Cerebrovascular ETB, 5-HT1B, and AT1 receptor upregulation correlates with reduction in regional CBF after subarachnoid hemorrhage

We hypothesize that cerebral ischemia leads to enhanced expression of endothelin (ET), 5-hydroxytryptamine (5-HT), and angiotensin II (ANG II) receptors in the vascular smooth muscle cells. Our aim is to correlate the upregulation of cerebrovascular receptors and the underlying molecular mechanisms with the reduction in regional and global cerebral blood flow (CBF) after subarachnoid hemorrhage (SAH). SAH was induced by injecting 250 microl blood into the prechiasmatic cistern in rats. The cerebral arteries were removed 0, 1, 3, 6, 12, 24, and 48 h after the SAH for functional and molecular studies. The contractile responses to ET-1, 5-carboxamidotryptamine (5-CT), and ANG II were investigated with myograph. The receptor mRNA and protein levels were analyzed by quantitative real-time PCR and immunohistochemistry, respectively. In addition, regional and global CBFs were measured by an autoradiographic method. As a result, SAH resulted in enhanced contractions to ET-1 and 5-CT. ANG II [via ANG II type 1 (AT(1)) receptors] induced increased contractile responses [in the presence of the ANG II type 2 (AT(2)) receptor antagonist PD-123319]. In parallel the ET(B), 5-HT(1B), and AT(1) receptor, mRNA and protein levels were elevated by time. The regional and global CBF showed a successive reduction with time after SAH. In conclusion, the results demonstrate for the first time that SAH induces the upregulation of ET(B), 5-HT(1B), and AT(1) receptors in a time-dependent manner both at functional, mRNA, and protein levels. These changes occur in parallel with a successive decrease in CBF. Thus there is a temporal correlation between the changes in receptor expression and CBF reduction, suggesting a linkage.     

A non-toxic Hsp90 inhibitor protects neurons from Abeta-induced toxicity

The molecular chaperones have been implicated in numerous neurodegenerative disorders in which the defining pathology is misfolded proteins and the accumulation of protein aggregates. In Alzheimer's disease, hyperphosphorylation of tau protein results in its dissociation from microtubules and the formation of pathogenic aggregates. An inverse relationship was demonstrated between Hsp90/Hsp70 levels and aggregated tau, suggesting that Hsp90 inhibitors that upregulate these chaperones could provide neuroprotection. We recently identified a small molecule novobiocin analogue, A4 that induces Hsp90 overexpression at low nanomolar concentrations and sought to test its neuroprotective properties. A4 protected neurons against Abeta-induced toxicity at low nanomolar concentrations that paralleled its ability to upregulate Hsp70 expression. A4 exhibited no cytotoxicity in neuronal cells at the highest concentration tested, 10 microM, thus providing a large therapeutic window for neuroprotection. In addition, A4 was transported across BMECs in vitro, suggesting the compound may permeate the blood-brain barrier in vivo. Taken together, these data establish A4, a C-terminal inhibitor of Hsp90, as a potent lead for the development of a novel class of compounds to treat Alzheimer's disease.     

Association analysis of the common varieties of IL17A and IL17F genes with the risk of knee osteoarthritis

Osteoarthritis is mediated by various types of cytokines, growth factors, and inflammatory factors that the role of the interleukin-17 family in this disease is becoming increasingly apparent. The aim of this study is to determine the association between the common polymorphisms of IL17A (including rs2275913) and IL17F (including rs2397084 and rs763780) genes with the knee osteoarthritis risk which was followed by a bioinformatics approach. In a case-control study, 254 participants consisting of 127 healthy individuals and 127 subjects with knee osteoarthritis referring to Shahid Beheshti Hospital dependents on Kashan University of Medical Sciences (Kashan, Iran) were enrolled. After samples collection, the polymorphisms genotyping was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Finally, some bioinformatics tools were used to analyze the molecular effects of the three studied polymorphisms. Data analysis showed a significant association between rs2275913-GA genotype and the decreased risk of knee osteoarthritis (OR = 0.57, 95% CI = 0.33-0.97, P = .040). However, rs763780-AG genotype (OR = 2.29, 95%CI = 1.11-4.69, P = .024) and rs763780-G allele (OR = 2.01, 95% CI = 1.09-3.72, P = .026) were associated with an increased risk of knee osteoarthritis. However, no significant associations were found between the rs2397084 polymorphism and knee osteoarthritis risk. Our structural analysis revealed that the rs2275913 polymorphism could create a new binding site for TFII-I at the promoter region of IL17A. Also, rs2397084 and rs763780 could significantly affect the function and structure of IL17A. Based on our findings, rs2275913 and rs763780 could be considered as protective and risk factors for knee osteoarthritis, respectively. Therefore, these polymorphisms can be considered as biomarkers for the screening of knee osteoarthritis susceptible persons.     

