Molecular mechanisms mediate roflumilast protective effect against isoprenaline-induced myocardial injury.

BACKGROUND: Myocardial necrosis is one of the most common cardiac and pathological diseases. Unfortunately, using the available medical treatment is not sufficient to rescue the myocardium. So that, we aimed in our model to study the possible cardioprotective effect of roflumilast (ROF) in an experimental model of induced myocardial injury using a toxic dose of isoprenaline (ISO) and detecting the role of vascular endothelial growth factor/endothelial nitric oxide synthase (VEGF/eNOS) and cyclic guanosine monophosphate/cyclic adenosine monophosphate/ sirtuin1 (cGMP/cAMP/SIRT1) signaling cascade. MATERIALS AND METHODS: Animals were divided into five groups; control, ISO given group (150 mg/kg) i.p. on the 4th and 5th day, 3 ROF co-administered groups in different doses (0.25, 0.5, 1 mg/kg/day) for 5 days. RESULTS: Our data revealed that ISO could induce cardiac toxicity as manifested by significant increases in troponin I, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), and cleaved caspase-3 with toxic histopathological changes. Meanwhile, there were significant decreases in reduced glutathione (GSH), total antioxidant capacity (TAC), VEGF, eNOS, cGMP, cAMP and SIRT1. However, co-administration of ROF showed significant improvement and normalization of ISO induced cardiac damage. CONCLUSION: We concluded that ROF successfully reduced ISO induced myocardial injury and this could be attributed to modulation of PDE4, VEGF/eNOS and cGMP/cAMP/SIRT1 signaling pathways with antioxidant, anti-inflammatory, and anti-apoptotic properties.

Testicular cytoprotective effect of glucagon like peptide-1 in diabetic rats involves inhibition of apoptosis, endoplasmic reticulum stress and activation of autophagy.

This study aimed to explore the possible cytoprotective effects of exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in the testicles of diabetic rats. Exenatide has numerous advantageous properties in addition to its hypoglycemic effect. However, its impact on testicular tissue in diabetes needs more clarification. Therefore, rats were divided into control, exenatide-treated, diabetic and exenatide-treated diabetic groups. Blood glucose and serum levels of insulin, testosterone, pituitary gonadotropins and kisspeptin-1 were measured. Real-time PCR for beclin-1, p62, mammalian target of rapamycin (mTOR), and AMP-activated protein kinase (AMPK), were estimated in testicular tissue in addition to markers of oxidative stress, inflammation, and endoplasmic reticulum stress. Also, immuno-expression of protein P53, nuclear erythroid factor2 (Nrf2) and vimentin was conducted. Exenatide was able to attenuate diabetic toxic changes and enhance autophagy in testicular tissue. These results indicate the protective effect of exenatide against diabetic testicular dysfunction.

Paeonol Attenuates Hepatic Ischemia/Reperfusion Injury by Modulating the Nrf2/HO-1 and TLR4/MYD88/NF-κB Signaling Pathways.

Hepatic ischemia/reperfusion (HIR) is the most common type of liver injury following several clinical situations. Modulating oxidative stress and inflammation by Nrf2/HO-1 and TLR4/MYD88/NF-κB pathways, respectively, is involved in alleviating HIR injury. Paeonol is a natural phenolic compound that demonstrates significant antioxidant and anti-inflammatory effects. The present study explored the possible protective effect of paeonol against HIR injury and investigated its possible molecular mechanisms in rats. Rats were randomly divided into four groups: sham-operated control, paeonol-treated sham-operated control, HIR untreated, and HIR paeonol-treated groups. The results confirmed that hepatic injury was significantly aggravated biochemically by elevated serum levels of alanine transaminase and aspartate transaminase, as well as by histopathological alterations, while paeonol reduced the increase in transaminases and alleviated pathological changes induced by HIR. Additionally, paeonol inhibited the HIR-induced oxidative stress in hepatic tissues by decreasing the upraised levels of malondialdehyde and nitric oxide and enhancing the suppressed levels of reduced glutathione and superoxide dismutase activity. Furthermore, paeonol activated the protective antioxidative Nrf2/HO-1 pathway. The protective effect of paeonol was associated with inhibiting the expression of the inflammatory key mediators TLR4, MYD88, NF-κB, and TNF-α. Finally, paeonol inhibited the increased mRNA levels of the pro-apoptotic marker Bax and enhanced the reduced mRNA levels of the anti-apoptotic marker Bcl-2. Taken together, our results proved for the first time that paeonol could protect against HIR injury by inhibiting oxidative stress, inflammation, and apoptosis.

