RESUMEN
PURPOSE: The present study investigated the nephron-testicular protective effects of sesamin against cisplatin (CP)-induced acute renal and testicular injuries. METHODS: Thirty-two male Wistar rats were allocated to receive carboxymethylcellulose (0.5%, as sesamin vehicle), CP (a single i.p. 5 mg/kg dose), CP plus sesamin at 10 or 20 mg/kg orally for 10 days. RESULTS: Data analysis showed significant increases in serum urea, creatinine, interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α), as well as renal and testicular tissue malondialdehyde and nitric-oxide concentrations in CP-intoxicated rats in comparison to control animals. On the contrary, rats treated with CP only exhibited significantly lower (p < .05) serum testosterone, tissue glutathione, and activities of endogenous antioxidant enzymes compared to control rats. Histopathologically examining CP-intoxicated rats' tissues using H&E and PAS stains showed atrophied glomeruli, interstitial inflammatory cells, atypic tubular epithelium with focal apoptosis, and reduced mucopolysaccharide content. Further, immunohistochemical staining of the same group revealed an increase in p53 and cyclooxygenase-II (Cox-II) expression in renal and testicular tissues. Treatment with sesamin alleviated almost all the changes mentioned above in a dose-dependent manner, with the 20 mg/kg dose restoring several parameters' concentrations to normal ranges. CONCLUSIONS: In brief, sesamin could protect the kidneys and testes against CP toxicity through its antioxidant, anti-inflammatory, and anti-apoptotic effects.
Asunto(s)
Antiinflamatorios , Antioxidantes , Apoptosis , Cisplatino , Dioxoles , Riñón , Lignanos , Ratas Wistar , Testículo , Animales , Masculino , Lignanos/farmacología , Lignanos/uso terapéutico , Cisplatino/toxicidad , Cisplatino/efectos adversos , Ratas , Dioxoles/farmacología , Antioxidantes/farmacología , Testículo/efectos de los fármacos , Testículo/patología , Testículo/metabolismo , Apoptosis/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Antiinflamatorios/farmacología , Estrés Oxidativo/efectos de los fármacos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/patología , Lesión Renal Aguda/metabolismo , Antineoplásicos/toxicidadRESUMEN
OBJECTIVE: Cisplatin, a widely used anticancer agent, induces hepatotoxicity alongside organ damage. Understanding Cisplatin's toxicity mechanism and developing preventive measures are crucial. Our study explores Myricetin, a flavonoid, for its protective effects against Cisplatin-induced hepatotoxicity. METHODS: In our study, a total of 32 Wistar albino male rats were utilized, which were categorized into four distinct groups: Control, Myricetin, Cisplatin, and Myricetin+Cisplatin. For the histological assessment of hepatic tissues, hematoxylin-eosin and periodic acid Schiff staining were employed, alongside immunohistochemical measurements of TNF-α, interleukin-17, and interleukin-6 immunoreactivity. Additionally, aspartate transaminase and alanine transaminase values were examined by biochemical analysis. RESULTS: In the histological evaluation of the tissues, a normal healthy cell structure and a strong periodic acid Schiff (+) reaction were observed in the hepatocyte cells in the tissues of the Control and Myricetin groups, while intense eosinophilia, minimal vacuolization, congestion, and sinusoidal expansions were observed in the hematoxylin-eosin stainings, and a decrease in the positive reaction in the periodic acid Schiff staining was observed in the Cisplatin group. Consistent with these histological findings, an increase in TNF-α, interleukin-17, and interleukin-6 expressions (p<0.0001) and a concomitant increase in aspartate transaminase and alanine transaminase values were observed in the Cisplatin group. In the group protected by Myricetin, a significant improvement was observed in all these histological and biochemical values. CONCLUSION: Cisplatin induces notable histopathological alterations in the liver. In this context, Myricetin exhibits the potential to alleviate Cisplatin-induced damage by modulating histological parameters and biochemical processes.