Comparative analysis of the gut microbiota of sand fly vectors of zoonotic visceral leishmaniasis (ZVL) in Iran; host-environment interplay shapes diversity

The development of Leishmania parasites within sand fly vectors occurs entirely in the insect gut lumen, in the presence of symbiotic and commensal bacteria. The impacts of host species and environment on the gut microbiome are currently poorly understood. We employed MiSeq sequencing of the V3-16S rRNA gene amplicons to characterize and compare the gut microbiota of field-collected populations of Phlebotomus kandelakii, P. perfiliewi, P. alexandri, and P. major, the primary or secondary vectors of zoonotic visceral leishmaniasis (ZVL) in three distinct regions of Iran where ZVL is endemic. In total, 160,550 quality-filtered reads of the V3 region yielded a total of 72 operational taxonomic units (OTUs), belonging to 23 phyla, 47 classes, 91 orders, 131 families, and 335 genera. More than 50% of the bacteria identified were Proteobacteria, followed by Firmicutes (22%), Deinococcus-Thermus (9%), Actinobacteria (6%), and Bacteroidetes (5%). The core microbiome was dominated by eight genera: Acinetobacter, Streptococcus, Enterococcus, Staphylococcus, Bacillus, Propionibacterium, Kocuria, and Corynebacterium. Wolbachia were found in P. alexandri and P. perfiliewi, while Asaia sp. was reported in P. perfiliewi. Substantial variations in the gut bacterial composition were found between geographically distinct populations of the same sand fly species, as well as between different species at the same location, suggesting that sand fly gut microbiota is shaped by both the host species and geographical location. Phlebotomus kandelakii and P. perfiliewi in the northwest, and P. alexandri in the south, the major ZVL vectors, harbor the highest bacterial diversity, suggesting a possible relationship between microbiome diversity and the capacity for parasite transmission. In addition, large numbers of gram-positive human or animal pathogens were found, suggesting that sand fly vectors of ZVL could pose a potential additional threat to livestock and humans in the region studied. The presence of Bacillus subtilis, Enterobacter cloacae, and Asaia sp suggests that these bacteria could be promising candidates for a paratransgenesis approach to the fight against Leishmaniasis.     

Common gene polymorphism in ATP-binding cassette transporter A1 and coronary artery disease: A genetic association study and a structural analysis

ATP-binding cassette transporter A1 (ABCA1) has a crucial role in removing intracellular cholesterol and plays a protective role against atherosclerosis. Therefore, genetic polymorphisms in this gene may alter the susceptibility to coronary artery disease (CAD). This study was aimed to examine the association of rs2230806 (c.1051 G > A; p.R219K) variation in the ABCA1 gene with CAD in a case-control design which was followed by a meta-analysis and in silico approach. In the case-control study, 300 subjects including 150 individuals with CAD and 150 healthy controls were recruited. The c.1051 G > A genotyping was done by polymerase chain reaction-restriction fragment length polymorphism method. In the meta-analysis, eligible studies were collected from PubMed, Google Scholar, and ScienceDirect databases and pooled odds ratio, heterogeneity, publication bias, and sensitivity analyses were carried. Finally, some bioinformatics tools were employed to assess the impacts of p.R219K variation on ABCA1 protein structure. Our case-control examination showed a statistically significant association between c.1051 G > A genetic polymorphism and CAD risk. In addition, the meta-analysis showed reliable significant associations between c.1051 G > A transition and risk of CAD in the Caucasian population. In silico analysis showed that the p.R219K substitution could alter the secondary structure, hydrophobicity pattern, and Ramachandran plot of ABCA1. These findings elucidate that the c.1051 G > A variation could be a genetic risk factor for CAD and it could be considered as a prognostic and predictive biomarker for susceptible individuals.     

New melampolide sesquiterpene lactones from Melampodium leucanthum

The isolation of five germacranolide sesquiterpene lactones from Melampodium leucanthum Torrey and Gray (Compositae-Heliantheae) is reported. The structures of three new melampolides, melampodin-A acetate, leucanthin-A and leucanthin-B, have been determined by spectral methods and chemical correlations.     

MicroRNAs in breast cancer: Roles,functions, and mechanism of actions

Breast cancer is one of the most lethal malignancies in women in the world. Various factors are involved in the development and promotion of the malignancy; most of them involve changes in the expression of certain genes, such as microRNAs (miRNAs). MiRNAs can regulate signaling pathways negatively or positively, thereby affecting tumorigenesis and various aspects of cancer progression, particularly breast cancer. Besides, accumulating data demonstrated that miRNAs are a novel tool for prognosis and diagnosis of breast cancer patients. Herein, we will review the roles of these RNA molecules in several important signaling pathways, such as transforming growth factor, Wnt, Notch, nuclear factor-κ B, phosphoinositide-3-kinase/Akt, and extracellular-signal-regulated kinase/mitogen activated protein kinase signaling pathways in breast cancer.     

A molecular dynamics simulation on the effect of different parameters on thermal resistance of graphene-argon interface

Molecular dynamics simulations of argon molecules confined between two parallel graphene sheets are carried out to investigate the parameters affecting heat transfer and thermal properties. These parameters include wall–fluid interaction strength, fluid density and wall temperature. For constant wall temperature simulations, we show that the first two parameters have influence on near-wall fluid density. As a result, the heat transfer at wall–fluid interfaces and thus through argon molecules across the domain will change. Also, we demonstrate that variations in wall temperature rarely affects the density profiles of argon molecules next to the walls. Therefore, in these cases, the variations in thermal resistance at the interface is most dominantly due to wall temperature itself. To analyse the results, the density and temperature profiles and also other parameters including heat flux and temperature gradient of bulk of argon molecules, Kapitza length and argon thermal conductivity are considered. The Kapitza length describes thermal resistance at liquid–solid interface. According to the results, increasing wall–fluid interaction strength leads to greater molecular aggregation of argon molecules near the walls and, consequently, decreasing the Kapitza length. Furthermore, higher fluid density leads to greater thermal resistance at wall–fluid interactions and therefore greater temperature jumps are observed in temperature profiles.