ErbB4 deficiency exacerbates olfactory dysfunction in an early-stage Alzheimer's disease mouse model.

Olfactory dysfunction is increasingly recognized as an early indicator of Alzheimer's disease (AD). Aberrations in GABAergic function and the excitatory/inhibitory (E/I) balance within the olfactory bulb (OB) have been implicated in olfactory impairment during the initial stages of AD. While the neuregulin 1 (NRG1)/ErbB4 signaling pathway is known to regulate GABAergic transmission in the brain and is associated with various neuropsychiatric disorders, its specific role in early AD-related olfactory impairment remains incompletely understood. This study demonstrated that olfactory dysfunction preceded cognitive decline in young adult APP/PS1 mice and was characterized by reduced levels of NRG1 and ErbB4 in the OB. Further investigation revealed that deletion of ErbB4 in parvalbumin interneurons reduced GABAergic transmission and increased hyperexcitability in mitral and tufted cells (M/Ts) in the OB, thereby accelerating olfactory dysfunction in young adult APP/PS1 mice. Additionally, ErbB4 deficiency was associated with increased accumulation of Aß and BACE1-mediated cleavage of APP, along with enhanced CDK5 signaling in the OB. NRG1 infusion into the OB was found to enhance GABAergic transmission in M/Ts and alleviate olfactory dysfunction in young adult APP/PS1 mice. These findings underscore the critical role of NRG1/ErbB4 signaling in regulating GABAergic transmission and E/I balance within the OB, contributing to olfactory impairment in young adult APP/PS1 mice, and provide novel insights for early intervention strategies in AD. This work has shown that ErbB4 deficiency increased the burden of Aß, impaired GABAergic transmission, and disrupted the E/I balance of mitral and tufted cells (M/Ts) in the OB, ultimately resulting in olfactory dysfunction in young adult APP/PS1 mice. NRG1 could enhance GABAergic transmission, rescue E/I imbalance in M/Ts, and alleviate olfactory dysfunction in young adult APP/PS1 mice. OB: olfactory bulb, E/I: excitation/inhibition, Pr: probability of release, PV: parvalbumin interneurons, Aß: ß-amyloid, GABA: gamma-aminobutyric acid.

[The advance in synthetic biology: towards a microbe-derived paclitaxel intermediates].

The synthetic biology matures to promote the heterologous biosynthesis of the well-known drug paclitaxel that is one of the most important and active chemotherapeutic agents for the first-line clinical treatment of cancer. This review focuses on the construction and regulation of the biosynthetic pathway of paclitaxel intermediates in both Escherichia coli and Saccharomyces cerevisiae. In particular, the review also features the early efforts to design and overproduce taxadiene and the bottleneck of scale fermentation for producing the intermediates.

Amelioration of olfactory dysfunction in a mouse model of Parkinson's disease via enhancing GABAergic signaling.

BACKGROUND: Olfactory dysfunction is among the earliest non-motor symptoms of Parkinson's disease (PD). As the foremost pathological hallmark, α-synuclein initiates the pathology in the olfactory pathway at the early stage of PD, particularly in the olfactory epithelium (OE) and olfactory bulb (OB). However, the local neural microcircuit mechanisms underlying olfactory dysfunction between OE and OB in early PD remain unknown. RESULTS: We observed that odor detection and discrimination were impaired in 6-month-old SNCA-A53T mice, while their motor ability remained unaffected. It was confirmed that α-synuclein increased and accumulated in OB but not in OE. Notably, the hyperactivity of mitral/tufted cells and the excitation/inhibition imbalance in OB were found in 6-month-old SNCA-A53T mice, which was attributed to the impaired GABAergic transmission and aberrant expression of GABA transporter 1 and vesicular GABA transporter in OB. We further showed that tiagabine, a potent and selective GABA reuptake inhibitor, could reverse the impaired olfactory function and GABAergic signaling in OB of SNCA-A53T mice. CONCLUSIONS: Taken together, our findings demonstrate potential synaptic mechanisms of local neural microcircuit underlying olfactory dysfunction at the early stage of PD. These results highlight the critical role of aberrant GABAergic signaling of OB in early diagnosis and provide a potential therapeutic strategy for early-stage PD.

The Protective Effects of Zornia diphylla (L.) Pers. Against Acute Liver Injury Induced by Carbon Tetrachloride in Mice.