Effects of platelet rich plasma on experimentally induced diabetic heart injury.

Diabetic heart is one of the common complications of diabetes mellitus. Platelet-rich plasma (PRP) is an autologous product rich in growth factors that can enhance tissue regeneration. This work was conducted to study the PRP ability to improve diabetes-inducing cardiac changes. Also, it sheds more light on the possible mechanisms through which PRP induces its effects. Rats were divided into; control, PRP, diabetic, and PRP-diabetic groups. Cardiac specimens were obtained and processed for biochemical, histological, and immunohistochemical study. The diabetic group exhibited a significant increase in cardiac oxidative stress, inflammation, and cardiac injury markers if compared with the control group. Additionally, the cardiac tissue showed variable morphological changes in the form of focal distortion and loss of cardiac myocytes. Distorted mitochondria and heterochromatic nuclei were observed in the cardiac muscle fibers. The mean number of charcoal-stained macrophages, and mean area fraction for collagen fibers, mean number of PCNA-immune positive cardiac muscle were significantly decrease in PRP- diabetic group. Collectively, the results showed that PRP treatment ameliorated most of all these previous changes. CONCLUSION: PRP ameliorated the diabetic cardiac injury via inhibition of oxidative stress and inflammation. It was confirmed by biochemical, histological, and immunohistochemical study. It could be concluded that PRP could be used as a potential therapy for diabetic heart.

C-peptide corrects hepatocellular dysfunction in a rat model of type 1 diabetes.

C-peptide is gaining much interest recently due to its well-documented beneficial effects on multiple organ dysfunction induced by diabetes. Our study was designed to investigate the effect of C-peptide on hepatocellular dysfunction in diabetic rats. Wistar male rats were separated into four groups: control, diabetic, diabetic + insulin, and diabetic + C-peptide. Serum levels of glucose, insulin, and liver biomarkers were assessed. Liver sections were collected for histopathological examination and immuno-histochemical assessment of tumor necrosis factor alpha (TNF-α). Oxidative stress markers and gene expression of inducible nitric oxide synthase (iNOS), transforming growth factor beta 1 (TGF-ß1), and glucose-6-phosphatase (G6Pase) were also measured in liver tissues. C-peptide administration prevented hepatic dysfunction induced by diabetes to a similar extent as that of insulin which was confirmed microscopically. We concluded that C-peptide could be used as an alternative therapy to insulin to correct hepatocellular dysfunction associated with type 1 diabetes mellitus (T1DM).

Mechanisms underlying the protective effect of leukotriene receptor antagonist montelukast against doxorubicin induced testicular injury in rats.

The obligatory use of cytotoxic drugs to face the malignant tumors results in survivors that suffer from long term health problems. Fertility problems, especially in young boys, exert one of the major consequences of chemotherapy treatment that needs resolution. We investigate the potential effect of the cysteinyl leukotriene receptor antagonist montelukast on doxorubicin-induced testicular damage. Five groups of adult Wistar male rats were subjected to the following treatment; vehicle for the control group, montelukast (20 mg/kg orally daily for 10 days) for the drug control, doxorubicin (12 mg/kg intraperitoneal injection once at 5th day) for the toxic group, montelukast at 10 mg/kg + doxorubicin, montelukast at 20 mg/kg + doxorubicin. The period of the experiment was 10 days administration of montelukast, while doxorubicin was injected at the 5th day. Results of serum testosterone, testicular lipid peroxidation, antioxidant status, and histopathology revealed protection of montelukast against doxorubicin-induced testicular damage. The pro-apoptotic caspase 3 and the pro-inflammatory tumor necrosis factor-alpha were examined immunohistochemically and showed a significant decrease with montelukast treatment as compared to doxorubicin group. Doxorubicin increased gene expression of matrix metalloproteinase 9 and decreased peroxisome proliferator activated receptor gamma. Montelukast treatment restored their expressions to normal values. In conclusion, montelukast administration can ameliorate the testicular damage induced by doxorubicin based on its anti-inflammatory, antioxidant and anti-apoptotic effects as well as by of modulation of important genes expression.

Paeonol Attenuates Methotrexate-Induced Cardiac Toxicity in Rats by Inhibiting Oxidative Stress and Suppressing TLR4-Induced NF-κB Inflammatory Pathway.

