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1.
Eur Rev Med Pharmacol Sci ; 28(3): 1103-1110, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38375716

RESUMO

OBJECTIVE: The aim of this study was to explore the protective effect of candesartan against cisplatin-induced kidney damage, with a specific focus on the growth differentiation factor 15 (GDF-15) pathway. MATERIALS AND METHODS: 24 adult female Wistar rats, with a weight range of 200-210 grams, were enrolled in the study. Eight rats were included as a normal control group and did not receive any medication. 16 rats were administered cisplatin at a dosage of 2.5 mg/kg/day twice a week for 4 weeks (total dose 20 mg/kg). Then, they were randomly divided into two groups and treated with 1 ml/kg/day tap water or 8 mg/kg/day candesartan via oral gavage daily for 4 weeks. At the end of the treatment period, animals were sacrificed, and their kidneys were assessed histologically. In addition, plasma malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), creatinine, and GDF-15 levels were assessed. RESULTS: Treatment with candesartan resulted in a significant rise in serum GDF-15 levels and a significant reduction in levels of serum MDA, TNF-α, IL-6, and creatinine compared to the cisplatin and saline group. Candesartan treatment effectively protected the kidney injury, and histopathological examinations of the kidneys confirmed these results. CONCLUSIONS: This study demonstrates that candesartan alleviates cisplatin-induced renal toxicity by further increasing GDF-15, downregulating inflammatory markers, and reducing oxidative stress.


Assuntos
Benzimidazóis , Compostos de Bifenilo , Cisplatino , Nefropatias , Tetrazóis , Ratos , Feminino , Animais , Cisplatino/toxicidade , Fator 15 de Diferenciação de Crescimento , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Creatinina , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Nefropatias/prevenção & controle , Rim/patologia , Estresse Oxidativo
2.
Int J Nanomedicine ; 19: 1385-1408, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38371457

RESUMO

Background: Acute kidney injury (AKI) is a syndrome, posing a substantial healthcare burden. The pathological basis of AKI is associated with inflammation and oxidative stress which cause additional damage to mitochondria. Artesunate (ATS) is a derivative of artemisinin isolated from Artemisia annua L. that is an effective treatment for malaria and favored for the prevention and treatment of kidney diseases. However, there are still challenges related to its efficacy, including poor water solubility, limited oral bioavailability and short half-life. Liposome-based nanoparticles are used for drug delivery due to their ideal biocompatibility and their ability to improve the bioavailability of specific drugs and enhance drug efficacy. Methods: In this study, a novel TPP-based natural ATS-nanoliposome, namely T-A-Ls, was applied for the treatment of AKI. ATS was encapsulated with or without triphenylphosphonium (TPP)-modified nanoliposomes. AKI was induced by cisplatin in C57BL/6J mice and a cisplatin-induced injury model was generated in HK-2 cells in vitro. Blood urea nitrogen (BUN), serum creatinine (Scr) measurements and section staining were utilized to assess renal protective effect of T-A-Ls. Inflammatory-related factors and proteins were quantified via Elisa, Immunofluorescence and Western Blot (WB). The anti-mitochondrial oxidative stress effect of T-A-Ls was determined by ROS, JC-1 and oxygen consumption rate (OCR) kits. Immunohistochemistry and WB were conducted to measure associated protein expressions. In vivo biodistribution and the concentration of T-A-Ls in kidney were also explored. Results: T-A-Ls exhibited good oxidative resistance, preferential renal uptake, mitochondrial targeting, and it ameliorated kidney injury in cisplatin-induced AKI mice. Mitochondrial dysfunction, ATP production and respiratory capacity were improved in damaged HK-2 cells; ROS content decreased while mitochondrial membrane potential recovered. T-A-Ls exerted renal protection by inhibiting inflammation and reducing oxidative stress; these effects were mediated by a downregulation in the expression of RAGE and iNOS and an upregulation in both Nrf2 and HO-1. Conclusion: T-A-Ls could improve the delivery of ATS to the kidney, offering a promising avenue to treat AKI.


Assuntos
Injúria Renal Aguda , Cisplatino , Compostos Organofosforados , Animais , Camundongos , Cisplatino/toxicidade , Artesunato , Espécies Reativas de Oxigênio/metabolismo , Distribuição Tecidual , Camundongos Endogâmicos C57BL , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , Rim , Estresse Oxidativo , Mitocôndrias/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Sistemas de Liberação de Medicamentos/efeitos adversos
3.
Neurotox Res ; 42(1): 8, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38194189

