Search

Background: Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined., Methods: Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD., Results: We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration., Conclusions: This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases., (© 2024. The Author(s).)

Intestinal fibrosis is a common complication of inflammatory bowel disease. There is still a lack of effective drugs for the prevention or treatment of intestinal fibrosis. Heat shock protein 47 (HSP47) plays a key role in the development of intestinal fibrosis. In this study we investigated the therapeutic potential and underlying mechanisms of fraxinellone, a degraded limonoid isolated from the root bark of Dictamnus dasycarpus, in the treatment of intestinal fibrosis. Intestinal fibrosis was induced in mice by dextran sodium sulfate (DSS) treatment. DDS-treated mice were administered fraxinellone (7.5, 15, 30 mg·kg -1 ·d -1 , i.g.) for 45 days. We showed that fraxinellone administration dose-dependently alleviated DSS-induced intestinal impairments, and reduced the production of intestinal fibrosis biomarkers such as α-smooth muscle actin (SMA), collagen I, hydroxyproline, fibronectin and laminin, and cytokines such as TGF-β, TNF-α and IL-β. We then established in vitro intestinal fibrosis cell models in SW480 and HT-29 cells, and demonstrated that treatment with fraxinellone (3, 10, 30 μM) significantly relieved TGF-β-induced fibrosis responses by inhibiting the TGF-β/Smad2/3 signaling pathway. Molecular docking suggested that the fraxinellone might disrupt the interaction between HSP47 and collagen, which was confirmed by coimmunoprecipitation experiments. SPR analysis showed that fraxinellone had a high affinity for HSP47 with a K d value of 3.542 × 10 -5  M. This study provides a new example of HSP47-collagen intervention by a natural compound and has important implications for the clinical treatment of inflammation-induced issue fibrosis., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

The NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in the pathogenesis of a wide variety of human diseases. So far, drugs directly and specifically targeting the NLRP3 inflammasome are not available for clinical use since the safety and efficacy of new compounds are often unclear. A promising approach is thus to identify NLRP3 inhibitors from existing drugs that are already in clinical use. Here, we show that mefloquine, a well-known antimalarial drug, is a highly selective and potent NLRP3 inhibitor by screening a FDA-approved drug library. Mechanistically, mefloquine directly binds to the NLRP3 NACHT and LRR domains to prevent NLRP3 inflammasome activation. More importantly, mefloquine treatment attenuates the symptoms of lipopolysaccharide-induced systemic inflammation and Parkinson's disease-like neural damage in mice. Our findings identify mefloquine as a potential therapeutic agent for NLRP3-driven diseases and migth expand its clinical use considerably., (© 2023 The Authors.)

Recent studies provide clues that astrocyte senescence is correlated with Parkinson's disease (PD) progression, while little is known about the molecular basis for astrocyte senescence in PD. Here, we found that cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) was upregulated in senescent astrocytes of PD and aged mice. Strikingly, deletion of astrocytic cGAS significantly prevented senescence of astrocytes and neurodegeneration. Furthermore, we identified LCN2 as the effector of cGAS-STING signal by RNA-Seq analysis. Genetic manipulation of LCN2 expression proved the regulation of cGAS-STING-LCN2 axis in astrocyte senescence. Additionally, YY1 was discovered as the transcription factor of LCN2 by chromatin immunoprecipitation. Binding of STING to YY1 impedes nuclear translocation of YY1. Herein, we determine the involvement of the cGAS-STING-YY1-LCN2 signaling cascade in the control of astrocyte senescence and PD progression. Together, this work fills the gap in our understanding of astrocyte senescence, and provides potential targets for delaying PD progression., (© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Rationale: Astrocyte dysfunction is one of the important pathological mechanisms of depression. Stress contributes to the onset of depression. As metabolic stress sensor, Kir6.1-contaning K-ATP channel (Kir6.1/K-ATP) is prominently expressed in astrocytes. However, the involvement of Kir6.1/K-ATP channel in depression remains obscure. Methods: Astrocyte-specific Kir6.1 knockout mice were used to prepare two mouse models of depression to explore the role of astrocytic Kir6.1/K-ATP channel in depression. Primary astrocytes were cultured to reveal the underlying mechanism for Kir6.1-regulated astrocytic pyroptosis. Results: We identified that chronic stress reduced the astrocytic Kir6.1 expression in hippocampus of mice. We further observed astrocyte-specific knockout of Kir6.1 induced depressive-like behaviors in mice. Moreover, we found that astrocytic Kir6.1 deletion increased NLRP3-mediated astrocytic pyroptosis in response to stress. Mechanistically, Kir6.1 associated with NLRP3, and this interaction prevented the assembly and activation of NLRP3 inflammasome, thereby inhibition of astrocytic pyroptosis. More importantly, VX-765, an effective and selective inhibitor for NLRP3 inflammasome, could reverse the astrocytic pyroptosis and rescue the deterioration of behaviors in astrocytic Kir6.1 knockout mice. Conclusions: Our findings illustrate that Kir6.1/K-ATP channel in astrocytes is an essential negative modulator of astrocytic pyroptosis and plays a crucial role in depression and suggest that astrocytic Kir6.1/K-ATP channel may be a promising therapeutic target for depression., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Loss of secretory IgA (SIgA) is common in chronic obstructive pulmonary disease (COPD) small airways and likely contributes to disease progression. We hypothesized that loss of SIgA results from reduced expression of pIgR (polymeric immunoglobulin receptor), a chaperone protein needed for SIgA transcytosis, in the COPD small airway epithelium. pIgR-expressing cells were defined and quantified at single-cell resolution in human airways using RNA in situ hybridization, immunostaining, and single-cell RNA sequencing. Complementary studies in mice used immunostaining, primary murine tracheal epithelial cell culture, and transgenic mice with secretory or ciliated cell-specific knockout of pIgR. SIgA degradation by human neutrophil elastase or secreted bacterial proteases from nontypeable Haemophilus influenzae was evaluated in vitro . We found that secretory cells are the predominant cell type responsible for pIgR expression in human and murine airways. Loss of SIgA in small airways was not associated with a reduction in secretory cells but rather a reduction in pIgR protein expression despite intact PIGR mRNA expression. Neutrophil elastase and nontypeable H. influenzae -secreted proteases are both capable of degrading SIgA in vitro and may also contribute to a deficient SIgA immunobarrier in COPD. Loss of the SIgA immunobarrier in small airways of patients with severe COPD is complex and likely results from both pIgR-dependent defects in IgA transcytosis and SIgA degradation.