Methotrexate (MTX) is a commonly used chemotherapeutic agent. Oxidative stress and inflammation have been proved in the development of MTX toxicity. Paeonol is a natural phenolic compound with various pharmacological activities including antioxidant and anti-inflammatory properties. The aim of the present study was to evaluate the protective effect of paeonol against MTX-induced cardiac toxicity in rats and to evaluate the various mechanisms that underlie this effect. Paeonol (100 mg/kg) was administered orally for 10 days. MTX cardiac toxicity was induced at the end of the fifth day of the experiment, with or without paeonol pretreatment. MTX-induced cardiac damage is evidenced by a distortion in the normal cardiac histological structure, with significant oxidative and nitrosative stress shown as a significant increase in NADPH oxidase-2, malondialdehyde, and nitric oxide levels along with a decrease in reduced glutathione concentration and superoxide dismutase activity compared to the control group. MTX-induced inflammatory effects are evidenced by the increased cardiac toll-like receptor 4 (TLR4) mRNA expression and protein level as well as increased cardiac tumor necrosis factor- (TNF-) α and interleukin- (IL-) 6 levels along with increased nuclear factor- (NF-) κB/p65 immunostaining. MTX increased apoptosis as shown by the upregulation of cardiac caspase 3 immunostaining. Paeonol was able to correct the oxidative and nitrosative stress as well as the inflammatory and apoptotic parameters and restore the normal histological structure compared to MTX alone. In conclusion, paeonol has a protective effect against MTX-induced cardiac toxicity through inhibiting oxidative and nitrosative stress and suppressing the TLR4/NF-κB/TNF-α/IL-6 inflammatory pathway, as well as causing an associated reduction in the proapoptotic marker, caspase 3.

The effect of peptide tyrosine tyrosine (PYY3-36), a selective Y2 receptor agonist on streptozotocin-induced diabetes in albino rats.

OBJECTIVE: The aim of the present study was to assess the effect of the PYY3-36, as a potential therapy for the type 2 diabetes mellitus (T2DM), induced by high fat diet (HFD) and an intraperitoneal (i.p.) administration of streptozotocin (STZ) in albino rats. METHODS: Forty adult male albino Wistar rats were divided into: 1) control group (C, in which the rats were fed with a standard diet and received vehicle; 2) diabetic group (D, in which T2DM was induced by feeding the rats with HFD for four weeks followed by a single i.p. injection of 35 mg/kg STZ, this group was also allowed to have HFD till the end of the study; and 3) D+PYY3-36 group (in which the diabetic rats were treated with 50 µg/kg i.p. PYY3-36 twice a day for one week). Food intake, water intake, body weight (b.w.), visceral fat weight (VFW), liver glycogen content, serum levels of glucose, insulin, and interleukin-6 (IL-6), were measured. Homeostatic-model assessment of insulin resistance (HOMA-IR) was estimated. The gene expression of the hypothalamic neuropeptide Y (NPY) and visceral nuclear factor kappa B (NF-κB) were assessed by a reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The PYY3-36 administration to the diabetic group of rats significantly increased the serum insulin levels and liver glycogen content, decreased the body weight, VFW, food intake, water intake, serum levels of the glucose, IL-6, and HOMA-IR. It also decreased the expression of both the hypothalamic NPY and the visceral fat NF-κB. CONCLUSION: With respect to the fact of improved insulin release and enhanced insulin sensitivity (an effect that may be mediated via suppressing accumulation of visceral fat and inflammatory markers), in the rats treated with PYY3-36, the PYY3-36 might be considered for the future as a promising therapeutic tool in T2DM.

Therapeutic effect of liraglutide on expression of CTGF and BMP-7 in induced diabetic nephropathy.

INTRODUCTION: Diabetic nephropathy (DN) is one of the critical complications of diabetes mellitus and the main cause of chronic renal dysfunction. The pathogenic mechanism causing the disease remains unclear and there is a lack of effective treatment methods so novel strategies are needed for DN management. The aim of this study, therefore, is to evaluate the effect of liraglutide as glucagon-like peptide-1 analogue and its underlying mechanisms on induced DN in rats MATERIALS AND METHODS: Sixty rats were divided into control group, diabetic group, and liraglutide-treated group. At the end of experiment, renal CTGF and BMP-7 messeger RNA expression were determined. Blood sugar, serum urea, and creatinine were measured. Also, histopathological changes were studied. RESULTS: Liraglutide can improve renal alterations associated with diabetes as it reduced CTGF expression and increased BMP-7 expression. In the same time, it could improve histopathological changes and renal function tests. CONCLUSION: These findings influence the beneficial use of liraglutide for the management of DN in patients with diabetes mellitus.