RESUMO

Chemotherapy-induced neuropathic pain (CIPN) is a common side effect of antitumor chemotherapeutic agents. It describes a pathological state of pain related to the cumulative dosage of the drug, significantly limiting the efficacy of antitumor treatment. Sofas strategies alleviating CIPN still lack. Calcitonin gene-related peptide (CGRP) is a neuropeptide involved in many pathologic pains. In this study, we explored the effects of CGRP blocking on CIPN and potential mechanisms. Total dose of 20.7 mg/kg cisplatin was used to establish a CIPN mouse model. Mechanical and thermal hypersensitivity was measured using von Frey hairs and tail flick test. Western blot and immunofluorescence were utilized to evaluate the levels of CGRP and activated astrocytes in mouse spinal cord, respectively. In addition, real-time quantitative PCR (RT-qPCR) was used to detect the level of inflammatory cytokines such as IL-6, IL-1ß, and NLRP3 in vitro and in vivo. There are markedly increased CGRP expression and astrocyte activation in the spinal cord of mice following cisplatin treatment. Pretreatment with a monoclonal antibody targeting CGRP (ZR8 mAb) effectively reduced cisplatin-induced mechanical hypersensitivity and thermal nociceptive sensitization and attenuated neuroinflammation as marked by downregulated expression of IL-6, IL-1ß, and NLRP3 in the mice spinal cord and spleen. Lastly, ZR8 mAb does not interfere with the antitumor effects of cisplatin in tumor-bearing mice. Our findings indicate that neutralizing CGRP with monoclonal antibody could effectively alleviate CIPN by attenuating neuroinflammation. CGRP is a promising therapeutic target for CIPN.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Neuralgia , Animais , Camundongos , Cisplatino/toxicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR , Interleucina-6 , Doenças Neuroinflamatórias , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Anticorpos Monoclonais , Interleucina-1beta
4.
Int J Biol Sci ; 20(2): 784-800, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38169643

RESUMO

As an anti-tumor drug widely used in the clinic, cisplatin is limited by its ototoxic side effects associated with various factors, including inflammatory responses. Receptor for Advanced Glycation Endproducts (RAGE) recognizes damage-associated molecular patterns (DAMPs) and promotes stress and inflammation. This study intended to determine the potential behavior of the HMGB1/RAGE axis after cisplatin injury and whether it has a protective effect after inhibiting this pathway. We used FPS-ZM1, a RAGE inhibitor, to modulate the axis of HMGB1/RAGE in neonatal mouse cochlear explants and C57BL/6 mice in vivo. Apoptosis was identified by Annexin V-FITC/PI assay, Cleaved Caspase-3, and TUNEL staining. Reactive oxygen species (ROS) level was assessed by MitoSOX Red and CellROX Green assay. The expression of proteins associated with the HMGB1/RAGE axis and apoptosis was observed by western blotting. The expression of inflammatory cytokines was evaluated by qPCR. The protective effect of HMGB1/RAGE knockdown was also assessed on cisplatin-induced ototoxicity. These results demonstrated that cisplatin could activate the HMGB1/RAGE pathway in cochlear hair cells and release inflammatory factors. Pretreatment with FPS-ZM1 alleviated cisplatin-induced ototoxicity in vivo and in vitro. Knocking down HMGB1 and RAGE achieved specific protective effects. Altogether, inhibiting HMGB1/RAGE axis can reverse the increase of ROS accumulation, the activation of apoptosis, and the production of inflammatory reactions after cisplatin injury. FPS-ZM1 could resist the ototoxicity of cisplatin by suppressing the HMGB1/RAGE signal pathway, and it may be considered the new otoprotective potential strategy for hearing loss.


Assuntos
Proteína HMGB1 , Ototoxicidade , Camundongos , Animais , Cisplatino/toxicidade , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Espécies Reativas de Oxigênio , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Inflamação/tratamento farmacológico , Inflamação/metabolismo
5.
Neurotox Res ; 42(1): 10, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38294571

RESUMO

Therapy-Induced Senescence (TIS) is a form of senescence that is typically described in malignant cells in response to the exposure of cancer chemotherapy or radiation but can also be precipitated in non-malignant cells. TIS has been shown to contribute to the development of several cancer therapy-related adverse effects; however, evidence on its role in mediating chemotherapy-induced neurotoxicity, such as Chemotherapy-induced Peripheral Neuropathy (CIPN), is limited. We here show that cisplatin treatment over two cycles (cumulative dose of 23 mg/kg) provoked mechanical allodynia and thermal hyperalgesia in Sprague-Dawley rats. Isolation of dorsal root ganglia (DRG) from the cisplatin-treated rats demonstrated robust SA-ß-gal upregulation at both day 8 (after the first cycle) and day 18 (after the second cycle), decreased lmnb1 expression, increased expression of cdkn1a and cdkn2a, and of several factors of the Senescence-associated Secretory Phenotype (SASP) (Il6, Il1b, and mmp9). Moreover, single-cell calcium imaging of cultured DRGs revealed a significant increase in terms of the magnitude of KCl-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats. No significant change was observed in terms of the magnitude of capsaicin-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats but with decreased area under the curve of the responses in cisplatin-treated rats. Further evidence to support the contribution of TIS to therapy adverse effects is required but should encourage the use of senescence-modulating agents (senotherapeutics) as novel palliative approaches to mitigate chemotherapy-induced neurotoxicity.