Asunto(s)
Alanina Transaminasa , Antineoplásicos , Aspartato Aminotransferasas , Enfermedad Hepática Inducida por Sustancias y Drogas , Cisplatino , Flavonoides , Interleucina-6 , Ratas Wistar , Factor de Necrosis Tumoral alfa , Animales , Flavonoides/farmacología , Flavonoides/uso terapéutico , Cisplatino/toxicidad , Masculino , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad , Interleucina-6/análisis , Interleucina-6/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Ratas , Interleucina-17/metabolismo , InmunohistoquímicaRESUMEN
Background: Cisplatin (CIS) is a broad-spectrum anticancer drug, with cytotoxic effects on either malignant or normal cells. We aimed to evaluate the hepatotoxicity in rats caused by CIS and its amelioration by the co-administration of either curcumin or resveratrol. Materials and Methods: Forty adult male rats divided into four equal groups: (control group): rats were given a saline solution (0.9%) once intraperitoneally, daily for the next 28 days; (cisplatin group): rats were given a daily oral dose of saline solution (0.9%) for 28 days after receiving a single dose of cisplatin (3.3 mg/kg) intraperitoneally for three successive days; (CIS plus curcumin/resveratrol groups): rats received the same previous dose of cisplatin (3.3 mg/kg) daily for three successive days followed by oral administration of either curcumin/resveratrol solution at a dose of (20 mg/kg) or (10 mg/kg) consequently daily for 28 days. Different laboratory tests (ALT, AST, ALP, bilirubin, oxidative stress markers) and light microscopic investigations were done. Results: Administration of CIS resulted in hepatotoxicity in the form of increased liver enzymes, oxidative stress markers; degenerative and apoptotic changes, the co-administration of CIS with either curcumin or resveratrol improved hepatotoxicity through improved microscopic structural changes, reduction in liver enzymes activity, decreased oxidative stress markers, improved degenerative, and apoptotic changes in liver tissues. Conclusion: Co-administration of either curcumin or resveratrol with cisplatin treatment could ameliorate hepatotoxicity caused by cisplatin in rats via anti-inflammatory and oxidative stress-apoptotic pathways.
Asunto(s)
Apoptosis , Enfermedad Hepática Inducida por Sustancias y Drogas , Cisplatino , Curcumina , Estrés Oxidativo , Resveratrol , Animales , Resveratrol/farmacología , Resveratrol/administración & dosificación , Cisplatino/toxicidad , Cisplatino/administración & dosificación , Curcumina/farmacología , Curcumina/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Masculino , Ratas , Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Antioxidantes/farmacología , Antioxidantes/administración & dosificación , Estilbenos/administración & dosificación , Estilbenos/farmacología , Estilbenos/uso terapéutico , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Ratas WistarRESUMEN
Cisplatin is a widely used chemotherapy drug for the treatment of various cancers. However, although cisplatin is effective in targeting cancer cells, it has severe side effects including skeletal muscle atrophy. In this study, we aimed to characterize the role of Dihydromyricetin in cisplatin-induced muscle atrophy in mice. 5-week-old male C57BL/6 mice were treated with Dihydromyricetin for 14 days orally followed by in intraperitoneally cisplatin administration for 6 days. Gastrocnemius muscles were isolated for the following experiments. Antioxidative stress were determined by peroxidative product malondialdehyde (MDA) and antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Quadriceps muscle mass and grip strength were significantly restored by Dihydromyricetin in a dose-dependent manner. Moreover, muscle fibers were improved in Dihydromyricetin treated group. Excessive skeletal muscle E3 ubiquitin-protein ligases in cisplatin group were significantly repressed by Dihydromyricetin treatment. Dihydromyricetin significantly reduced oxidative stress induced by cisplatin by decreasing MDA level and restored SOD and GPx activities. In addition, ferroptosis was significantly reduced by Dihydromyricetin characterized by reduced iron level and ferritin heavy chain 1 and improved Gpx4 level. The present study demonstrated that Dihydromyricetin attenuated cisplatin-induced muscle atrophy by reducing skeletal muscle E3 ubiquitin-protein ligases, oxidative stress, and ferroptosis.
Asunto(s)
Cisplatino , Ferroptosis , Flavonoles , Ratones Endogámicos C57BL , Atrofia Muscular , Estrés Oxidativo , Animales , Masculino , Flavonoles/farmacología , Flavonoles/uso terapéutico , Atrofia Muscular/inducido químicamente , Atrofia Muscular/patología , Atrofia Muscular/metabolismo , Atrofia Muscular/prevención & control , Atrofia Muscular/tratamiento farmacológico , Ferroptosis/efectos de los fármacos , Cisplatino/toxicidad , Ratones , Estrés Oxidativo/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Antineoplásicos/toxicidad , Antioxidantes/farmacologíaRESUMEN
Nephrotoxicity remains a major adverse reaction of the anticancer drug cisplatin (CDDP) chemotherapy, which is an important risk factor for chronic renal disease. Ginsenoside Rh2 from Panax ginseng has been shown to protect against CDDP-induced nephrotoxicity in vivo, but its pharmacological effect on renal tubular epithelial cells is not clearly understood. This study examined the molecular mechanisms underlying the nephroprotective effects of Rh2 on CDDP-induced HK-2 cells and acute kidney injury (AKI) mice. As a result of Rh2 treatment, CDDP-induced HK-2 cells showed increased cell viability and reduced lactate dehydrogenase release. Moreover, Rh2 ameliorated CDDP-induced mitochondrial membrane potential, increased antioxidant enzyme activities, and reduced pro-inflammatory cytokine expression to reduce damage. Rh2 inhibited apoptosis and enhanced the antioxidant capacity of HK-2 cells by reducing proteins associated with endoplasmic reticulum (ER) stress, as well as by attenuating tunicamycin-induced ER stress. In addition, treatment of CDDP-induced AKI mice with Rh2 substantially reduced blood urea nitrogen and serum creatinine levels, attenuated histological damage of kidney. Further, Rh2 also improved kidney function by inhibiting ER stress to support in vitro findings. These results consistently demonstrated that Rh2 protects renal tubular epithelial cells from CDDP-induced nephrotoxicity and apoptosis by restoring ER homeostasis, which might suggest a therapeutic potential and providing new insights into AKI alternative therapies.