Melatonin reduced endometrial hyperplasia induced by estradiol in female albino rats.

Melatonin, the pineal gland hormone, plays a crucial role in regulation of neuroendocrine and defensive functions, free radicals neutralization, and suppresses angiogenesis, proliferation and cancer. The purpose of designing our study is to assess the effect of estradiol benzoate and its combination with melatonin on uteri of female albino rats. For 4 weeks, the present study was conducted on thirty six female rats separated into 3 groups: Control group (rats received the vehicle), EB group (rats were treated by estradiol benzoate (600 µg/kg intramuscular) for induction of endometrial hyperplasia), and EB+Mel group (rats were treated with estradiol benzoate (600 µg/kg) plus melatonin (50 µg/ml) added to drinking water. Melatonin administration reduced estradiol benzoate-induced endometrial hyperplasia and prevented the occurrence of atypia associated with a significant reduction in lipid peroxide level and NF-κB mRNA and a significant rise in immune-expression of caspase-3, interleukin-2 (IL-2) mRNA and total antioxidant levels in uterine tissues. The results demonstrated that melatonin reduced estradiol benzoate action on the endometrium.

Role of Nrf2/HO-1 and PI3K/Akt Genes in the Hepatoprotective Effect of Cilostazol.

BACKGROUND: Cilostazol, a phosphodiesterase 3 inhibitor (PDE3I), is a platelet aggregation inhibitor and vasodilator that is useful for treating intermittent claudication. Experimental studies have shown that cilostazol has potent anti-inflammatory, anti-oxidant effects effects. OBJECTIVES: Although the hepatoprotective effect cilostazol has been studied, the molecular mechanisms of such protection, including: the nuclear factor-erythroid 2-related factor 2 (Nrf2) / hemoxygenase (HO-1) and the phosphoinositide 3-kinase (PI3K) /serine/threonine kinase (Akt) pathways are not fully explored, which is the aim of this study. METHODS: To achieve the aim of this study, 35 rats were grouped into: control groups, liver injury group (model- non treated: injected with thioacetamide (TAA), 150 mg/kg, i.p.), and two cilostazoltreated groups (treated with cilostazol 10 and 50 mg/kg, p.o.). The rats were treated for 8 days and injected with TAA on the 7th day of the experiment and sacrificed 48 hours after TAA injection. RESULTS: The model group showed evidence of liver injury as indicated by the elevation of liver enzymes and confirmed by histopathological findings. TAA-induced liver injury was accompanied by down-regulation of the cytoprotective pathways: PI3K/Akt and Nrf2/HO-1 mRNAs. Cilostazol administration ameliorated TAA-induced liver injury, where it caused a significant improvement in the activity of liver enzymes as well as in the histopathological changes. Such an effect was associated with a significant increase in the expression of PI3K/Akt and Nrf2/HO-1 mRNAs as detected by Real-time reverse transcription polymerase chain reaction (RT-PCR). CONCLUSION: Cilostazol protected rats against TAA hepatotoxicity through up-regulation of PI3K/Akt and Nrf2/HO-1 gene expression.

Effect of experimentally induced hypertension on cerebellum of postmenopausal rat.

