Dynamics and concordance alterations of regional brain function indices in vestibular migraine: a resting-state fMRI study.

BACKGROUND: Prior MRI studies on vestibular migraine (VM) have revealed abnormalities in static regional intrinsic brain activity (iBA) and dynamic functional connectivity between brain regions or networks. However, the temporal variation and concordance of regional iBA measures remain to be explored. METHODS: 57 VM patients during the interictal period were compared to 88 healthy controls (HC) in this resting-state functional magnetic resonance imaging (fMRI) study. The dynamics and concordance of regional iBA indices, including amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo), were examined by utilizing sliding time-window analysis. Partial correlation analyses were performed between clinical parameters and resting-state fMRI indices in brain areas showing significant group differences. RESULTS: The VM group showed increased ALFF and ReHo dynamics, as well as increased temporal concordance between ALFF and ReHo in the bilateral paracentral lobule and supplementary motor area relative to the HC group. We also found decreased ReHo dynamics in the right temporal pole, and decreased ALFF dynamics in the right cerebellum posterior lobe, bilateral angular gyrus and middle occipital gyrus (MOG) in the VM group compared with the HC group. Moreover, a positive correlation was observed between ALFF dynamics in the left MOG and vertigo disease duration across all VM patients. CONCLUSION: Temporal dynamics and concordance of regional iBA indices were altered in the motor cortex, cerebellum, occipital and temporoparietal cortex, which may contribute to disrupted multisensory processing and vestibular control in patients with VM. ALFF dynamics in the left MOG may be useful biomarker for evaluating vertigo burden in this disorder.

Insights into multisource sludge distributed in the Yangtze River basin, China: Characteristics, correlation, treatment and disposal.

Sludge is the by-product of wastewater treatment process. Multisource sludge can be defined as sludge from different sources. Based on the sludge properties of five typical cities in the Yangtze River basin, including Jiujiang, Wuhu, Lu'an, Zhenjiang and Wuhan, this study investigated and summarized the characteristic variations and distribution differences of multiple indicators and substances from municipal sludge, dredged sludge, and river and lake sediments. The results demonstrated pH of multisource sludge was relatively stable in the neutral range. Organic matter and water content among municipal sludge were high and varied considerably between different wastewater treatment plants. Dredged sludge had an obviously higher sand content and wider particle distribution, which could be considered for graded utilization depending on its size. The nutrients composition of river and lake sediments was usually stable and special, with lower nitrogen and phosphorus content but higher potassium levels. The sources of heavy metals and persistent organic pollutants in multisource sludge were correlated, generally much higher among municipal sludge than dredged sludge and river and lake sediments, which were the most important limitation for final land utilization. Despite various properties of multisource sludge, the final fate and destination have some overall similarities, which need to be supplemented and improved by standards and laws. The study provided a preliminary analysis of suitable technical routes for municipal sludge, dredged sludge, river and lake sediments based on their different characteristics respectively, which was of great significance for multisource sludge co-treatment and disposal in the future of China.

Chronic acrylamide exposure resulted in dopaminergic neuron loss, neuroinflammation and motor impairment in rats.

Acrylamide (ACR) as a by-product of Maillard reaction is widely present in food. Although ACR is known to exhibit neurotoxicity, most studies about ACR neurotoxicity are currently short-term high-dose providing limited reference value for human exposure. The present study aims to determine the effects of chronic ACR exposure on dopaminergic neurons in rat nigra and the potential mechanism from the perspective of NLRP3 inflammasome-mediated neuroinflammation. The SD rats were maintained on treated drinking water providing dosages of 0, 0.5, or 5 mg/kg/day ACR for 12 months. ACR exposure caused motor dysfunction in rats, which was associated with dopaminergic neuron loss, α-Synuclein (α-Syn) accumulation and decreased brain-derived neurotrophic factor (BDNF) in nigra. ACR activated microglia by increasing Iba-1+, Iba-1+CD68+ positive cells and the percentage of ameboid-shaped ones in rat nigra. ACR markedly upregulated the protein levels of NLRP3 inflammasome constituents NLRP3 and caspase-1 and inflammatory cytokine IL-1ß. ACR chronic exposure increased the risk of Parkinson's disease (PD) like dopaminergic neuron depletion in nigra potentially through NLRP3 inflammasome-mediated neuroinflammtion.

