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Aberrant activation of Wnt/[beta]-catenin induces renal dysfunction by initiating pro-apoptotic cascades, fibrosis, oxidative and inflammatory burden. This study tested the therapeutic effects of Wnt/[beta]-catenin inhibitor pyrvinium against cisplatin-induced acute kidney injury (AKI) in rats. Cisplatin was administered at a single dose of 5 mg/kg (i.p.) and renal cisplatin accumulation and uptake in cortical slices were determined after the fifth day by atomic absorption spectroscopy. Levels of pro- inflammatory cytokines were checked by ELISA, and organic cation transporter-2 (OCT-2) transcription and expression in renal tissue were evaluated by RT-PCR and immunohistochemical technique. Cisplatin administration produced renal dysfunction manifested as increase in serum creatinine, blood urea nitrogen, proteinuria, reduced clearance and electrolyte imbalance. Oxidative stress indices, pro-inflammatory cytokines, fibronectin, and caspase-3 activity were elevated in cisplatin-challenged rats. Moreover, increased renal OCT-2 transcription and immunostaining were detected in cisplatin kidneys which resulted in platinum accumulation. Additional docking studies depicted strong interaction between the [beta]-catenin and OCT-2 protein. These manifestations induced mitochondrial dysfunction, histological damage and fibrosis. Notably, Wnt/[beta]-catenin inhibitor pyrvinium (60 [micro]g/kg; p.o.) treatment reduced the renal OCT-2 gene transcription causing a decline in platinum levels. Thus, the present study concludes that Wnt/[beta]-catenin inhibition attenuates cisplatin-induced AKI in rats, partly by down-regulating OCT-2 expression. Key words: cisplatin, acute kidney injury, fibrosis, Wnt/ [beta]-catenin pathway, oxidative stress, inflammation L'activation aberrante de la voie de signalisation Wnt/catenine [beta] entraine une insuffisance renale par l'amorce de cascades proapoptotiques, de fibrose et d'une charge oxydative et inflammatoire. Cette etude a porte sur les effets therapeutiques du pyrvinium, un inhibiteur de la Wnt/ catenine ft, contre l'insuffisance renale aigue (IRA) entrainee par le cisplatine chez le rat. Nous avons administre du cisplatine a une dose unique de 5 mg/kg par voie i.p. et, a l'aide de la spectroscopie d'absorption atomique, nous avons etabli l'accumulation et l'assimilation renales du cisplatine dans des coupes de cortex apres le 5e jour. A l'aide de la technique d'ELISA, nous avons verifie les taux de cytokines proinflammatoires, de meme que la transcription et l'expression du transporteur de cations organiques 2 (OCT-2) dans le tissu renal a l'aide des techniques de PCR en temps reel et d'immunohistochimie. L'administration de cisplatine entrainait une insuffisance renale qui se manifestait par une hausse de la creatinine et de l'azote ureique dans le serum avec une proteinurie, une diminution de la clairance et un desequilibre electrolytique. Nous avons observe une hausse des indices du stress oxydatif de meme que de l'activite des cytokines proinflammatoires, de la fibronectine et de la caspase 3 avec la provocation par le cisplatine chez le rat. En outre, nous avons observe une augmentation de la transcription d'OCT-2 et de l'immunocoloration dans les reins soumis au cisplatine, ce qui a mene a une accumulation de platine. Des etudes d'amarrages supplementaires ont montre la presence d'une forte interaction entre la catenine p et l'OCT-2 proteique. Ces manifestations entrainaient un dysfonctionnement mitochondrial, des dommages histologiques et de la fibrose. Il est interessant de noter que l'administration de pyrvinium a 60 [micro]g/kg par voie orale entrainait un abaissement de la transcription renale d'OCT-2 menant a une diminution des taux de platine. Par consequent, la presente etude permet de conclure que chez le rat, l'inhibition de la voie de signalisation Wnt/catenine [beta] permet d'attenuer l'IRA provoquee par le cisplatine, en partie par la regulation a la baisse de l'expression d'OCT-2. [Traduit par la Redaction] Mots-cles : cisplatine, insuffisance renale aigue, fibrose, voie de signalisation Wnt/ catenine [beta], stress oxydatif, inflammation, 1. Introduction Cisplatin (cis-diamminedichloroplatinum II) is an anticancer agent and has been extensively utilized in the treatment of metastatic testicular, lung, neck, and ovarian carcinoma (Pabla and Dong 2008). Dose-dependent [...]

