Distinct Subsets of Noncoding RNAs Are Strongly Associated With BMD and Fracture, Studied in Weight-Bearing and Non-Weight-Bearing Human Bone.

We investigated mechanisms resulting in low bone mineral density (BMD) and susceptibility to fracture by comparing noncoding RNAs (ncRNAs) in biopsies of non-weight-bearing (NWB) iliac (n = 84) and weight bearing (WB) femoral (n = 18) postmenopausal bone across BMDs varying from normal (T-score > -1.0) to osteoporotic (T-score ≤ -2.5). Global bone ncRNA concentrations were determined by PCR and microchip analyses. Association with BMD or fracture, adjusted by age and body mass index, were calculated using linear and logistic regression and least absolute shrinkage and selection operator (Lasso) analysis. At 10% false discovery rate (FDR), 75 iliac bone ncRNAs and 94 femoral bone ncRNAs were associated with total hip BMD. Eight of the ncRNAs were common for the two sites, but five of them (miR-484, miR-328-3p, miR-27a-5p, miR-28-3p, and miR-409-3p) correlated positively to BMD in femoral bone, but negatively in iliac bone. Of predicted pathways recognized in bone metabolism, ECM-receptor interaction and proteoglycans in cancer emerged at both sites, whereas fatty acid metabolism and focal adhesion were only identified in iliac bone. Lasso analysis and cross-validations identified sets of nine bone ncRNAs correlating strongly with adjusted total hip BMD in both femoral and iliac bone. Twenty-eight iliac ncRNAs were associated with risk of fracture (FDR < 0.1). The small nucleolar RNAs, RNU44 and RNU48, have a function in stabilization of ribosomal RNAs (rRNAs), and their association with fracture and BMD suggest that aberrant processing of rRNAs may be involved in development of osteoporosis. Cis-eQTL (expressed quantitative trait loci) analysis of the iliac bone biopsies identified two loci associated with microRNAs (miRNAs), one previously identified in a heel-BMD genomewide association study (GWAS). In this comprehensive investigation of the skeletal genetic background in postmenopausal women, we identified functional bone ncRNAs associated to fracture and BMD, representing distinct subsets in WB and NWB skeletal sites. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Mitochondrial biogenesis is altered in HIV+ brains exposed to ART: Implications for therapeutic targeting of astroglia.

The neuropathogenesis of HIV associated neurocognitive disorders (HAND) involves disruption of mitochondrial homeostasis and increased neuroinflammation. However, it is unknown if alterations in mitochondrial biogenesis in the brain underlie the neuropathogenesis of HAND. In this study, neuropathological and molecular analyses of mitochondrial biogenesis and inflammatory pathways were performed in brain specimens from a well-characterized cohort of HIV+ cases that were on antiretroviral regimens. In vitro investigations using primary human astroglia and neurons were used to probe the underlying mechanisms of mitochondrial alterations. In frontal cortices from HAND brains compared to cognitive normal brains, total levels of transcription factors that regulate mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and transcription factor A, mitochondrial (TFAM) were decreased. Immunohistochemical analyses revealed that TFAM was decreased in neurons and increased in astroglia. These changes were accompanied by decreased total mitochondrial DNA per cell and increased levels of messenger RNA for the proinflammatory cytokine interleukin (IL)-1ß. To determine how IL-1ß affects astroglial bioenergetic processes and mitochondrial activity, human astroglial cultures were exposed to recombinant IL-1ß. IL-1ß induced mitochondrial activity within 30 min of treatment, altered mitochondrial related gene expression, altered mitochondrial morphology, enhanced adenoside triphosphate (ATP) utilization and increased the expression of inflammatory cytokines. WIN55,212-2 (WIN), an aminoalkylindole derivative and cannabinoid receptor agonist, blocked IL-1ß-induced bioenergetic fluctuations and inflammatory gene expression in astroglia independent of cannabinoid receptor (CB)1 and peroxisome proliferator-activated receptor (PPAR) γ. A PPARα antagonist reversed the anti-inflammatory effects of WIN in human astroglia. These results show that mitochondrial biogenesis is differentially regulated in neurons and astroglia in HAND brains and that targeting astroglial bioenergetic processes may be a strategy to modulate neuroinflammation.

Air pollution during pregnancy and placental adaptation in the levels of global DNA methylation.