Assuntos
Antineoplásicos , Neoplasias , Ratos , Animais , Cálcio , Cisplatino/toxicidade , Nociceptividade , Ratos Sprague-Dawley , Hiperalgesia , Antineoplásicos/toxicidade
6.
Life Sci ; 339: 122450, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38262575

RESUMO

Acute kidney injury (AKI) is a clinical syndrome characterized by a sudden and continuous decline in renal function. The drug cisplatin is commonly used as chemotherapy for solid tumors, and cisplatin-induced acute kidney injury (CI-AKI), which is characterized by acute tubular necrosis and inflammation, frequently occurs in tumor patients. Renal tubular epithelial cells (RTECs) are severely damaged early in this process and play an important role in renal tubular injury and the recruitment of immune cells. Macrophages are the most common infiltrating immune cells in the kidney and have a significant impact on CI-AKI and subsequent repair. This article reviews the latest research progress on the effects of RTECs and macrophages on CI-AKI and their interactions in AKI to provide a direction for identifying therapeutic targets for treating AKI.


Assuntos
Injúria Renal Aguda , Cisplatino , Humanos , Cisplatino/toxicidade , Injúria Renal Aguda/patologia , Rim/patologia , Macrófagos/patologia , Células Epiteliais/patologia
7.
Sci Rep ; 14(1): 1565, 2024 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-38238398

RESUMO

Impaired spermatogenesis and male infertility are common consequences of chemotherapy drugs used in patients with testicular cancer. The present study investigated the effects of sodium alginate (NaAL) on testicular toxicity caused by bleomycin, etoposide, and cisplatin (BEP). Rats in group 1 received normal saline, while groups 2 and 3 were treated with 25 and 50 mg/kg of NaAL, respectively. Group 4 was treated with a 21-day cycle of BEP (0.5 mg/kg bleomycin, 5 mg/kg etoposide, and 1 mg/kg cisplatin), and groups 5 and 6 received BEP regimen plus 25 and 50 mg/kg of NaAL, respectively. Then, sperm parameters, testosterone levels, testicular histopathology and stereological parameters, testicular levels of malondialdehyde (MDA), nitric oxide (NO), and total antioxidant capacity (TAC), and the expression of apoptosis-associated genes including Bcl2, Bax, Caspase3, p53, and TNF-α were evaluated. Our findings revealed that NaAL improved sperm parameters, testosterone levels, histopathology, and stereology parameters in BEP-administrated rats. NaAL also improved testis antioxidant status by enhancing TAC and ameliorating MDA and NO. Further, modifications to the expression of Bcl2, Bax, Caspase3, p53, and TNF-α suggested that NaAL alleviated BEP-induced apoptosis and inflammation. Collectively, NaAL protects rats' testes against BEP-evoked toxicity damage through the modulation of nitro-oxidative stress, apoptosis, and inflammation.


Assuntos
Cisplatino , Neoplasias Testiculares , Humanos , Masculino , Ratos , Animais , Cisplatino/toxicidade , Cisplatino/metabolismo , Etoposídeo/farmacologia , Neoplasias Testiculares/patologia , Bleomicina/toxicidade , Bleomicina/metabolismo , Antioxidantes/metabolismo , Alginatos/farmacologia , Alginatos/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sêmen/metabolismo , Testosterona/metabolismo , Estresse Oxidativo , Apoptose , Inflamação/induzido quimicamente
8.
Int J Pharm ; 652: 123839, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38266944

RESUMO

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse effect of cisplatin. The current study aimed to determine whether PEGylated nanoliposomal cisplatin can limit CIPN in an animal model. METHODS: Cisplatin-loaded PEGylated liposome nanoparticles (Cis-PL) were produced as a combination of lecithin, cholesterol, and DSPE-mPEG2000 in a molar ratio of 50:45:5 and were characterized by polydispersity index (PDI), zeta potential, Field emission scanning electron microscopy (FESEM) analysis, as well as encapsulation efficiency (EE). Fifteen male rats were provided and randomly divided into 3 groups including Cis-PL group, cisplatin group, and control group. Behavioural tests (hot-plate test and acetone drop test) were used for evaluating CIPN. Moreover, oxidative stress markers and histopathological analysis were applied. Treatment-related toxicity was assessed by haematological analysis as well as liver and renal function tests. RESULTS: Cis-PL had an average particle size of 125.4, PDI of 0.127, and zeta potential of -40.9 mV. Moreover, the Cis-PL exhibited a high EE as well as low levels of leakage rate at 25 °C. In a hot-plate test, paw withdrawal latency was longer in Cis-PL group in comparison to rats treated with cisplatin. A lower number of withdrawal responses was detected during acetone drop test in Cis-PL group than in cisplatin-treated rats. Assessment of oxidative stress markers showed that Cis-PL could improve oxidative stress. Additionally, histopathological assessment demonstrated that the number of satellite cells was significantly reduced in the dorsal root ganglion (DRG) of Cis-PL-treated rats compared with those treated with cisplatin. The cisplatin group had elevated white blood cells counts, reduced platelet counts, and higher levels of bilirubin, ALT (alanine aminotransferase, and AST (aspartate aminotransferase), and creatinine compared with the control group, which was ameliorated in Cis-PL group. CONCLUSIONS: Data from the current study support the previous hypothesis that Cisplatin-loaded PEGylated liposome could be a promising solution for CIPN in the future by modulating oxidative stress and preventing glial cell activation in DRG, suggesting further clinical studies to investigate the efficacy of this agent and its potential application in clinical practice.