Asunto(s)
Lesión Renal Aguda , Cisplatino , Estrés del Retículo Endoplásmico , Células Epiteliales , Ginsenósidos , Túbulos Renales , Ginsenósidos/farmacología , Cisplatino/efectos adversos , Cisplatino/toxicidad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Animales , Ratones , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Túbulos Renales/efectos de los fármacos , Túbulos Renales/patología , Túbulos Renales/metabolismo , Humanos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/tratamiento farmacológico , Masculino , Línea Celular , Apoptosis/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
Cisplatin is a widely used anticancer drug with notable side effects including ototoxicity and nephrotoxicity. Macrophages, the major resident immune cells in the cochlea and kidney, are important drivers of both inflammatory and tissue repair responses. To investigate the roles of macrophages in cisplatin-induced toxicities, we used PLX3397, a U.S. Food and Drug Administration-approved inhibitor of the colony-stimulating factor 1 receptor, to eliminate tissue-resident macrophages. Mice treated with cisplatin alone had considerable hearing loss (ototoxicity) and kidney injury (nephrotoxicity). Macrophage ablation resulted in significantly reduced hearing loss and had greater outer hair cell survival. Macrophage ablation also protected against cisplatin-induced nephrotoxicity, as evidenced by markedly reduced tubular injury and fibrosis. Mechanistically, our data suggest that the protective effect of macrophage ablation against cisplatin-induced ototoxicity and nephrotoxicity is mediated by reduced platinum accumulation in both the inner ear and the kidney. Together, our data indicate that ablation of tissue-resident macrophages represents an important strategy for mitigating cisplatin-induced ototoxicity and nephrotoxicity.
Asunto(s)
Cisplatino , Macrófagos , Ototoxicidad , Cisplatino/efectos adversos , Cisplatino/toxicidad , Animales , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ototoxicidad/etiología , Ototoxicidad/prevención & control , Ratones , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/prevención & control , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Enfermedades Renales/patología , Cóclea/efectos de los fármacos , Cóclea/metabolismo , Cóclea/patología , Ratones Endogámicos C57BL , Aminopiridinas , PirrolesRESUMEN
Cisplatin (CDDP) is a platinum-based anticancer drug widely prescribed for its effectiveness in treating various forms of cancer. However, its major side effect is nephrotoxicity. Although several methods have been developed to mitigate CDDP-induced nephrotoxicity, an optimal approach has yet to be established. This study aimed to investigate the "chronotoxicity" of CDDP as a potential strategy to reduce its side effects. Male ICR mice were treated with CDDP (20 mg/kg, intraperitoneal injection, one shot) at zeitgeber time (ZT) 2 or ZT14 (light or dark phase). After 72 h, we collected plasma and kidney and evaluated several markers. We found that body weight change between ZT2 and ZT14 by CDDP was comparable. In contrast, many toxicological factors, such as plasma blood urine nitrogen, plasma creatinine, renal oxidative stress (malondialdehyde), DNA damage (γH2AX), acute kidney injury biomarker (KIM-1), and inflammation (Tnfα), were significantly induced at ZT14 compared to than that of ZT2. Our present data suggested that chronotoxicology might provide beneficial information on the importance of administration timings for toxic evaluations and unacceptable side effects.