Rationale: Constrictive bronchiolitis (ConB) is a relatively rare and understudied form of lung disease whose underlying immunopathology remains incompletely defined. Objectives: Our objectives were to quantify specific pathological features that differentiate ConB from other diseases that affect the small airways and to investigate the underlying immune and inflammatory phenotype present in ConB. Methods: We performed a comparative histomorphometric analysis of small airways in lung biopsy samples collected from 50 soldiers with postdeployment ConB, 8 patients with sporadic ConB, 55 patients with chronic obstructive pulmonary disease, and 25 nondiseased control subjects. We measured immune and inflammatory gene expression in lung tissue using the NanoString nCounter Immunology Panel from six control subjects, six soldiers with ConB, and six patients with sporadic ConB. Measurements and Main Results: Compared with control subjects, we found shared pathological changes in small airways from soldiers with postdeployment ConB and patients with sporadic ConB, including increased thickness of the smooth muscle layer, increased collagen deposition in the subepithelium, and lymphocyte infiltration. Using principal-component analysis, we showed that ConB pathology was clearly separable both from control lungs and from small airway disease associated with chronic obstructive pulmonary disease. NanoString gene expression analysis from lung tissue revealed T-cell activation in both groups of patients with ConB with upregulation of proinflammatory pathways, including cytokine-cytokine receptor interactions, NF-κB (nuclear factor-κB) signaling, TLR (Toll-like receptor) signaling, T-cell receptor signaling, and antigen processing and presentation. Conclusions: These findings indicate shared immunopathology among different forms of ConB and suggest that an ongoing T-helper cell type 1-type adaptive immune response underlies airway wall remodeling in ConB.

After deployment to Southwest Asia, some soldiers develop persistent respiratory symptoms, including exercise intolerance and exertional dyspnea. We identified 50 soldiers with a history of deployment to Southwest Asia who presented with unexplained dyspnea and underwent an unrevealing clinical evaluation followed by surgical lung biopsy. Lung tissue specimens from 17 age-matched, nonsmoking subjects were used as controls. Quantitative histomorphometry was performed for evaluation of inflammation and pathologic remodeling of small airways, pulmonary vasculature, alveolar tissue and visceral pleura. Compared with control subjects, lung biopsies from affected soldiers revealed a variety of pathologic changes involving their distal lungs, particularly related to bronchovascular bundles. Bronchioles from soldiers had increased thickness of the lamina propria, smooth muscle hypertrophy, and increased collagen content. In adjacent arteries, smooth muscle hypertrophy and adventitial thickening resulted in increased wall-to-lumen ratio in affected soldiers. Infiltration of CD4 and CD8 T lymphocytes was noted within airway walls, along with increased formation of lymphoid follicles. In alveolar parenchyma, collagen and elastin content were increased and capillary density was reduced in interalveolar septa from soldiers compared to control subjects. In addition, pleural involvement with inflammation and/or fibrosis was present in the majority (92%) of soldiers. Clinical follow-up of 29 soldiers (ranging from 1 to 15 y) showed persistence of exertional dyspnea in all individuals and a decline in total lung capacity. Susceptible soldiers develop a postdeployment respiratory syndrome that includes exertional dyspnea and complex pathologic changes affecting small airways, pulmonary vasculature, alveolar tissue, and visceral pleura., Competing Interests: Conflicts of Interest and Source of Funding: Supported by the Department of Defense W81XWH-17-1-0503, National Institutes of Health HL126176, generous donation by Ms. Carol Odess. S.I.R. was an employee of AstraZeneca from 2015 to 2019 and continues to own shares that were received as part of his compensation. As part of that employment, he represented AstraZeneca on the Board of Directors of Dizal Pharma without additional compensation. In the last 3 years, he has consulted for Bergenbio, GlaxoSmithKline, NovoVentures and Verona. Between 1996 and 2007, his university received funding from tobacco companies that supported studies relating to harm reduction and to the impact of tobacco smoke on stem cells. As part of this work, he consulted with RJ Reynolds without personal fee on the topic of harm reduction, received funding from RJ Reynolds to evaluate the effect of a harm reduction product in normal smokers (1996) and in subjects with chronic bronchitis (1999) and to assess the effect of smoking cessation on lower respiratory tract inflammation (2000); he participated in a Philip Morris multi-center study to assess biomarkers of smoke exposure (2002); he received funding for a clinical trial from the Institute for Science and Health (2005), which receives support from the tobacco industry, to evaluate biomarkers in exhaled breath associated with smoking cessation and reduction. This study was supplemented with funding from Lorillard and RJ Reynolds to expand the spectrum of biomarkers assessed. He received a grant from the Philip Morris External Research Program (2005) to assess the impact of cigarette smoking on circulating stem cells in the mouse. There are no active tobacco-industry funded projects. All ties with tobacco industry companies and entities supported by tobacco companies were terminated in 2007. For the remaining authors none were declared., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Without an effective vaccine against SARS-CoV-2, the build-up of herd immunity through natural infection has been suggested as a means to control COVID-19. Although population immunity is typically estimated by the serological investigation of recovered patients, humoral immunity in asymptomatic subjects has not been well studied, although they represent a large proportion of all SARS-CoV-2 infection cases. In this study, we conducted a serosurvey of asymptomatic infections among food workers and performed serological and cellular response analyses of asymptomatic subjects in Wuhan, the original epicenter of the COVID-19 outbreak. Our data showed that up to 5.91% of the food workers carried SARS-CoV-2 IgG antibodies asymptomatically; however, in 90.4% of them, the antibody level declined over a 2-week period. IgM and IgG antibodies, including neutralizing antibodies, were significantly lower in asymptomatic subjects than in recovered symptomatic patients with similar disease courses. Furthermore, the asymptomatic subjects showed lymphopenia and a prominent decrease in the B-cell population, as well as a low frequency of antibody-secreting cells and a low cytokine response. These factors probably contributed to the low and unsustained antibody levels in asymptomatic subjects. Our results show that asymptomatic subjects are likely to be vulnerable to SARS-CoV-2 reinfection, and neither the proportion of population immunity nor the breadth of immune responses is sufficient for herd immunity.

