Cardioprotective effect of abscisic acid in a rat model of type 3 cardio-renal syndrome: Role of NOX-4, P-53, and HSP-70.

Cardiorenal syndrome (CRS) is a complex heart and kidney pathophysiologic disorder that leads to a bidirectional interrelationship between them. Abscisic acid (ABA) is a phytohormone that is present in plants, and is known to regulate fundamental physiological functions. This study aimed to explore the efficacy of ABA in surgically induced-CRS type 3 rats. Rats were randomly and equally divided into four groups. Rats in Group 1 received saline (Sham group), Group 2 included control induced-CRS rats, Group 3 rats (CRS+ABA) included CRS rats treated with ABA and Group 4 (CRS + ABA + Verapamil + propofol) were CRS rats treated with Verapamil, propofol and ABA. The rats were treated with the drugs daily for four weeks. At the end of the study, relative heart weight corrected QT interval (QTc), mean blood pressure (MBP), kidney functions, oxidative stress, NADPH oxidase 4 (NOX4), protein 53 (P53), and heat shock proteins-70 (HSP-70) expression was assessed and recorded. ABA led to a significant shortening of the ventricular action potential duration indicated by QTc. Furthermore, it significantly lowered heart weight, MBP, serum creatinine, NOX-4, and P-53 expression and augmented HSP-70 expression. In contrast, adding calcium channel blockers (CCBs) to ABA mitigated this effect. The results suggested that ABA has a potential protective role in CRS-induced cardiac hypertrophy and arrhythmia that could be mediated through inhibition of P-53, NOX-4, and an increase in HSP-70 expression.

The immunomodulatory effects of roflumilast on tachyzoite-bradyzoite transition in a murine model of Toxoplasma gondii.

Roflumilast, a phosphodiesterase 4-inhibitor (PDE-4), shows immunomodulatory and anti-inflammatory properties. It modulates cAMP and TNF-α levels that play a role in the differentiation of Toxoplasma gondii (T. gondii) tachyzoite to bradyzoite stage. Thus, the potential effect of Roflumilast on the tachyzoite-bradyzoite transition in Me49 murine toxoplasmosis using 36 female Swiss Webster mice was studied. The mice were divided into six equal groups; normal control, infected control, two groups treated earlier with Roflumilast at 5 mg/kg and 10 mg/kg, and two groups treated later with Roflumilast at 5 mg/kg and 10 mg/kg. The T. gondii infection was assessed by cyst count and size, measuring serological levels of TNF-α and IL-12 using ELISA kits, brain immunohistochemistry examination of INF-γ and iNOS expression and histopathological examinations of the brain, liver, and spleen. The early-Roflumilast treated group at 10 mg/kg showed a statistically significant of reduction of T. gondii cyst count, size, and IL-12 level. In contrast, TNF-α levels were lower in both the early-Roflumilast treated groups. IFN-γ and iNOS expression showed non-significant changes in the different Roflumilast treated groups associated with mild inflammatory reactions in the brain, liver, and spleen tissues of the early-Roflumilast treated groups that were statistically significant (p < 0.05). This study showed that the earlier treated group at 10 mg/kg halted better tachyzoite-bradyzoite transition than the other groups. The results indicated Roflumilast to be promising for toxoplasmosis control.

Pentosan Polysulfate Sodium augments the therapeutic effect of 5-Aminosalicylic Acid in DSS colitis model; the role of IL-35 expression.

Ulcerative colitis (UC) primarily affects the mucosa of the distal colon. Dysregulated immune response in genetically-prone persons is claimed to be responsible for chronic intestinal inflammation. This study aimed to explore the efficacy and the hematological effects of pentosan polysulfate sodium (PPS) in a dextran sulfate sodium (DSS)-induced colitis model. Forty C57BL/6 female mice were equally divided into five groups: control group, DSS-colitis group, DSS-colitis treated with 5-aminosalicylic acid, DSS-colitis treated with PPS, and DSS-colitis treated with both drugs. Disease activity index (DAI) and colon length were calculated. Colonic IL-6 and IL-35 levels were assayed by ELISA. IL-35 gene expression was evaluated by qRT-PCR. Colon tissue samples were examined by H&E stain and immunohistochemistry (IHC) of Ki67. The colitis group subjected to combined treatment showed the best outcome with significant improvement of DAI and increased colon length. Colonic IL-6 was significantly lower in both PPS- and combination-treated groups accompanied by a significantly higher IL-35 level and its EBI3 subunit mRNA expression. However, the PPS-treated colitis group showed higher gene expression of IL-35 EBI3 subunit by 1.5-fold compared with the combined group. The colon mucosa and crypts were significantly preserved in mice treated with both drugs with the best Ki67 positive cell density. PPS is a safe and promising drug in the treatment of UC as it exerted the best positive effect on the anti-inflammatory IL-35 level and gene expression. However, superior improvement of DAI was seen when PPS was added to ASA with a greater mucosal proliferation and repair.