Cerebellum seems to be a specific target for both the decrease of estrogen and hypertension in menopause. The aim of this study was to investigate the hypertension and menopause-induced changes in rat's cerebellar cortex and the possible mechanisms of these changes. Rats were divided into four groups: the sham-operated control (SC-group), the ovariectomized (OVX-group), the hypertensive (H-group), and the ovariectomized-hypertensive (OVX-H-group) group. The mean arterial pressure (MAP), serum nitric oxide (NO), lipid peroxides and antioxidant catalase enzyme levels were assayed. Cerebellar tissue homogenization for analysis of lipid peroxides, antioxidant catalase enzyme, tumor necrosis factor-α (TNF-α), and estradiol was done. Quantification of adrenomedullin (AM) and interleukin-10 (IL-10) mRNA was also done. Cerebella were processed for histological, immunohistochemical and transmission electron microscopic examination. In the OVX-group, insignificant structural and biochemical changes were observed compared with the SC-group apart from the significantly increased lipid peroxides and decreased NO and catalase levels in serum. The H-group showed an elevated lipid peroxides and TNF-α levels, reduced catalase level, numerous degenerated Purkinje cells, vacuolations of the neuropil, some axonal degeneration, and few ghosts in the granular cell layer (GL). However, in OVX-H-group, oxidative stress, inflammation, and cerebellar damage were exacerbated and cerebellar estrogen was reduced associated with reduction in GL thickness and decreased Purkinje cells number. Most axoplasms had degenerated neurofilaments with abnormal myelination. The immunoexpression of glial fibrillary acidic protein were significantly increased in both OVX-group and H-group and significantly decreased in OVX-H group. Gene expression of AM and IL-10 were increased in cerebellar tissues of H-group compared with the SC-group but it was significantly decreased in OVX-H-group compared with H-group. Taken together, postmenopausal rats with hypertension suffered from structural cerebellar changes than rats with only hypertension or estrogen deficiency separately due to augmentation of the increased oxidative stress markers and the proinflammatory cytokines (TNF-α) with down regulation of the anti-inflammatory cytokine (IL-10) and the blood pressure regulator, AM. These suggested that high blood pressure is a critical factor for postmenopausal cerebellum.

Association of IL-1ß, IL-1RN, and ESR1 genes polymorphism with risk of infection and response to sofosbuvir plus daclatasvir combination therapy in hepatitis C virus genotype-4 patients.

Sofosbuvir (SOF) and daclatasvir combination with or without ribavirin proved to be effective and safe in the treatment of hepatitis C virus infection. The study aimed to assess the efficacy of (SOF plus daclatasvir) combination + ribavirin in the treatment of treatment-experienced HCV genotype 4 Egyptian patients and to investigate the impact of IL-1ß _31, IL-1ß _511, and IL-1RN and T29C of ESR1 genes polymorphisms on treatment outcome. The study also aimed to assess the effect of the treatment on liver fibrosis. The sustained virologic response was assessed at 0, 4, 12, and 24 weeks from the beginning of treatment by RT-PCR. IL-1ß _31, IL-1ß _511, IL-1RN, and T29C genes polymorphisms were examined by PCR-based techniques in two groups of patients (responders and non-responders) and a control group of healthy subjects. A significant association between IL-1ß_511 gene polymorphism and SOF/DAV-induced response was observed, where the "CC" genotype was the most frequent in responders while the "CT" genotype was the most frequent among non-responders (P = 0.0001, OR = 39; 95% CI = 4.7-316). IL-1RN gene polymorphism also showed significant associations with response to treatment, genotypes that include allele "1" were the most frequent in responders, particularly the homozygous genotype "1/1" (P = 0.0001, OR = 2.3; 95% CI = 1.57-3.2). However, the genotypes "4/4" and "2/4" were the most frequent in non-responders; (P = 0.0001). At least 71% of the responders carry allele "1" while 54% of non-responders were allele "4" carriers (P value = 0.0001. OR = 2.8; 95% CI = 6.4-134.2). Liver fibrosis is significantly improved regardless of the response. © 2018 IUBMB Life, 70(11):1156-1163, 2018.

Role of PPAR-α agonist fenofibrate in the treatment of induced benign prostatic hyperplasia with dysplastic changes in rats.

Nearly all men who reach average life expectancy have prostate disease. The most common is benign prostatic hyperplasia (BPH). Peroxisome proliferator-activated receptor alpha (PPARα) had protective effect in different models, but still, there are no studies explain its role in BPH. So that we investigated the effect of fenofibrate (FEN) on induced BPH by testosterone propionate (TP) (3 mg/kg/day for 4 weeks) subcutaneous injection followed by FEN (300 mg/kg/day) was given orally for 4 weeks. We measured prostate weights changes, prostatic tissue superoxide dismutase (SOD), and malondialdehyde (MDA) levels. Prostate-specific antigen (PSA), dihydrotestosterone (DHT), and total antioxidant capacity (TAC) in serum were determined. The mRNA gene expressions of proliferating cell nuclear antigen (PCNA), PPARα, and glutathione peroxidase (GPx) in prostatic tissue were also measured by quantitative real-time polymerase chain reaction. In addition, the histopathological changes and activated caspase3 immunoexpression were evaluated. Our results showed that TP succeeded in induction of BPH, which was detected by significant increase in prostate weights, prostatic tissue MDA, serum levels of DHT, PSA, and mRNA gene expression of PCNA but significant decrease in PPARα and GPx gene expression. Moreover, TAC in serum and SOD level in prostate tissue decreased. The histopathological examination showed typical changes of BPH with dysplastic changes with marked decrease in activated caspase3 immunoexpression indicating marked suppression of the apoptotic process. FEN significantly improved all disturbed parameters of BPH model. Moreover, there are no dysplastic changes with co-administration of FEN to BPH induced group.