Assuntos
Antineoplásicos , Doenças do Sistema Nervoso Periférico , Ratos , Masculino , Animais , Cisplatino/toxicidade , Lipossomos , Acetona , Antineoplásicos/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/patologia , Polietilenoglicóis/efeitos adversos
9.
Free Radic Biol Med ; 212: 22-33, 2024 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-38101584

RESUMO

Cisplatin is an effective chemotherapy drug widely used in the treatment of various solid tumors. However, the clinical usage of cisplatin is limited by its nephrotoxicity. Isorhamnetin, a natural flavanol compound, displays remarkable pharmacological effects, including anti-inflammatory and anti-oxidation. In this study, we aimed to investigate the potential of isorhamnetin in alleviating acute kidney injury induced by cisplatin. In vitro study showed that isorhamnetin significantly suppressed the cytotoxic effects of cisplatin on human tubular epithelial cells. Furthermore, isorhamnetin exerted significantly inhibitory effects on cisplatin-induced apoptosis and inflammatory response. In acute kidney injury mice induced by a single intraperitoneal injection with 20 mg/kg cisplatin, oral administration of isorhamnetin two days before or 2 h after cisplatin injection effectively ameliorated renal function and renal tubule injury. Transcriptomics RNA-seq analysis of the mice kidney tissues suggested that isorhamnetin treatment may protect against cisplatin-induced nephrotoxicity via PGC-1α mediated fatty acid oxidation. Isorhamnetin achieved significant enhancements in the lipid clearance, ATP level, as well as the expression of PGC-1α and its downstream target genes PPARα and CPT1A, which were otherwise impaired by cisplatin. In addition, the protection effects of isorhamnetin against cisplatin-induced nephrotoxicity were abolished by a PGC-1α inhibitor, SR-18292. In conclusion, our findings indicate that isorhamnetin could protect against cisplatin-induced acute kidney injury by inducing PGC-1α-dependent reprogramming of fatty acid oxidation, which highlights the clinical potential of isorhamnetin as a therapeutic approach for the management of cisplatin-induced nephrotoxicity.


Assuntos
Injúria Renal Aguda , Antineoplásicos , Quercetina/análogos & derivados , Camundongos , Humanos , Animais , Cisplatino/toxicidade , Antineoplásicos/toxicidade , Antineoplásicos/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Rim/metabolismo , Apoptose , Ácidos Graxos/metabolismo
10.
Bioorg Med Chem Lett ; 97: 129192, 2024 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36813052

RESUMO

To investigate the renal protective effects of the polysaccharide LEP-1a and derivatives of selenium (SeLEP-1a) from Lachnum YM38, cisplatin (CP) was used to establish an acute kidney model. LEP-1a and SeLEP-1a could effectively reverse the decrease in renal index and improved renal oxidative stress. LEP-1a and SeLEP-1a significantly reduced the contents of the inflammatory cytokines. They could inhibit the release of cyclooxygenase 2 (COX-2) and nitric oxide synthase (iNOS) and increase the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1). At the same time, the PCR results indicated that SeLEP-1a could significantly inhibit the mRNA expression levels of toll-like receptor 4 (TLR4), nuclear factor-kB (NF-κB) p65 and inhibitor of kappa B-alpha (IκBα). Western blot analysis showed that LEP-1a and SeLEP-1a significantly downregulated the expression levels of Bcl-2-associated X protein (Bax) and cleaved caspase-3 and upregulated phosphatidylinositol 3-kinase (p-PI3K), protein kinase B (p-Akt) and B-cell lymphoma 2 (Bcl-2) protein expression levels in the kidney. LEP-1a and SeLEP-1a could improve CP-induced acute kidney injury by regulating the oxidative stress response, NF-κB-mediated inflammation and the PI3K/Akt-mediated apoptosis signalling pathway.