Asunto(s)
Antineoplásicos , Ritmo Circadiano , Cisplatino , Riñón , Ratones Endogámicos ICR , Animales , Cisplatino/toxicidad , Masculino , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Antineoplásicos/toxicidad , Antineoplásicos/efectos adversos , Ratones , Ritmo Circadiano/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Enfermedades Renales/patologíaRESUMEN
Cisplatin (CDDP) is administered as an anticancer drug across a broad spectrum of cancer treatments, but it causes severe renal damage. Several studies have attempted to elucidate the cause of CDDP-induced renal injury, but the detailed mechanism remains unclear. We previously found that S3 cells are more sensitive to CDDP than S1 and S2 cells by using immortalized cells derived from S1, S2, and S3 segments of proximal tubules. In this study, we investigated the potential contribution of reactive oxygen species (ROS) to the sensitivity of S3 cells to CDDP. The results showed that S3 cells have high sensitivity to CDDP, paraquat (PQ) and three ROS substances. To examine the mechanisms underlying the sensitivity to ROS in S3 cells, we compared the cellular responses of CDDP- and PQ-exposed S3 cells. The results indicated that the levels of intracellular ROS and lipid peroxides were increased in S3 cells after CDDP and PQ exposure. The intracellular levels of antioxidant proteins such as thioredoxin, thioredoxin reductase 1 and glutathione peroxidase 4 were also increased by exposure to PQ, but these proteins were decreased by CDDP exposure in S3 cells. Furthermore, the levels of intracellular free Fe2+ were increased by CDDP exposure only in S3 cells but not S1 or S2 cells, and cytotoxicity by exposure to CDDP in S3 cells was suppressed by ferroptosis inhibitors. These results suggested that the induction of ferroptosis due to the ROS production through attenuation of the antioxidant system and elevated free Fe2+ is partly responsible for the sensitivity of S3 cells to CDDP.
Asunto(s)
Antineoplásicos , Cisplatino , Ferroptosis , Túbulos Renales Proximales , Especies Reactivas de Oxígeno , Cisplatino/toxicidad , Cisplatino/farmacología , Ferroptosis/efectos de los fármacos , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos/toxicidad , Antineoplásicos/farmacología , Animales , Paraquat/toxicidad , Línea Celular , Línea Celular Transformada , Ratones , Supervivencia Celular/efectos de los fármacosRESUMEN
As a broad-spectrum anticancer drug, cisplatin is widely used in the treatment of tumors in various systems. Unfortunately, several serious side effects of cisplatin limit its clinical application, the most common of which are nephrotoxicity and ototoxicity. Studies have shown that cochlear hair cell degeneration is the main cause of cisplatin-induced hearing loss. However, the mechanism of cisplatin-induced hair cell death remains unclear. The present study aimed to explore the potential role of activating transcription factor 6 (ATF6), an endoplasmic reticulum (ER)-localized protein, on cisplatin-induced ototoxicity in vivo and in vitro. In this study, we observed that cisplatin exposure induced apoptosis of mouse auditory OC-1 cells, accompanied by a significant increase in the expression of ATF6 and C/EBP homologous protein (CHOP). In cell or cochlear culture models, treatment with an ATF6 agonist, an ER homeostasis regulator, significantly ameliorated cisplatin-induced cytotoxicity. Further, our in vivo experiments showed that subcutaneous injection of an ATF6 agonist almost completely prevented outer hair cell loss and significantly alleviated cisplatin-induced auditory brainstem response (ABR) threshold elevation in mice. Collectively, our results revealed the underlying mechanism by which activation of ATF6 significantly improved cisplatin-induced hair cell apoptosis, at least in part by inhibiting apoptosis signal-regulating kinase 1 expression, and demonstrated that pharmacological activation of ATF6-mediated unfolded protein response is a potential treatment for cisplatin-induced ototoxicity.
Asunto(s)
Factor de Transcripción Activador 6 , Apoptosis , Cisplatino , Ototoxicidad , Respuesta de Proteína Desplegada , Cisplatino/toxicidad , Animales , Factor de Transcripción Activador 6/metabolismo , Ototoxicidad/prevención & control , Ototoxicidad/etiología , Ototoxicidad/patología , Ratones , Respuesta de Proteína Desplegada/efectos de los fármacos , Apoptosis/efectos de los fármacos , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Línea Celular , Masculino , Antineoplásicos/toxicidad , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patología , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/metabolismo , Pérdida Auditiva/patología , Pérdida Auditiva/prevención & control , Ratones Endogámicos C57BL , Factor de Transcripción CHOP/metabolismoRESUMEN
Nephrotoxicity is a major constraint of cisplatin application in many solid tumors. Since the lack of preventive strategies, the necessity exists to identify critical molecular targets involved in cisplatin nephrotoxicity. The Purinergic ligand-gcotedion channel 7 receptor (P2X7R) is a ligand-gated ion channel that is predominantly implicated in inflammation and cell death. Our aim is to investigate the role P2X7R in cisplatin-induced acute and chronic kidney injury, as well as the underlying mechanism. In this study, we found that cisplatin can cause an increase in the expression of P2X7R in mouse kidney tissue, and P2X7R knockout can alleviate acute renal function damage caused by cisplatin, as well as the expression of kidney injury molecule 1 (KIM-1) and interleukin-18 (IL-18). Cisplatin can cause an increase in the expression of nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome in mouse kidney tissue. Compared with wild-type mice, P2X7R -/- mice showed decreased expression of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved Caspase-1, and cleaved IL-1ß in kidney tissue after cisplatin administration, and the apoptosis of renal tubular epithelial cells were also decreased. In addition, we also found that NLRP3 knockout can improve cisplatin induced degeneration, detachment, and necrosis of renal tubular epithelial cells. Furthermore, P2X7R -/- mice also showed reduced renal fibrosis and better long-term renal prognosis. In conclusion, our study identified that P2X7R knockout can improve cisplatin induced acute renal injury and chronic renal fibrosis by inhibiting the activation of NLRP3 inflammasome.
