Yanjun Lu

MicroRNA‐138 promotes tau phosphorylation by targeting retinoic acid receptor alpha

Alzheimers disease (AD) is a progressive neurodegenerative dementia characterized by Aβ deposition and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Emerging evidence shows that microRNAs (miRNAs) contribute to the pathogenesis of AD. Herein, we investigated the role of miR‐138, a brain enriched miRNA, which is increased in AD patients. We found that miR‐138 is increased in AD models, including N2a/APP and HEK293/tau cell lines. Overexpression of miR‐138 activates glycogen synthase kinase‐3β (GSK‐3β), and increases tau phosphorylation in HEK293/tau cells. Furthermore, we confirm that retinoic acid receptor alpha (RARA) is a direct target of miR‐138, and supplement of RARA substantially suppresses GSK‐3β activity, and reduces tau phosphorylation induced by miR‐138. In conclusion, our data suggest that miR‐138 promotes tau phosphorylation by targeting the RARA/GSK‐3β pathway.

Genetic association of RIT2 rs12456492 polymorphism and Parkinson’s disease susceptibility in Asian populations: a meta-analysis

Recent studies investigating the association of the Ras-like without CAAX 2 (RIT2) polymorphism, rs12456492, with Parkinson’s disease (PD) are controversial. We performed a meta-analysis to study the association between rs12456492 and PD susceptibility in Asian populations. Literature searches of PubMed and Embase were performed up to June 3, 2015, and the strength of the association between rs12456492 and PD was evaluated by odds ratios (OR) and 95% confidence intervals (CI). Four studies conducted between 2013 and 2015, comprising 2017 PD cases and 2010 controls, were included in the meta-analysis. Significant association of rs12456492 with PD was found in the dominant (GG + AG vs. AA: OR = 1.26, 95% CI = 1.20–1.44, P = 0.00) and additive models (GG vs. AA: OR = 1.38, 95% CI = 1.03–1.83, P = 0.030). Although sensitivity analysis found that the overall result was stable only in the dominant genetic model, a publication bias was also detected. Therefore, the results should be treated with caution. The current meta-analysis suggested that rs12456492 might be associated with increased PD risk in Asian populations, but studies using larger sample sizes and different ethnic populations will be needed to further confirm this association.

Tim-3 negatively mediates natural killer cell function in LPS-induced endotoxic shock.

Sepsis is an exaggerated inflammatory condition response to different microorganisms with high mortality rates and extremely poor prognosis. Natural killer (NK) cells have been reported to be the major producers of IFN-γ and key players in promoting systematic inflammation in lipopolysaccharide (LPS)-induced endotoxic shock. T-cell immunoglobulin and mucin domain (Tim)-3 pathway has been demonstrated to play an important role in the process of sepsis, however, the effect of Tim-3 on NK cell function remains largely unknown. In this study, we observed a dynamic inverse correlation between Tim-3 expression and IFN-γ production in NK cells from LPS-induced septic mice. Blockade of the Tim-3 pathway could increase IFN-γ production and decrease apoptosis of NK cells in vitro, but had no effect on the expression of CD107a. Furthermore, NK cell cytotoxicity against K562 target cells was enhanced after blocking Tim-3 pathway. In conclusion, our results suggest that Tim-3 pathway plays an inhibitory role in NK cell function, which might be a potential target in modulating the excessive inflammatory response of LPS-induced endotoxic shock.

Association of autophagy-related IRGM polymorphisms with latent versus active tuberculosis infection in a Chinese population

The autophagy-related immunity-related GTPase family M protein, IRGM, plays an important role in the defense against tuberculosis (TB) infection. IRGM polymorphisms are associated with TB infection susceptibility, and recent studies demonstrate host genetic differences between active and latent TB. Here, we investigated the association between IRGM polymorphisms and TB infection type in a Chinese population. We recruited 268 and 321 patients with confirmed or latent TB, respectively, and 475 TB-free healthy controls. Three single nucleotide polymorphisms, rs10065172, rs10051924, and rs13361189 within IRGM were genotyped using TaqMan-based assays. Interferon-gamma release levels were tested by T-SPOT. rs10065172 (P = 0.024, OR 0.67 (95% CI 0.48-0.95)), rs10051924 (P = 0.01, OR 0.64 (95% CI 0.46-0.90)), and rs13361189 (P = 0.055, OR 0.72 (95% CI 0.51-1.01)) were associated with a protective role against latent TB progression. Haplotype analysis showed that TCC was protective for latent TB (P = 0.022, OR 0.74 (95% CI 0.57-0.96)) whereas TTC conferred a higher risk of active TB. Additionally, patients with the rs10065172 TT genotype had a higher response to TB specific antigens. Thus, IRGM polymorphism differences between latent and active TB suggests that genetic differences in autophagy might partly affect host TB infection status.