Assuntos
Injúria Renal Aguda , Polissacarídeos , Selênio , Animais , Camundongos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , Cisplatino/farmacologia , Cisplatino/toxicidade , Rim/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Polissacarídeos/farmacologia , Polissacarídeos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Selênio/farmacologia , Compostos de Organossilício/metabolismo , Compostos de Organossilício/farmacologia
11.
Life Sci ; 336: 122352, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38104863

RESUMO

BACKGROUND: During aging, excessive ROS production in the kidneys leads to redox imbalance, which contributes to oxidative damage and impaired organ homeostasis. However, whether and how aging-related NOX4-Nrf2 redox imbalance increases susceptibility to cisplatin-induced acute kidney injury remain largely unknown. METHODS: In this study, we used cisplatin-challenged aging mouse models and senescent HK-2 cells to investigate the effects and mechanisms of aging on susceptibility to cisplatin-induced acute kidney injury. RESULTS: In vivo, we found that cisplatin stimulation caused more severe renal damage, oxidative stress, mitochondrial dysfunction and mitophagy impairment in aging mice than in young mice. Moreover, Nrf2 deficiency aggravated cisplatin-induced acute kidney injury by exacerbating NOX4-Nrf2 redox imbalance and defective mitophagy. In vitro experiments on D-gal-treated human renal tubular epithelial cells (HK-2) demonstrated that senescent renal epithelial cells exhibited increased susceptibility to cisplatin-induced apoptosis, NOX4-Nrf2 redox imbalance-mediated oxidative stress and defective mitophagy. Mechanistically, we found that knockdown of Nrf2 in HK2 cells resulted in increased ROS and aggravated mitophagy impairment, whereas these effects were reversed in NOX4-knockdown cells. CONCLUSION: The present study indicates that NOX4-Nrf2 redox imbalance is critical for mitophagy deficiency in aged renal tubular epithelial cells and is a therapeutic target for alleviating cisplatin-induced acute kidney injury in elderly patients.


Assuntos
Injúria Renal Aguda , Cisplatino , Humanos , Camundongos , Animais , Idoso , Cisplatino/toxicidade , Cisplatino/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Mitofagia , Espécies Reativas de Oxigênio/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Envelhecimento , Rim/metabolismo , Estresse Oxidativo , Oxirredução , NADPH Oxidase 4/metabolismo
12.
FASEB J ; 38(1): e23382, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38145344

RESUMO

Cisplatin (Cis) is among the most powerful antineoplastic medications, nevertheless, its serious side effects; particularly nephrotoxicity designates a major concern. Previous studies reported that ezetimibe (Eze), a well-known antihyperlipidemic drug, exerts additional trivial pharmacological effects. In this work, we displayed Eze as an intriguing protective candidate in a cisplatin-induced nephrotoxicity rat model through AMPK activation. Eze (10 mg/kg, p.o.) was administered for two weeks and Cis (10 mg/kg, i.p.) was administered on the 10th day to induce nephrotoxicity in male Wistar rats. Treatment with Eze greatly augmented the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and the antioxidant regulator; nuclear factor erythroid 2-related factor 2 (Nrf2), thus, mitigating oxidative injury through induction of the antioxidant enzymes, such as heme oxygenase-1 (HO-1) and glutathione reductase (GR). As well, Eze relieved inflammation by reducing protein expression of thioredoxin-interacting protein (TXNIP) and nucleotide-binding domain-like receptor protein 3 (NLRP3), which led to a decrease in the release of caspase-1, in addition to, the inflammatory markers IL-18 and IL-1 ß. Besides, Eze ameliorated apoptosis in the renal cells through inhibiting the phosphorylated Apoptosis signal-regulating kinase-1(p-ASK1), caspase-3 and reducing Bax/Bcl2ratio. Correspondingly, histopathological examination corroborated the previous biochemical findings. Collectively, Eze exerts significant renal protection against Cis-induced nephrotoxicity via antioxidant, anti-inflammatory and anti-apoptotic pathways that are probably mediated, at least partly, via activating AMPK/Nrf2/HO-1 pathway and conquering both TXNIP/NLRP3 inflammasome and TXNIP/ASK1 signaling pathways. To confirm the protective effect of Eze via AMPK-activation, an AMPK-inhibitor, dorsomorphin (Dors), when co-administered with Eze abolished its protective effect.


