ER stress response plays an important role in aggregation of α-synuclein

<p>Abstract</p> <p>Background</p> <p>Accumulation of filamentous α-synuclein as Lewy bodies is a hallmark of Parkinson's disease. To identify the mechanisms involved in α-synuclein assembly and determine whether the assemblies are cytotoxic, we developed a cell model (3D5) that inducibly expresses wild-type human α-synuclein and forms inclusions that reproduce many morphological and biochemical characteristics of Lewy bodies. In the present study, we evaluated the effects of several histone deacetylase inhibitors on α-synuclein aggregation in 3D5 cells and primary neuronal cultures. These drugs have been demonstrated to protect cells transiently overexpressing α-synuclein from its toxicity.</p> <p>Results</p> <p>Contrary to transient transfectants, the drug treatment did not benefit 3D5 cells and primary cultures. The treated were less viable and contained more α-synuclein oligomers, active caspases 3 and 9, as well as ER stress markers than non-treated counterparts. The drug-treated, induced-3D5 cells, or primary cultures from transgenic mice overexpressing (<2 fold) α-synuclein, displayed more α-synuclein oligomers and ER stress markers than non-induced or non-transgenic counterparts. Similar effects were demonstrated in cultures treated with tunicamycin, an ER stressor. These effects were blocked by co-treatment with salubrinal, an ER stress inhibitor. In comparison, co-treatment with a pan caspase inhibitor protected cells from demise but did not reduce α-synuclein oligomer accumulation.</p> <p>Conclusions</p> <p>Our results indicate that an increase of wild-type α-synuclein can elicit ER stress response and sensitize cells to further insults. Most importantly, an increase of ER stress response can promote the aggregation of wild type α-synuclein.</p

Association of Chinese Herbal Medicine use with the depression risk among the long-term breast cancer survivors: A longitudinal follow-up study

Background Breast cancer patients are at elevated risk of depression during treatment, thus provoking the chance of poor clinical outcomes. This retrospective cohort study aimed to investigate whether integrating Chinese herbal medicines citation(CHM) into conventional cancer therapy could decrease the risk of depression in the long-term breast cancer survivors. Methods A cohort of patients aged 20–70 years and with newly diagnosed breast cancer during 2000–2008 was identified from a nationwide claims database. In this study, we focused solely on survivors of breast cancer at least1 year after diagnosis. After one-to-one matching for age, sex, and baseline comorbidities, breast cancer patients who received (n = 1,450) and did not receive (n = 1,450) CHM treatment were enrolled. The incidence rate and hazard ratio citation(HR) for depression between the two groups was estimated at the end of 2012. A Cox proportional hazard model was constructed to examine the impact of the CHM use on the risk of depression. Results During the study period, the incidence rate of depression was significantly lower in the treated cohort than in the untreated cohort [8.57 compared with 11.01 per 1,000 person-years citation(PYs)], and the adjusted HR remained significant at 0.74 (95% CI 0.58–0.94) in a Cox proportional hazards regression model. The corresponding risk further decreasing to 43% among those using CHM for more than 1 year. Conclusion Finding from this investigation indicated that the lower risk of depression observed in breast cancer patients treated with CHM, suggesting that CHM treatment should be considered for disease management toward breast cancer. Yet, the optimal administered dose should be determined in further clinical trials

Taipei's Use of a Multi-Channel Mass Risk Communication Program to Rapidly Reverse an Epidemic of Highly Communicable Disease

BACKGROUND: In September 2007, an outbreak of acute hemorrhagic conjunctivitis (AHC) occurred in Keelung City and spread to Taipei City. In response to the epidemic, a new crisis management program was implemented and tested in Taipei. METHODOLOGY AND PRINCIPAL FINDINGS: Having noticed that transmission surged on weekends during the Keelung epidemic, Taipei City launched a multi-channel mass risk communications program that included short message service (SMS) messages sent directly to approximately 2.2 million Taipei residents on Friday, October 12th, 2007. The public was told to keep symptomatic students from schools and was provided guidelines for preventing the spread of the disease at home. Epidemiological characteristics of Taipei's outbreak were analyzed from 461 sampled AHC cases. Median time from exposure to onset of the disease was 1 day. This was significantly shorter for cases occurring in family clusters than in class clusters (mean+/-SD: 2.6+/-3.2 vs. 4.39+/-4.82 days, p = 0.03), as well as for cases occurring in larger family clusters as opposed to smaller ones (1.2+/-1.7 days vs. 3.9+/-4.0 days, p<0.01). Taipei's program had a significant impact on patient compliance. Home confinement of symptomatic children increased from 10% to 60% (p<0.05) and helped curb the spread of AHC. Taipei experienced a rapid decrease in AHC cases between the Friday of the SMS announcement and the following Monday, October 15, (0.70% vs. 0.36%). By October 26, AHC cases reduced to 0.01%. The success of this risk communication program in Taipei (as compared to Keelung) is further reflected through rapid improvements in three epidemic indicators: (1) significantly lower crude attack rates (1.95% vs. 14.92%, p<0.001), (2) a short epidemic period of AHC (13 vs. 34 days), and (3) a quick drop in risk level (1 approximately 2 weeks) in Taipei districts that border Keelung (the original domestic epicenter). CONCLUSIONS AND SIGNIFICANCE: The timely launch of this systematic, communication-based intervention proved effective at preventing a dangerous spike in AHC and was able to bring this high-risk disease under control. We recommend that public health officials incorporate similar methods into existing guidelines for preventing pandemic influenza and other emerging infectious diseases