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Lesión Renal Aguda , Cisplatino , Inflamasomas , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Receptores Purinérgicos P2X7 , Animales , Cisplatino/toxicidad , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/deficiencia , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/deficiencia , Ratones , Inflamasomas/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/patología , Masculino , Antineoplásicos/toxicidadRESUMEN
Background: Cisplatin is a commonly used nephrotoxic drug and can cause acute kidney injury (AKI). In the present study, isobaric tags for relative and absolute quantification (iTRAQ) and parallel reaction monitoring (PRM)-based comparative proteomics were used to analyze differentially expressed proteins (DEPs) to determine the key molecular mechanism in mice with cisplatin-induced AKI in the presence or absence of SIS3, a specific p-smad3 inhibitor, intervention. Methods: The cisplatin-induced AKI mouse model was established and treated with SIS3. We used iTRAQ to search for DEPs, PRM to verify key DEPs and combined Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for bioinformatics analysis. We then assessed lipid deposition, malondialdehyde (MDA) and reactive oxygen species (ROS) and detected the expression of SREBF1, SCD1, CPT1A, PPARα and NDRG1 in vitro. Results: Proteomic analysis showed that the identified DEPs were mainly enriched in energy metabolism pathways, especially in lipid metabolism. When SIS3 was applied to inhibit the phosphorylation of Smad3, the expression of NDRG1 and fatty acid oxidation key proteins CPT1A and PPARα increased, the expression of lipid synthesis related proteins SREBF1 and SCD1 decreased and the production of lipid droplets, MDA and ROS decreased. Conclusion: SIS3 alleviates oxidative stress, reduces lipid accumulation and promotes fatty acid oxidation through NDRG1 in cisplatin-induced AKI. Our study provides a new candidate protein for elucidating the molecular mechanisms of fatty acid metabolism disorders in cisplatin-induced acute kidney injury.
Asunto(s)
Lesión Renal Aguda , Cisplatino , Proteómica , Cisplatino/efectos adversos , Cisplatino/toxicidad , Animales , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Proteómica/métodos , Ratones , Modelos Animales de Enfermedad , Masculino , Proteína smad3/metabolismo , Proteína smad3/genética , Metabolismo de los Lípidos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidadRESUMEN
Neurotoxicity is a major obstacle in the effectiveness of Cisplatin in cancer chemotherapy. In this process, oxidative stress and inflammation are considered to be the main mechanisms involved in brain and lung toxicity. The aim of the present work was to study the influence of the amount of protein on some oxidative parameters in the brain and lungs of rats treated with Cisplatin (CP) and N-Acetylcysteine (NAC) as neuroprotectors. Four groups of Wistar rats, each containing six animals, were fed with a protein diet at 7% for 15 days. Thereafter, the groups were given either a unique dose of CP® 5 mg/kg or NAC® 5 mg/kg as follows: group 1 (control), NaCl 0.9% vehicle; group 2, CP; group 3, NAC; and group 4, NAC + CP. The animals were sacrificed immediately after the treatments. Blood samples were collected upon sacrifice and used to measure blood triglycerides and glucose. The brain and lungs of each animal were obtained and used to assay lipid peroxidation (TBARS), glutathione (GSH), serotonin metabolite (5-HIAA), catalase, and the activity of Ca+2, and Mg+2 ATPase using validated methods. TBARS, H2O2, and GSH were found to be significantly decreased in the cortex and cerebellum/medulla oblongata of the groups treated with CP and NAC. The total ATPase showed a significant increase in the lung and cerebellum/medulla oblongata, while 5-HIAA showed the same tendency in the cortex of the same group of animals. The increase in 5-HIAA and ATPase during NAC and CP administration resulted in brain protection. This effect could be even more powerful when membrane fluidity is increased, thus proving the efficacy of combined NAC and CP drug therapy, which appears to be a promising strategy for future chemotherapy in malnourished patients.
