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1.
Arch Biochem Biophys ; 755: 109986, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38582273

RESUMO

Sunitinib (SUN) is a chemotherapeutic agent clinically approved for treatment of metastatic renal carcinoma. Despite its remarkable benefits, various renal toxicities have been reported that limit its clinical uses. Oleuropein (OLE) is the main polyphenolic constituent of olive tree and mediates the majority of its valuable pharmacological activities. The current study examined the probable renoprotective effects of OLE against SUN-induced nephrotoxicity. Adult male albino rats were co-treated by SUN (25 mg/kg, 3 times/week, PO) with either a drug vehicle or OLE (60 mg/kg/day, daily, PO) for four weeks. A control group comprising of age-matched rats was used. Four weeks later, blood specimens were collected to assess kidney functions. Kidneys were harvested for biochemical and histopathological analyses. Administration of SUN induced kidney dysfunction, along with marked rises in endothelin-1 (ET-1) and monocyte chemotactic protein-1 (MCP-1) levels in renal tissues. Histological abnormalities were also detected in kidneys of SUN-treated rats including glomerular and tubular interstitial congestion along with interstitial fibrosis. On molecular levels, there was a decline in renal SIRT6 expression along with significant up-regulation of Notch-1, NLRP-3, interleukin -1ß (IL-1ß) and cleaved caspsase-3. All these changes were almost alleviated by OLE co-treatment. These findings suggest the implication of SIRT6/Notch-1/NLRP3/IL-1ß axis in the pathogenesis of SUN-induced nephrotoxicity and highlight OLE as a prospective renoprotective agent during SUN chemotherapy to halt its renal toxicity likely through promotion of SIRT6 and suppression of Notch-1/NLRP3/IL-1ß signaling pathway.

2.
Int Immunopharmacol ; 132: 111963, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38560962

RESUMO

We aimed in this study to investigate the possible cardioprotective effects of sacubitril/valsartan against sunitinib-induced cardiac fibrosis (CF) and oxidative stress via targeting thioredoxin-interacting protein/thioredoxin (TXNIP/TRX) system and nuclear factor-kappa B (NF-κB)/Wingless-related MMTV integration site (Wnt)/ß-catenin/Sex-determining region Y box 9 (SOX9) signaling. CF was induced in male Wistar albino rats by cumulative dose of sunitinib (300 mg/kg, given over 4 weeks as: 25 mg/kg orally, three times a week), which were co-treated with sacubitril/valsartan (68 mg/kg/day, orally) for four weeks. Significant elevation in blood pressure, cardiac inflammatory and fibrotic markers besides cardiac dysfunction were observed. These alterations were associated with disruption of TXNIP/TRX system, upregulation of NF-κB/Wnt/ß-catenin/SOX9 pathway along with marked increase in lysyl oxidase (LOX) and matrix metalloproteinase-1 (MMP-1) expressions and extensive deposition of collagen fibers in cardiac tissues. Luckily, sacubitril/valsartan was able to reverse all of the aforementioned detrimental effects in sunitinib-administered rats. These findings illustrate a potential role of sacubitril/valsartan in alleviating CF and oxidative stress induced by sunitinib via antioxidant, anti-inflammatory and antifibrotic properties. These remarkable effects of sacubitril/valsartan were mediated by its ability to improve TXNIP/TRX system and downregulate NF-κB/Wnt/ß-catenin/SOX9 signaling in addition to decreasing LOX and MMP-1 expressions in cardiac tissues. In summary, this study highlights sacubitril/valsartan as a potential therapeutic agent in mitigating CF and oxidative stress especially in cancer cases treated with sunitinib.


