A novel role for SIRT-1 in L-arginine protection against STZ induced myocardial fibrosis in rats.

BACKGROUND: L-arginine (L-ARG) effectively protects against diabetic impediments. In addition, silent information regulator (SIRT-1) activators are emerging as a new clinical concept in treating diabetic complications. Accordingly, this study aimed at delineating a role for SIRT-1 in mediating L-ARG protection against streptozotocin (STZ) induced myocardial fibrosis. METHODS: Male Wistar rats were allocated into five groups; (i) normal control rats received 0.1 M sodium citrate buffer (pH 4.5); (ii) STZ at the dose of 60 mg/kg dissolved in 0.1 M sodium citrate buffer (pH 4.5); (iii) STZ + sirtinol (Stnl; specific inhibitor of SIRT-1; 2 mg/Kg, i.p.); (iv) STZ + L-ARG given in drinking water (2.25%) or (v) STZ + L-ARG + Stnl. RESULTS: L-ARG increased myocardial SIRT-1 expression as well as its protein content. The former finding was paralleled by L-ARG induced reduction in myocardial fibrotic area compared to STZ animals evidenced histopathologically. The reduction in the fibrotic area was accompanied by a decline in fibrotic markers as evident by a decrease in expression of collagen-1 along with reductions in myocardial TGF-β, fibronectin, CTGF and BNP expression together with a decrease in TGF-β and hydroxyproline contents. Moreover, L-ARG increased MMP-2 expression in addition to its protein content while decreasing expression of PAI-1. Finally, L-ARG protected against myocardial cellular death by reduction in NFκ-B mRNA as well as TNF-α level in association with decline in Casp-3 and FAS expressions andCasp-3protein content in addition to reduction of FAS positive cells. However, co-administration of L-ARG and Stnl diminished the protective effect of L-ARG against STZ induced myocardial fibrosis. CONCLUSION: Collectively, these findings associate a role for SIRT-1 in L-ARG defense against diabetic cardiac fibrosis via equilibrating the balance between profibrotic and antifibrotic mediators

Association of CARD10 rs6000782 and TNF rs1799724 variants with paediatric-onset autoimmune hepatitis

Although the pathogenesis of paediatric-onset autoimmune hepatitis (pAIH) remains incompletely understood, genetic variants and environmental factors are known to be involved. Caspase recruitment domain family member 10 (CARD10) is a scaffold protein that participates in a complex pathway activating nuclear factor kappa-B (NFκB) and tumour necrosis factor alpha (TNF-α). This study aimed to investigate the association of CARD10 rs6000782 (g.37928186A > C) and TNF gene promoter rs1799724 (c.-1037C > T) variants with pAIH susceptibility in a cohort of Egyptian children. The research was also extended to assess the relationship of these variants with levels of NFκB-p65 and TNF-α. Fifty-six pAIH patients and 44 age- and sex-matched healthy controls were included. Variant genotyping was performed by polymerase chain reaction (PCR). Serum NFκB-p65 and TNF-α levels were measured using enzyme-linked immunosorbent assays (ELISAs). rs6000782 C and rs1799724 T alleles, separate or in combination, were significantly increased in pAIH patients compared to controls. Serum levels of NFκB-p65 and TNF-α were higher in pAIH differentiating both groups. Moreover, the recessive model of rs6000782 revealed a significant association with the levels of both NFκB-p65 and TNF-α. In conclusion, rs6000782 and rs1799724 variants are potential genetic risk factors for pAIH predisposition, with the former affecting NFκB-p65 and TNF-α levels. Overall, the inflammatory cascade was associated with the degree of liver cell destruction. Clinically, screening and genetic counselling are recommended for relatives of pAIH patients. Keywords: Hepatitis, Autoimmune, Variants, Paediatrics, Cytokines, Tumour necrosis facto

Antihyperglycemic activity of Caralluma quadrangula in streptozotocin-induced diabetic rats

Diabetes of type 2 is a worldwide epidemic disease of global prevalence. Caralluma quadrangula is wild Saudi plant used by traditional healers as antidiabetic, in case of hunger, and many other diseases. Nothing was reported to justify the use of the plant in case of diabetes. The plant material was extracted with water and with methanol, the methanol fraction was further fractionated into chloroform, n-butanol, in addition to the remaining mother liquor. The water and methanolic extracts as well as different methanolic fractions were evaluated in STZ-induced diabetic rats for their antihyperglycaemic activity. The results showed a significant decrease in fasting blood glucose levels in diabetic treated rats after the administration of most of the extracts and fractions of C. quadrangula and glibenclamide. The most potent activity was shown by administration of the methanolic extract (200 mg/kg), chloroform, n-butanol fraction at dose of 100 mg/kg, as well as the major pregnane glycoside russelioside B isolated from C. quadrangula. In conclusion, this study proved the traditional use of C. quadrangula in diabetes mellitus. Keywords: Asclepiadaceae, Caralluma quadrangula, Antihyperglycemic, Fast blood glucose, G-6-Pase, Insuli

Effect of STZ alone or in combination with Stnl, L-ARG or Stnl+ L-ARG on incidence of fibrosis depicted histopathologically (A) and (B) % of fibrotic area in left ventricle (LV) as well as (C) LV hydroxylproline content.