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Acetilcisteína , Cisplatino , Pulmón , Ratas Wistar , Animales , Cisplatino/efectos adversos , Cisplatino/toxicidad , Acetilcisteína/farmacología , Ratas , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Peroxidación de Lípido/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Masculino , Cerebro/efectos de los fármacos , Cerebro/metabolismo , Glutatión/metabolismo , Fármacos Neuroprotectores/farmacología , Antineoplásicos/efectos adversosRESUMEN
This study investigates the chronic impact of two of the most widely consumed antineoplastic drugs, Ifosfamide (IF) and Cisplatin (CDDP), on the bivalve species Mytilus galloprovincialis under current (17 °C) and predicted warming conditions (21 °C). Accompanying the expected increase in worldwide cancer incidence, antineoplastics detection in the aquatic environment is also expected to rise. Mussels were exposed to varying concentrations of IF (10, 100, 500 ng/L) and CDDP (10, 100, 1000 ng/L) for 28 days. Biochemical analyses focused on metabolic, antioxidant and biotransformation capacities, cellular damage, and neurotoxicity. Results showed temperature-dependent variations in biochemical responses. Metabolic capacity remained stable in mussels exposed to IF, while CDDP exposure increased it at 1000 ng/L for both temperatures. Antioxidant enzyme activities were unaffected by IF, but CDDP activated them, particularly at 21 °C. Biotransformation capacity was unchanged by IF but enhanced by CDDP. Nevertheless, cellular damage occurred at CDDP concentrations above 100 ng/L, regardless of temperature. Integrated biomarker responses highlighted CDDP's greater impact, emphasizing the critical role of temperature in shaping organismal responses and underscoring the complexity of environmental stressor interactions.
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Antineoplásicos , Cisplatino , Ifosfamida , Mytilus , Temperatura , Contaminantes Químicos del Agua , Animales , Cisplatino/toxicidad , Mytilus/fisiología , Mytilus/efectos de los fármacos , Ifosfamida/toxicidad , Contaminantes Químicos del Agua/toxicidad , Antineoplásicos/toxicidadRESUMEN
Cisplatin is an effective chemotherapy agent against various solid malignancies; however, it is associated with irreversible bilateral sensorineural hearing loss, emphasizing the need for drug development to prevent this complication, with the current options being very limited. Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine-threonine protein kinase involved in various cellular processes, including apoptosis regulation. In this study, we used a transgenic zebrafish model (Brn3C: EGFP) in which hair cells within neuromasts are observed in green under fluorescent microscopy without the need for staining. Zebrafish larvae were exposed to cisplatin alone or in combination with various concentrations of Y-27632, a potent ROCK inhibitor. Hair cell counts, apoptosis assessments using the terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay, FM1-43FX labeling assay and behavioral analyses (startle response and rheotaxis) were performed to evaluate the protective effects of Y-27632 against cisplatin-induced ototoxicity. Cisplatin treatment reduced the number of hair cells in neuromasts, induced apoptosis, and impaired zebrafish larval behaviors. Y-27632 demonstrated a dose-dependent protective effect against cisplatin-induced hair cell loss and apoptosis. These findings suggest that Y-27632, as a ROCK inhibitor, mitigates cisplatin-induced hair cell loss and associated ototoxicity in zebrafish.
Asunto(s)
Amidas , Apoptosis , Cisplatino , Ototoxicidad , Piridinas , Pez Cebra , Animales , Cisplatino/toxicidad , Amidas/farmacología , Piridinas/farmacología , Ototoxicidad/prevención & control , Apoptosis/efectos de los fármacos , Animales Modificados Genéticamente , Antineoplásicos/toxicidad , Células Ciliadas Auditivas/efectos de los fármacos , Larva/efectos de los fármacos , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismo , Modelos Animales de EnfermedadRESUMEN
OBJECTIVES: Acute kidney injury (AKI) caused by cisplatin (CDDP) is a complex, critical illness with no effective or specific treatment. The purpose of the study was to assess the protective effect of protopanaxadiol (PPD) on the kidneys in CDDP-induced AKI models and its possible mechanisms. METHODS: In vitro, the protection of PPD was assessed in HK-2. KM mice were injected with CDDP to induce AKI models in vivo. The determination of blood urea nitrogen and serum creatinine (SCr) was performed, and pathological changes were examined by histopathological examination. Immunostaining and western blot analyses were used to analyze the expression levels of proteins. RESULTS: PPD can increase the viability of HK-2 cells damaged by CDDP, improve cell morphology, and alleviate the symptoms of AKI in mice. In addition, PPD can down-regulate the protein expression of TRF and up-regulate the protein expression of Ferritin heavy chain, Glutathione peroxidase 4, and ferroptosis suppressor protein 1 reduce the iron content in cells and kidney tissues, and restore the antioxidant defense system. CONCLUSION: PPD has an inhibitory effect on cisplatin-induced nephrotoxicity, which may be related to the inhibition of ferroptosis by regulating iron metabolism and lipid peroxidation.