Background: Although a variety of pathological changes have been described in small airways of patients with COPD, the critical anatomic features determining airflow limitation remain incompletely characterised., Methods: We examined lung tissue specimens from 18 non-smokers without chronic lung disease and 55 former smokers with COPD for pathological features of small airways that could contribute to airflow limitation. Morphometric evaluation was performed for epithelial and subepithelial tissue thickness, collagen and elastin content, luminal mucus and radial alveolar attachments. Immune/inflammatory cells were enumerated in airway walls. Quantitative emphysema scoring was performed on chest CT scans., Results: Small airways from patients with COPD showed thickening of epithelial and subepithelial tissue, mucus plugging and reduced collagen density in the airway wall (in severe COPD). In patients with COPD, we also observed a striking loss of alveolar attachments, which are connective tissue septa that insert radially into the small airway adventitia. While each of these parameters correlated with reduced airflow (FEV 1 ), multivariable regression analysis indicated that loss of alveolar attachments was the major determinant of airflow limitation related to small airways. Neutrophilic infiltration of airway walls and collagen degradation in airway adventitia correlated with loss of alveolar attachments. In addition, quantitative analysis of CT scans identified an association between the extent of emphysema and loss of alveolar attachments., Conclusion: In COPD, loss of radial alveolar attachments in small airways is the pathological feature most closely related to airflow limitation. Destruction of alveolar attachments may be mediated by neutrophilic inflammation., Competing Interests: Competing interests: SR was an employee of AstraZeneca from 2015 to 2019 and continues to own shares that were received as part of his compensation. As part of that employment, he represented AstraZeneca on the Board of Directors of Dizal Pharma without additional compensation. In the last three years, he has consulted for Bergenbio, GlaxoSmithKline, NovoVentures and Verona. Between 1996 and 2007, his university received funding from tobacco companies that supported studies relating to harm reduction and to the impact of tobacco smoke on stem cells. As part of this work, he consulted with RJ Reynolds without personal fee on the topic of harm reduction, received funding from RJ Reynolds to evaluate the effect of a harm reduction product in normal smokers (1996) and in subjects with chronic bronchitis (1999) and to assess the effect of smoking cessation on lower respiratory tract inflammation (2000); he participated in a Philip Morris multicentre study to assess biomarkers of smoke exposure (2002); he received funding for a clinical trial from the Institute for Science and Health (2005), which receives support from the tobacco industry, to evaluate biomarkers in exhaled breath associated with smoking cessation and reduction. This study was supplemented with funding from Lorillard and RJ Reynolds to expand the spectrum of biomarkers assessed. He received a grant from the Philip Morris External Research Program (2005) to assess the impact of cigarette smoking on circulating stem cells in the mouse. There are no active tobacco-industry funded projects. All ties with tobacco industry companies and entities supported by tobacco companies were terminated in 2007., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Complement pathway over-activation has been implicated in a variety of neurological diseases. However, the signaling pathways governing astrocytic complement activation in Parkinson's disease (PD) are poorly understood. Kir6.1, a pore-forming subunit of ATP-sensitive potassium (K-ATP) channel, is prominently expressed in astrocytes and exhibits anti-inflammatory effects. Therefore, we hypothesize that Kir6.1/K-ATP channel may regulate astrocytic complement activation in the pathogenesis of PD. In this study, astrocytic Kir6.1 knockout (KO) mice were used to examine the effect of astrocytic Kir6.1/K-ATP channel on astrocytic complement activation triggered by the lipopolysaccharide (LPS). Here, we found that astrocytic Kir6.1 KO mice showed more dopaminergic neuron loss and more astrocyte reactivity in substantia nigra compacta than controls. We also found that astrocytic Kir6.1 KO increased the expression of complement C3 in astrocytes in LPS-induced mouse model of PD. Mechanistically, astrocytic Kir6.1 KO promoted astroglial NF-κB activation to elicit extracellular release of C3, which in turn interacted with neuronal C3aR to induce neuron death. Blocking complement function by NF-κB inhibitor or C3aR antagonist rescued the aggravated neuron death induced by Kir6.1 KO. Collectively, our findings reveal that astrocytic Kir6.1/K-ATP channel prevents neurodegeneration in PD via astrocyte-neuron cross talk through NF-κB/C3/C3aR signaling and suggest that targeting astroglial Kir6.1/K-ATP channel-NF-κB-C3-neuronal C3aR signaling represents a novel therapeutic strategy for PD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Although activation of adaptive immunity is a common pathological feature of chronic obstructive pulmonary disease (COPD), particularly during later stages of the disease, the underlying mechanisms are poorly understood. In small airways of COPD patients, we found that localized disruption of the secretory immunoglobulin A (SIgA)-containing mucosal immunobarrier correlated with lymphocyte accumulation in airway walls and development of tertiary lymphoid structures (TLS) around small airways. In SIgA-deficient mice, we observed bacterial invasion into the airway epithelial barrier with lymphocytic infiltration and TLS formation, which correlated with the progression of COPD-like pathology with advanced age. Depletion of either CD4 + or CD8 + T lymphocytes reduced the severity of emphysema in SIgA-deficient mice, indicating that adaptive immune activation contributes to progressive lung destruction. Further studies revealed that lymphocyte infiltration into the lungs of SIgA-deficient mice was dependent on monocyte-derived dendritic cells (moDCs), which were recruited through a CCR2-dependent mechanism in response to airway bacteria. Consistent with these results, we found that moDCs were increased in lungs of COPD patients, along with CD4 + and CD8 + effector memory T cells. Together, these data indicate that endogenous bacteria in SIgA-deficient airways orchestrate a persistent and pathologic T lymphocyte response through monocyte recruitment and moDC differentiation.

Following acute infection, individuals COVID-19 may still shed SARS-CoV-2 RNA. However, limited information is available regarding the active shedding period or whether infectious virus is also shed. Here, we monitored the clinical characteristics and virological features of 38 patients with COVID-19 (long-term carriers) who recovered from the acute disease, but still shed viral RNA for over 3 months. The median carrying history of the long-term carriers was 92 days after the first admission, and the longest carrying history was 118 days. Negative-positive viral RNA-shedding fluctuations were observed. Long-term carriers were mostly elderly people with a history of mild infection. Infectious SARS-CoV-2 was isolated from the sputum, where high level viral RNA was found. All nine full-length genomes of samples obtained in March-April 2020 matched early viral clades circulating in January-February 2020, suggesting that these patients persistently carried SARS-CoV-2 and were not re-infected. IgM and IgG antibodies and neutralizing-antibody profiles were similar between long-term carriers and recovered patients with similar disease courses. In summary, although patients with COVID-19 generated neutralizing antibodies, they may still shed infectious SARS-CoV-2 for over 3 months. These data imply that patients should be monitored after discharge to control future outbreaks.