Prediction of long-term mortality by using machine learning models in Chinese patients with connective tissue disease-associated interstitial lung disease.

BACKGROUND: The exact risk assessment is crucial for the management of connective tissue disease-associated interstitial lung disease (CTD-ILD) patients. In the present study, we develop a nomogram to predict 3­ and 5-year mortality by using machine learning approach and test the ILD-GAP model in Chinese CTD-ILD patients. METHODS: CTD-ILD patients who were diagnosed and treated at the First Affiliated Hospital of Zhengzhou University were enrolled based on a prior well-designed criterion between February 2011 and July 2018. Cox regression with the least absolute shrinkage and selection operator (LASSO) was used to screen out the predictors and generate a nomogram. Internal validation was performed using bootstrap resampling. Then, the nomogram and ILD-GAP model were assessed via likelihood ratio testing, Harrell's C index, integrated discrimination improvement (IDI), the net reclassification improvement (NRI) and decision curve analysis. RESULTS: A total of 675 consecutive CTD-ILD patients were enrolled in this study, during the median follow-up period of 50 (interquartile range, 38-65) months, 158 patients died (mortality rate 23.4%). After feature selection, 9 variables were identified: age, rheumatoid arthritis, lung diffusing capacity for carbon monoxide, right ventricular diameter, right atrial area, honeycombing, immunosuppressive agents, aspartate transaminase and albumin. A predictive nomogram was generated by integrating these variables, which provided better mortality estimates than ILD-GAP model based on the likelihood ratio testing, Harrell's C index (0.767 and 0.652 respectively) and calibration plots. Application of the nomogram resulted in an improved IDI (3- and 5-year, 0.137 and 0.136 respectively) and NRI (3- and 5-year, 0.294 and 0.325 respectively) compared with ILD-GAP model. In addition, the nomogram was more clinically useful revealed by decision curve analysis. CONCLUSIONS: The results from our study prove that the ILD-GAP model may exhibit an inapplicable role in predicting mortality risk in Chinese CTD-ILD patients. The nomogram we developed performed well in predicting 3­ and 5-year mortality risk of Chinese CTD-ILD patients, but further studies and external validation will be required to determine the clinical usefulness of the nomogram.

Use of machine learning models to predict prognosis of combined pulmonary fibrosis and emphysema in a Chinese population.

BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is a novel clinical entity with a poor prognosis. This study aimed to develop a clinical nomogram model to predict the 1-, 2- and 3-year mortality of patients with CPFE by using the machine learning approach, and to validate the predictive ability of the interstitial lung disease-gender-age-lung physiology (ILD-GAP) model in CPFE. METHODS: The data of CPFE patients from January 2015 to October 2021 who met the inclusion criteria were retrospectively collected. We utilized LASSO regression and multivariable Cox regression analysis to identify the variables associated with the prognosis of CPFE and generate a nomogram. The Harrell's C index, the calibration curve and the area under the receiver operating characteristic (ROC) curve (AUC) were used to evaluate the performance of the nomogram. Then, we performed likelihood ratio test, net reclassification improvement (NRI), integrated discrimination improvement (IDI) and decision curve analysis (DCA) to compare the performance of the nomogram with that of the ILD-GAP model. RESULTS: A total of 184 patients with CPFE were enrolled. During the follow-up, 90 patients died. After screening out, diffusing lung capacity for carbon monoxide (DLCO), right ventricular diameter (RVD), C-reactive protein (CRP), and globulin were found to be associated with the prognosis of CPFE. The nomogram was then developed by incorporating the above five variables, and it showed a good performance, with a Harrell's C index of 0.757 and an AUC of 0.800 (95% CI 0.736-0.863). Moreover, the calibration plot of the nomogram showed good concordance between the prediction probabilities and the actual observations. The nomogram also improved the discrimination ability of the ILD-GAP model compared to that of the ILD-GAP model alone, and this was substantiated by the likelihood ratio test, NRI and IDI. The significant clinical utility of the nomogram was demonstrated by DCA. CONCLUSION: Age, DLCO, RVD, CRP and globulin were identified as being significantly associated with the prognosis of CPFE in our cohort. The nomogram incorporating the 5 variables showed good performance in predicting the mortality of CPFE. In addition, although the nomogram was superior to the ILD-GAP model in the present cohort, further validation is needed to determine the clinical utility of the nomogram.