Assuntos
Cisplatino , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos , Masculino , Animais , Cisplatino/toxicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Antioxidantes/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ezetimiba/farmacologia , Ratos Wistar , Estresse Oxidativo , Proteínas de Ciclo Celular/metabolismo
13.
J Ethnopharmacol ; 319(Pt 3): 117282, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37802374

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cisplatin (CP) results in acute kidney injury (AKI) and negatively affects patients' therapy and survival. The dried rhizome of Gastrodia elata Blume has been used to treat clinical kidney diseases. Gastrodin (GAS) is an active ingredient of the G. elata tuber. It is unknown whether GAS can alleviate CP-induced AKI. AIM OF THE STUDY: This study aimed to investigate whether GAS, an active ingredient of G. elata Blume, can alleviate CP-induced AKI and to explore its underlying mechanisms. MATERIALS AND METHODS: Experiments were conducted with a CP-induced AKI mouse model and an immortalized human renal tubular epithelial cell line (HK-2). Serum creatinine, Periodic acid-Schiff staining, tissue iron, glutathione, malondialdehyde, and 4-Hydroxynonenal were detected in serum and kidney samples to observe whether GAS inhibits CP-induced tubule ferroptosis. The drug target was verified by detecting the effects of GAS on sirtuin-1 (SIRT1) activity in vitro. Transcriptional regulation of glutathione peroxidase 4 (GPX4) by forkhead box O3A (FOXO3A) was verified by siRNA knockdown, overexpression, and chromatin immunoprecipitation. The effects of FOXO3A, SIRT1, and GAS on CP-induced ferroptosis were measured with propidium iodide, dihydroethidium, monobromobimane, and dipyrromethene boron difluoride staining in HK-2 cells. The relationship between GAS and the SIRT1/FOXO3A/GPX4 pathway was studied using Western blotting. RESULTS: GAS treatment inhibited CP-induced reactive oxygen species, lipid peroxidation, and tubule death in the cell and animal models. GAS activated SIRT1 in vitro. The SIRT1 inhibitor blocked the protective role of GAS in reducing lipid peroxidation in HK-2 cells. FOXO3A transcriptionally regulated GPX4 expression and inhibited CP-induced cell ferroptosis. Compared to CP-damaged mouse kidneys, GAS-treated mice demonstrated significantly increased SIRT1 and GPX4 expression levels, decreased CP-induced acetylation of FOXO3A, and inhibited lipid peroxidation and cell death. CONCLUSIONS: GAS alleviated CP-induced AKI by inhibiting ferroptosis via the SIRT1/FOXO3A/GPX4 signaling pathway. The results offer new insights into the development of new anti-AKI drugs from traditional Chinese medicine.


Assuntos
Injúria Renal Aguda , Ferroptose , Sirtuínas , Humanos , Camundongos , Animais , Cisplatino/toxicidade , Sirtuína 1/metabolismo , Sirtuínas/metabolismo , Linhagem Celular , Transdução de Sinais , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo
14.
Aging (Albany NY) ; 15(23): 14372-14383, 2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-38097341

RESUMO

Cisplatin has the potential to cause kidney and reproductive organ injuries, prompting the search for protective agents against cisplatin-induced toxicity. Melatonin, an antioxidant hormone, has shown promise in mitigating oxidative stress in various organs. However, its protective effects on cisplatin-induced kidney and reproductive injuries have not been extensively investigated. The aim of this study was to explore the potential protective effects of melatonin on cisplatin-induced kidney and reproductive injuries when administered in combination with gemcitabine in mice. Male C57BL/6 mice were subjected to a seven-week treatment with gemcitabine plus cisplatin, with or without melatonin intervention. The testis, epididymis, and kidney were assessed through histological analysis and measurement of blood parameters. Treatment with cisplatin led to a significant reduction in testicular weight, histological abnormalities, and alterations in reproductive hormone levels. Melatonin exhibited a slight protective effect on the testis, with higher doses of melatonin yielding better outcomes. However, melatonin did not reverse the effects of cisplatin on the epididymis. Administration of melatonin before and during treatment with cisplatin plus gemcitabine in mice demonstrated a modest protective effect on testicular injuries, while showing limited effects on epididymal injuries. Serum creatinine levels in the group treated with gemcitabine plus cisplatin treatment and high-dose melatonin approached those of the control group, indicating a protective effect on the kidney. These findings underscore the potential of melatonin as a protective agent against cisplatin-induced kidney and reproductive injuries and emphasize the need for further research to optimize its dosage and evaluate its long-term effects.


Assuntos
Cisplatino , Melatonina , Camundongos , Masculino , Animais , Cisplatino/toxicidade , Melatonina/farmacologia , Melatonina/metabolismo , Gencitabina , Camundongos Endogâmicos C57BL , Testículo/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Estresse Oxidativo , Rim/patologia , Substâncias Protetoras/farmacologia
15.
Physiol Rep ; 11(23): e15879, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38030388

