Luteolin alleviates cognitive impairment in Alzheimer's disease mouse model via inhibiting endoplasmic reticulum stress-dependent neuroinflammation.

Luteolin is a flavonoid in a variety of fruits, vegetables, and herbs, which has shown anti-inflammatory, antioxidant, and anti-cancer neuroprotective activities. In this study, we investigated the potential beneficial effects of luteolin on memory deficits and neuroinflammation in a triple-transgenic mouse model of Alzheimer's disease (AD) (3 × Tg-AD). The mice were treated with luteolin (20, 40 mg · kg-1 · d-1, ip) for 3 weeks. We showed that luteolin treatment dose-dependently improved spatial learning, ameliorated memory deficits in 3 × Tg-AD mice, accompanied by inhibiting astrocyte overactivation (GFAP) and neuroinflammation (TNF-α, IL-1ß, IL-6, NO, COX-2, and iNOS protein), and decreasing the expression of endoplasmic reticulum (ER) stress markers GRP78 and IRE1α in brain tissues. In rat C6 glioma cells, treatment with luteolin (1, 10 µM) dose-dependently inhibited LPS-induced cell proliferation, excessive release of inflammatory cytokines, and increase of ER stress marker GRP78. In conclusion, luteolin is an effective agent in the treatment of learning and memory deficits in 3 × Tg-AD mice, which may be attributable to the inhibition of ER stress in astrocytes and subsequent neuroinflammation. These results provide the experimental basis for further research and development of luteolin as a therapeutic agent for AD.

Therapeutic mechanisms of traditional Chinese medicine to improve metabolic diseases via the gut microbiota.

Metabolic diseases such as obesity, type 2 diabetes mellitus, and hyperlipidemia are associated with the dysfunction of gut microbiota. Traditional Chinese medicines (TCMs) have shown considerable effects in the treatment of metabolic disorders by regulating the gut microbiota. However, the underlying mechanisms are unclear. Studies have shown that TCMs significantly affect glucose and lipid metabolism by modulating the gut microbiota, particularly mucin-degrading bacteria, bacteria with anti-inflammatory properties, lipopolysaccharide- and short-chain fatty acid (SCFA)-producing bacteria, and bacteria with bile-salt hydrolase activity. In this review, we explored potential mechanisms by which TCM improved metabolic disorders via regulating gut microbiota composition and functional structure. In particular, we focused on the protection of the intestinal barrier function, modulation of metabolic endotoxemia and inflammatory responses, regulation of the effects of SCFAs, modulation of the gut-brain axis, and regulation of bile acid metabolism and tryptophan metabolism as therapeutic mechanisms of TCMs in metabolic diseases.

A sensitive electrochemiluminescent aptasensor based on perylene derivatives as a novel co-reaction accelerator for signal amplification.

Herein, a novel signal amplification strategy was designed using the perylene derivative as the co-reaction accelerator toward graphene-CdTe quantum dots (G-CdTe)/S2O8(2-) system to construct a highly sensitive electrochemiluminescent (ECL) aptasensor for thrombin (TB) detection. Firstly, the G-CdTe nanocomposites were prepared by one-step method of in situ generating CdTe quantum dots onto the surface of the graphene oxide by using 3-mercaptopropionic acid as the CdTe QDs stabilizer. Then, a kind of perylene derivative (PTC-Lys), was synthesized by covalently binding L-lysine to 3,4,9,10-perylenetetracarboxylic acid, which was further immobilized onto the G-CdTe by the π-π* stacking and cross-linked the detection thrombin aptamer (TBA II) to obtain the TBA II/PTC-Lys/G-CdTe signal probes. It is worth pointing out that PTC-Lys acting as an efficient co-reaction accelerator interacted with the co-reactant of S2O8(2-) rather than G-CdTe to promote the more oxidant mediators of SO4(•-), which could further react with G-CdTe to produce excited state species G-CdTe* for emitting light. Compared with the G-CdTe/S2O8(2-) ECL system, our proposed strategy with the introduction of co-reaction accelerator of PTC-Lys exhibited ultra-high sensitivity to quantify the concentration of TB from 1.0×10(-7)nM to 10nM with a detection limit of 34aM.

Higher frequency of peripheral blood interleukin 21 positive follicular helper T cells in patients with ankylosing spondylitis.