The present study was designed to check the serum levels of protease‐activated receptor (PAR‐1) in patients during different phases of dengue severity. Moreover, a correlation between serum PAR‐1 levels and hematological parameters, inflammatory cytokine levels, and liver functional changes was also determined. Based on the World Health Organization criteria, the study population was divided into: nonsevere dengue fever (DF; n = 30), severe dengue hemorrhagic fever (DHF; n = 19), and severe dengue shock syndrome (DSS; n = 11). The platelet count (PLT) and hematocrit (HCT) were analyzed using an automated hematology analyzer and liver function enzymes aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphate (ALP), bilirubin were checked by auto‐analyzer using diagnostic kits. Moreover, the levels of inflammatory mediators C‐reactive protein (CRP), tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), interleukin‐17 (IL‐17), and PAR‐1 were determined using respective ELISA kits. The HCT levels were elevated and platelet count decreased significantly during dengue complications (DHF and DSS) compared to the DF patients, while the levels of liver functional biomarkers AST, ALT, ALP, and bilirubin remained elevated in DHF and DSS groups than in the corresponding DF group. Similarly, the inflammatory cytokine levels of CRP, TNF‐α, IL‐6, and IL‐17 in DHF and DSS subjects were markedly increased when observed against DF subjects. Notably, the PAR‐1 levels were significantly elevated in DHF and DSS groups than in the DF group and positively correlated with changes in HCT levels, inflammatory biomarkers, and liver enzymes. Our findings conclude that PAR‐1 levels persistently increased with the severity of the dengue infection and are strongly associated with various clinical manifestations. Thus, PAR‐1 levels can be used as a diagnostic marker for assessing dengue severity. [ABSTRACT FROM AUTHOR]

Some evidence has demonstrated that both inflammation and immune cell dysregulation are coincident at late phase (post 24 h) of sepsis. The present study was designed to determine the pathological role of hyperinflammation and renal immune cells mobilization during late phase of sepsis induced acute kidney injury (S‐AKI) and tests the pharmacological effects of PDE‐4 inhibitor on these events. Sepsis was induced by cecal ligation puncture and renal function, oxidative–inflammatory stress biomarkers were assessed after 24 h. PDE‐4 inhibitor was administered for 7 days prior to induction of S‐AKI. Renal immune cells infiltration during sepsis was analyzed by H&E staining and papanicolaou staining method was used for detecting leukocytes and cast in urinary sediments, periodic acid schiff (PAS) staining was used for detection of brush border loss. AKI developed 24 h post sepsis insult as depicted by increase in serum creatinine, blood urea nitrogen (BUN), renal oxidative stress, and elevated inflammatory biomarkers levels. Moreover, septic rats displayed increased bacterial load, renal expression of phosphodiesterase‐4B, 4D isoforms, enhanced vascular permeability, caspase‐3 and myeloperoxidase activity, electrolyte imbalance, reduced Na+K+ATPase activity, declined cAMP levels, increased interstitial leukocyte infiltration, and leakage in urinary sediments along with histological alterations. Pre‐treatment with roflumilast at high dose completely prevented the various AKI associated manifestations in septic rats. Renal hyper‐inflammation and leukocyte infiltration was detected in late phase of S‐AKI. Roflumilast pre‐treatment resolved sepsis induced renal dysfunction and histological damage by suppressing late phase renal immune cells invasion and anti‐inflammatory effects mediated by up‐regulation of renal cAMP levels. [ABSTRACT FROM AUTHOR]

Isoproterenol (ISO) administration produces significant biochemical and histological changes including oxidative stress, reactive oxygen species (ROS) overproduction, and inflammation that leads to aggravation of myocardial injury. Subcutaneous or intraperitoneal ISO injection into rats can replicate several features of human heart disease, making it a useful tool for comprehending the underlying mechanisms and evaluating potential therapeutic strategies. In the present chapter, we elaborate on how depending on the precise experimental goals and the intended level of severity, different dosages and regimens are employed to induce myocardial injury., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)