<p>Data represent the means of six experiments ±SEM; *, ^#, ^ω and ^δ P<0.05 compared with CONT, STZ, STZ + Stnl and STZ + Stnl + L-ARG, respectively, using one-way ANOVA followed by Tukey's Multiple Comparison Test.</p

Effect of STZ alone or in combination with L-ARG or L-ARG + Stnl on metalloproteinase (MMP)-2 mRNA expression (A) and protein content (B).

<p>Data represent the means of six experiments ±SEM; *, ^#, ^ω and ^δP<0.05 compared with CONT, STZ, STZ+ Stnl and STZ+ Stnl + L-ARG, respectively, using one-way ANOVA followed by Tukey's Multiple Comparison Test.</p

Effect of STZ alone or in combination with L-ARG on or L-ARG + Stnl: A-brain naturetic peptide (BNP), B- connective tissue growth factor (CTGF), C-Plasminogen activator inhibitor-1 (PAI-1), D-collagen-1, E-fibronectin and tansforming growth factor (TGF)-β.

<p>Data represent the means of six experiments ±SEM; *, ^#, ^ω and ^δ P<0.05 compared with CONT, STZ, STZ + Stnl and STZ + Stnl + L-ARG, respectively, using one-way ANOVA followed by Tukey's Multiple Comparison Test.</p

Effect of STZalone, or in combination with Stnl, L-ARG or L-ARG + Stnl on Fasting serum glucose (FSG), insulin and HbA1c%.

<p>Data represent the means of sixexperiments ±SEM.</p><p>*^{, #} and ^ωP<0.05 compared with CONT; STZ and STZ+ Stnl, respectively, using one-way ANOVA followed by Tukey's Multiple Comparison Test.</p><p>Effect of STZalone, or in combination with Stnl, L-ARG or L-ARG + Stnl on Fasting serum glucose (FSG), insulin and HbA1c%.</p

Altered Lnc-EGFR, SNHG1, and LincRNA-Cox2 Profiles in Patients with Relapsing-Remitting Multiple Sclerosis: Impact on Disease Activity and Progression

Relapsing–remitting multiple sclerosis (RRMS) is the most prevalent MS subtype. Ample evidence has indicated that long noncoding RNAs (lncRNAs) are crucial players in autoimmune and inflammatory disorders. This study investigated the expression of lnc-EGFR, SNHG1, and lincRNA-Cox2 in RRMS patients during active relapses and in remission. Additionally, the expression of FOXP3, a master transcription factor for regulatory T cells, and NLRP3-inflammasome-related genes were determined. Relationships between these parameters and MS activity and annualized relapse rate (ARR) were also evaluated. The study included 100 Egyptian participants: 70 RRMS patients (35 during relapse and 35 in remission) and 30 healthy controls. RRMS patients showed significant downregulation of lnc-EGFR and FOXP3 and dramatic upregulation of SNHG1, lincRNA-Cox2, NLRP3, ASC, and caspase-1 compared to controls. Lower serum TGF-β1 and elevated IL-1β levels were observed in RRMS patients. Notably, patients during relapses displayed more significant alterations than those in remission. Lnc-EGFR was positively correlated with FOXP3 and TGF-β1 and negatively correlated with ARR, SNHG1, lincRNA-Cox2, and NLRP3 inflammasome components. Meanwhile, SNHG1 and lincRNA-Cox2 were positively correlated with ARR, NLRP3, ASC, caspase-1, and IL-1β. Excellent diagnostic performance for lnc-EGFR, FOXP3, and TGF-β1 was demonstrated, while all biomarkers exhibited strong prognostic potential for predicting relapses. Finally, the differential expression of lnc-EGFR, SNHG1, and lincRNA-Cox2 in RRMS patients, especially during relapses, suggests their involvement in RRMS pathogenesis and activity. Correlation between their expression and ARR implies relationships to disease progression. Our findings also highlight their promising roles as biomarkers for RRMS

Effect of STZ alone or in combination with L-ARG or L-ARG + Stnl on (A) nuclear factor kappa (NFκ)-B mRNA expression, (B) tumor necrosis factor alpha (TNF-α) protein content, (C) interleukin 1 (IL-) β protein content, (D) silent information regulator (SIRT-1) mRNA expression and (E) its protein content.

<p>Data represent the means of six experiments ±SEM; *, ^#, ^ω and ^δ P<0.05 compared with CONT, STZ, STZ + Stnl and STZ + Stnl + L-ARG, respectively, using one-way ANOVA followed by Tukey's Multiple Comparison Test.</p

Effect of STZ alone or in combination with L-ARG or L-ARG + Stnl on caspase-3 (Casp-3) mRNA expression (A) and activity (B) as well as (C) FAS mRNA expression and (D) % FAS positive cells.

<p>Data represent the means of six experiments ±SEM; *, ^#, ^ω and ^δ P<0.05 compared with CONT, STZ, STZ + Stnl and STZ + Stnl + L-ARG, respectively, using one-way ANOVA followed by Tukey's Multiple Comparison Test.</p