OBJECTIVE: The role of follicular Th (TFH) cells remains unclear in the pathogenesis of ankylosing spondylitis (AS). Our study examined the frequency of different subsets of circulating CXCR5+CD4+ T cells in patients with AS before and after receiving therapy. METHODS: Percentages of peripheral blood inducible costimulator (ICOS)+, programmed death 1 (PD-1)+, and interleukin 21 (IL-21)+ CXCR5+CD4+ T cells in 26 patients with AS and 12 healthy controls (HC) were examined by flow cytometry, and the disease activity of individual patients was measured by Bath AS Disease Activity Index (BASDAI). The concentrations of serum IL-21, IgG, IgA, IgM, and C-reactive protein (CRP) were examined and the values of erythrocyte sedimentation rate (ESR) were measured. The potential association among these measures was analyzed. RESULTS: In comparison with that in HC, significantly increased percentages of CXCR5+CD4+, CXCR5+CD4+PD-1+, and CXCR5+CD4+IL-21+, but not CXCR5+CD4+ICOS+ and PD-1+ICOS+CXCR5+CD4+ T cells, and elevated concentrations of serum IL-21 were detected in patients with AS (p = 0.001, p = 0.012, p < 0.001, p = 0.233, p = 0.216, p < 0.001, respectively). Treatment with meloxicam, thalidomide, and etanercept for 1 month significantly reduced percentages of IL-21+CXCR5+CD4+ T cells and concentrations of serum IL-21 (p < 0.001, p < 0.001, respectively), accompanied by significantly minimized disease activity in drug responders, but not in the drug nonresponders. Further, percentages of IL-21+CXCR5+CD4+ T cells were positively correlated with BASDAI in patients (r = 0.6, p = 0.0012) and in the drug-responders 1 month after treatment (r = 0.68, p = 0.005), while the percentages of PD-1+CXCR5+CD4+ T cells were negatively correlated with BASDAI (r = -0.58, p = 0.0018). CONCLUSION: These data suggest that IL-21+CXCR5+CD4+ T cells may be associated with development of AS and that the frequency of IL-21+CXCR5+CD4+ T cells may be a biomarker for evaluation of disease activity and drug responses in patients with AS, particularly in drug-responding patients.

Peripheral B-cell activation and exhaustion markers in patients with ankylosing spondylitis.

AIMS: Ankylosing spondylitis (AS) is an autoimmune disease and is associated with abnormal B cell function. However, the roles of different B cell subsets are less clear. This study aimed to examine the frequency of different subsets of B cells in AS patients following standard therapies. MAIN METHODS: Eighteen newly diagnosed AS patients and 10 healthy controls (HC) were recruited in this study. The expression of CD27, CD38, CD86, CD95 and IgD on CD19(+) B cells was examined by flow cytometry. The disease activity was scored according to the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Serum levels of C-reactive protein (CRP), rheumatoid factor (RF), IgG, IgA and IgM, and the erythrocyte sedimentation rate (ESR) were measured. KEY FINDINGS: The frequency of CD27(+) B cells was decreased in AS patients compared with HC (p=0.018), while CD86(+) and CD27(-)CD95(+) B cell subsets increased in AS patients (p<0.001). Meanwhile, the frequencies of CD38(+) and CD95(+) B cell positively correlated with BASDAI (r=0.6505, p=0.0035; r=0.6854, p=0.0017, respectively), while CD38(-)CD86(+) B cell negatively correlated with BASDAI (r=-0.7329, p<0.001). We also found that CD27(-) and CD95(+) B cell negatively correlated with RF levels (r=-0.5141, p=0.0290; r=-0.4944, p=0.0370, respectively), while CD27(+) B cell positively correlated with IgG levels (p=0.0148, r=0.5640). Moreover, CD86(+) and CD27(-)CD95(+) B cell subsets increased following treatment with Meloxicam and Etanercept for one month (p<0.001; p<0.001). SIGNIFICANCE: These findings suggest that CD27(-)CD95(+)CD19(+) and CD86(+)CD19(+) B cells may be reasonable cellular targets for the therapeutic intervention of AS.

Molecular epidemiology of Orientia tsutsugamushi in chiggers and ticks from domestic rodents in Shandong, northern China.

