G protein-coupled estrogen receptor (GPER) selective agonist G1 attenuates the neurobehavioral, molecular and biochemical alterations induced in a valproic acid rat model of autism.

AIMS: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with a rising prevalence in boys rather than girls. G protein-coupled estrogen receptor (GPER) activation by its agonist G1 showed a neuroprotective effect, similar to estradiol. The present study aimed to examine the potential of the selective GPER agonist G1 therapy on the behavioral, histopathological, biochemical, and molecular alterations induced in a valproic acid (VPA)-rat model of autism. MAIN METHODS: VPA (500 mg/kg) was intraperitoneally administered to female Wistar rats (on gestational day 12.5) to induce the VPA-rat model of autism. The male offspring were intraperitoneally administered with G1 (10 and 20 µg/kg) for 21 days. After the treatment process, rats performed behavioral assessments. Then, sera and hippocampi were collected for biochemical and histopathological examinations and gene expression analysis. KEY FINDINGS: GPER agonist G1 attenuated behavioral deficits, including hyperactivity, declined spatial memory and social preferences, anxiety, and repetitive behavior in VPA rats. G1 improved neurotransmission and reduced oxidative stress and histological alteration in the hippocampus. G1 reduced serum free T levels and interleukin-1ß and up-regulated GPER, RORα, and aromatase gene expression levels in the hippocampus. SIGNIFICANCE: The present study suggests that activation of GPER by its selective agonist G1 altered the derangements induced in a VPA-rat model of autism. G1 normalized free T levels via up-regulation of hippocampal RORα and aromatase gene expression. G1 provoked estradiol neuroprotective functions via up-regulation of hippocampal GPER expression. The G1 treatment and GPER activation provide a promising therapeutic approach to counteract the autistic-like symptoms.

Association study of HIF-1α rs11549465 and VEGF rs3025039 genetic variants with diabetic retinopathy in Egyptian patients: crosslinks with angiogenic, inflammatory, and anti-inflammatory markers.

BACKGROUND: Genetic factors are implicated in the progression of DR-a global cause of blindness. Hence, the current work investigated the association of HIF-1α rs11549465 and VEGF rs3025039 genetic variants with the different stages of retinopathy among T2DM Egyptian patients. The crosslinks of these variants were explored with angiogenesis (VEGF), inflammation (AGEP and VCAM-1), and anti-inflammation (CTRP3) markers. Two hundred eighty-eight subjects were recruited in this study: 72 served as controls and 216 were having T2DM and were divided into diabetics without retinopathy (DWR), diabetics with non-proliferative retinopathy (NPDR), and diabetics with proliferative retinopathy (PDR). The genetic variants were analyzed using PCR-RFLP and their associations with NPDR and PDR were statistically tested. The circulating levels of AGEP, VCAM-1, HIF-1α, VEGF, and CTRP3 were assayed followed by analyzing their associations statistically with the studied variants. RESULTS: Only HIF-1α rs11549465 genetic variant (recessive model) was significantly associated with the development of NPDR among T2DM patients (p < 0.025) with a significant correlation with the circulating HIF-1α level (p < 0.0001). However, this variant was not associated with PDR progression. Neither HIF-1α rs11549465 nor VEGF rs3025039 genetic variants were associated with the PDR progression. The circulating AGEP, VCAM-1, HIF-1α, and VEGF were significantly elevated (p < 0.0001) while the CTRP3 was significantly decreased (p < 0.0001) in NPDR and PDR groups. The HIF-1α rs11549465 CT and/or TT genotype carriers were significantly associated with AGEP and VCAM-1 levels in the NPDR group, while it showed a significant association with the CTRP3 level in the PDR group. The VEGF rs3025039 TT genotype carriers showed only a significant association with the CTRP3 level in the PDR group. CONCLUSION: The significant association of HIF-1α rs11549465 other than VEGF rs3025039 with the initiation of NPDR in T2DM Egyptian patients might protect them from progression to the proliferative stage via elevating circulating HIF-1α. However, this protective role was not enough to prevent the development of NPDR because of enhancing angiogenesis and inflammation together with suppressing anti-inflammation. The non-significant association of HIF-1α rs11549465 with PDR among T2DM patients could not make this variant a risk factor for PDR progression.

Circulating microRNAs panel as a diagnostic tool for discrimination of HCV-associated hepatocellular carcinoma.

Early diagnosis of hepatocellular carcinoma (HCC) can significantly improve the overall survival of HCC patients. However, current diagnostic markers are compromised and limited by their low sensitivity and specificity. In this work, circulating microRNAs (miRs) were utilized as a diagnostic tool to test their efficiency to segregate HCC and hepatitis C virus (HCV)-infected patients from healthy subjects. Nine HCC-related miRs (miR-21, miR-30c, miR-93, miR-122, miR-125b, miR-126, miR-130a, miR-193b and miR-222) were analyzed by Real-Time PCR in 86 serum samples; 34 HCC and 52 HCV patients in addition to 25 healthy subjects. The sensitivity and specificity of these miRs were assessed. Our results demonstrated that the median serum level of seven miRs was significantly reduced (P ranges from <0.01 to<0.001) in HCC patients whereas nine miRs were reduced (P<0.001) in HCV compared to healthy controls. Receiver operating characteristic (ROC) curve analyses had shown high diagnostic accuracy (AUC=1.0) when seven and nine combined miRs were considered in HCC and HCV groups, respectively compared to their counterparts. However, a combination of differentially expressed miRs did not improve the discriminatory power (AUC=0.742) when HCC compared to non-HCC groups. miR-122 showed the highest sensitivity and specificity to stratify HCC and HCV versus normal individuals and HCC versus HCV patients. We conclude that differentially expressed miRs in the serum of HCV and HCC patients can be utilized as surrogate and non-invasive biomarker for segregation of HCV and HCC patients from healthy subjects.