Background: Zornia diphylla (L.) Pers. (ZDP) is a traditional Chinese herbal medicine that has been used for several decades to treat patients with liver diseases. Whether ZDP is best administered as a single agent or adjunctive therapy has yet to be determined as does the mechanism whereby it exerts its effects on antagonizing acute liver injury (ALI). Aim of the study: To investigate the protective effects of ZDP on ALI induced by carbon tetrachloride (CCl4) and the potential underlying mechanisms. Materials and Methods: Sixty adult mice were randomized into six study groups (n = 10/group). Three groups were treated with different concentrations of ZDP (2.5, 1.25, 0.625 g/kg), one with bifendate (0.0075 g/kg) alone (positive control) and one with physiologic saline (normal, negative control). All groups were treated for 14 days. Two hours after the last administration, the normal group received an intraperitoneal injection of peanut oil, and the other five groups received an intraperitoneal injection of an equal dose of CCl4 peanut oil solution. At 24 h, the liver index, histology and serum or tissue levels and/or protein expression of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), alkaline phosphatase (ALP), superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), glutathione (GSH), Akt, phosphorylated Akt (p-Akt), nuclear factor kappa B p65 (NF-κB p65), inhibitor of NF-κB α (IκB-α), interleukin-1 ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), E-cadherin and vimentin were determined. Results: Compared to the model controls, the degree of inflammatory cell infiltration and hepatocyte injury of liver tissue was relieved in the bifendate and three ZDP groups; liver index in the ZDP (2.5, 1.25 g/kg) groups and serum liver function indices in the ZDP (2.5, 1.25 and 0.625 g/kg) groups were decreased; antioxidants SOD, CAT and GSH in liver tissue were increased but the lipid peroxidation index MDA was decreased; protein expression of inflammatory cytokines Akt, p-Akt, NF-κB p65, IκB-α, IL-1ß, IL-6 and TNF-α in the liver was ameliorated, and E-cadherin expression was increased. The results of liver histopathology also showed that ZDP had a significant effect on ALI. Conclusion: ZDP has obvious protective effects on CCl4-induced ALI as a single therapy and appears to act by inhibiting oxidation, reducing the release of inflammatory factors and promoting hepatocyte repair.

Ginsenoside Rb1 confers neuroprotection via promotion of glutamate transporters in a mouse model of Parkinson's disease.

Ginsenoside Rb1 has been demonstrated to protect dopaminergic (DA) neurons from death in vitro. However, the neuroprotective effects and underlying mechanism of Rb1 in treating Parkinson's disease (PD) remain uncharacterized. In this study, we explored the effects of Rb1 on the movement disorder and the underlying mechanisms based on the glutamatergic transmission and excitotoxicity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Here, for the first time, we report that Rb1 treatment ameliorates motor deficits, prevents DA neuron death, and suppresses α-synuclein expression and astrogliosis in the MPTP mouse model of PD. Rb1 attenuates glutamate excitotoxicity by upregulating glutamate transporter expression and function, and modulating the nigrostriatal and cortico-nigral glutamatergic transmission pathways. Our results demonstrate that Rb1 increases glutamate transporter expression via nuclear translocation of nuclear factor-kappa B, regulates glutamate receptor expression and promotes synaptic protein expression. These results indicate that Rb1 suppresses glutamate excitotoxicity and modulates synaptic transmission to improve the impairments in motor functions of the MPTP model of PD, suggesting that Rb1 may serve as a potential therapeutic agent for PD.

QiShenYiQi pill attenuates atherosclerosis by promoting regulatory T cells, inhibiting T helper 17 cells and accelerating cholesterol excretion.

OBJECTIVE: The aim of this study was to explore potential immunoregulatory mechanisms underlying the suppressive effect on atherosclerosis of QiShenYiQi pill (QSYQ). METHODS AND RESULTS: Male ApoE-/- mice were maintained on a Western-type diet and QSYQ treatment for eight weeks. Determination of atherosclerosis demonstrated that QSYQ attenuated plaque formation and decreased the level of blood low-density lipoproteins-cholesterol. QSYQ treatment did not affect body weight but reduced the ratio of liver weight and body weight. Western blots of liver showed that QSYQ increased the expression of liver X receptor alpha and ATP-binding cassette sub-family G member 5. Western blots of atherosclerotic aorta revealed that QSYQ inhibited the expression of cluster of differentiation 36, promoted the expression of forkhead box P3 and decreased interleukin-17A expression. Western blots of spleen showed that QSYQ decreased the expression of mothers against decapentaplegic homolog 2/3 and forkhead box P3, as well as attenuated the expression of spleen interleukin-6, RAR-related orphan receptor gamma and interleukin-17A. CONCLUSIONS: QSYQ exerted an anti-atherosclerosis effect by promoting regulatory T cells in atherosclerotic lesion, inhibiting T helper 17 cells in plaque and spleen and accelerating liver cholesterol excretion.

Anti-angiogenic activity of gecko aqueous extracts and its macromolecular components in CAM and HUVE-12 cells.