BACKGROUND: Scrub typhus is endemic to a 13,000,000-km² area of the Asia-Pacific region, and causes an annual incidence of 1 million people. The mortality rate of scrub typhus ranges from 6.1% to 25% in Southeast Asia. Natural infection of Orientia tsutsugamushi has been identified in domestic rodents in Shandong Province. However, infestation of chiggers and ticks on the domestic rodents and prevalence and genotypes of O. tsutsugamushi in these Acarina remain unclear. METHODS: During September 2010 to March 2012, 3134 chiggers and 89 ticks were collected from domestic rodents captured in three counties of Shandong Province. We amplified and sequenced the 56-kDa type-specific antigen gene of O. tsutsugamushi from DNA samples of these Acarina and designated to genotype according to sequence analysis. RESULTS: Overall, the infestation rate of chiggers on domestic rodents was 17.0%, and the chigger index was 5.38. The infestation rate of ticks on rodents was 3.1%. Natural infection of O. tsutsugamushi was found in Leptotrombidium taishanicum, L. linhuaikongense, L. intermedium, L. scutellare, L. palpale, and Ixodes spp., the minimum positive rates of which were 5.9%, 3.2%, 1.2%, 0.8%, 0.8%, and 2.2%, respectively. Kawasaki-like genotypes were predominant in chiggers and ticks on domestic rodents, which were detected from L. taishanicum, L. intermedium, L. scutellare, L. palpale, and Ixodes spp. Shimokoshi-like genotype was detected from L. palpale. CONCLUSIONS: In the present study we investigated the infestation of chiggers and ticks on domestic rodents in Shandong Province, and identified the prevalence and genotypes of O. tsutsugamushi in the Acarina. Infestation of vector chiggers in domestic rodents, prevalence of O. tsutsugamushi in infested chiggers, and high nucleotide homologies among the O. tsutsugamushi sequences from the Acarina, their animal hosts and scrub typhus patients, implied that domestic rodents may play an important role in the transmission of scrub typhus in Shandong, China. Further studies are needed to verify the vector significance of chiggers and ticks that tested positive for O. tsutsugamushi, and to assess the risk of human exposure to chiggers and ticks on domestic rodents.

Comparisons of multiple characteristics between young and old lung cancer patients.

BACKGROUND: Risk factors that contribute to younger patients with lung cancer are still relatively unknown. The aim of this study was to compare the clinical characteristics, histological types, stages at diagnosis, treatment modalities and survival rates between young and old patients with lung cancer. METHODS: The study was designed as a retrospective review of all lung cancer patients admitted to the Third Affiliated Hospital of Harbin Medical University from 1998 to 2008. Survival analyses using univariate and multivariate approaches were performed to compare the survival rates between different age groups and to discover potential prognostic factors. RESULTS: This research included 3320 patients with primary lung cancer, of whom 626 (18.8%) were 45 years old or younger at the time of diagnosis. The percentage of smokers and the male to female ratios between the young and old patient groups were 51.27% vs. 70.6% (P < 0.001) and 1.99 vs. 2.13 (P = 0.4801), respectively. The young patient group had a higher incidence of adenocarcinoma and fewer surgeries. The 1-year, 3-year and 5-year survival rates in the young patient group were generally lower than those of the old patient group, with significant differences (P = 0.0232). The clinical stage of the tumor was a prognostic factor for both non-small cell lung cancer patients (P < 0.0001) and small cell lung cancer patients (P = 0.0002). Symptoms, diagnostic method, histology, smoking, treatment modality and body mass index were shown to have significant relationships with the survival of lung cancer patients (P < 0.05). CONCLUSIONS: Patients with lung cancer who are younger than 45 years old might have a significantly poorer prognosis than that of older patients. Symptoms, diagnosis method, histology, smoking, treatment modality and body mass index can be independent prognostic factors for lung cancer.

The WW domain protein PRO40 is required for fungal fertility and associates with Woronin bodies.

Fruiting body formation in ascomycetes is a highly complex process that is under polygenic control and is a fundamental part of the fungal sexual life cycle. However, the molecular determinants regulating this cellular process are largely unknown. Here we show that the sterile pro40 mutant is defective in a 120-kDa WW domain protein that plays a pivotal role in fruiting body maturation of the homothallic ascomycete Sordaria macrospora. Although WW domains occur in many eukaryotic proteins, homologs of PRO40 are present only in filamentous ascomycetes. Complementation analysis with different pro40 mutant strains, using full-sized or truncated versions of the wild-type pro40 gene, revealed that the C terminus of PRO40 is crucial for restoring the fertile phenotype. Using differential centrifugation and protease protection assays, we determined that a PRO40-FLAG fusion protein is located within organelles. Further microscopic investigations of fusion proteins with DsRed or green fluorescent protein polypeptides showed a colocalization of PRO40 with HEX-1, a Woronin body-specific protein. However, the integrity of Woronin bodies is not affected in mutant strains of S. macrospora and Neurospora crassa, as shown by fluorescence microscopy, sedimentation, and immunoblot analyses. We discuss the function of PRO40 in fruiting body formation.