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3-Nitropropionic acid (3-NP)-induced neurotoxicity is an experimental model which mimics the pathology and motor abnormalities seen in Huntington's disease (HD) in human. The present investigation was directed to estimate the role of rho kinase (ROCK) inhibition in the possible protective effect of fasudil and simvastatin in 3-NP-induced striatal neurodegeneration in rats. Animals were injected s.c. with 3-NP (20 mg/kg/day) for 1 week with or without administration of fasudil (10 mg/kg/day, p.o.) or simvastatin (20 mg/kg/day, p.o.). At the end of experiment, motor and behavioral abnormalities were evaluated. Animals were then sacrificed for measurement of mitochondrial membrane potential as well as succinate dehydrogenase (SDH) and caspase-3 activities in striatum. Moreover, tumor necrosis factor-alpha (TNF-α) level and protein expressions of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), ROCK, phosphorylated-Akt (p-Akt), endothelial and inducible nitric oxide synthase (eNOS and iNOS), Bax, and Bcl-2 were estimated. Finally, histological changes as demonstrated by striatum injury score, glial activation, and percentage of altered mitochondria were assessed. Both fasudil and simvastatin effectively inhibited 3-NP-induced behavioral, biochemical, and histological changes through inhibition of ROCK activity. However, fasudil provided more amelioration in histological changes, mitochondrial membrane potential and SDH activity in addition to p-Akt and PGC-1α protein expressions. The present study highlights a significant role of ROCK/p-Akt/eNOS pathway in the protective effects of fasudil and simvastatin on neurotoxicity and mitochondrial dysfunction induced by 3-NP in rats. Thus, specific inhibition of ROCK may be considered a promising new approach in the management of HD.

Although Tamoxifen (TAM) is one of the most widely used drugs in managing breast cancer, many women still relapse after long-term therapy. Caffeic acid phenethyl ester (CAPE) is a polyphenolic compound present in many medicinal plants and in propolis. The present study examined the effect of CAPE on TAM cytotoxicity in MCF-7 cells. MCF-7 cells were treated with different concentrations of TAM and/or CAPE for 48 h. This novel combination exerted synergistic cytotoxic effects against MCF-7 cells via induction of apoptotic machinery with activation of caspases and DNA fragmentation, along with downregulation of Bcl-2 and Beclin 1 expression levels. However, the mammalian microtubule-associated protein light chain LC 3-II level was unchanged. Vascular endothelial growth factor level was also decreased, whereas levels of glutathione and nitric oxide were increased. In conclusion, CAPE augmented TAM cytotoxicity via multiple mechanisms, providing a novel therapeutic approach for breast cancer treatment that can overcome resistance and lower toxicity. This effect provides a rationale for further investigation of this combination.

Autosomal recessive primary microcephaly (MCPH) is an abnormal proliferation of neurons during brain development that leads to a small brain size but architecturally normal in most instances. Mutations in the ASPM gene have been identified to be the most prevalent. Thirty-seven patients from 30 unrelated families with a clinical diagnosis of MCPH were enrolled in this study. Screening of ASPM gene mutations was performed by targeted linkage analysis followed by direct sequencing. Thirteen protein truncating mutations of the ASPM were identified in 15 families (50%), eight of which were novel mutations. The mutations detected were eight nonsense, four frameshift, and one splice site. Two of these mutations (p.R1327* and p.R3181*) were recurrent and shared similar haplotypes suggesting founder effect. Patients with ASPM mutations had mild to severe intellectual disability and variable degrees of simplified gyral pattern and small frontal lobe. In addition, hypoplasia of corpus callosum (18 patients), mildly small cerebellar vermis (10 patients), and relatively small pons (13 patients) were found in 85.7%, 47.6%, and 61.9%, respectively. Furthermore, one patient had porencephaly and another had a small midline cyst. Epilepsy was documented in two patients (9.5%). Non-neurologic abnormalities consisted of growth retardation (four patients), and co-incidental association of oculo-cutaneous albinism (one patient). Our study expands the mutation spectrum of ASPM. Moreover, the simplified gyral pattern and small frontal lobe together with hypoplastic corpus callosum, small cerebellum and pons enable ASPM mutated patients to be distinguished. © 2016 Wiley Periodicals, Inc.

Nonalcoholic fatty liver disease (NAFLD) is a metabolic-related disorder ranging from steatosis to steatohepatitis, which may progress to cirrhosis and hepatocellular carcinoma (HCC). This study aimed at assessing the regulatory and protective role of miR-26a on lipid metabolism and progression of NAFLD in human HepG2 cells loaded with free fatty acids (FFA). Lentivirus expressing miR-26a or negative control miR was used to transduce HepG2 cells and to establish stable cell lines. Gain or loss of function using an miR-26a inhibitor was used to compare triglyceride content (TG), total cholesterol level (CL), total antioxidant capacity (TAC), malondialdehyde (MDA) and the level of apoptosis. In addition, quantitative reverse transcription polymerase chain reaction (qPCR) was used to assess the mRNA levels of lipogenesis, TG synthesis, storage genes, inflammatory and fibrogenic markers, and autophagic besides endoplasmic reticulum (ER) stress markers after gaining or losing the function of miR-26a. miR-26a levels decreased in response to FFA in human HepG2 cells. After the establishment of a stable cell line, the upregulation of miR-26a resulted in the downregulation of TG, CL, and MDA levels, through regulating mRNA levels of genes involved in lipid homeostasis, ER stress marker, inflammatory and fibrogenic markers. Nevertheless, there was a marked increment in the mRNA expression of autophagic marker genes. Moreover, miR-26a overexpression protects the cells from apoptosis, whereas inhibition of miR-26a, using an anti-miR-26a oligonucleotide, decreased the expression of miR-26a which potentially contributes to altered lipid metabolism in HepG2 cells loaded with FFA. In conclusion, these findings suggested that miR-26a has a crucial role in regulating fatty acid and cholesterol homeostasis in HepG2 cells, along with the offered protection against the progression of NAFLD in vitro. Hence, miRNAs could receive growing attention as useful noninvasive diagnostic markers to follow the progression of NAFLD and to identify novel therapeutic targets.

This study investigated the effect of curcumin against diethylnitrosamine (DEN)‐induced hepatocarcinogenesis. Rats were divided into three groups. The first group served as a control. The second group received DEN (orally, 20 mg/kg) five times a week for 8 weeks, followed by 10 mg/kg for another 7 weeks. The third group was supplemented with 2% curcumin diet simultaneously with DEN. The results showed normalization of serum level of total antioxidant capacity, γ‐glutamyl transferase and aminotransferase activities along with deoxyribonucleic acid, ribonucleic acid and malondialdehyde levels, glutathione reductase and glutathione peroxidase activities in the liver of curcumin group. Significant decreases in the elevated level of glutathione, glutathione‐S‐transferase and glucose‐6‐P dehydrogenase activities were observed. Serum alkaline phosphatase activity and the relative liver weight were not significantly altered. Concomitantly, the histopathological damage was attenuated by curcumin. In conclusion, curcumin exerted a potential chemopreventive effect in DEN‐induced hepatocarcinogenesis. PRACTICAL APPLICATIONS Various therapeutic effects, such as anti‐inflammatory, anti‐cancer, anti‐angiogenic and wound‐healing effects, have been described for curcumin. The present study is an endeavor in the direction of determining its possible mechanism of protection in diethylnitrosamine‐induced hepatocarcinogenesis in rats. Our study proved that curcumin exhibits a hepatoprotective potential, and hence, it can be used as value‐added agents to limit both exposure to and the adverse health effects from dietary hepatocarcinogens.