Background: Since the outbreak of coronavirus disease 2019 (COVID-19) in China in December 2019, considerable attention has been focused on its elucidation. However, it is also important for clinicians and epidemiologists to differentiate COVID-19 from other respiratory infectious diseases such as influenza viruses., Research Question: The aim of this study was to explore the different clinical presentations between COVID-19 and influenza A (H1N1) pneumonia in patients with ARDS., Study Design and Methods: This analysis was a retrospective case-control study. Two independent cohorts of patients with ARDS infected with either COVID-19 (n = 73) or H1N1 (n = 75) were compared. Their clinical manifestations, imaging characteristics, treatments, and prognosis were analyzed and compared., Results: The median age of patients with COVID-19 was higher than that of patients with H1N1, and there was a higher proportion of male subjects among the H1N1 cohort (P < .05). Patients with COVID-19 exhibited higher proportions of nonproductive coughs, fatigue, and GI symptoms than those of patients with H1N1 (P < .05). Patients with H1N1 had higher Sequential Organ Failure Assessment (SOFA) scores than patients with COVID-19 (P < .05). The Pao 2 /Fio 2 of 198.5 mm Hg in the COVID-19 cohort was significantly higher than the Pao 2 /Fio 2 of 107.0 mm Hg in the H1N1 cohort (P < .001). Ground-glass opacities was more common in patients with COVID-19 than in patients with H1N1 (P < .001). There was a greater variety of antiviral therapies administered to COVID-19 patients than to H1N1 patients. The in-hospital mortality of patients with COVID-19 was 28.8%, whereas that of patients with H1N1 was 34.7% (P = .483). SOFA score-adjusted mortality of H1N1 patients was significantly higher than that of COVID-19 patients, with a rate ratio of 2.009 (95% CI, 1.563-2.583; P < .001)., Interpretation: There were many differences in clinical presentations between patients with ARDS infected with either COVID-19 or H1N1. Compared with H1N1 patients, patients with COVID-19-induced ARDS had lower severity of illness scores at presentation and lower SOFA score-adjusted mortality., (Copyright © 2020. Published by Elsevier Inc.)

Rationale: The current outbreak of coronavirus disease (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, spreads across national and international borders. The overall death rate of COVID-19 pneumonia in the Chinese population was 4%. Objectives: To describe the process of hospitalization and critical care of patients who died of COVID-19 pneumonia. Methods: This was a multicenter observational study of 109 decedents with COVID-19 pneumonia from three hospitals in Wuhan. Demographic, clinical, laboratory, and treatment data were collected and analyzed, and the final date of follow-up was February 24, 2020. Results: The mean age of 109 decedents with COVID-19 pneumonia was 70.7 years, 35 patients (32.1%) were female, and 85 patients (78.0%) suffered from one or more underlying comorbidities. Multiple organ failure, especially respiratory failure and heart failure, appeared in all patients even at the early stage of disease. Overall, the mean time from onset of symptoms to death was 22.3 days. All 109 hospitalized patients needed admission to an intensive care unit (ICU); however, because of limited availability, only 51 (46.8%) could be admitted. The period from hospitalization to death in the ICU group and non-ICU group was 15.9 days (standard deviation = 8.8 d) and 12.5 days (8.6 d, P  = 0.044), respectively. Conclusions: Mortality due to COVID-19 pneumonia was concentrated in patients above the age of 65 years, especially those with major comorbidities. Patients who were admitted to the ICU lived longer than those who were not. Our findings should aid in the recognition and clinical management of such infections, especially with regard to ICU resource allocation.

Background: Senescent astrocytes have been implicated in the aging brain and neurodegenerative disorders, including Parkinson's disease (PD). Astragaloside IV (AS-IV) is an antioxidant derivative from a traditional Chinese herbal medicine Astragalus membraneaceus Bunge and exerts anti-inflammatory and longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined., Methods: Long culture-induced replicative senescence model and lipopolysaccharide/1-methyl-4-phenylpyridinium (LPS/MPP + )-induced premature senescence model and a mouse model of PD were used to investigate the effect of AS-IV on astrocyte senescence in vivo and in vitro. Immunocytochemistry, qPCR, subcellular fractionation, flow cytometric analyses, and immunohistochemistry were subsequently conducted to determine the effects of AS-IV on senescence markers., Results: We found that AS-IV inhibited the astrocyte replicative senescence and LPS/MPP + -induced premature senescence, evidenced by decreased senescence-associated β-galactosidase activity and expression of senescence marker p16, and increased nuclear level of lamin B1, and reduced pro-inflammatory senescence-associated secretory phenotype. More importantly, we showed that AS-IV protected against the loss of dopamine neurons and behavioral deficits in the mouse model of PD, which companied by reduced accumulation of senescent astrocytes in substantia nigra compacta. Mechanistically, AS-IV promoted mitophagy, which reduced damaged mitochondria accumulation and mitochondrial reactive oxygen species generation and then contributed to the suppression of astrocyte senescence. The inhibition of autophagy abolished the suppressive effects of AS-IV on astrocyte senescence., Conclusions: Our findings reveal that AS-IV prevents dopaminergic neurodegeneration in PD via inhibition of astrocyte senescence through promoting mitophagy and suggest that AS-IV is a promising therapeutic strategy for the treatment of age-associated neurodegenerative diseases such as PD.

In December 2019, a novel coronavirus (2019-nCoV) caused an outbreak in Wuhan, China, and soon spread to other parts of the world. It was believed that 2019-nCoV was transmitted through respiratory tract and then induced pneumonia, thus molecular diagnosis based on oral swabs was used for confirmation of this disease. Likewise, patient will be released upon two times of negative detection from oral swabs. However, many coronaviruses can also be transmitted through oral-fecal route by infecting intestines. Whether 2019-nCoV infected patients also carry virus in other organs like intestine need to be tested. We conducted investigation on patients in a local hospital who were infected with this virus. We found the presence of 2019-nCoV in anal swabs and blood as well, and more anal swab positives than oral swab positives in a later stage of infection, suggesting shedding and thereby transmitted through oral-fecal route. We also showed serology test can improve detection positive rate thus should be used in future epidemiology. Our report provides a cautionary warning that 2019-nCoV may be shed through multiple routes.