RESUMO

In this study, we investigated the nephroprotective effects of Umbelliferone (UMB) against cisplatin-induced acute kidney injury (AKI). C57BL/6J mice were treated with cisplatin via a single intraperitoneal injection (25 mg/kg) with or without UMB (40 mg/kg/day) by gavage. Renal function, apoptosis, oxidative stress, inflammation, and mitochondrial function were analyzed to evaluate kidney injury. In vitro, human proximal tubule epithelial cells were treated with cisplatin, with or without UMB, for 24 h. Western blotting and immunohistochemistry were performed to explore the mechanisms underlying the nephroprotective effects of UMB. Cisplatin-induced renal dysfunction, including increases in blood urea nitrogen, serum creatinine, and renal tubular injury indices (NGAL and KIM-1), were significantly attenuated by UMB treatment, along with renal phenotypic changes and renal tubular injury, as evidenced by improved renal histology. Moreover, NRF2 was activated by UMB pretreatment, along with the inhibition of oxidative stress and inflammatory response, as evidenced by decreased levels of antioxidant genes and inflammatory cytokines in cisplatin-induced AKI. Our results demonstrate that UMB can protect against cisplatin-induced nephrotoxicity, which is mediated by the NRF2 signaling pathway via antioxidant and anti-inflammatory activities, suggesting the clinical potential of UMB for the treatment of AKI.


Assuntos
Injúria Renal Aguda , Cisplatino , Camundongos , Animais , Humanos , Cisplatino/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Camundongos Endogâmicos C57BL , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , Rim/metabolismo , Estresse Oxidativo , Inflamação/metabolismo , Apoptose , Umbeliferonas/farmacologia , Umbeliferonas/uso terapêutico , Umbeliferonas/metabolismo
16.
BMC Biol ; 21(1): 276, 2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38031056

RESUMO

BACKGROUND: The individual lifestyle and environment of an organism can influence its phenotype and potentially the phenotype of its offspring. The different genetic and non-genetic components of the inheritance system and their mutual interactions are key mechanisms to generate inherited phenotypic changes. Epigenetic changes can be transmitted between generations independently from changes in DNA sequence. In Caenorhabditis elegans, epigenetic differences, i.e. epimutations, mediated by small non-coding RNAs, particularly 22G-RNAs, as well as chromatin have been identified, and their average persistence is three to five generations. In addition, previous research showed that some epimutations had a longer duration and concerned genes that were enriched for multiple components of xenobiotic response pathways. These results raise the possibility that environmental stresses might change the rate at which epimutations occur, with potential significance for adaptation. RESULTS: In this work, we explore this question by propagating C. elegans lines either in control conditions or in moderate or high doses of cisplatin, which introduces genotoxic stress by damaging DNA. Our results show that cisplatin has a limited effect on global small non-coding RNA epimutations and epimutations in gene expression levels. However, cisplatin exposure leads to increased fluctuations in the levels of small non-coding RNAs derived from tRNA cleavage. We show that changes in tRNA-derived small RNAs may be associated with gene expression changes. CONCLUSIONS: Our work shows that epimutations are not substantially altered by cisplatin exposure but identifies transient changes in tRNA-derived small RNAs as a potential source of variation induced by genotoxic stress.


Assuntos
Caenorhabditis elegans , Metilação de DNA , Animais , Caenorhabditis elegans/genética , Cisplatino/toxicidade , Mutação , Epigênese Genética , RNA , RNA de Transferência/genética
17.
Reprod Biol ; 23(4): 100824, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37976616

RESUMO

Arbutin (ARB) is a glycosylated hydroquinone with potent antioxidant effects. Although cisplatin (CP) is widely used in chemotherapy, its toxicity in healthy tissues, including ovotoxicity, is an insurmountable problem. This study aimed to evaluate the therapeutic effect of ARB against CP-related ovototoxicity by including nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in rats for the first time. Rats treated one dose of CP (5 mg/kg) on the first day, followed by ARB (5 and 10 mg/kg) for three days. Serum reproductive hormone levels were determined using ELISA kits. Oxidative stress (OS), inflammation, endoplasmic reticulum stress (ERS) and apoptosis markers in ovarian tissue were also determined colorimetrically. In addition, how CP affects Nrf2 pathway and the effect of ARB on this situation were also addressed. ARB treatment reduced the levels of markers of OS, inflammation, ERS and apoptosis in ovarian tissue of CP-stimulated animals. ARB regenerated the depleted antioxidant system by triggering Nrf2 pathway in the ovarian tissues of animals stimulated by CP. Histological findings also supported the therapeutic efficacy of ARB. The results indicate that ARB may have therapeutic effects against CP-induced reproductive toxicity with its Nrf2 activator potential. ARB should be tested in more extensive studies as a new generation chemopreventive candidate molecule.