Altered local and distant functional connectivity density in chronic migraine: a resting-state functional MRI study.

PURPOSE: Previous studies have indicated disrupted functional connectivity in multiple brain regions and resting-state networks in episodic migraine, but it is unclear how brain network property is disrupted in chronic migraine. METHODS: Using resting-state functional magnetic resonance imaging and voxel-wise functional connectivity density analysis, we examined the large-scale functional connectivity pattern over the whole brain in 17 patients with chronic migraine without medication overuse compared to 35 healthy controls. The associations between functional connectivity density and clinical variables were also explored. RESULTS: Compared with controls, chronic migraine patients showed decreased local and distant functional connectivity density in the dorsolateral and medial prefrontal cortexes and precuneus and increased local and distant functional connectivity density in the hippocampal complex. The patients also presented increased local functional connectivity density in the orbital frontal gyrus and cerebellum and increased distant functional connectivity density in the temporal pole. Moreover, local functional connectivity density in several brain regions, such as the left superior temporal gyrus and dorsal anterior cingulate cortex, was found to be correlated with headache frequency or pain intensity. CONCLUSION: Chronic migraine is associated with functional connectivity alterations in regions involved in multisensory integration, affective and cognitive processing, and pain modulation. Both local and distant functional connectivity density are complementary biomarkers for investigating the neural mechanism of this disorder. Some local functional connectivity density alterations may be useful for assessing the disease burden of chronic migraine.

Efficacy of simplified-cognitive behavioral therapy for insomnia(S-CBTI) among female COVID-19 patients with insomnia symptom in Wuhan mobile cabin hospital.

BACKGROUND: The outbreak of Coronavirus Disease-2019 (COVID-19) caused great psychological distress often with comorbid insomnia. Insomnia is common in patients with COVID-19 admitted to mobile cabin hospitals. Insomnia may lead to immune dysfunction, a condition not conducive to recovery from COVID-19. The use of sedative-hypnotic drugs is limited by their inhibitory effect on the respiratory system. A paucity of research is available regarding psychotherapy interventions to improve insomnia symptoms among  patients with COVID-19. In the general population, sleep problems are more common in women than in men; insomnia in women patients requires special attention. The aim of this study was to develop simplified-cognitive behavioral therapy for insomnia (S-CBTI) for patients with COVID-19 and comorbid insomnia symptoms and to verify its effectiveness through a self-control trial. A second aim was to compare the effectiveness of S-CBTI between acute and chronic insomnia among women with COVID-19 and comorbid insomnia symptoms in Wuhan Jianghan Cabin Hospital. METHODS: S-CBTI consisted of education on COVID-19 and sleep hygiene, stimulus control, sleep restriction, and self-suggestion relaxation training over a period of two consecutive weeks. Of 67 women, 66 completed psychological intervention and baseline and post-intervention assessments. There were 31 women with acute insomnia and 35 with chronic insomnia. The Insomnia Severity Index (ISI) score and self-compiled sleep data were assessed at baseline and post-intervention, and subjective sleep evaluations were assessed at days 4, 7, 12, and 14. RESULTS: The ISI score, sleep latency, night sleep time, and sleep efficiency were statistically significantlly improved from baseline to post-intervention by paired T-test. After the intervention, the mean ISI score of the acute insomnia group was lower than that of the chronic insomnia group. The reduction of the ISI score and the improvement of sleep time from baseline to post-intervention in the acute insomnia group were greater than those in the chronic insomnia group. Utilization of sedative-hypnotic drugs in the acute insomnia group was less than that in the chronic insomnia group, and the difference was statistically significant. CONCLUSIONS: S-CBTI can improve the insomnia symptoms of women with COVID-19 in mobile cabin hospitals, especially for stress-related acute insomnia.

