upregulated the expression levels of antioxidant enzymes (superoxide dismutase and catalase expression), nuclear factor-erythroid-2-related factor 2 (Nrf2) and its downstream proteins, including heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic (GCLC) and modulatory (GCLM) subunits, thus eventually reducing cisplatin-induced reactive oxygen species (ROS) production. Moreover, DHM partially inhibited the phosphorylation of the active fragments of caspase-8 and -3 and mitogen-activated protein kinase and restored glutathione peroxidase 4 expression, which attenuated renal apoptosis and ferroptosis in cisplatin-treated animals. DHM also mitigated the activation of NLRP3 inflammasome and nuclear factor (NF)-κB, attenuating the inflammatory response. In addition, it reduced cisplatin-induced HK-2 cell apoptosis and ROS production, both of which were blocked by the Nrf2 inhibitor ML385. ConclusionsDHM suppressed cisplatin-induced oxidative stress, inflammation and ferroptosis probably through regulating of Nrf2/HO-1, MAPK and NF-κB signaling pathways.

Effects of Ethanol Extract of Rauwolfia vomitoria Leaf on Lipid Profile and Cerebellar Histology in Cisplatin-induced Oxidative Stress

Effects of Ethanol Extract of Rauwolfia vomitoria Leaf on Lipid Profile and Cerebellar Histology in Cisplatin-induced Oxidative Stress

Aspirin alleviates cisplatin-induced acute kidney injury through the AMPK-PGC-1α signaling pathway

Cisplatin (CIS) is a widely used clinical chemotherapeutic agent for solid malignancies such as lung, testicular and ovarian cancers, but the development of nephrotoxicity has limited the use of this class of drugs. Some studies have shown that aspirin can reduce cisplatin-induced nephrotoxicity, but the mechanism of protection is not yet clear. By establishing a mouse model of cisplatin-induced acute kidney injury and a mouse model of aspirin combination, we observed a reduction in creatinine, blood urea nitrogen, and tissue damage, thus verifying that aspirin can alleviate cisplatin-induced acute kidney injury in mice. Aspirin was found to have a significant protective effect against cisplatin-induced acute kidney injury, as evidenced by the reduction in levels of ROS, NO, and MDA and the increase in T-AOC, CAT, SOD, and GSH. Furthermore, aspirin was observed to down-regulate the expression of pro-inflammatory factors TNF-α, NF-κB, IL-1β, and IL-6 mRNA and proteins, increase the expression of BAX and Caspase3 as indicators of apoptosis, decrease the expression of Bcl-2, and improve the reduced expression of mtDNA, ATP content, ATPase activity and mitochondrial respiratory chain complex enzyme-related genes ND1, Atp5b, and SDHD. These findings suggest that the protective effects of aspirin are associated with its anti-inflammatory, antioxidant, anti-apoptotic properties, and its ability to maintain mitochondrial function, as demonstrated by the detection of AMPK-PGC-1α pathway-related genes. The results showed that the reduced expression of p-AMPK and mitochondrial production-related mRNA PGC-1α, NRF1, and TFAM in the kidney tissue of mice in the cisplatin group was alleviated by the effect of aspirin, indicating that aspirin could activate the p-AMPK, regulate mitochondrial production and alleviate cisplatin acute kidney injury through the AMPK-PGC-1α pathway. In summary, certain doses of aspirin protect the body from acute kidney injury by alleviating the cisplatin-induced inflammatory response oxidative stress, mitochondrial dysfunction, and apoptosis. Further studies have shown that the protective effect of aspirin is associated with AMPK-PGC-1α pathway activation.