Standardized study of atorvastatin possible osteoarthritis disease-modifying effect in a rat model of osteoarthritis.

We studied the osteoarthritis (OA)-modifying effects of atorvastatin in an experimental OA rat model and possible underlining mechanisms. We used 62 adult male Sprague-Dawley rats (250-300 g): 32 rats were used to assess the effects of atorvastatin on surgically induced OA in the knee, and 30 rats were used to assess the potential inflammatory effects of carrageenan-induced paw edema. In the OA model, joint stiffness was assessed by measuring the knee extension angle, and pathological changes in the OA knee joint were determined by histological examination and the measurement of serum biochemical markers, including interleukin-1ß (IL-1ß), matrix metalloproteinase-13 (MMP-13), and reduced glutathione (GSH). In the carrageenan-induced paw edema model, both paw thickness and pain threshold were assessed in different groups. Atorvastatin significantly improved joint stiffness, pathological changes, a significant mitigation of the higher MMP-13 and IL-1ß, and a significant increase of reduced GSH in OA rats. Additionally, atorvastatin significantly improved both paw thickness and pain threshold in animals. Atorvastatin is a potential OA-modifying drug that warrants further clinical investigation.

Modulation of COX-2 and NADPH oxidase-4 by alpha-lipoic acid ameliorates busulfan-induced pulmonary injury in rats.

AIMS: This study aimed to explore the potential protective effect of α-lipoic acid on busulfan-induced pulmonary fibrosis in rats. MAIN METHODS: Eighteen adult male rats were divided into 3 groups; control, busulfan, and busulfan plus α-lipoic acid groups. Lung index ratio, serum level of proinflammatory cytokine were assessed. The activities of antioxidant enzymes and lipid peroxidation products were estimated in the lung tissues in addition to the histopathological analyses. The deposition of the collagen in the lung tissues was evaluated by Sirius red staining. The expressions of α-smooth muscle actin (α-SMA), TNF-α, and Caspase 3 were determined immunohistochemically. The pulmonary expression of COX-2 and NOX-4 mRNA was assessed using qRT-PCR. KEY FINDINGS: Administration of ALA significantly protect the lung against BUS-induced pulmonary fibrosis, besides the upregulation of antioxidants, and downregulation of pro-inflammatory cytokines. Also, it reduced collagen deposition that associated with a decreased expression of α-SMA, TNF-α, and Caspase 3 in the lung tissues. Moreover, ALA significantly upregulated the expression of COX-2 concomitant with the downregulation of elevated NOX-4. SIGNIFICANCE: ALA attenuates the lung cytotoxicity of busulfan through its anti-inflammatory, anti-apoptotic, and antifibrotic effects that may be mediated by upregulation of COX-2 and downregulation of NOX-4.

Possible cardioprotective role of NaHS on ECG and oxidative stress markers in an unpredictable chronic mild stress model in rats.

The protective effect of H2S against various body organ injuries has been described. The aim of this work is to investigate the potential role of sodium hydrosulfide (NaHS) as an H2S donor in chronic mild stress induced changes in the rat heart. Forty adult male Sprague Dawley rats were assigned to four groups: control, stressed group, stressed rats treated with aminooxyacetic acid (AOAA), and stressed rats treated with NaHS. Arterial blood pressure (ABP) was recorded. Serum adrenaline, MDA, and GSH levels were measured. Chronic stress significantly increased HR and ABP. AOAA produced similar changes, while NaHS mitigated the rise in HR and ABP. Both stressed and AOAA-treated stressed groups showed a significant decrease in QRS amplitude and a shortening of the RR, QT, and QTc intervals with an elevation of the ST segment. NaHS produced a significant improvement in ECG recordings. Chronic stress produced a significant rise of adrenaline and MDA levels with a significant decline in GSH levels. The AOAA-treated stressed group showed similar elevations. NaHS treatment caused significant reduction in adrenaline and MDA levels but significantly improved GSH levels. In conclusion, H2S donor has a cardioprotective effect against stress-induced cardiovascular diseases through amelioration of the oxidative stress and raised adrenaline levels induced by chronic stress exposure.