ATP-sensitive potassium (K-ATP) channels, coupling cell metabolism to cell membrane potential, are involved in brain diseases, including Parkinson's disease (PD). Kir6.1, a pore-forming subunit of K-ATP channel, is prominently expressed in astrocytes and participates in regulating its function. However, the precise role of astrocytic Kir6.1-contaning K-ATP channel (Kir6.1/K-ATP) in PD is not well characterized. In this study, astrocytic Kir6.1 knockout (KO) mice were used to examine the effect of astrocytic Kir6.1/K-ATP channel on dopaminergic (DA) neurodegeneration triggered by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Here, we found that astrocytic Kir6.1 KO mice showed more DA neuron loss in substantia nigra compacta (SNc), lower level of dopamine in the striatum, and more severe motor dysfunction than controls. Interestingly, this companied by increased neuroinflammation and decreased autophagy level in SNc in vivo and astrocytes in vitro. Mechanistically, astrocytic Kir6.1 KO inhibited mitophagy which resulted in an increase in the accumulation of damaged mitochondria, production of reactive oxygen species and neuroinflammation in astrocytes. Restoration of astrocytic mitophagy rescued the deleterious effects of astrocytic Kir6.1 ablation on mitochondrial dysfunction, inflammation and DA neuron death. Collectively, our findings reveal that astrocytic Kir6.1/K-ATP channel protects against DA neurodegeneration in PD via promoting mitophagy and suggest that astrocytic Kir6.1/K-ATP channel may be a promising therapeutic target for PD., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Excessive activation of the NLRP3 inflammasome is a key component contributing to the pathogenesis of various inflammatory diseases. However, the molecular mechanisms underlying its activation and regulation remain poorly defined. The objective of this study was to explore the possible function of the K + channel pore-forming subunit Kir6.1 in regulating NLRP3 inflammasome activation and insulin resistance. Here, we demonstrate that Kir6.1 depletion markedly activates the NLRP3 inflammasome, whereas enhanced Kir6.1 expression produces opposing effects both in mice in vivo and in primary cells in vitro. We also demonstrate that Kir6.1 controls insulin resistance by inhibiting NLRP3 inflammasome activation in mice. We further show that Kir6.1 physically associates with NLRP3 and thus inhibits the interactions between the NLRP3 inflammasome subunits. Our results reveal a previously unrecognized function of Kir6.1 as a negative regulator of the NLRP3 inflammasome and insulin resistance, which is mediated by virtue of its ability to inhibit NLRP3 inflammasome assembly. These data provide novel insights into the regulatory mechanism of NLRP3 inflammasome activation and suggest that Kir6.1 is a promising therapeutic target for inflammasome-mediated inflammatory diseases.

ATP-sensitive potassium (K-ATP) channels, coupling cell metabolism to cell membrane potential, are involved in brain diseases including stroke. Emerging evidence shows that astrocytes play important roles in the pathophysiology of cerebral ischemia. Kir6.1, a pore-forming subunit of K-ATP channel, is prominently expressed in astrocytes and participates in regulating its function. However, the exact role of astrocytic Kir6.1-containg K-ATP channel (Kir6.1/K-ATP) in ischemic stroke remains unclear. Here, we found that astrocytic Kir6.1 knockout (KO) mice exhibited larger infarct areas and more severe brain edema and neurological deficits in middle cerebral artery occlusion stroke model. Both activated gliosis and neuronal loss were aggravated in astrocytic Kir6.1 KO mice. Furthermore, the protein levels of pro-apoptotic protein Bcl-2 associated X (Bax) and active caspase-3 were up-regulated and the expression of anti-apoptotic protein Bcl-2 was down-regulated in astrocytic Kir6.1 KO mice. This is accompanied by enhanced endoplasmic reticulum stress (ER stress) responses in brain tissues and in astrocytes during ischemia/reperfusion (I/R) injury. Finally, inhibition of ER stress rescued astrocyte apoptosis induced by Kir6.1 deletion during I/R injury. Collectively, our findings reveal that astrocytic Kir6.1/K-ATP channel protects brain from cerebral ischemia/reperfusion injury through inhibiting ER stress and suggest that astrocytic Kir6.1/K-ATP channel is a promising therapeutic target for ischemic stroke., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: α-Synuclein (α-Syn)-induced neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Dopamine D2 receptor (Drd2) has been regarded as a potential anti-inflammatory target in the therapy of neurodegenerative diseases. However, the effect of astrocytic Drd2 in α-Syn-induced neuroinflammation remains unclear., Methods: The effect of Drd2 on neuroinflammation was examined in mouse primary astrocyte in vitro and A53T transgenic mice in vivo. The inflammatory responses of astrocyte were detected using immunofluorescence, ELISA, and qRT-PCR. The details of molecular mechanism were assessed using Western blotting and protein-protein interaction assays., Results: We showed that the selective Drd2 agonist quinpirole suppressed inflammation in the midbrain of wild-type mice, but not in α-Syn-overexpressed mice. We also found that Drd2 agonists significantly alleviated LPS-induced inflammatory response in astrocytes, but failed to suppress α-Syn-induced inflammatory response. The anti-inflammation effect of Drd2 was dependent on β-arrestin2-mediated signaling, but not classical G protein pathway. α-Syn reduced the expression of β-arrestin2 in astrocytes. Increased the β-arrestin2 expression restored in the anti-inflammation of Drd2 in α-Syn-induced inflammation. Furthermore, we demonstrated that α-Syn disrupted the anti-inflammation of Drd2 via inhibiting the association of β-arrestin2 with transforming growth factor-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and promoting TAK1-TAB1 interaction in astrocytes., Conclusions: Our study illustrates that astrocytic Drd2 inhibits neuroinflammation through a β-arrestin2-dependent mechanism and provides a new strategy for treatment of PD. Our findings also reveal that α-Syn disrupts the function of β-arrestin2 and inflammatory pathways in the pathogenesis of PD.

Stroke is the third most common cause of death in most industrialized countries. Polygonum multiflorum (He-Shou-Wu, HSW) is one of the traditional Chinese medicines with multiple pharmacological activities which is widely used in Chinese recipe. This study aims to explore the protective effect of HSW on ischemic stroke rat model and to elucidate the underlying mechanisms. The mortality rate, neurological deficit, cerebral infarct size, histopathology, immunohistochemistry, biochemical parameters, quantitative real-time polymerase chain reaction and western blotting were used to access the treatment effects of HSW on ischemic stroke. Proton nuclear magnetic resonance ( 1 H NMR) based metabolomics analysis disclosed that HSW could relieve stroke rats suffering from the ischemia/reperfusion injury by ameliorating the disturbed energy and amino acids metabolisms, alleviating the oxidative stress from reactive oxygen species and reducing the inflammation. HSW treatment increased levels of cellular antioxidants that scavenged reactive oxygen species during ischemia-reperfusion via the nuclear erythroid 2-related factor 2 signaling pathway, and exert anti-inflammatory effect by decreasing the levels of inflammatory factors such as cyclooxygenase-2, interleukin-1β, interleukin-6 and tumor necrosis factor-α. The integrated metabolomics approach showed its potential in understanding mechanisms of HSW in relieving ischemic stroke. Further study to develop HSW as an effective therapeutic agent to treat ischemic stroke is warranted., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Loss of secretory IgA is common in the small airways of patients with chronic obstructive pulmonary disease and may contribute to disease pathogenesis. Using mice that lack secretory IgA in the airways due to genetic deficiency of polymeric Ig receptor (pIgR -/- mice), we investigated the role of neutrophils in driving the fibrotic small airway wall remodeling and emphysema that develops spontaneously in these mice. By flow cytometry, we found an increase in the percentage of neutrophils among CD45 + cells in the lungs, as well as an increase in total neutrophils, in pIgR -/- mice compared with wild-type controls. This increase in neutrophils in pIgR -/- mice was associated with elastin degradation in the alveolar compartment and around small airways, along with increased collagen deposition in small airway walls. Neutrophil depletion using anti-Ly6G antibodies or treatment with broad-spectrum antibiotics inhibited development of both emphysema and small airway remodeling, suggesting that airway bacteria provide the stimulus for deleterious neutrophilic inflammation in this model. Exogenous bacterial challenge using lysates prepared from pathogenic and nonpathogenic bacteria worsened neutrophilic inflammation and lung remodeling in pIgR -/- mice. This phenotype was abrogated by antiinflammatory therapy with roflumilast. Together, these studies support the concept that disruption of the mucosal immune barrier in small airways contributes to chronic obstructive pulmonary disease progression by allowing bacteria to stimulate chronic neutrophilic inflammation, which, in turn, drives progressive airway wall fibrosis and emphysematous changes in the lung parenchyma.