Mycobacterium tuberculosis-specific TNF-α is a potential biomarker for the rapid diagnosis of active tuberculosis disease in Chinese population.

Interferon-gamma release assays (IGRAs) have proven to be useful to accurately detect Mycobacterium tuberculosis (Mtb) infection, but they cannot reliably discriminate between active tuberculosis (TB) and latent tuberculosis infection (LTBI). This study aims to test whether Mtb-specific tumor necrosis factor-alpha (TNF-α) could be used as a new tool for the rapid diagnosis of active TB disease. The secretion of TNF-α by Mtb-specific antigen-stimulated peripheral blood mononuclear cells (PBMCs) of sixty seven participants was investigated in the study. Our results showed that the total measurement of TNF-α secretion by Mtb-specific antigen-stimulated PBMCs is not a good biomarker for active TB diagnosis. However, we found that calculation of Mtb-specific TNF-α not only distinguish between active and latent TB infection, but also can differentiate active TB from non-TB patients. Using the cutoff value of 136.9 pg/ml for Mtb-specific TNF-α, we were able to differentiate active TB from LTBI. Sensitivity and specificity were 72% and 90.91%. These data suggest that Mtb-specific TNF-α could be a potential biomarker for the diagnosis of active TB disease.

Genotype Distribution and Molecular Epidemiology of Hepatitis C Virus in Hubei, Central China

Background Little is known about the molecular epidemiology of hepatitis C virus (HCV) infection in Central China. Methodology/Principal Findings A total of 570 patients from Hubei Province in central China were enrolled. These patients were tested positive for HCV antibody prior to blood transfusion. Among them, 177 were characterized by partial NS5B and/or Core-E1 sequences and classified into five subtypes: 1b, 83.0% (147/177); 2a, 13.0% (23/177); 3b, 2.3% (4/177); 6a, 1.1% (2/177); 3a, 0.6% (1/177). Analysis of genotype-associated risk factors revealed that paid blood donation and transfusion before 1997 were strongly associated with subtypes 1b and 2a, while some subtype 2a cases were also found in individuals with high risk sexual behaviors; subtypes 3b, 6a, and 3a were detected only in intravenous drug users. Phylogeographic analyses based on the coalescent datasets demonstrated that 1b, 2a, 3b, and 6a were locally epidemic in Hubei Province. Among them, subtype 1b Hubei strains may have served as the origins of this subtype in China, and 2a and 3b Hubei strains may have descended from the northwest and southwest of China, respectively, while 6a Hubei strains may have been imported from the central south and southwest. Conclusion/Significance The results suggest that the migration patterns of HCV in Hubei are complex and variable among different subtypes. Implementation of mandatory HCV screening before donation has significantly decreased the incidence of transfusion-associated HCV infection since 1997. More attention should be paid to intravenous drug use and unsafe sexual contact, which may have become new risk factors for HCV infection in Hubei Province.

Tim-3 signaling pathway as a novel negative mediator in lipopolysaccharide-induced endotoxic shock

Sepsis is a complex clinical condition caused by a dysregulated immune response to an infection. However, the mechanism by which our immune system controls this amplified inflammation is largely unknown. In this study, we investigated whether Tim-3 pathway could serve as a negative mediator in lipopolysaccharide (LPS)-induced endotoxic shock. Our results showed that Tim-3 was expressed on CD4(+) T cells, CD8(+) T cells, and NK cells, and was significantly increased in the peritoneal cavity of septic mice. Tim-3 acted as a marker of immune exhaustion and Tim-3-positive T cells and NK cells had a lower interferon (IFN)-γ production. Furthermore, blockade of Tim-3 pathway significantly accelerated mortality in septic mice, while activation of this pathway prolonged survival time. In vitro administration of Tim-3 blocking antibody restored the release of IFN-γ from splenocytes and decreased splenocyte apoptosis, and increased levels of IFN-γ and tumor necrosis factor (TNF)-α were also detected in septic mice at 24h post in vivo administration of the antibody. In contrast, activation of Tim-3 pathway prevented cell proliferation. Thus, Tim-3 signaling pathway acts as a novel negative mediator in LPS-induced endotoxic shock and could be a potential therapeutic target for the treatment of sepsis.

