Foxtherkelsen7122

AIMS To investigate the impact of microRNA target SNPs (mirSNPs) and their interaction with miRNAs on important drug-metabolizing enzymes, transporters and target genes for prediction of clopidogrel drug response in cardiovascular disease individuals. MAIN METHODS A prospective cross-sectional study was conducted on 292 individuals undergoing clopidogrel drug therapy. All the enrolled participants were administered 300 mg loading dose followed by 75 mg dose of maintenance therapy. Platelet aggregations were measured before administration of the loading dose and 2 h post fifth day dose of clopidogrel maintenance therapy. Clopidogrel carboxylic acid metabolite from plasma and urine were analyzed post maintenance therapy using the RP-HPLC method. Genotyping of mirSNP's shortlisted through in silico analysis was performed by tetra ARMS PCR and validated by Sanger DNA sequencing. The levels of selected miRNAs were estimated by the TaqMan-PCR assay. Functional validation of mirSNPs was performed in HepG2 cells after transfecting with the selected gene and miRNA mimics. Protein expressions were analyzed by western blot. KEY FINDINGS 23% of enrolled individuals showed resistance to clopidogrel therapy. Out of 13 mirSNP's analyzed, CYP2C19 rs4244285 was associated with clopidogrel drug resistance and clopidogrel carboxylic acid metabolite in urine and plasma. JAK/stat pathway hsa-miR-1343-3p and hsa-miR-6783-3p levels were significantly high in individuals with CYP2C19 rs4244285 mutant genotype and these miRNAs down-regulated the protein expression of CYP2C19. SIGNIFICANCE We demonstrated the role of coding mirSNP (rs4244285) in the regulation of the CYP2C19 gene through miRNAs and its implications to clopidogrel drug response prediction in the Indian population. AIMS Inhibition of P53-MDM2/X interaction is known as an effective cancer therapy strategy. In this regard, pDI peptide was introduced previously with the potential of targeting MDM2. In this research, the large-scale peptide mutation screening was used to achieve the best sequence of pDI with the highest affinity for inhibition activity against MDM2/X. MAIN METHODS Three mutant peptides of pDI as dual inhibitor peptides including single mutations of pDIm/4W, pDIm/11M and double mutations of pDIdm/4W11M were presented with the high affinities to inhibit both MDM2/X. The selected mutants were then evaluated comprehensively to confirm their ability as potent MDM2/X inhibitors, using a theoretical simulation approach. KEY FINDINGS MD simulations analyses confirmed their dual inhibition potential against both MDM2/X interactions with p53 protein. The developed pDIm and mainly pDIdm peptides showed stable conformations over the simulation time with conserved secondary structure and effective interaction with MDM2/X by physical binding such as hydrogen bonding. Besides, umbrella sampling free energy calculation indicated higher binding energy, ΔGbinding, of pDIm-MDM2/X and pDIdm-MDM2/X compared to pDI-MDM2/X. SIGNIFICANCE The optimized and improved mutant pDI, pDIdm, with more effective ΔGbinding values of -30 and -25 kcal/mol to MDMX and MDM2, respectively, is recommended as a promising anticancer agent and suitable candidate for experimental evaluations. The isoquinoline 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) has been studied due to its multitarget properties, such as modulation of GABAergic and glutamatergic systems, antioxidant, and anti-inflammatory. This study investigated the contribution of oxidative stress, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase (HO-1) signaling, and the cholinergic system to the anti-amnesic action of FDPI in mice. Adult male Swiss mice received FDPI for 5 days (5-25 mg/kg, i.g.); the animals received scopolamine (1 mg/kg, i.p) from day 3-5. The vehicle-control group was carried out. Afterward, mice performed object recognition tests (ORTs). Scopolamine induced amnesia and cholinergic dysfunction by increasing the acetylcholinesterase (AChE) activity and content, decreasing the muscarinic M1 receptor levels in the prefrontal cortex and hippocampus of mice. This study reveals that scopolamine altered oxidative stress parameters differently in the prefrontal cortex and hippocampus of mice. Whereas the prefrontal cortex was susceptible to oxidative stress, none of the parameters evaluated was altered in the hippocampus of scopolamine-treated mice. FDPI at doses of 10 and 25 mg/kg had an anti-amnesic effect in the ORT tests. FDPI 10 mg/kg reversed the increase in the AChE activity and content, oxidative stress parameters, and modulated Nrf2/HO-1 signaling in the prefrontal cortex of scopolamine-exposed mice. Pearson's correlation analyses reinforced the contribution of the prefrontal cortical cholinergic system, oxidative stress as well as Nrf2/HO-1 signaling in the anti-amnesic effect of FDPI. Considering FDPI effects on the hippocampus, it was effective against the cholinergic dysfunction, AChE activity and content, and M1 receptor levels, which collectively could contribute to its anti-amnesic effect. Endocrine therapies (e.g. tamoxifen and aromatase inhibitors) targeting estrogen action are effective in decreasing mortality of breast cancer. However, their efficacy is limited by intrinsic and acquired resistance. Our previous study demonstrated that overexpression of a histone methyltransferase NSD2 drives tamoxifen resistance in breast cancer cells and that NSD2 is a potential biomarker of tamoxifen resistant breast cancer. Here, we found that DZNep, an indirect inhibitor of histone methyltransferases, potently induces the degradation of NSD2 protein and inhibits the expression of NSD2 target genes (HK2, G6PD, GLUT1 and TIGAR) involved in the pentose phosphate pathway (PPP). DZNep treatment of tamoxifen-resistant breast cancer cells and xenograft tumors also strongly inhibits tumor growth and the cancer cell survival through decreasing cell production of