Lipoic acid inhibits cognitive impairment induced by multiple cell phones in young male rats: role of Sirt1 and Atg7 pathway.

The utilization of digital technology has grown rapidly in the past three decades. With this rapid increase, cell phones emit electromagnetic radiation; that is why electromagnetic field (EMF) has become a substantial new pollution source in modern civilization, mainly having adverse effects on the brain. While such a topic attracted many researchers' scopes, there are still minimal discoveries made regarding chronic exposure to EMF. The extensive use of cell phones may affect children's cognition even indirectly if parents and guardians used their phones repeatedly near them. This study aims to investigate possible lipoic acid (LA) effects on cognitive functions and hippocampal structure in young male rats exposed to electromagnetic fields (EMF) emitted from multiple cell phones. Forty young male Wistar rats were randomly allocated into three groups: control, multiple cell phones-exposed and lipoic acid-treated rats. By the end of the experimental period, the Morris water maze was used as a cognitive test. The rats were sacrificed for the collection of serum and hippocampal tissue. These serum samples were then utilized for assessment of Liver function tests. The level ofglutamate, acetylcholine (Ach) and malondialdehyde (MDA) was estimated, in addition to evaluating the expression of autophagy-related protein-7 (Atg7) and Sirt1 genes. The left hippocampal specimens were used for histopathological studies. Results showed that multiple cell phone-exposed rats exhibited shorter latency time to reach the platform by the fifth day of training; additionally, there was a reduction in consolidation of spatial long-term memory. Correspondingly, there was an elevation of hippocampal Ach, glutamate, and MDA levels; accompanied by up-regulation of hippocampal Sirt1 and Atg7 gene expression. Compared to the EMF-exposed group, LA administration improved both learning and memory, this was proved by the significant decline in hippocampal MDA and Ach levels, the higher hippocampal glutamate, the downregulated hippocampal Sirt1 gene expression and the upregulated Atg7 gene expression. In conclusion, EMF exposure could enhance learning ability; however, it interfered with long-term memory consolidation shown by higher hippocampal Ach levels. Lipoic acid treatment improved both learning and memory by enhancing autophagy and hippocampal glutamate level and by the reduced Ach levels and Sirt1 gene expression.

Memantine/Aripiprazole Combination Alleviates Cognitive Dysfunction in Valproic Acid Rat Model of Autism: Hippocampal CREB/BDNF Signaling and Glutamate Homeostasis.

Significant efforts are increasingly directed towards identifying novel therapeutic targets for autism spectrum disorder (ASD) with a rising role of aberrant glutamatergic transmission in the pathogenesis of ASD-associated cellular and behavioral deficits. This study aimed at investigating the role of chronic memantine (20 mg/kg/day) and aripiprazole (3 mg/kg/day) combination therapy in the management of prenatal sodium valproate (VPA)-induced autistic-like/cognitive deficits in male Wistar rats. Pregnant female rats received a single intraperitoneal injection of VPA (600 mg/kg) to induce autistic-like behaviors in their offspring. Prenatal VPA induced autistic-like symptoms (decreased social interaction and the appearance of stereotyped behavior) with deficits in spatial learning (in Morris water maze) and cognitive flexibility (in the attentional set-shifting task) in addition to decreased hippocampal protein levels of phosphorylated cAMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and gene expression of glutamate transporter-1 (Glt-1) with a decline in GABA/glutamate ratio (both measured by HPLC). These were accompanied by the appearance of numerous neurofibrillary tangles (NFTs) with enhanced apoptosis in hippocampal sections. Memantine/aripiprazole combination increased the protein levels of p-CREB, BDNF, and Glt-1 gene expression with restoration of GABA/glutamate balance, attenuation of VPA-induced neurodegenerative changes and autistic-like symptoms, and improvement of cognitive performance. This study draws attention to the favorable cognitive effects of memantine/aripiprazole combination in autistic subjects which could be mediated via enhancing CREB/BDNF signaling with increased expression of astrocytic Glt-1 and restoration of GABA/glutamate balance, leading to inhibition of hippocampal NFTs formation and neuronal apoptosis.

Hepatoprotective Role of Carvedilol against Ischemic Hepatitis Associated with Acute Heart Failure via Targeting miRNA-17 and Mitochondrial Dynamics-Related Proteins: An In Vivo and In Silico Study.