Assuntos
Aminobutiratos , Compostos de Bifenilo , Combinação de Medicamentos , Fibrose , NF-kappa B , Estresse Oxidativo , Ratos Wistar , Sunitinibe , Tetrazóis , Tiorredoxinas , Valsartana , Via de Sinalização Wnt , Animais , Valsartana/farmacologia , Valsartana/uso terapêutico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Compostos de Bifenilo/uso terapêutico , Compostos de Bifenilo/farmacologia , NF-kappa B/metabolismo , Aminobutiratos/farmacologia , Aminobutiratos/uso terapêutico , Ratos , Tetrazóis/farmacologia , Tetrazóis/uso terapêutico , Tiorredoxinas/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Regulação para Baixo/efeitos dos fármacos , Miocárdio/patologia , Miocárdio/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética
3.
Eur J Pharmacol ; 872: 172959, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-32004528

RESUMO

Infliximab (IFX), a monoclonal antibody for tumor necrosis factor-alpha (TNF-α), is known to restore blood glucose homeostasis. However, its effects on improving renal insulin resistance (IR) are not yet studied. So we investigate the impact of infliximab on renal insulin signaling pathway in IR rat model regarding to metformin (MET). The induced IR was confirmed by a high oral glucose tolerance test, an elevation of lipid profile and the homeostatic model assessment of insulin resistance 2 (HOMA-IR 2) values. Subsequently, IR rats were concurrently treated with either MET (100 mg/kg/day) or IFX (one dose 5 mg/kg) besides IR and normal control (NC) groups. Four weeks later, IR control rats displayed hyperglycemia, hyperinsulinemia and elevation in HOMA-IR 2, renal function markers and renal tissue TNF-α, interleukins-1ß and 6 (Il-1ß, IL-6) and suppressor of cytokines signaling 3 (SOCS3) contents as well as glomerulosclerosis when compared to NC group. Additionally, the phosphorylation of renal insulin receptor substrate 1 (IRS1), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) were markedly impaired. Treatment with either MET or IFX significantly improved IR and kidney functions. The effects of the drugs were achieved by the downregulation of renal inflammatory cytokines and SOCS3 levels and the amelioration of the renal IRS1/PI3K/Akt pathway. In conclusion, MET and IFX ameliorated the TNF-α worsening effect on IR in rat renal tissues by regulating insulin signaling. Interestingly, infliximab was superior to metformin in regulating insulin signaling pathway. Therefore, infliximab could be used as an adjuvant therapy in improving renal IR.


Assuntos
Infliximab/farmacologia , Resistência à Insulina , Insulina/metabolismo , Rim/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Glicemia/análise , Glicemia/metabolismo , Modelos Animais de Doenças , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/sangue , Hiperglicemia/complicações , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Infliximab/uso terapêutico , Proteínas Substratos do Receptor de Insulina/metabolismo , Rim/metabolismo , Masculino , Metformina/farmacologia , Metformina/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/prevenção & controle , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
4.
Mol Cell Biochem ; 466(1-2): 45-54, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31933108

RESUMO

Insulin resistance (IR) has emerged as one of the main risk factors for renal fibrosis (RF) that represents a common stage in almost all chronic kidney disease. The present study aims to investigate the inhibitory effect of empagliflozin (EMPA "a sodium-glucose co-transporter 2 inhibitor") and infliximab [IFX "a tumor necrosis factor-α (TNF-α) antibody"] on RF in rats with induced IR. IR was induced by adding 10% fructose in drinking water for 20 weeks. Thereafter, fructose-induced IR rats were concurrently treated with EMPA (30 mg/kg), IFX (1 dose 5 mg/kg), or EMPA + IFX for 4 weeks, in addition to IR control group (received 10% fructose in water) and normal control (NC) group. Rats with IR displayed hyperglycemia, deterioration in kidney functions, glomerulosclerosis, and collagen fiber deposition in renal tissues as compared to NC. This was associated with downregulation of the renal sirtuin 1 (Sirt 1) expression along with higher renal tissue TNF-α and transforming growth factor-ß1 (TGF-ß1) levels. Both EMPA and IFX significantly modulated the aforementioned fibrotic cytokines, upregulated the renal Sirt 1 expression, and attenuated RF compared to IR control group. Of note, IFX effect was superior to that of EMPA. However, the combination of EMPA and IFX alleviated RF to a greater extent surpassing the monotherapy. This may be attributed to the further upregulation of renal Sirt 1 in addition to the downregulation of fibrotic cytokines. These findings suggest that the combination of EMPA and IFX offers additional benefits and may represent a promising therapeutic option for RF.


Assuntos
Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Infliximab/farmacologia , Resistência à Insulina , Nefropatias/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
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