Effect of long-term exposure to acrylamide on endoplasmic reticulum stress and autophagy in rat cerebellum.

Acrylamide (ACR) is a widely used chemical compound that has neurotoxicity in human, but whether ACR could impair the cerebellum and the related mechanism were still unknown. This study aimed to observe the changes in behavioral performance and cerebellar morphology caused by chronic ACR exposure, and to evaluate its influence on apoptosis, endoplasmic reticulum stress (ERS) and autophagy. Rats were treated with 0, 0.5 and 5 mg/kg ACR by drinking water for 12 months. Results showed that 5 mg/kg ACR treatment damaged the gait, balance ability, hindlimb muscle strength and motor coordination ability of rats. The results of hematoxylin and eosin and Nissl staining indicated that ACR impaired the structures of all three layers of the cerebellum, especially the Purkinje cell layer, showing abnormal morphology with nucleus condensation and pyknosis. Accumulation of autophagosomes, dilated endoplasmic reticulum and swollen mitochondria were observed in neurons under transmission electron microscopy. The enhanced apoptotic rates and the increased Bax expression indicated the elevated level of apoptosis. The results of Western blot showed that ACR treatment elevated protein levels of Beclin1, LC3-II/LC3-I, p-PERK/t-PERK, ATF4 and CHOP, indicating the initiation of autophagy, the activation of PERK pathway in ERS. This work helps to demonstrate the ACR neurotoxicity on cerebellum under chronic treatment and its underlying mechanism.

Comparison of anaerobic phosphorus release from activated sludge with three carbon sources.

Three carbon sources, namely sodium acetate, sewage and effluent, were used to simulate the process of phosphorus release in an actual sewage treatment plant, in order to explore the phosphorus release performance of the sludge, the relationship between phosphorus release and chemical oxygen demand (COD) in sewage, and the stability of phosphorus-rich sludge. The results showed that the type and concentration of carbon sources had significant effects on the rate of phosphorus release, reaction equilibrium time and phosphorus release amount. When sodium acetate was used as the carbon source, the phosphorus release rate reached 12.54 mg P (g VSS·h)-1, and tended to be stable at 4.0 hours. The phosphorus release amount in the first 2.5 hours accounted for 36.88% of the total phosphorus in the sludge. When sewage was used as the carbon source, the phosphorus release rate did not reach equilibrium even at 5.0 hours, and the phosphorus release amount increased by 1.0 mg L-1 for every 10.5 mg L-1 increase sewage COD within a certain range. When effluent was used as the carbon source, the visual phosphorus release amount was only 0.83 mg L-1 after standing for 24 hours and the actual phosphorus release amount was 17.98 mg L-1. These conclusions can provide technical support for the optimization of phosphorus removal in sewage treatment plants.

[Evidence of clinical randomized controlled trial study in treatment of acute cerebral infarction with traditional Chinese medicine in recent five years].

To systematically search and sort out the clinical randomized controlled trial(RCT) on the prevention and treatment of acute cerebral infarction with traditional Chinese medicine(TCM) by using the method of evidence map, and to understand the evidence distribution of related studies. CNKI, Wanfang, VIP, CBM, PubMed, EMbase, Cochrane Library and Web of Science were retrieved from January 2016 to September 2020, and literatures related to the prevention and treatment of acute cerebral infarction with traditional Chinese medicine were included. Text description combined with table and bubble chart were used to analyze the distribution characteristics of evidence. A total of 1 102 clinical articles in recent five years were retrieved. The annual trend of clinical study publication, study size, TCM therapy category and main scheme, and study literature quality were analyzed. We find that TCM treatment of acute cerebral infarction has become a hot topic of clinical research, the number of literature showed a trend of increased year by year, various means of intervention of TCM in the treatment of the advantages of increasingly highlight. Follow-up clinical research should highlight the characteristics of TCM: in the analysis of outcome indicators; increase the neuropsychological patients after stroke and cognitive ability, and the theory of combined treatment of TCM disease when thoughts; At the same time, the quality of clinical research needs to be improved. At present, there is still a lack of unified standards for the production of evidence map. This study is the first to explore the application of evidence map to summarize and display the clinical research status of TCM treatment of acute cerebral infarction, and combine it with the setting of priority areas of TCM clinical research, so as to provide a reference basis for determining the priority topic selection of TCM treatment optimization research.