Acute heart failure (AHF) is one of the most common diseases in old age that can lead to mortality. Systemic hypoperfusion is associated with hepatic ischemia-reperfusion injury, which may be irreversible. Ischemic hepatitis due to AHF has been linked to the pathogenesis of liver damage. In the present study, we extensively investigated the role of mitochondrial dynamics-related proteins and their epigenetic regulation in ischemic liver injury following AHF and explored the possible hepatoprotective role of carvedilol. The biochemical analysis revealed that the ischemic liver injury following AHF significantly elevated the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) enzymes, the level of total and direct bilirubin, and the expression of hepatic mitogen-activated protein kinase (MAPK), dynamin-1-like protein (DNM1L), and hepatic miRNA-17. At the same time, it significantly reduced the serum albumin level, the activity of hepatic superoxide dismutase (SOD), and the expression of mitochondrial peroxisome proliferator-activated receptor-1α (PGC-1α), and mitofusin 2 (Mtf2). The histological examination of the liver tissue revealed degenerated hepatocytes. Interestingly, administration of carvedilol either prior to or after isoprenaline-induced AHF significantly improved the liver function and reversed the deterioration effect of AHF-induced ischemic hepatitis, as demonstrated by biochemical, immunohistochemical, and histological analysis. Our results indicated that the hepatoprotective effect of carvedilol in ameliorating hepatic ischemic damage could be attributed to its ability to target the mitochondrial dynamics-related proteins (Mtf2, DNM1L and PGC-1α), but also their epigenetic regulator miRNA-17. To further explore the mode of action of carvedilol, we have investigated, in silico, the ability of carvedilol to target dynamin-1-like protein and mitochondrial dynamics protein (MID51). Our results revealed that carvedilol has a high binding affinity (-14.83 kcal/mol) toward the binding pocket of DNM1L protein. In conclusion, our study highlights the hepatoprotective pharmacological application of carvedilol to attenuate ischemic hepatitis associated with AHF.

N-acetylcysteine (NAC) alleviates the peripheral neuropathy associated with liver cirrhosis via modulation of neural MEG3/PAR2/ NF-Ò¡B axis.

BACKGROUND AND AIM: Oxidative stress (OS) is accused in pathogenesis of many diseases, including liver cirrhosis by many mechanisms. One of them is the disturbance of long non coding maternally expressed 3 (MEG3)/protease activated receptor 2 (PAR2) downstream pathway. We aimed to investigate the role of this axis in cirrhotic neuropathy and whether an antioxidant compound such as N-acetylcysteine (NAC) could improve the peripheral nerve function through repression of MEG3/PAR2. METHODS: Thirty Wistar rats were used and divided into 5 groups; naive, thiacetamide (TAA) (200 mg/kg 3 times/week. i.p. for 8 weeks) and TAA+NAC (50 or 100 or 200 mg/kg/day) groups. Von Frey (VF) test for mechanical nociceptive responses, hepatic& neural MEG3, NF-Ò¡B and neural PAR2 expression by PCR, histological studies for liver and sciatic nerve together with the dorsopedal skin thickness were done. RESULTS: TAA induced significant decrease in liver function, negative VF test, an increase in the expression of hepatic& neural MEG3, NF-Ò¡B and neural PAR2. The histological studies showed cirrhotic changes with atrophy of the sciatic nerve and the dorsal skin. NAC improved the liver function together with reversal of the neural: functional, biochemical and histological changes in a dose dependent manner. CONCLUSIONS: NAC could improve the peripheral neuropathy in cirrhotic rat through suppression of MEG3/PAR2 expression.

Evaluation of the diagnostic and therapeutic roles of non-coding RNA and cell proliferation related gene association in hepatocellular carcinoma.

Micro RNA-34a-5p (miR-34a-5p) is an important molecule that can act as a modulator of tumor growth. It controls expression of a plenty of proteins controlling cell cycle, differentiation and apoptosis and opposing processes that favor viability of cancer cells, their metastasis and resistance to chemotherapy. Bioinformatics analysis indicated that minichromosome maintenance protein 2 (MCM2) is a target gene of miR-34a-p. In this study, RT-qPCR was employed to detect the expression of miR-34a-5p and MCM2 in 10 hepatocellular carcinoma (HCC) tissues. The functional role of miR-34a-5p in HCC was investigated and the interaction between miR-34a-5p and MCM2 was explored. Results showed miR-34a-5p expression in HCC tissues was significantly lower than in non HCC liver tissues (P < 0.05), but MCM2 expression in HCC tissues was markedly higher than in non HCC liver tissues (P < 0.05). In addition, miR-34a-5p expression was negatively related to MCM2 expression. To confirm effect of miR-34a-5p on tumor growth and its possible effect on MCM2, miR-34a-5p mimic and inhibitor was transfected into HCC cell lines (HepG2). MTS assay, showed miR-34a-5p over-expression could inhibit the proliferation of HCC cells. RT-qPCR was done to detect the expression of miR-34a-5p and MCM2 in HepG2 cells before and after transfection. Results showed that MCM2 expression in HCC tissues was markedly lower in mimic transfected group than in inhibitor transfected group and control group (P < 0.05) while miR-34a-5p expression in HepG2 cells was significantly higher in mimic transfected group than in inhibitor transfected group and control group (P < 0.05). Thus, miR-34a-5p may inhibit the proliferation of HCC cells via regulating MCM2 expression. These findings provide an evidence for the emerging role of microRNAs as diagnostic markers and therapeutic targets in HCC.