Early Histone Deacetylase Inhibition Mitigates Ischemia/Reperfusion Brain Injury by Reducing Microglia Activation and Modulating Their Phenotype.

Histone deacetylase inhibitors (HDACi) are a promising therapeutic intervention for stroke. The involvement of the anti-inflammatory effects of HDACi in their neuroprotection has been reported, but the underlying mechanisms are still uncertain. Given the post-stroke inflammation is a time-dependent process, starting with acute and intense inflammation, and followed by a prolonged and mild one, we proposed whether target the early inflammatory response could achieve the neuroprotection of HDACi? To test this hypothesis, a single dose of suberoylanilide hydroxamic acid (SAHA) (50 mg/kg), a pan HDACi, was intraperitoneally (i.p.) injected immediately or 12 h after ischemia onset in a transient middle cerebral artery occlusion (tMCAO) mouse model. Compared with delayed injection, immediate SAHA treatment provided more protection, evidenced by smaller infarction volume, and a better outcome. This protection was accompanied by suppression of pro-inflammatory cytokines and reduction of activated microglia in the early stage of post-stroke inflammation. Moreover, SAHA treatment suppressed M1 cytokine expression (IL-6, TNF-α, and iNOS) while promoted the transcription of M2 cytokines (Arg-1 and IL-10) in LPS-challenged mouse microglia, and enhanced CD206 (M2 marker) but decreased CD86 (M1 markers) levels in microglia isolated from the ipsilateral hemisphere of MCAO mice. Collectively, our data suggested that the protection of SAHA on ischemic brain injury was closely associated with its inhibition on the early inflammatory response, and this inhibition was related to its reducing microglia activation and priming the activated microglia toward a more protective phenotype.

BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls.

OBJECTIVE: To investigate the BRCA status in Chinese patients with ovarian cancer (OC). Though there were two large prevalence studies in Chinese OC patients, this was the first time to observe it in healthy controls. METHODS: We performed BRCA mutation screening using next-generation sequencing to determine the prevalence of BRCA germline deleterious mutations in an unselected cohort of Chinese OC patients (n = 1331) versus healthy controls (n = 1763) and describe the types and spectrum of BRCA deleterious variants. RESULTS: Among the 1331 patients with OC, 227 (17.1%) carried deleterious variants in BRCA1 and 70 (5.3%) carried deleterious variants in BRCA2. Of 1763 control subjects, 6 (0.3%) and 2 (0.1%) had deleterious variants in BRCA1 and BRCA2. No patient carried mutations in both BRCA1 and BRCA2 simultaneously. Sixty-three novel mutations were identified, and three Chinese specific hot-spot mutations were notified as BRCA1 c.5470_5477delATTGGGCA, BRCA1 c.981_982delAT, and BRCA1 c.3770_3771delAG. Interestingly, all these high-frequency recurrent mutations were distributed on exon 10, which may also be the Chinese OC BRCA mutations' distinct characteristics. In addition, in our study, the estimated odds ratio (OR) of OC associated with BRCA1 positive variants were approximately 34.6 (95% CI, 12.5-95.7) in age group under 40 and 42.4 (95% CI, 5.9-305.2) in group older than 50 in the Chinese population, respectively. CONCLUSIONS: We recommend BRCA testing to all Chinese OC patients and those general Chinese who have family members with hereditary breast and ovarian related cancer (HBOC)-related cancers. Variants carriers would not only benefit from early prevention of OC but also for the medical management.

Characterization of mouse serum exosomal small RNA content: The origins and their roles in modulating inflammatory response.

In the last decade, although studies on exosomal microRNAs (miRNAs) derived from serum and other body fluids have increased dramatically; the contents and biological significance of serum exosomes under normal conditions remain unclear. In the present study, we profiled the small RNA content of mouse serum exosomes (mSEs) using small RNAseq and found that fragments of transfer RNAs (tRNAs) and miRNAs were the two predominant exosomal RNA species, accounting for approximately 60% and 10% of mapped reads, respectively. Moreover, 466 known and 5 novel miRNAs were identified from two independent experiments, among which the five most abundant miRNAs (miR-486a-5p, miR-22-3p, miR-16-5p, miR-10b-5p and miR-27b-3p) accounted for approximately 60% of all the aligned miRNA sequences. As inferred from the identities of the well known cell- or tissue-specific miRNAs, mSEs were primarily released by RBCs, liver and intestinal cells. Bioinformatics analysis revealed over half of the top 20 miRNAs by abundance were involved in inflammatory responses and further in vitro experiments demonstrated that mSEs potently primed macrophages towards the M2 phenotype. To the best of our knowledge, this is the first study to profile small RNAs from mSEs. In addition to providing a reference for future biomarker studies and extrapolating their origins, our data also suggest the roles of mSEs in maintaining internal homeostasis under normal conditions.

The association between HDAC9 gene polymorphisms and stroke risk in the Chinese population: A meta-analysis.

Several recent genome-wide association studies (GWASs) have suggested that the histone deacetylase 9 (HDAC9) gene is associated with stroke, but the reliability of these findings remains controversial, particularly for the data derived from different ethnicities and geographical locations. Therefore, we performed a meta-analysis to explore the associations between HDAC9 polymorphisms and the risk of stroke in the Chinese population. All eligible case-control studies that met the search criteria were retrieved from multiple databases, and six case-control studies with a total of 2,356 stroke patients and 3,420 healthy controls were included. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to assess the strengths of the associations of 3 HDAC9 gene polymorphisms with stroke risk. Our results revealed statistically significant associations of the rs2107595 (T/C) polymorphism with an increased risk of stroke in the allele, codominant and dominant models. Additionally, the rs2389995 (G/A) polymorphism was found to be significantly associated with a decreased risk of stroke in all genetic models. In conclusion, this meta-analysis suggested that the T allele of rs2107595 in HDAC9 increases the risk of stroke but that the G allele of rs2389995 decreases the risk of stroke in the Chinese population.

Longitudinal and transverse dispersion coefficients in braided rivers.

The dispersion characteristics of braided rivers are presently unclear. The comprehensive flow structure in a physical braided river model was measured and was used to estimate its dispersion coefficient tensor. The largest values of the longitudinal and transverse dispersion coefficients occurred in the separation zone in two anabranches. The separation zone disappeared in a small diversion angle model of braided rivers where the coefficients were smaller. As for the sectional transverse distribution, the two coefficients varied markedly and an interesting negative correlation between them appeared in several sections. The dispersion coefficients increased with upstream flow rates. Comparison between the coefficients for different anabranch widths revealed higher values in wider sections. Finally, the values of the laboratory tests were compared with those in a real braided river, and relatively larger coefficients were found in natural rivers. The findings of this paper could be helpful in understanding the dispersion characteristics and in estimating pollutant concentration in braided rivers.