Asunto(s)
Lesión Renal Aguda , Cisplatino , Ferroptosis , Sapogeninas , Cisplatino/toxicidad , Animales , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/metabolismo , Ferroptosis/efectos de los fármacos , Ratones , Sapogeninas/farmacología , Humanos , Masculino , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Modelos Animales de Enfermedad , Línea Celular , Peroxidación de Lípido/efectos de los fármacos , Hierro/metabolismo , Antioxidantes/farmacología , Supervivencia Celular/efectos de los fármacosRESUMEN
Early detection of drug-induced kidney injury is essential for drug development. In this study, multiple low-dose aristolochic acid (AA) and cisplatin (Cis) injections increased renal mRNA levels of inflammation, fibrosis, and renal tubule injury markers. We applied a serum amyloid A3 (Saa3) promoter-driven luciferase reporter (Saa3 promoter-luc mice) to these two tubulointerstitial nephritis models and performed in vivo bioluminescence imaging to monitor early renal pathologies. The bioluminescent signals from renal tissues with AA or CIS injections were stronger than those from normal kidney tissues obtained from normal mice. To verify whether the visualized bioluminescence signal was specifically generated by the injured kidney, we performed in vivo bioluminescence analysis after opening the stomachs of Saa3 promoter-luc mice, and the Saa3-mediated bioluminescent signal was specifically detected in the injured kidney. This study showed that Saa3 promoter activity is a potent non-invasive indicator for the early detection of drug-induced nephrotoxicity.
Asunto(s)
Ácidos Aristolóquicos , Luciferasas , Regiones Promotoras Genéticas , Proteína Amiloide A Sérica , Animales , Proteína Amiloide A Sérica/genética , Proteína Amiloide A Sérica/metabolismo , Ratones , Luciferasas/metabolismo , Luciferasas/genética , Ácidos Aristolóquicos/toxicidad , Genes Reporteros , Cisplatino/toxicidad , Cisplatino/efectos adversos , Mediciones Luminiscentes/métodos , Masculino , Enfermedades Renales/inducido químicamente , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Riñón/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
Cisplatin-induced cognitive impairment (chemobrain) affects a considerable percentage of cancer patients and has no established pharmacological treatment. Chemobrain can be associated with neuroinflammation and oxidative stress. Melatonin, a pineal hormone, is known to have antioxidant, anti-inflammatory and neuroprotective potential. In this study, we investigated cisplatin-induced cognitive impairment in rats and whether melatonin can improve or reverse this impairment. Behavioral testing involved measuring working memory using the novel location recognition test (NLRT) under conditions of cisplatin or cisplatinâ +â melatonin treatment, followed by the collection of rats' brains. The brains were subsequently stained with Golgi-Cox stain and then the hippocampus area CA3 of each one was examined, and dendritic spine density was calculated. Treatment with cisplatin resulted in deficits in the rats' performance in the NLRT (Pâ <â 0.05). These deficits were prevented by the coadministration of melatonin (Pâ <â 0.05). Cisplatin also reduced the density of dendritic spines in the hippocampus (Pâ <â 0.0001), specifically CA3 area, while the coadministration of melatonin significantly reversed this reduction (Pâ <â 0.001). This study showed that melatonin can ameliorate cisplatin-induced spatial memory deficits and dendritic spines density abnormalities in rats. Given that melatonin is a safe and wildly used supplement, it is feasible to explore its use as a palliative intervention in cancer treatment.
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Cisplatino , Espinas Dendríticas , Hipocampo , Melatonina , Animales , Melatonina/farmacología , Cisplatino/toxicidad , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/patología , Masculino , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipocampo/metabolismo , Ratas , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/prevención & control , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/patología , Antineoplásicos/toxicidad , Fármacos Neuroprotectores/farmacología , Antioxidantes/farmacología , Ratas Wistar , Deterioro Cognitivo Relacionado con la Quimioterapia , Memoria a Corto Plazo/efectos de los fármacosRESUMEN
Acute kidney injury (AKI) stands as a prevalent and economically burdensome condition worldwide, yet its complex molecular mechanisms remain incompletely understood. To address this gap, our study employs a multifaceted approach, combining mass spectrometry and RNA sequencing technologies, to elucidate the intricate molecular landscape underlying nephrotoxin-induced AKI in mice by cisplatin- and LPS-induced. By examining the protein and RNA expression profiles, we aimed to uncover novel insights into the pathogenesis of AKI and identify potential diagnostic and therapeutic targets. Our results demonstrate significant down-regulation of Slc34a1 and Slc34a3, shedding light on their crucial roles in AKI pathology and highlighting their promise as actionable targets for diagnosis and treatment. This comprehensive analysis not only enhances our understanding of AKI pathophysiology but also offers valuable avenues for the development of targeted interventions to mitigate its clinical impact. SIGNIFICANCE: Nephrotoxicity acute kidney injury (AKI) is a common clinical condition whose pathogenesis is the process by which some drugs, chemicals or other factors cause damage to the kidneys, resulting in impaired kidney function. Although it has been proved that different nephrotoxic substances can affect the kidney through different pathways, whether they have a commonality has not been registered. Here, we combined transcriptomics and proteomics to study the molecular mechanism of LPS and cisplatin-induced nephrotoxic acute kidney injury finding that the down-regulation of Slc34a1 and Slc34a3 may be a critical link in nephrotoxic acute kidney injury, which can be used as a marker for its early diagnosis.
