PGC-1α Agonist Rescues Doxorubicin-Induced Cardiomyopathy by Mitigating the Oxidative Stress and Necroptosis

Cardiomyopathy (particularly dilated cardiomyopathy (DCM)) significantly contributes to development and progression of heart failure (HF), and inflammatory factors further deteriorate the symptoms. Morphological and functional defects of the heart in doxorubicin (DOX)-induced cardiomyopathy (cardiotoxicity) are similar to those of DCM. We used anagonist of PGC-1α (PPAR (peroxisome proliferator-activated receptor-gamma)-γ coactivator-1α) that is considered as the ‘master regulator’ of mitochondrial biogenesis with an aim to rescue the DOX-induced deleterious effects on the heart. Forty male C57BL/6J mice (8 weeks old) were divided in four groups, Control, DOX, ZLN005, and ZLN005 + DOX (n = 10 each group). The DOX-induced (10 mg/kg, single dose) cardiomyopathy mimics a DCM-like phenotype with marked morphologic alteration in cardiac tissue and functional derangements. Significant increased staining was observed for Masson Trichrome/Picrosirius red and α-Smooth Muscle Actinin (α-SMA) that indicated enhanced fibrosis in the DOX group compared to the control that was attenuated by (peroxisome proliferator-activated receptor-gamma (PPAR-γ) coactivator) (PGC)-1α (alpha) agonist (four doses of 2.5 mg/kg/dose; cumulative dose = 10 mg/kg). Similarly, elevated expression of necroptosis markers along with enhanced oxidative stress in the DOX group were alleviated by PGC-1α agonist. These data collectively suggested the potent therapeutic efficacy of PGC-1α agonist in mitigating the deleterious effects of DOX-induced cardiomyopathy, and it may be targeted in developing the future therapeutics for the management of DCM/HF

Defensive role of Rosmarinus officinalis in carbon tetrachloride-induced nephrotoxicity and oxidative stress in rats

Abstract Background There is a growing demand for remedies from natural sources to substitute synthetic therapeutic drugs and minimize their side effects and toxicity. The present study aims to evaluate the defensive ability of an ethanolic extract of Rosmarinus officinalis L. in carbon tetrachloride (CCl4)-induced nephrotoxicity in male albino rats. Materials and methods Thirty-six rats were divided into 6 groups (n = 6). Group I (control) received distilled water for 30 days orally. Nephrotoxicity was induced by CCl4 (11% v/v with olive oil, i.p) 2 ml/kg body weight (b.wt.) in group II once a week for 30 days. Groups III and IV received the only herb in two doses 100 and 250 mg/kg of b.wt. respectively. Groups V and VI received an ethanolic extract of Rosmarinus officinalis (EERO, 100 and 250 mg/kg of b.wt.) along with 2 ml/kg b.wt. CCl4 weekly for 30 days. Results CCl4 treatment induced highly significant (P < 0.001) elevation in kidney biomarkers, i.e., blood urea nitrogen and creatinine, kidney biochemicals, i.e., LPO and XOD, and decrease the levels of superoxide dismutase, catalase, glutathione peroxidase, and glutathione in tissue. However, EERO significantly (P < 0.001) restored the altered levels of these biomarkers in a dose-dependent manner. Furthermore, EERO also prevents histological alteration caused due to the toxicity of CCl4. Conclusion Our findings strongly support that ethanolic extract of Rosmarinus officinalis acts as a potent scavenger of free radicals to prevent the toxic effect of CCl4 and hence validate its ethnomedicinal use

Interleukin-33 Induces Neutrophil Extracellular Trap (NET) Formation and Macrophage Necroptosis via Enhancing Oxidative Stress and Secretion of Proatherogenic Factors in Advanced Atherosclerosis

Interleukin-33 (IL-33) acts as an &lsquo;alarmin&rsquo;, and its role has been demonstrated in driving immune regulation and inflammation in many human diseases. However, the precise mechanism of action of IL-33 in regulating neutrophil and macrophage functioning is not defined in advanced atherosclerosis (aAT) patients. Further, the role of IL-33 in neutrophil extracellular trap (NET) formation in aAT and its consequent effect on macrophage function is not known. In the present study, we recruited n = 52 aAT patients and n = 52 control subjects. The neutrophils were isolated from both groups via ficoll/percoll-based density gradient centrifugation. The effect of IL-33 on the NET formation ability of the neutrophils was determined in both groups. Monocytes, isolated via a positive selection method, were used to differentiate them into macrophages from each of the study subjects and were challenged by IL-33-primed NETs, followed by the measurement of oxidative stress by calorimetric assay and the expression of the proinflammatory molecules by quantitative PCR (qPCR). Transcript and protein expression was determined by qPCR and immunofluorescence/ELISA, respectively. The increased expression of IL-33R (ST-2) was observed in the neutrophils, along with an increased serum concentration of IL-33 in aAT compared to the controls. IL-33 exacerbates NET formation via specifically upregulating CD16 expression in aAT. IL-33-primed NETs/neutrophils increased the cellular oxidative stress levels in the macrophages, leading to enhanced macrophage necroptosis and the release of atherogenic factors and matrix metalloproteinases (MMPs) in aAT compared to the controls. These findings suggested a pathogenic effect of the IL-33/ST-2 pathway in aAT patients by exacerbating NET formation and macrophage necroptosis, thereby facilitating the release of inflammatory factors and the release of MMPs that may be critical for the destabilization/rupture of atherosclerotic plaques in aAT. Targeting the IL-33/ST-2-NETs axis may be a promising therapeutic target for preventing plaque instability/rupture and its adverse complications in aAT