Gecko is a kind of traditional Chinese medicine with remarkable antineoplastic activity. However, undefined mechanisms and ambiguity regarding active ingredients limit new drug development from gecko. This study was conducted to assess anti-angiogenic properties of the aqueous extracts of fresh gecko (AG) or macromolecular components separated from AG (M-AG). An enzyme-linked immunosorbent assay (ELISA) approach was applied to detect the vascular endothelial growth factor (VEGF) secretion of the tumor cells treated with AG or M-AG. The effect of AG or M-AG on vascular endothelial cell proliferation and migratory ability was analyzed by tetrazolium dye colorimetric method, transwell and wound-healing assays. Chick embryo chorioallantoic membrane (CAM) assays were used to ensure the anti-angiogenic activity of M-AG in vivo. The results showed that AG or M-AG inhibited the VEGF secretion of tumor cells, the relative inhibition rates of AG and M-AG being 27.2% and 53.2% respectively at a concentration of 20 µL/mL. AG and M-AG inhibited the vascular endothelial (VE) cell proliferation with IC50 values of 11.5 ± 0.5 µL/mL and 12.9 ± 0.4 µL/mL respectively. The VE cell migration potential was inhibited significantly (p<0.01) by the AG (≥ 24 µL/mL) or M-AG (≥ 12 µL/ mL) treatment. In vivo, neovascularization of CAM treated with M-AG was inhibited significantly (p<0.05) at a concentration of 0.4 µL/mL. This study provided evidence that anti-angiogenesis is one of the anti-tumor mechanisms of AG and M-AG, with the latter as a promising active component.

Predicting the incidence risk of ischemic stroke in a hospital population of southern China: a classification tree analysis.

OBJECTIVE: To determine the major risk factors and their interactions of ischemic stroke (IS) and to develop a classification tree model to predict the incidence risk of IS for a Chinese population. METHODS: Exhaustive Chi-squared Automatic Interaction Detection (Exhaustive CHAID) algorithm of classification tree method was applied to build a prediction model for the incidence risk of IS under the design of 1:1 matched case-control study. The statistics of misclassification risk was used to evaluate the fitness of the model. RESULTS: In the prediction model, six variables of physical exercise, history of hypertension, tea drinking, HDL-c level, smoking status and educational level were in turn selected as the predictors of IS incidence risk. In the subgroup of lacking of physical exercise, individuals who had history of hypertension would have a significantly higher IS risk (92%) than that of the ones who had no history of hypertension (64%). The misclassification risk estimate of the prediction model was 0.21 with the standard error of 0.02, indicating that 79% of the cases could be classified correctly based on current prediction model. CONCLUSIONS: Lacking of physical exercise and history of hypertension are identified to be the prominent predicting variables of IS risk for a hospital population of southern China. Although CHAID analysis could provide detailed information and insight about interactions among risk factors of IS, we still need to validate our model and improve the vascular risk prediction for Chinese subjects in further studies.

Point prevalence surveys of healthcare-associated infection in 13 hospitals in Hubei Province, China, 2007-2008.

Successive point prevalence surveys were conducted in November 2007 and 2008 to monitor the prevalence of healthcare-associated infection (HCAI) in 13 grade III, 1st class hospitals in Hubei Province of China, using the case definition criteria established by the Ministry of Health in the People's Republic of China. In total, of 20 350 patients surveyed, 833 (4.09%) HCAIs were observed in 790 (3.88%) patients. There was no significant difference between the overall prevalence of HCAI in 2007 (4.14%) and 2008 (3.72%). Respiratory tract infection was the most common HCAI (63.15%), followed by surgical site infection (9.60%) and urinary tract infection (8.64%). Only 35.29% (294/833) of HCAI patients had positive microbiology results. Gram-negative bacteria were isolated most frequently and the most frequent organism was Pseudomonas aeruginosa, followed by Escherichia coli, Acinetobacter baumannii and Staphylococcus aureus. Antibiotic use was documented for 10,344 (50.83%) patients, and cephalosporins, penicillins, and quinolones were the most commonly used agents for treatment or prophylaxis.

[Application of complex networks model in preventing and controlling communicable disease].

To discuss the application of complex networks models in preventing and controlling communicable disease, analyze and control the spread of infectious diseases by using the models and the software of complex networks based on its basic properties. Compared with conventional epidemiological approach, the complex networks theory, as a new theory, not only can describe the dynamic process of infections diseases spreading but also forecast the situation of infectious disease. The influence of the network's topology on the infections diseases transmission can be deeply understood through the research on disease spreading by its theory, so to control the spread of diseases. Complex networks theory approach can be used in epidemiological research for having much advantage compared with those conventional epidemiological approaches.