Classical activation (M1 phenotype) and alternative activation (M2 phenotype) are the two polars of microglial activation states that can produce either neurotoxic or neuroprotective effects in the immune pathogenesis of Parkinson's disease (PD). Exploiting the beneficial properties of microglia cells by modulating their polarization states provides great potential for the treatment of PD. However, the mechanism that regulates microglia polarization remains elusive. Here we demonstrated that Kir6.1-containing ATP-sensitive potassium (Kir6.1/K-ATP) channel switched microglia from the detrimental M1 phenotype toward the beneficial M2 phenotype. Kir6.1 knockdown inhibited M2 polarization and simultaneously exaggerated M1 microglial inflammatory responses, while Kir6.1 overexpression promoted M2 polarization and synchronously alleviated the toxic phase of M1 microglia polarization. Furthermore, we observed that the Kir6.1 deficiency dramatically exacerbated dopaminergic neuron death companied by microglia activation in mouse model of PD. Mechanistically, Kir6.1 deficiency enhanced the activation of p38 MAPK-NF-κB pathway and increased the ratio of M1/M2 markers in the substantia nigra compacta of mouse model of PD. Suppression of p38 MAPK in vivo partially rescued the deleterious effects of Kir6.1 ablation on microglia phenotype and dopaminergic neuron death. Collectively, our findings reveal that Kir6.1/K-ATP channel modulates microglia phenotypes transition via inhibition of p38 MAPK-NF-κB signaling pathway and Kir6.1/K-ATP channel may be a promising therapeutic target for PD.

Objective: To evaluate the accuracy of Xpert MTB/RIF assay in the diagnosis of cervical tuberculous lymphadenitis. Method: A total of 160 patients with cervical lymph node tuberculosis confirmed by pathology in Wuhan Pulmonary Hospital between January 2015 and June 2016 were enrolled. Cervical lymph node biopsy tissue specimens from these patients were collected and tested with acid-fast bacilli smear, TB-DNA assays, culture, and Xpert Mtb/RIF, respectively. The results were analyzed using SPSS 17.0 statistical software. Result: Using pathological diagnosis as the standard, the sensitivity of acid-fast bacilli smear was 8.12%(13/160), the sensitivity of TB-DNA assay was 69.38%(111/160), the sensitivity of culture was 31.88%(51/160), and the sensitivity of Xpert Mtb/RIF was 74.38%(119/160). The detection rate of multidrug-resistant lymphoid tuberculosis using a combination of Xpert Mtb/RIF, line probe assay (LPA), and culture methods was 9.38%(15/160). Conclusion: Xpert Mtb/RIF can rapidly detect cervical lymph node tuberculosis and assess rifampicin resistance. TB-DNA assay exhibited similar sensitivity as compared to Xpert Mtb/RIF and can detect both isoniazid and rifampicin resistant genes through LPA.These two methods are more effective than the traditional culture and smear methods., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Rationale: Maintenance of a surface immune barrier is important for homeostasis in organs with mucosal surfaces that interface with the external environment; however, the role of the mucosal immune system in chronic lung diseases is incompletely understood., Objectives: We examined the relationship between secretory IgA (SIgA) on the mucosal surface of small airways and parameters of inflammation and airway wall remodeling in chronic obstructive pulmonary disease (COPD)., Methods: We studied 1,104 small airways (<2 mm in diameter) from 50 former smokers with COPD and 39 control subjects. Small airways were identified on serial tissue sections and examined for epithelial morphology, SIgA, bacterial DNA, nuclear factor-κB activation, neutrophil and macrophage infiltration, and airway wall thickness., Measurements and Main Results: Morphometric evaluation of small airways revealed increased mean airway wall thickness and inflammatory cell counts in lungs from patients with COPD compared with control subjects, whereas SIgA level on the mucosal surface was decreased. However, when small airways were classified as SIgA intact or SIgA deficient, we found that pathologic changes were localized almost exclusively to SIgA-deficient airways, regardless of study group. SIgA-deficient airways were characterized by (1) abnormal epithelial morphology, (2) invasion of bacteria across the apical epithelial barrier, (3) nuclear factor-κB activation, (4) accumulation of macrophages and neutrophils, and (5) fibrotic remodeling of the airway wall., Conclusions: Our findings support the concept that localized, acquired SIgA deficiency in individual small airways of patients with COPD allows colonizing bacteria to cross the epithelial barrier and drive persistent inflammation and airway wall remodeling, even after smoking cessation.

Background: Previous research has demonstrated that ClC-3 is responsible for volume-regulated Cl - current (I Cl.vol ) in vascular smooth muscle cells (VSMCs). However, it is still not clear whether and how ClC-3 is transported to cell membranes, resulting in alteration ofI Cl.vol .Methods and Results:Volume-regulated chloride current (I Cl.vol ) was recorded by whole-cell patch clamp recording, and Western blotting and co-immunoprecipitation were performed to examine protein expression and protein-protein interaction. Live cell imaging was used to observe ClC-3 transporting. The results showed that an overexpression of endophilin A2 could increaseI Cl.vol , while endophilin A2 knockdown decreasedI Cl.vol . In addition, the SH3 domain of endophilin A2 mediated its interaction with ClC-3 and promotes ClC-3 transportation from the cytoplasm to cell membranes. The regulation of ClC-3 channel activity was also verified in basilar arterial smooth muscle cells (BASMCs) isolated from endophilin A2 transgenic mice. Moreover, endophilin A2 increase VSMCs proliferation induced by endothelin-1 or hypo-osmolarity., Conclusions: The present study identified endophilin A2 as a ClC-3 channel partner, which serves as a new ClC-3 trafficking insight in regulatingI Cl.vol in VSMCs. This study provides a new mechanism by which endophilin A2 regulates ClC-3 channel activity, and sheds light on how ClC-3 is transported to cell membranes to play its critical role as a chloride channel in VSMCs function, which may be involved in cardiovascular diseases. (Circ J 2016; 80: 2397-2406).