Effect of Sofosbuvir Plus Daclatasvir in Hepatitis C Virus Genotype-4 Patients: Promising Effect on Liver Fibrosis.

BACKGROUND/PURPOSE: The effect of sofosbuvir and daclatasvir in treatment of genotype 4 Hepatitis C Virus (HCV) is not well documented. This study investigated the safety and efficacy of sofosbuvir plus daclatasvir with or without ribavirin in treatment of HCV genotype 4 patients. The impact of therapy on liver fibrosis as well as the role of IL18 polymorphism in therapeutic outcome was assessed. METHODS: One hundred HCV genotype 4 patients were categorized into 2 groups. The group 1 comprised treatment naïve patients, with total serum bilirubin ≤ 1.2 mg/10-1 L, serum albumin ≥ 3.5 g/10-1 L, INR ≤ 1.2, and platelet count ≥ 150 × 109/L. This group was treated with sofosbuvir plus daclatasvir for 12 weeks. The group 2 included Peg-IFN-α-or sofosbuvir treatment experienced, or patients with at least 2 of the following findings: total serum bilirubin > 1.2 mg/10-1 L, serum albumin < 3.5 g/10-1 L, INR > 1.2, and platelet count < 150 × 109 L-1. Group 2 was treated with sofosbuvir-daclatasvir + ribavirin for 12 weeks, with the exception of sofosbuvir treatment experienced patients, who were treated with sofosbuvir/daclatasvir + ribavirin for 24 weeks. RESULTS: Sustained Virological Response (SVR12) (undetectable viremia12 weeks post-treatment), was 93.3% in group 1 and 87.5% in group 2 (total = 91%). Such high efficacy was accompanied with tolerable adverse effects as well as with significant improvement in liver fibrosis. No significant association was observed between IL18 polymorphism (rs1946518) at position -607 and achievement of SVR12 in HCV patients after treatment. CONCLUSION: Sofosbuvir plus daclatasvir, with or without ribavirin achieved high efficacy and safety in HCV genotype 4 patients. Their effects were accompanied with attenuation of liver fibrosis. Further wider-scale studies are needed to evaluate the actual role of IL18 polymorphisms in treatment response with sofosbuvir/daclatasvir.

Cilostazol alleviates streptozotocin-induced testicular injury in rats via PI3K/Akt pathway.

AIMS: Male infertility prevalence is higher in diabetic patients. Those patients exhibit testicular oxidative damage due to sustained hyperglycemia and inflammation. The study has investigated the efficacy of cilostazol, a phosphodiesterase 3 inhibitor, on testicular damage of diabetic rats. MAIN METHODS: Streptozotocin-induced diabetes in rats was used as a model. Six control male rats and 24 diabetic male rats were divided into the following: diabetic, cilostazol at low dose, cilostazol at high dose, and sildenafil treated rat groups. Treatment period was 4 weeks. Then, serum testosterone, testicular oxidative parameters, and testicular oxidant defenses were assayed. Real time PCR was done for quantification of Phosphoinositide 3-kinase (PI3K), Akt, and nuclear factor (NF)-κB mRNA. Expression of testicular inducible nitric oxide synthase (iNOS) was assessed. KEY FINDINGS: Diabetes negatively affected the testicular tissue as evident by biochemical analysis and histopathology. Four weeks of cilostazol or sildenafil treatment improved anti-oxidative capacity, ameliorated lipid peroxidation and the pro-inflammatory iNOS expression in testicular tissue. Testosterone level and the spermatogenesis showed marked improvement. Quantitative mRNA expression showed an elevation in PI3K and Akt by cilostazol with decreasing in NF-κB level by both drugs. SIGNIFICANCE: Our findings suggest the beneficial role of cilostazol and sildenafil in diabetic testicular damage dependent on anti-inflammatory and anti-oxidant effects.

Effect of histone deacetylase inhibitor on epithelial-mesenchymal transition of liver fibrosis.