Assuntos
Cisplatino , Fator 2 Relacionado a NF-E2 , Ratos , Animais , Cisplatino/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Arbutina/farmacologia , Arbutina/uso terapêutico , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antioxidantes/metabolismo , Estresse Oxidativo , Estresse do Retículo Endoplasmático , Inflamação/metabolismo , Apoptose
18.
Tissue Cell ; 85: 102256, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37918215

RESUMO

Reproductive toxicity is a serious side effect of cisplatin (CP) chemotherapy. Gentisic acid (GTA) is a phenolic acid with strong antioxidant properties. Here, we aimed to determine therapeutic effect of GTA against CP-induced testicular toxicity in rats for the first time. Male Sprague-Dawley rats received a single dose of CP (5 mg/kg; intraperitoneal) and treated with GTA (1.5 and 3 mg/kg; intraperitoneal; 3 consecutive days). The levels of oxidative stress (OS), inflammation, endoplasmic reticulum stress (ERS) and apoptosis biomarkers were assessed in the testicular tissue of rats. In addition, how CP affects the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway and the effect of GTA on this situation were also addressed in the testicular tissue. CP administration induced histopathological changes in testicular tissue of rats with a significant increase in OS, inflammation, ERS and apoptosis biomarkers and a decrease in antioxidant capacity and Nrf2 expression levels. Administrations of GTA resulted in an amelioration of these altered parameters. These data suggest that GTA may be a potential therapeutic agent against CP-induced testicular toxicity. Activation of the Nrf2 pathway plays a key role of this therapeutic effect of GTA.


Assuntos
Antioxidantes , Cisplatino , Ratos , Masculino , Animais , Cisplatino/toxicidade , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Ratos Sprague-Dawley , Fator 2 Relacionado a NF-E2/metabolismo , Apoptose , Transdução de Sinais , Testículo/metabolismo , Estresse Oxidativo , Estresse do Retículo Endoplasmático , Inflamação/patologia , Biomarcadores/metabolismo
19.
Tissue Cell ; 85: 102226, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37793209

RESUMO

This study aimed to investigate the protective effect of melatonin against the acute toxicity of cisplatin in ocular tissues. The eyes of 40 rats were divided into 4 groups: Control group (10 rats), Melatonin (Mel) group (10 rats), Cisplatin (Cis) group (10 rats), Melatonin (Mel) + Cisplatin (Cis) group (10 rats). Retina, cornea, and ciliary body tissues were examined after hematoxylin-eosin staining of sections obtained from the eyes and were scored for disorganization and degeneration. Apoptotic cells were counted for the retina, cornea, and ciliary body with the TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) method. The total antioxidant status (TAS) / total oxidant status (TOS) of homogenized eye tissues were measured. While apoptotic cells were found to increase in the cornea of the Cisplatin (Cis) group, no difference was found regarding the retina and ciliary body cell count. An increased number of apoptotic cells in the cornea of the Cis group was found while there was a decrease in the group where Cisplatin and Melatonin were administered together (Mel+Cis group). There was no statistically significant difference amongst groups for TOS or TAS. Melatonin had a partial protective effect against histological damage.


Assuntos
Antioxidantes , Melatonina , Ratos , Animais , Antioxidantes/farmacologia , Cisplatino/toxicidade , Melatonina/farmacologia , Neuropatia Óptica Tóxica , Apoptose , Estresse Oxidativo
20.
Toxicology ; 499: 153653, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37863467

RESUMO

There is an increasing evidence suggesting that myo-inositol (MI) may be a renoprotective factor. Our previous study revealed that decreased MI concentrations and increased excretion are often observed in animal models of renal injury and in patients with nephropathy. However, the role of MI supplementation in renal injury remains unclear. In this study, we aimed to explore the role of MI in cisplatin-induced acute kidney injury (AKI). We established a model of acute kidney injury caused by cisplatin (CDDP). Male Kunming mice were randomly divided into six groups: Sham (normal saline), CDDP (15 mg/kg), + MI (150 mg/kg), + MI (300 mg/kg), + MI (600 mg/kg) and MI (600 mg/kg). Human renal tubular epithelial cell line HK-2 cells were likewise separated into six groups at random: Control (normal saline), CDDP (20 µM), + MI (200 µM), + MI (400 µM), + MI (800 µM) and MI (800 µM). After the model was established, renal function indexes were subsequently detected, and experiments such as pathological staining analysis and protein expression analysis were performed. Our results showed that cisplatin administration led to AKI and apoptosis in mice and HK-2 cells, accompanied by markedly increased levels of MIOX, kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), whereas exogenous MI significantly attenuated kidney injury and HK-2 cell damage induced by cisplatin both in vivo and in vitro by inhibiting excessive apoptosis. Overall, our findings demonstrate that exogenous MI can reduce excessive apoptosis, thus playing a protective role in cisplatin-induced AKI, indicating that exogenous MI may be used as an adjunctive treatment modality in cisplatin-induced AKI.


Assuntos
Injúria Renal Aguda , Cisplatino , Camundongos , Humanos , Masculino , Animais , Cisplatino/toxicidade , Solução Salina/toxicidade , Solução Salina/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/metabolismo , Rim , Apoptose
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