Predicting the catalytic sites of isopenicillin N synthase (IPNS) related non-haem iron-dependent oxygenases and oxidases (NHIDOX) through a structural superimposition and molecular docking approach

Isopenicillin N synthase (IPNS) related Non-haem iron-dependent oxygenases and oxidases (NHIDOX) demonstrated a striking structural conservativeness, even with low protein sequence homology. It is evident that these enzymes have an architecturally similar catalytic centre with active ligands lining the reactive pocket. Deacetoxycephalosporin C synthase (DAOCS), isopenicillin N synthase (IPNS), deacetylcephalosporin C synthase (DACS), clavaminate synthase 1 and 2 (CAS1 and 2) are important bacterial enzymes that catalyze the formation of β-lactam antibiotics belonging to this enzyme family. Most plant enzyme members within this subfamily namely flavonol synthase (FLS), leucoanthocyanidin dioxygenase (LDOX), anthocyanidin synthase (ANS), 1-aminocyclopropane-1-carboxylic acid oxidase (ACCO), gibberellin 20-oxidase (G20O), desacetoxyvindoline-4-hydroxylase (D4H), flavanone 3β-hydroxylase (F3H), and hyoscyamine 6β-hydroxylase (H6H) are involved in catalyzing the biosyntheses of plant secondary metabolites. With the advancement of protein structural analysis software, it is possible to predict the catalytic sites of protein that shared a structural resemblance. By exploiting the superimposition model of DAOCS-IPNS, DAOCS-IPNS-CAS, G20O-LDOX, FLS-LDOX, ACCO-LDOX, D4H-LDOX, F3H-LDOX and H6H-LDOX model; a computational protocol for predicting the catalytic sites of proteins is now made available. This study shows that without the crystallized or nuclear magnetic resonance (NMR) structures of most NHIDOX enzyme, the plausible catalytic sites of protein can be forecasted using this structural bioinformatics approach.Keywords: Enzyme, catalytic sites, isopenicillin N synthase, ligand

TRPV1 is a Responding Channel for Acupuncture Manipulation in Mice Peripheral and Central Nerve System

Background/Aims: Acupuncture involves inserting a fine needle into a specific point, often called an acupoint, thereby initiating a therapeutic effect accompanied by phenomena such as soreness, heaviness, fullness, and numbness. Acupoints are characterized as points located in deep tissues with abundant sensory nerve terminals, which suggests that there is a strong relationship between acupoints and peripheral sensory afferents. In this study, we determined whether manual acupuncture (MA) or different frequencies of electroacupuncture (EA) share similar mechanisms for activating excitatory neurotransmission. Methods: We performed MA or EA at acupoint ST36 and we also used western blot and immunostaining techniques to determine neural changes at the peripheral dorsal root ganglion (DRG), spinal cord (SC), and somatosensory cortex (SSC) levels. Results: Our results show that either MA or EA at the ST36 acupoint significantly increased components of the TRPV1-related signaling pathway, such as pPKA, pPI3K, pPKC-pERK, and pAKT (but not pp38 or pJNK) at the peripheral DRG and central SC-SSC levels. Furthermore, excitatory phosphorylated N-methyl-D-aspartate receptor (pNMDA) and pCaMKIIα (but not pNR2B, pCaMKIIδ, or pCaMKIIγ) also increased. These molecules could not increase in the DRG and SC-SSC of TRPV1–/–mice. Conclusion: Our data demonstrates that both MA and EA can activate excitatory signals in either peripheral or central levels. We also define that TRPV1 is crucial for an acupuncture effect and then initiate excitatory pNR1-pCaMKII pathway, at peripheral DRG and central SC-SSC level. We suggest that the TRPV1 signaling pathway is highly correlated to Acupuncture effect that implies the real clinical significance

Cytomegalovirus excretion in pregnant and nonpregnant women.

