Sacubitril/valsartan alleviates sunitinib-induced cardiac fibrosis and oxidative stress via improving TXNIP/TRX system and downregulation of NF-ĸB/Wnt/ß-catenin/SOX9 signaling.

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.

Infliximab substantially re-silenced Wnt/ß-catenin signaling and ameliorated doxorubicin-induced cardiomyopathy in rats.

The release of inflammatory cytokines, namely tumor necrosis factor-α (TNF-α), plays an important role in the pathogenesis of cardiomyopathy. TNF-α increases in plasma and in myocardium of heart failure patients. We aimed to investigate the role of TNF-α inhibitor (infliximab; IFX) in regulating dilated cardiomyopathy (DCM) induced in rats. DCM was induced in rats by doxorubicin (DOX; 3.5 mg. kg-1 , i.p) twice weekly for 3 weeks (21 mg. kg-1 cumulative dose). DCM rats were treated with RPL (1 mg. kg-1 orally, daily), IFX (5 mg. kg-1 ; i.p. once) or their combination for 4 weeks starting next day of last DOX dose. Echocardiography was conducted followed by a collection of blood and left ventricle (LV) for biochemical and histological investigations. DCM rats revealed deteriorated cardiac function (increased CK-MB activity, LVIDs, LVIDd, ESV, and EDV, while decreased EF% and FS%), hypertrophy (increased HW/TL, ß-MHC, and α-actin), inflammation (increased IL-1ß, IL-6, and TNF-α). The activation of Wnt/ß-catenin along with increased gene expression of RAS components (RENIN, ACE, and AT1) were evident. LV architecture also revealed abnormalities and some degree of fibrosis. Treatment with RPL and/or IFX suppressed TNF-α and consequently improved most of these parameters suppressing Wnt/ß-catenin/RAS axis. Combined RPL and IFX treatment was the best among all treatments. In conclusion, Wnt/ß-catenin/RAS axis is implicated in DOX-induced cardiomyopathy. The upstream TNF-α was proved for the first time in-vivo to stimulate this axis where its inhibition by RPL or IFX prevented DCM. Targeting this axis at two points using RPL and IFX showed better therapeutic efficacy.

Nephrotoxicity Induced by Cisplatin Intake in Experimental Rats and Therapeutic Approach of Using Mesenchymal Stem Cells and Spironolactone.

Chronic kidney disease may lead to subsequent tissue fibrosis. However, many factors can combat injurious stimuli in these tissues aiming to repair, heal, and alleviate any disturbance. Chemokines release, migration of inflammatory cells to the affected site, and activation of fibroblasts for the production of extracellular matrix are commonly observed in this disease. In the last years, many studies have focused on spironolactone (SPL), a mineralocorticoid receptor antagonist, and its pharmacological effects. In the present study, SPL was selected as an anti-inflammatory agent to combat nephrotoxicity and renal fibrosis induced by cisplatin. Mesenchymal stem cells (MSCs) were also selected in addition as a referring agent. Renal fibrosis induced by cisplatin intake significantly increased creatinine, urea, nuclear factor kappa B, insulin-like growth factor-1, fibroblast growth factor-23, and kidney malondialdehyde (MDA) content. Hepatocyte growth factor and renal content of reduced glutathione demonstrated a significant decrease. Histopathological examination of kidney tissues demonstrated marked cellular changes which are correlated with the biochemical results. Oral SPL intake (20 mg/kg/body weight) daily for 4 weeks and MSCs administration (3 × 106 cell/rat) intravenous to the experimental rats resulted in a significant improvement of both the biomarkers studied and the histopathological profile of the renal tissue. Individual administration of spironolactone and MSCs exhibited a marked anti-inflammatory potential and alleviated to a great extent the nephrotoxicity and renal fibrotic pattern induced by cisplatin.

Vanillin as a new modulator candidate for renal injury induced by cisplatin in experimental rats.

Cisplatin is commonly prescribed for the treatment of various solid tumors but its use is limited due to certain side effects and renal injury is a true example. Oxidative stress and inflammation may contribute to the cisplatin induced nephrotoxicity. Accordingly, we evaluated the effect of oral vanillin intake (100mg/kg body weight) daily for 4weeks to combat this hazard. The present results have demonstrated significant attenuation of oxidative stress and renal injury where reduced glutathione (GSH) showed significant increase along with malondialdehyde (MDA) decrease. Fibrotic markers like fibroblast growth factor-23 (FGF-23), transforming growth factor-ß1 (TGF-ß1), inflammatory mediators such as nuclear factor-κB (NF-κB) and tumor necrosis factor-α (TNF-α) showed also significant decrease in vanillin treated rats as compared with the control group. Renal function showed also significant improvement where urea and creatinine demonstrated significant decrease and the histopathological study presented a good support to the biochemical markers results. Our conclusion that vanillin is a potent antioxidant, anti-inflammatory and anti-fibrotic agent. Additionally, it is a good modulator candidate for the renal injury induced by cisplatin intake.

Management of cardiac fibrosis in diabetic rats; the role of peroxisome proliferator activated receptor gamma (PPAR-gamma) and calcium channel blockers (CCBs).

BACKGROUND: Diabetes mellitus (DM) and hypertension (HTN) are accused of being responsible for the development of the cardiac fibrosis due to severe cardiomyopathy. METHODS: Blood glucose (BG) test was carried out, lipid concentrations, tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-ß), matrix metalloproteinase (MMP-2), collagen-I and collagen-III were measured in male Albino rats weighing 179-219 g. The rats were divided into five groups, kept on either control diet or high fat diet (HFD), and simultaneously treated with rosiglitazone (PPAR-gamma) only for one group with 3 mg/kg/day via oral route for 30 days, and with rosiglitazone and felodipine combination for another group with 3 mg/kg/day and 5 mg/kg/day, respectively via oral route for 30 days. RESULTS: Diabetic hypertensive (DH) rats which fed on a HFD, injected with streptozotocin (STZ) (i.p.) and obstruction for its right kidney was occurred develop hyperglycemia, hypertension, cardiac fibrosis, hypertriglyceridemia, hypercholesterolemia, increased TNF-α, increased TGF-ß, decreased MMP-2, increased collagen-I and increased collagen-III, when compared to rats fed on control diet. Treating the DH rats with rosiglitazone only causes a significant decrease for BG levels by 52.79%, triglycerides (TGs) by 24.05%, total cholesterol (T-Chol) by 30.23%, low density lipoprotein cholesterol (LDL-C) by 40.53%, TNF-α by 20.81%, TGF-ß by 46.54%, collagen-I by 48.11% and collagen-III by 53.85% but causes a significant increase for MMP-2 by 272.73%. Moreover, Treating the DH rats with rosiglitazone and felodipine combination causes a significant decrease for BG levels by 61.08%, blood pressure (BP) by 16.78%, TGs by 23.80%, T-Chol by 33.27%, LDL-C by 45.18%, TNF-α by 22.82%, TGF-ß by 49.31%, collagen-I by 64.15% and collagen-III by 53.85% but causes a significant increase for MMP-2 by 290.91%. Rosiglitazone alone failed to decrease the BP in DH rats in the current dosage and duration. CONCLUSION: Our results indicate that the co-existence of diabetes and hypertension could induce cardiomyopathy which could further result in cardiac fibrosis, and that combination treatment with rosiglitazone and felodipine has a great protective role against the metabolic abnormalities, meanwhile, the treatment with rosiglitazone alone has a protective role with a minimal effect against these abnormalities and has no effect on decreasing BP in these cases which may lead to coronary artery diseases (CADs) in future.