Liver fibrosis is an excessively reversible wound healing process and the fibrotic disorder is the activation of hepatic stellate cell that requires extensive alterations in gene expression. As reversible deacetylation of histone proteins modulate gene expression, we examined the effect of valproic acid (VPA) as selective histone deacetylase inhibitor on CCl-4 induced liver fibrosis. Thirty rats were divided into three equal groups; control group, fibrotic group and VPA-treated group. The rats were sacrificed after 6 weeks of liver fibrosis induction. The histopathological effect on liver tissue was examined. The expression of α-SMA and Smad-4 mRNA and serum levels of TGF-ß1, alanine aminotransferase, and aspartate aminotransferase were determined. Treatment of rats with VPA attenuated carbon tetrachloride-induced liver fibrosis. Moreover, α-SMA and Smad-4 expression was repressed under VPA treatment and both serum TGF-ß1 and liver enzymes were significantly decreased. The histone deacetylase inhibitor-1 VPA inhibits the epithelial-mesenchymal transition and affects hepatic stellate cell activation during liver fibrosis through downregulation of Smad4 and α-SMA expression which may serve as a promising agent in liver fibrosis treatment. © 2018 IUBMB Life, 70(6):511-518, 2018.

Protective role of nebivolol in cadmium-induced hepatotoxicity via downregulation of oxidative stress, apoptosis and inflammatory pathways.

Cadmium (Cd) intoxication in human occurs through inhalation of cigarette smoke and ingestion of contaminated water and food. We investigated the role of nebivolol (NEB) in Cd induced hepatotoxicity. In our study; NEB was given as (10 mg/kg/d) orally to rats for 6 weeks, in the presence or absence of hepatotoxicity induced by oral administration of Cd (7 mg/kg/d) for 6 weeks. Levels of serum liver enzyme biomarkers; alanine transaminase (ALT), aspartate transaminase (AST) and serum total antioxidant capacity (TAC) were measured. In addition; mean arterial pressure and total cholesterol levels were measured. Hepatic superoxide dismutase (SOD) and malondialdehyde (MDA) were detected. Hepatic histopathological features, inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) immunoexpressions were evaluated. Tumor necrosis factor alpha (TNF-α) and B-cell lymphoma-2 (Bcl-2) mRNA gene expressions were detected using real time-PCR (rt-PCR). Our results showed marked increase in all measured parameters except SOD, TAC, eNOS immunoexpression and Bcl2 mRNA gene expression which decreased in Cd induced hepatotoxicity group. NEB showed marvelous protective effect against Cd induced changes. NEB decreased liver enzymes (ALT and AST), mean arterial pressure, total cholesterol levels, MDA, iNOS immunoexpression and TNF-α gene expression but significantly increased SOD, TAC, eNOS immunoexpression and Bcl-2 gene expression. Moreover; NEB markedly improved the histopathological changes induced by Cd. These findings prove the antioxidant, anti-apoptotic and anti-inflammatory properties of NEB and its protective role in Cd induced hepatotoxicity.

STAT3 and Nrf2 pathways modulate the protective effect of verapamil on lung injury of diabetic rats.

OBJECTIVE: We aimed to assess the protective role of verapamil, L-type calcium channel blockers, against early lung damage in diabetic rats. Lung injury has recently been recognized as a consequent complication of diabetes mellitus. Hyperglycemia induces inflammatory changes in lung tissue early in the disease. METHODS: Twenty four adult male rats were grouped into control, diabetic, diabetic treated with verapamil, and verapamil control. Streptozotocin (STZ) was used to induce diabetes. Oxidative parameters and antioxidative mechanisms were assessed in lung homogenate. Tumor necrosis factor alpha (TNFα) protein was measured as a pro-inflammatory mediator. Signal transducer and activator of transcription 3 (STAT3) gene expression and nuclear erythroid factor 2 (Nrf2) immunoexpression were screened. RESULTS: The lung showed oxidative damage and inflammatory infiltration in STZ diabetic rats early at 2 weeks. The parameters significantly improved in lung tissue treated with verapamil. Histopathology of the lung tissue confirmed the results. Inhibition of STAT3/TNFα pathway was involved in the protection offered by verapamil. Activation of Nrf2 together with an increasing antioxidant capacity of diabetic lung significantly ameliorates the injury induced by diabetes. CONCLUSIONS: Verapamil afforded protection in diabetic lung injury. The protection was mediated by the anti-inflammatory and antioxidant effects of verapamil.