Cervical and urinary excretion of cytomegalovirus by Taiwanese women was identified by the presence of a cytomegalovirus-specific immediate-early gene sequence amplified by the polymerase chain reaction. Excretion rates during the first trimester of pregnancy resembled rates for nonpregnant women. As pregnancy proceeded, the cervical excretion rate increased from 13 to 40% and the urinary excretion rate increased from 1 to 13%

Turbidity Currents, Submarine Landslides and the 2006 Pingtung Earthquake off SW Taiwan

Submarine landslides or slumps may generate turbidity currents consisting of mixture of sediment and water. Large and fast-moving turbidity currents can incise and erode continental margins and cause damage to artificial structures such as telecommunication cables on the seafloor. In this study, we report that eleven submarine cables across the Kaoping canyon and Manila trench were broken in sequence from 1500 to 4000 m deep, as a consequence of submarine landslides and turbidity currents associated with the 2006 Pingtung earthquakes offshore SW Taiwan. We have established a full-scale scenario and calculation of the turbidity currents along the Kaoping canyon channel from the middle continental slope to the adjacent deep ocean. Our results show that turbidity current velocities vary downstream ranging from 20 to 3.7 and 5.7 m/s, which demonstrates a positive relationship between turbidity current velocity and bathymetric slope. The violent cable failures happened in this case evidenced the destructive power of the turbidity current to seafloor or underwater facilities that should not be underestimated

Therapeutic Effect of Repurposed Temsirolimus in Lung Adenocarcinoma Model

Lung cancer is one of the major cause of cancer-related deaths worldwide. The poor prognosis and resistance to both radiation and chemotherapy urged the development of potential targets for lung cancer treatment. In this study, using a network-based cellular signature bioinformatics approach, we repurposed a clinically approved mTOR inhibitor for renal cell carcinomans, temsirolimus, as the potential therapeutic candidate for lung adenocarcinoma. The PI3K-AKT-mTOR pathway is known as one of the most frequently dysregulated pathway in cancers, including non-small-cell lung cancer. By using a well-documented lung adenocarcinoma mouse model of human pathophysiology, we examined the effect of temsirolimus on the growth of lung adenocarcinoma in vitro and in vivo. In addition, temsirolimus combined with reduced doses of cisplatin and gemcitabine significantly inhibited the lung tumor growth in the lung adenocarcinoma mouse model compared with the temsirolimus alone or the conventional cisplatin–gemcitabine combination. Functional imaging techniques and microscopic analyses were used to reveal the response mechanisms. Extensive immunohistochemical analyses were used to demonstrate the apparent effects of combined treatments on tumor architecture, vasculature, apoptosis, and the mTOR-pathway. The present findings urge the further exploration of temsirolimus in combination with chemotherapy for treating lung adenocarcinoma

Alternative Complement Pathway Is Activated and Associated with Galactose-Deficient IgA1 Antibody in IgA Nephropathy Patients

BackgroundGalactose-deficient IgA1 (Gd-IgA1) and alternative complement pathway activation are considered to be involved in the pathogenesis of IgA nephropathy (IgAN). Nevertheless, the relationships between alternative pathway activation and disease activity or Gd-IgA1 level remains unclear.MethodsNinety-eight biopsy-diagnosed IgAN, twenty-five primary focal segmental sclerosis (FSGS) patients and forty-two healthy individuals were recruited in this study. Among them, fifty IgAN patients received immunosuppression. Follow-up blood samples at 1 and 3~6 months after immunosuppression were collected. Plasma levels of complement C5a, factor Ba and Gd-IgA1 were measured and analyzed. Immunostaining for complement was performed in twenty-five IgAN and FSGS patients.ResultsAt baseline, IgAN patients had higher levels of plasma C5a, factor Ba and Gd-IgA1 than control subjects. Gd-IgA1 levels positively correlated with plasma C5a and factor Ba. In addition, levels of factor Ba and Gd-IgA1 were positively associated with proteinuria and negatively associated with renal function. Immunostaining revealed positive staining for factor Bb and C3c in glomeruli in IgAN patients, but not in FSGS patients. At baseline, patients receiving immunosuppression had more severe proteinuria and higher factor Ba. After 6 months, eGFR declined and proteinuria persisted in patients without immunosuppression. In contrast, patients who received immunosuppression exhibited decreased plasma levels of C5a, factor Ba, and Gd-IgA1 as early as 1 month after treatment. Proteinuria decreased and renal function also remained stable 6 months after immunosuppression.ConclusionsOur results indicate a close relationship between alternative complement pathway activation, Gd-IgA1 concentration and clinical severity of IgAN. Level of complement factor B may be a potential marker for disease activity and therapeutic target in IgAN patients