Asunto(s)
Lesión Renal Aguda , Cisplatino , Regulación hacia Abajo , Proteómica , Transcriptoma , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/genética , Animales , Ratones , Proteómica/métodos , Cisplatino/efectos adversos , Cisplatino/toxicidad , Lipopolisacáridos/toxicidad , Masculino , Perfilación de la Expresión GénicaRESUMEN
Real-time and non-invasive assessment of tissue health is crucial for maximizing the potential of microphysiological systems (MPS) for drug-induced nephrotoxicity screening. Although impedance has been widely considered as a measure of the barrier function, it has not been incorporated to detect cell detachment in MPS with top and bottom microfluidic channels separated by a porous membrane. During cell delamination from the porous membrane, the resistance between both channels decreases, while capacitance increases, allowing the detection of such detachment. Previously reported concepts have solely attributed the decrease in the resistance to the distortion of the barrier function, ignoring the resistance and capacitance changes due to cell detachment. Here, we report a two-channel MPS with integrated indium tin oxide (ITO) electrodes capable of measuring impedance in real time. The trans-epithelial electrical resistance (TEER) and tissue reactance (capacitance) were extracted from the impedance profiles. We attributed the anomalous initial increase observed in TEER, upon cisplatin administration, to the distortion of tight junctions. Cell detachment was captured by sudden jumps in capacitance. TEER profiles illuminated the effects of cisplatin and cimetidine treatments in a dose-dependent and polarity-dependent manner. The correspondence between TEER and barrier function was validated for a continuous tissue using the capacitance profiles. These results demonstrate that capacitance can be used as a real-time and non-invasive indicator of confluence and will support the accuracy of the drug-induced cytotoxicity assessed by TEER profiles in the two-channel MPS for the barrier function of a cell monolayer.
Asunto(s)
Cisplatino , Impedancia Eléctrica , Túbulos Renales Proximales , Cisplatino/toxicidad , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/citología , Túbulos Renales Proximales/patología , Animales , Compuestos de Estaño/química , Compuestos de Estaño/toxicidad , Cinética , Cimetidina/farmacología , Adhesión Celular/efectos de los fármacos , Electrodos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Línea Celular , Humanos , Uniones Estrechas/efectos de los fármacosRESUMEN
Small extracellular vesicles (sEVs) secreted by human umbilical cord have therapeutic effects on various degenerative diseases. However, the characteristics and potential functions of human umbilical cord mesenchymal stem cells (huMSCs)-derived sEVs, especially the role of premature ovarian failure (POF), are poorly understood. Here, we isolated and characterized huMSCs and their sEVs. huMSCs highly expressed CD73, CD90, and CD105. huMSC-sEVs showed typical exosomal features, highly expressing CD9, TSG101, and CD63. It was shown that huMSC-sEVs could be taken up by granulosa cells (GCs) and damaged ovarian tissue, which increased the levels of hormone secretion and reduced GCs apoptosis. We further confirmed that the levels of follicle-stimulating hormone in rat serum decreased dramatically, while the levels of estrogen (E2ï¼and anti-mullerian hormone (AMH) increased significantly with the treatment of huMSC-sEVs. Meanwhile, huMSC-sEVs treatment greatly reduced cell apoptosis and autophagy, while increased the phosphorylation levels of p-PI3K and p-Akt. Therefore, treatment with huMSC-sEVs significantly inhibited GCs apoptosis, improved ovarian morphology, promoted follicular development, inhibited follicular over-atresia, and improved ovarian reserve capacity in POF rats. Our study verified that activation of PI3K/Akt signaling pathway and regulation of cellular autophagy, thus reducing GCs death, are the mechanisms by which huMSC-sEVs restore ovarian tissue function.