BACKGROUND: Health in early life is crucial for health later in life. Exposure to air pollution during embryonic and early-life development can result in placental epigenetic modification and foetus reprogramming, which can influence disease susceptibility in later life. Objectives: The aim of this paper was to investigate the placental adaptation in the level of global DNA methylation and differential gene expression in the methylation cycle in new-borns exposed to high fine particulate matter in the foetal stage. STUDY DESIGN: This is a nested case-control study. We enrolled pregnant healthy women attending prenatal care clinics in Tehran, Iran, who were residents of selected polluted and unpolluted regions, before the 14th week of pregnancy. We calculated the regional background levels of particle mass- particles with aerodynamics diameter smaller than 2.5 µm (PM2.5) and 10 µm (PM10)-of two regions of interest. At the time of delivery, placental tissue was taken for gene expression and DNA methylation analyses. We also recorded birth outcomes (the new-born's sex, birth date, birth weight and length, head and chest circumference, gestational age, Apgar score, and level of neonatal care required). RESULTS: As regards PM2.5 and PM10 concentrations in different time windows of pregnancy, there were significantly independent positive correlations between PM10 and PM2.5 in the first trimester of all subjects and placental global DNA methylation levels (p-value = 0.01, p-value = 0.03, respectively). The gene expression analysis showed there was significant correlation between S-adenosylmethionine expression and PM2.5 (p = 0.003) and PM10 levels in the first trimester (p = 0.03). CONCLUSION: Our data showed prenatal exposures to air pollutants in the first trimester could influence placental adaptation by DNA methylation.

Lack of TNF-α Gene Polymorphism (rs1799724) Association with Sustained Virological Response in Iranian Patients with Chronic HCV Infection.

Infection with the hepatitis C virus is a major public health concern which can lead to carcinoma and liver failure. It has been shown that single nucleotide polymorphisms can affect the level of gene activity of tumor necrosis factor (TNF) which has an important role, especially in viral infections which can lead to apaptosis of infected hepatocellular cells. We investigated the impact of three possible genotypes for rs1800629 or A/G single nucleotide polymorphism located downstream of TNFα gene promoter in groups of control (n=76) and chronic hepatitis C patients (n=89) focusing on the response to treatment among sensitive and resistant groups. Genomic DNA was extracted from 500 µl prepheral whole blood and PCR and RFLP were used to amplify the region of interest and genotyping. With statistical analyzes a p-value <0.05 was considered meaningful. There was no significant difference in distribution of the possible three genotypes among healthy individuals and patients (P=0.906, OR=1.194, CI=0.063-22.790). However, the frequency of the G allele was higher in patients whereas A allele was more common among healthy individuals (p<0.0001). Further studies with more samples appears to be necessary.

Controlled release of doxorubicin from electrospun PEO/chitosan/graphene oxide nanocomposite nanofibrous scaffolds.

Polyethylene oxide (PEO)/chitosan (CS)/graphene oxide (GO) electrospun nanofibrous scaffolds were successfully developed via electrospinning process for controlled release of doxorubicin (DOX). The SEM analysis of nanofibrous scaffolds with different contents of GO (0.1, 0.2, 0.5 and 0.7wt.%) indicated that the minimum diameter of nanofibers was found to be 85nm for PEO/CS/GO 0.5% nanofibers. The π-π stacking interaction between DOX and GO with fine pores of nanofibrous scaffolds exhibited higher drug loading (98%) and controlled release of the DOX loaded PEO/CS/GO nanofibers. The results of DOX release from nanofibrous scaffolds at pH5.3 and 7.4 indicated strong pH dependence. The hydrogen bonding interaction between GO and DOX could be unstable under acidic conditions which resulted in faster drug release rate in pH5.3. The cell viability results indicated that DOX loaded PEO/CS/GO/DOX nanofibrous scaffold could be used as an alternative source of DOX compared with free DOX to avoid the side effects of free DOX. Thus, the prepared nanofibrous scaffold offers as a novel formulation for treatment of lung cancer.

Comparison between sequentional treatment with diode and alexandrite lasers versus alexandrite laser alone in the treatment of hirsutism.

Laser systems that are commonly used for the treatment of hirsutism include the ruby laser (694 nm), the diode laser (800 nm), the alexandrite laser (755 nm) and the Nd:YAG laser (1084 nm). The diode laser and alexandrite laser are considered effective in treatment of hirsutism in dark-skinned patients. The response of hairs to these laser systems is variable and not complete. In this study, we compared the efficacy of these two laser systems for permanent hair removal. This was a randomized, controlled clinical trial that was performed with women of the age range 15-45 years old. After obtaining informed consent, the samples were randomized into two groups using random allocation software. The first group was treated with alexandrite laser alone (four sessions, two months apart). The second group was treated sequentially with diode laser for the first two sessions and alexandrite laser for the next two sessions. Overall, 111 patients (57 patients in the alexandrite laser group and 54 patients in the sequential diode-alexandrite laser group) were evaluated. There was no significant difference regarding mean of hair reduction between the two groups during the courses of treatment. Except for the first session, there was no significant difference regarding percent of patient satisfaction between the two groups (P value >0.05). Comparison between the two groups showed no significant difference one month, three months and six months after the last treatment (P value >0.05). Regarding the results of our study, there is no significant difference between sequential treatment with diode and alexandrite lasers versus alexandrite laser alone in the treatment of hirsutism. We suggest that in further studies, the efficacy of sequential treatment with other laser systems is evaluated against single treatment methods.