Mitochondrial uncoupling protein 2 (UCP2) has been well characterized to control the production of reactive oxygen species (ROS) and astrocytes are the major cells responsible for the ROS production and the inflammatory responses in the brain. However, the function of UCP2 in astrocytes and the contribution of astrocytic UCP2 to depression remain undefined. Herein, we demonstrated that UCP2 knockout (KO) mice displayed aggravated depressive-like behaviors, impaired neurogenesis, and enhanced loss of astrocytes in the chronic mild stress (CMS)-induced anhedonia model of depression. We further found that UCP2 ablation significantly enhanced the activation of the nod-like receptor protein 3 (NLRP3) inflammasome in the hippocampus and in astrocytes. Furthermore, UCP2 deficiency promoted the injury of mitochondria, the generation of ROS and the physical association between thioredoxin-interacting protein (TXNIP) and NLRP3 in astrocytes. Moreover, transiently expressing exogenous UCP2 partially rescued the deleterious effects of UCP2 ablation on the astrocytes. These data indicate that UCP2 negatively regulates the activation of NLRP3 inflammasome and inhibited the ROS-TXNIP-NLRP3 pathway in astrocytes. Collectively, our findings reveal that UCP2 regulates inflammation responses in astrocytes and plays an important role in the pathogenesis of depression and that UCP2 may be a promising therapeutic target for depression., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Emerging evidence indicates that NLRP3 inflammasome-induced inflammation plays a crucial role in the pathogenesis of depression. Thus, inhibition of NLRP3 inflammasome activation may offer a therapeutic benefit in the treatment of depression. Fluoxetine, a widely used antidepressant, has been shown to have potential antiinflammatory activity, but the underlying mechanisms remain obscure., Methods: We used a chronic mild stress model and cultured primary macrophage/microglia to investigate the effects of fluoxetine on NLRP3 inflammasome and its underlying mechanisms., Results: We demonstrated that fluoxetine significantly suppressed NLRP3 inflammasome activation, subsequent caspase-1 cleavage, and interleukin-1β secretion in both peripheral macrophages and central microglia. We further found that fluoxetine reduced reactive oxygen species production, attenuated the phosphorylation of double-stranded RNA-dependent protein kinase, and inhibited the association of protein kinase with NLRP3. These data indicate that fluoxetine inhibits the activation of NLRP3 inflammasome via downregulating reactive oxygen species-protein kinase-NLRP3 signaling pathway. Correspondingly, in vivo data showed that fluoxetine also suppressed NLRP3 inflammasome activation in hippocampus and macrophages of chronic mild stress mice and alleviated chronic mild stress-induced depression-like behavior., Conclusions: Our findings reveal that fluoxetine confers an antidepressant effect partly through inhibition of peripheral and central NLRP3 inflammasome activation and suggest the potential clinical use of fluoxetine in NLRP3 inflammasome-driven inflammatory diseases such as depression., (© The Author 2016. Published by Oxford University Press on behalf of CINP.)

Aim: Ginkgolide B (GB) has shown neuroprotective effect in treating ischemic stroke, related to its property of anti-inflammation. Nevertheless, it is unclear whether GB is able to modulate microglia/macrophage polarization, which has recently been proven to be vital in the pathology of ischemic stroke., Methods: We performed transient middle cerebral artery occlusion (tMCAO) on C57BL/6J male mice and induced cultured BV2 microglia and primary bone marrow-derived macrophages to be M1/2 phenotype by LPS+ interferon-γ and IL-4, respectively. Immunofluorescence and flow cytometry were used for detecting the specialized protein expression of M1/2, such as CD206 and CD16/32. qPCR was utilized to detect the signature gene change of M1/2., Results: GB significantly reduced cerebral ischemic damage and ameliorated the neurological deficits of mice after tMCAO. More importantly, our experiments proved that GB promoted microglia/macrophage transferring from inflammatory M1 phenotype to a protective, anti-inflammatory M2 phenotype in vivo or vitro. CV3988 and silencing the platelet activator factor (PAF) receptor by siRNA demonstrated that PAF receptor was involved in the modulation of microglia/macrophage polarization., Conclusion: Our results reveal a novel pharmacological effect of GB in modulating microglia/macrophage polarization after tMCAO, thus deepening our understanding of neuroprotective mechanisms of GB in treatment of ischemic stroke. Furthermore, this new mechanism may allow GB to be used in many other microglia/macrophage polarization-related inflammatory diseases., (© 2016 John Wiley & Sons Ltd.)

Objective: To investigate the concentrations and clinical significance of interleukin (IL)-20 and IL-22 in pleural effusion with various etiologies., Methods: Pleural effusion (PE) and corresponding serum samples were obtained from 88 patients from Wuhan Tuberculosis Prevention and Control Institute from June 2011 to June 2013. There were 27 cases with malignant pleural effusion, 24 with tuberculous pleural effusion, 17 with bacterial pleural effusion and 20 with transudativeeffusion. The pleural and serum levels of IL-20 and IL-22 were determined by sandwich enzyme-linked immunosorbent assays (ELISA)., Results: (1) Except for transudativeeffusion, the concentration of IL-20 in malignant pleural effusion (36.8±5.1) ng/L, tuberculous pleural effusion (34.8±6) ng/L, bacterial pleural effusion (41.7±20.2) ng/L, were significantly higher than that of the corresponding serum concentration (29.7±5.97) ng/L, (27.3 ±6.7) ng/L, (25.6±4.7) ng/L (t=5.044, 3.804, 3.452, P<0.05). However, the concentration of IL-20 in pleural effusions of different causes showed no significant difference; malignant (36.8±5.1) ng/L, tuberculous(34.8±6.0) ng/L, bacterial (41.7±20.2) ng/L, transudate (34.1±7.3) ng/L (P>0.05). The concentration of IL-22 (median, quartiles) in tuberculouseffusion was 146.1 (39.8) ng/L and bacterial effusion 59.6 (484.3) ng/L was significantly higher than those in the corresponding serum concentrations 18.7 (9.8) ng/L, 15.7 (17.2) ng/L (Z value respectively -3.971, -3.290, P<0.05). The concentration of IL-22 in tuberculous pleural effusion, bacterial pleural effusion, transudative pleural effusion was significant higher than those in malignant pleural effusion respectively (all P<0.001). (2)The concentrations of IL-22 in malignant pleural effusion was correlated positively with those in serum (r=0.729, P<0.001). (3) With a cut-off value of 19.7 ng/L, pleural IL-22 exhibited a high sensitivity and specificity of 95.1% (39/41) and 88.9%(24/27) respectively, when used for distinguishing infectious pleural effusion (including tuberculous and bacterial effusion) from malignant pleural effusion (P<0.001)., Conclusions: Higher levels of IL-22 in tuberculous and bacterial pleural effusion were found when compared with corresponding serum levels and might be involved in the pathogenesis of infectious pleural effusion. Pleural IL-22 measurement provided reliable diagnostic efficiency for distinguishing infectious from malignant pleural effusion.