Effect of ghrelin on VEGF-B and connexin-43 in a rat model of doxorubicin-induced cardiomyopathy.

Background Since their discovery in the early 1960s, doxorubicin (DOX) remains the most effective anticancer drug. However, this drug has confirmed to be a double-edged sword because it causes a cardiomyopathy that leads to congestive heart failure. Ghrelin, a multi-functional peptide, plays an important role in cardiovascular protection. Therefore, we investigated the effects of ghrelin on vascular endothelial growth factor-beta (VEGF-B) and connexin-43 (Cx43) expression in DOX-induced cardiomyopathy. Methods Forty adult male rats were divided randomly into four groups: normal, normal + ghrelin, DOX-induced cardiomyopathy, and DOX-induced cardiomyopathy + ghrelin. Biochemical and histopathological analysis, electrocardiograph (ECG), heart rate, systolic blood pressure (SBP), and immunohistochemical staining of VEGF-B and Cx43 were assessed for all rats in heart tissue specimens. The duration of the study was 2 weeks. Results DOX-induced cardiomyopathy in rats showed significant ECG changes such as prolongation of PR, QT, QTC intervals and ST segment, a decrease in amplitude and an increase in the duration of QRS complex, bradycardia, and a decrease in SBP. Also, rats in the DOX group showed myocardial histopathological damage in the form of severe fibrosis with decreased expression of Cx43 and a non-significant difference in expression of VEGF-B when compared to normal rats. Treatment with ghrelin resulted in a significant improvement in all the studied parameters and was associated with an increase in VEGF-B and Cx43 expression. Conclusions Ghrelin has a beneficial effect against DOX-induced cardiomyopathy which may be mediated through VEGF-B and Cx43 expression in the myocardium. Ghrelin is a promising cardioprotective drug in DOX-induced cardiomyopathy patients, but further studies are needed to evaluate its use.

ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children's Oncology Group AAML0531 Trial.

Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-γ is a reemerging and promising drug for AML. Calicheamicin a key element of GO, induces DNA-damage and cell-death once the linked CD33-antibody facilitates its uptake. Calicheamicin efflux by the drug-transporter PgP-1 have been implicated in GO response thus in this study, we evaluated impact of ABCB1-SNPs on GO response. Genomic-DNA samples from 942 patients randomized to receive standard therapy with or without addition of GO (COG-AAML0531) were genotyped for ABCB1-SNPs. Our most interesting results show that for rs1045642, patients with minor-T-allele (CT/TT) had better outcome as compared to patients with CC genotype in GO-arm (Event-free survival-EFS: p = 0.022; and risk of relapse-RR, p = 0.007). In contrast, no difference between genotypes was observed for any of the clinical endpoints within No-GO arm (all p > 0.05). Consistent results were obtained when genotype groups were compared by GO and No-GO arms. The in vitro evaluation using HL60-cells further demonstrated consistent impact of rs1045642-T-allele on calicheamicin induced DNA-damage and cell-viability. Our results show the significance of ABCB1 SNPs on GO response in AML and warrants the need to investigate this in other cohorts. Once validated, ABCB1-SNPs in conjunction with CD33-SNPs can open up opportunities to personalize GO-therapy.

Simvastatin exerts antifibrotic effect and potentiates the antischistosomal effects of praziquantel in a murine model: Role of IL10.

Previous studies on simvastatin use in experimental schistosomiasis in mice did not provide a full explanation of its mechanism as antischisome. In this study, we tried to find out the role of IL-10 in the mechanism of action of simvastatin. We used 50 clear mice. Ten were used as normal not treated while 40 were infected with shistosome mansoni then divided into 4 groups; 3 treated groups by praziquantel, simvastatin and combined (praziquantel plus simvastatin) respectively and one group non-treated. The simvastatin treated group showed shortening and loss of the tubercles and disappearance of the spines with swelling and twisted shape of the worms. In addition, it also showed mitigation of ovideposition activity of the worms in the liver and reduction of the fibrous component of the liver granuloma producing a protective effect on the liver. This effect was associated with lowering of IL-10. This may explain the role of IL-10 in the protective effect of simvastatin. Combination of treatment with simvastatin plus praziquantel produced more significant effects in different parameters compared with praziquantel treated group. We recommend using simvastatin as add on therapy to standard antischistosomal therapy, praziquantel. Both drugs affect the worm motility and sucker activity and the ova deposition. Simvastatin has an additional pleiotropic effect halting inflammation and decreasing fibrosis due to increasing IL-10 leading to a hepatoprotective effect. Further clinical studies are needed to further validate these findings.