Possible association of CCDC62 rs12817488 polymorphism and Parkinson’s disease risk in Chinese population: a meta-analysis

Conflicting results identifying the association between coiled-coil domain containing 62 (CCDC62) polymorphism, rs12817488, and Parkinson’s disease (PD) have been reported. To clarify whether rs12817488 is related to PD risk in Chinese population, we carried out this meta-analysis by searching literature from PubMed and Embase database regarding this polymorphism. Three eligible studies involving 1616 cases and 1649 controls were included in this meta-analysis. Our results showed statistically significant association between rs12817488 and PD risk in all four genetic models. Stratification by gender revealed similar results in both subgroup in these genetic models except for recessive model, in which rs12817488 was not significantly associated with PD in male subgroup. Unstable result was found in recessive model via sensitivity analysis, and publication bias was observed in recessive model as well, indicating that the pooled result from recessive model should be cautiously treated. Our meta-analysis implicates a possible relationship between rs12817488 and PD risk in Chinese population. Further validation of this association in large sample size study with different gender is warranted.

FVIII p.Arg1800His mutation is associated with mild/moderate hemophilia A in Chinese population

Sir, Hemophilia A (HA) is the most common Xlinked bleeding disorder caused by absent, reduced, or dysfunction of factor FVIII coagulant activity (FVIII:C) due to mutations in the F8 gene. In mild/ moderate hemophilia A (MHA), bleeding occurs after trauma or surgery.1 F8 gene is located on the X chromosome, comprising 26 exons. F8 is translated into a 2351amino acid polypeptide containing a 19amino acid signal peptide, which will be cleaved to produce a 2332amino acid multidomain glycoprotein composed of 3 Atype domains, 1 B domain, 2 Ctype domains, and 3 small acidic atype regions (A1a1A2a2Ba3A3C1C2). The mature heterodimer FVIII is produced after intracellular cleavage, which is composed of 3 A domains homologous to a Copper binding protein ceruloplasmin, 2 C domains homologous to coagulation FV, and 1 B domain without any known homology. FVIII is released from VWF after specific proteolysis by thrombin, formed of heterotrimer activated FVIII (A1A2A3C1C2). The mutation spectrum of F8 gene is complex, including intron22/1 inversions, large segmental deletions spanning several exons, single nucleotide mutation, and total deletion due to chromosomal structural rearrangements. Many mutations have been included in HGMD (www.hgmd.cf.ac.uk) and EAHAD (www.factorviii-db.org) databases. More than 2703 mutations responsible for HA have been identified, and FVIII p.Arg1800His (Legacy Arg1781His) has been widely reported in patients with MHA in Caucasian population, but seldom identified in Asian population except for a patient in Taiwan.2-6 Herein, two families with MHA patients were studied. Hemizygous FVIII p.Arg1800His mutation was found in all included MHA patients, but these patients showed varied FVIII:C and phenotype, suggesting variable expressivity. This is the first report of FVIII p.Arg1800His mutation in China mainland.

Meta-analysis Reveals the Prognostic Value of Circulating Tumour Cells Detected in the Peripheral Blood in Patients with Non-Metastatic Colorectal Cancer

Detecting circulating tumour cells (CTCs) is considered as effective and minimally invasive technique to predict the prognosis of patients with metastatic colorectal cancer (CRC), but its clinical validity is still conflicting in patients without metastasis. We performed this meta-analysis to evaluate whether detection of CTCs in the peripheral blood can be used as a prognostic marker for patients with non-metastatic CRC. We performed a comprehensive search of the EMBASE, PubMed, and Web of Science databases (up to September 2016). Meta-analyses were conducted using a random-effects model with the hazard ratio (HR) and 95% confidence interval (95% CI) as the effect measures. Twenty studies including 3,687 patients were eligible for inclusion. Overall analyses demonstrated that the presence of CTCs was significantly associated with aggressive disease progression (HR = 2.57, 95% CI = 1.64–4.02, Pheterogeneity < 0.001, I2 = 81.0%) and reduced disease survival (HR = 2.41, 95% CI = 1.66–3.51, Pheterogeneity = 0.002, I2 = 59.7%). Subgroup analyses further supported the prognostic effect of CTCs based on different subsets, including sampling time, detection method and cancer type. Our findings suggest that detection of CTCs in the peripheral blood has the clinical utility to indicate poor prognosis in patients with non-metastatic CRC.