Background: α-Synuclein (α-Syn), a pathological hallmark of Parkinson's disease (PD), has been recognized to induce the production of interleukin-1β in a process that depends, at least in vitro, on nod-like receptor protein 3 (NLRP3) inflammasome in monocytes. However, the role of NLRP3 inflammasome activation in the onset of PD has not yet been fully established., Results: In this study, we showed that NLRP3 inflammasomes were activated in the serum of PD patients and the midbrain of PD model mice. We further clarified that α-syn activated the NLRP3 inflammasome through microglial endocytosis and subsequent lysosomal cathepsin B release. Deficiency of caspase-1, an important component of NLRP3 inflammasome, significantly inhibited α-syn-induced microglia activation and interleukin-1β production, which in turn alleviated the reduction of mesencephalic dopaminergic neurons treated by microglia medium. Specifically, we demonstrated for the first time that Nlrp3 is a target gene of microRNA-7 (miR-7). Transfection of miR-7 inhibited microglial NLRP3 inflammasome activation whereas anti-miR-7 aggravated inflammasome activation in vitro. Notably, stereotactical injection of miR-7 mimics into mouse striatum attenuated dopaminergic neuron degeneration accompanied by the amelioration of microglial activation in MPTP-induced PD model mice., Conclusions: Our study provides a direct link between miR-7 and NLRP3 inflammasome-mediated neuroinflammation in the pathogenesis of PD. These findings will give us an insight into the potential of miR-7 and NLRP3 inflammasome in terms of opening up novel therapeutic avenues for PD.

Mechanisms driving persistent airway inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. As secretory immunoglobulin A (SIgA) deficiency in small airways has been reported in COPD patients, we hypothesized that immunobarrier dysfunction resulting from reduced SIgA contributes to chronic airway inflammation and disease progression. Here we show that polymeric immunoglobulin receptor-deficient (pIgR(-/-)) mice, which lack SIgA, spontaneously develop COPD-like pathology as they age. Progressive airway wall remodelling and emphysema in pIgR(-/-) mice are associated with an altered lung microbiome, bacterial invasion of the airway epithelium, NF-κB activation, leukocyte infiltration and increased expression of matrix metalloproteinase-12 and neutrophil elastase. Re-derivation of pIgR(-/-) mice in germ-free conditions or treatment with the anti-inflammatory phosphodiesterase-4 inhibitor roflumilast prevents COPD-like lung inflammation and remodelling. These findings show that pIgR/SIgA deficiency in the airways leads to persistent activation of innate immune responses to resident lung microbiota, driving progressive small airway remodelling and emphysema.

The speed and paths of synchronization play a key role in the function of a system, which has not received enough attention up to now. In this work, we study the synchronization process of coupled logistic maps that reveals the common features of low-dimensional dissipative systems. A slowing down of synchronization process is observed, which is a novel phenomenon. The result shows that there are two typical kinds of transient process before the system reaches complete synchronization, which is demonstrated by both the coupled multiple-period maps and the coupled multiple-band chaotic maps. When the coupling is weak, the evolution of the system is governed mainly by the local dynamic, i.e., the node states are attracted by the stable orbits or chaotic attractors of the single map and evolve toward the synchronized orbit in a less coherent way. When the coupling is strong, the node states evolve in a high coherent way toward the stable orbit on the synchronized manifold, where the collective dynamics dominates the evolution. In a mediate coupling strength, the interplay between the two paths is responsible for the slowing down. The existence of different synchronization paths is also proven by the finite-time Lyapunov exponent and its distribution.

Secretory immunoglobulin A (SIgA) reaches the airway lumen by local transcytosis across airway epithelial cells or with tracheobronchial submucosal gland secretions. In chronic obstructive pulmonary disease (COPD), deficiency of SIgA on the airway surface has been reported. However, reduction of SIgA levels in sputum and bronchoalveolar lavage (BAL) fluid has not been consistently observed. To explain this discrepancy, we analyzed BAL fluid and lung tissue from patients with COPD and control subjects. Immunohistochemical analysis of large and small airways of COPD patients showed that MUC5AC is the predominant mucin expressed by airway epithelial cells, whereas MUC5B is expressed in submucosal glands of large airways. Dual immunostaining with anti-IgA and anti-MUC5B antibodies showed reduction of IgA on the airway surface as well as accumulation of IgA within MUC5B-positive luminal mucus plugs, suggesting that luminal SIgA originates from submucosal glands in COPD patients. We found that the concentration of SIgA in BAL is inversely correlated with forced expiratory volume in 1 s (FEV 1 ) in COPD, but that the ratio of SIgA/MUC5B is a better predictor of FEV 1 , particularly in patients with moderate COPD. Together, these findings suggest that SIgA production by submucosal glands, which are expanded in COPD, is insufficient to compensate for reduced SIgA transcytosis by airway epithelial cells. Localized SIgA deficiency on the surface of small airways is associated with COPD progression and represents a potential new therapeutic target in COPD., Competing Interests: We declare that we have no conflict of interest.

Objectives: Deterioration of cardiac performance under stress may be partly mediated by dysfunctional mitochondria and endoplasmic reticulum (ER) that is likely related to an activation of NADPH oxidase (NOX) and an increase in pro-inflammatory factors. We investigated if a new compound CPUY11018 (CPUY) derived from Azimilide could ameliorate the stress impaired cardiac performance., Methods: Forty-eight male Sprague Dawley rats were randomly divided into six groups and were injected with isoproterenol (ISO, 1 ml/kg, s.c.) for 10 days. Cardiac myocytes and fibroblasts from neonate rats were incubated with ISO. CPUY was employed and compared with apocynin (APO) - an inhibitor of NOX., Key Findings: In ISO-treated group, the compromised haemodynamics and cardiac remodelling were significant with dysfunctional mitochondria indicated by decreased MnSOD and mitochondrial membrane potential, and an enhanced reactive oxygen species genesis. Downregulation of FKBP12.6, CASQ2 and SERCA2a was also remarkable in vivo and in vitro implying an abnormal ER. Upregulated Nox4, p22(phox) and p47(phox) were significant, associated with upregulation of Src, IκBβ and NFκB, and downregulation of pAMPK/AMPK and Cx40 in vivo and in vitro. These abnormalities were relieved by CPUY and APO., Conclusions: CPUY is potential in managing cardiac insufficiency through normalizing mitochondria and ER in the affected heart., (© 2015 Royal Pharmaceutical Society.)