NADPH and glutathione (GSH) and invoking elevated ROS to cause apoptosis. These findings suggest that DZNep-like agents can be developed to target NSD2 histone methyltransferase for effective treatment of tamoxifen-resistant breast cancer. Sex-based differences in human disease are caused in part by the levels of endogenous sex steroid hormones which regulate mitochondrial metabolism. This review updates a previous review on how estrogens regulate metabolism and mitochondrial function that was published in 2017. Estrogens are produced by ovaries and adrenals, and in lesser amounts by adipose, breast stromal, and brain tissues. At the cellular level, the mechanisms by which estrogens regulate diverse cellular functions including reproduction and behavior is by binding to estrogen receptors α, β (ERα and ERβ) and G-protein coupled ER (GPER1). link2 ERα and ERβ are transcription factors that bind genomic and mitochondrial DNA to regulate gene transcription. A small proportion of ERα and ERβ interact with plasma membrane-associated signaling proteins to activate intracellular signaling cascades that ultimately alter transcriptional responses, including mitochondrial morphology and function. Although the mechanisms and targets by which estrogens act directly and indirectly to regulate mitochondrial function are not fully elucidated, it is clear that estradiol regulates mitochondrial metabolism and morphology via nuclear and mitochondrial-mediated events, including stimulation of nuclear respiratory factor-1 (NRF-1) transcription that will be reviewed here. NRF-1 is a transcription factor that interacts with coactivators including peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) to regulate nuclear-encoded mitochondrial genes. One NRF-1 target is TFAM that binds mtDNA to regulate its transcription. Nuclear-encoded miRNA and lncRNA regulate mtDNA-encoded and nuclear-encoded transcripts that regulate mitochondrial function, thus acting as anterograde signals. Other estrogen-regulated mitochondrial activities including bioenergetics, oxygen consumption rate (OCR), and extracellular acidification (ECAR), are reviewed. V.OBJECTIVE To advance our understanding of poststroke fatigue by investigating its momentary and time-lagged relationship with daily activities. DESIGN Longitudinal observational study using the experience sampling method (ESM). SETTING Outpatient rehabilitation care. PARTICIPANTS Thirty individuals with stroke (N=30). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES ESM is a structured diary method that allows assessing real-time symptoms, behavior, and environment characteristics in the flow of daily life, thereby capturing moment-to-moment variations in fatigue and related factors. Using a mobile application, individuals with stroke were followed during 6 consecutive days, and were prompted at 10 random moments daily to fill in a digital questionnaire about their momentary fatigue and current activity type of activity, perceived effort and enjoyment, and physical activity levels. RESULTS Based on all completed digital questionnaires (N=1013), multilevel regression analyses showed that fatigue was significantly associated with type of activity and that fatigue was higher when participants had engaged in physical activity. Fatigue was also higher during activities perceived as more effortful and during less enjoyable activities. Time-lagged analyses showed that fatigue was also predicted by physical activity and perceived effort earlier during the day. Importantly, the relationship between these daily activity characteristics and fatigue differed substantially across individuals. CONCLUSIONS This study illustrates the need for ESM to design personalized rehabilitation programs and to capture fatigue and other patient-reported outcomes in daily life. OBJECTIVE To conduct a scoping review on classifications of mild stroke based on stroke severity assessments and/or clinical signs and symptoms reported in the literature. DATA SOURCES Electronic searches of PubMed, PsycINFO (Ovid), and Cumulative Index to Nursing and Allied Health (CINAHL-EBSCO) databases included keyword combinations of mild stroke, minor stroke, mini stroke, mild cerebrovascular, minor cerebrovascular, transient ischemic attack, or TIA. STUDY SELECTION Inclusion criteria were limited to articles published between January 2003 and February 2018. Inclusion criteria included studies (1) with a definition of either mild or minor stroke, (2) written in English, and (3) with participants aged 18 years and older. Animal studies, reviews, dissertations, blogs, editorials, commentaries, case reports, newsletters, drug trials, and presentation abstracts were excluded. DATA EXTRACTION Five reviewers independently screened titles and abstracts for inclusion and exclusion criteria. Two reviewers indepeirectly affects treatment receipt, referral for services, and health service delivery. link3 OBJECTIVES To compare the quality of randomized controlled trials (RCTs) published in predatory and nonpredatory journals in the field of physical therapy. DATA SOURCES From a list of 18 journals included either on Beall's list (n=9) or in the Directory of Open Access Journals (DOAJ) (n=9), 2 independent assessors extracted all the RCTs published between 2014 and 2017. When journals published more than 40 RCTs, a sample of 40 trials was randomly extracted, preserving the proportions among years. Indexing in PubMed, country of journal publication, and dates of submission or acceptance were also recorded for each journal. MAIN OUTCOME MEASURES The PEDro (Physiotherapy Evidence Database) scale and duration of the peer review. RESULTS Four hundred ten RCTs were included. The mean PEDro score of articles published in non-Beall, DOAJ journals was higher than those published in Beall journals (mean score ± SD, 5.8±1.7 vs 4.5±1.5; P less then .001), with the differences increasing when the indexing in PubMed was also considered (6.