[Analysis of status quo of outcome indicators of randomized controlled trials in treatment of acute ischemic stroke with acupuncture in recent three years].

To analyze the use of outcome indicators of randomized controlled trial(RCT) of acupuncture in the treatment of acute ischemic stroke in recent three years, so as to provide a basis for building a study on the core outcome indicators for the treatment of acute ischemic stroke with acupuncture. The RCTs of acupuncture treatment for acute ischemic stroke in recent three years were collec-ted through computer retrieval of eight Chinese and English databases and two clinical trial registries at home and abroad. Literature was screened out, and data was extracted. Risk of assessment bias tool Cochrane 6.1 was used for bias risk assessment, outcome indicators were summarized and analyzed. A total of 47 RCTs were included, and 3 studies were trials registration scheme. Outcome indicators were divided into 6 categories according to functional attributes, namely physical symptoms/signs, physical and chemical examination, quality of life, traditional Chinese medicine symptoms/syndromes, safety events and long-term prognosis. The study found that in addition to the common problems in previous studies covered by the status quo of outcome indicators selection of RCT of acupuncture in the treatment of acute ischemic stroke, there were also the other problems as follows: emphasis on macroscopic efficacy indicators but neglect of acupuncture specific indicators, lack of characteristic indicators and economic indicators of traditional Chinese medicine therapy, and unification of indicators measurement tool and measurement time point. In the future, the outcome indicators set for the treatment of acute ischemic stroke with acupuncture shall be established, and the core outcome indicators set shall be in line with the characteristics of traditional Chinese medicine treatment.

[Overview of systematic reviews/Meta-analysis of Xingnaojing Injection in treatment of cerebral ischaemic stroke].

There have been many clinical trials, systematic reviews/Meta-analysis proving that Xingnaojing Injection has a good clinical efficacy in treatment of cerebral ischaemic stroke, but with fewer comprehensive descriptions. In this study, an overview of systematic reviews/Meta-analysis of Xingnaojing Injection in treating cerebral ischaemic stroke was performed to provide current situation of evidences and basis for clinical practice. CNKI, Wanfang, VIP, CBM, EMbase, PubMed, Cochrane Library, Web of Science were retrieved through computers. A total of 6 literatures were included in this study. By AMSTAR-2 checklist and GRADE, the quality of included systematic reviews and the efficacy of Xingnaojing Injection were evaluated. The results of AMSTAR-2 checklist showed an extremely low quality for all of the 6 systematic reviews. According to the results of GRADE evaluation, among 55 outcomes, there were 2 outcomes with a medium quality, 4 outcomes with a low quality and 49 outcomes with an extremely low quality. The 6 systematic reviews reached a consistent conclusion that Xingnaojing Injection was effective in the treatment of cerebral ischaemic stroke. This therapy could improve the total efficacy, neurological deficit scores, hemodynamic and hemodynamic parameters. However, the methodolo-gical quality of all literatures was extremely low. The evidence levels of outcomes were between extremely low to medium. The effectiveness of Xingnaojing Injection in the treatment of cerebral ischaemic stroke still needs to be further verified by more high-quality studies. In the future, relevant clinical studies and systematic reviews/Meta-analysis shall be carried out in a strict accordance with relevant regulations.

[Overview of systematic reviews of Panax notoginseng saponins in treatment of acute cerebral infarction].

To overview the systematic reviews of Panax notoginseng saponins in the treatment of acute cerebral infarction. CNKI, CBM, Wanfang, VIP, PubMed, Cochrane Library and EMbase databases were retrieved to collect the systematic reviews of the efficacy of P. notoginseng saponins in the treatment of acute cerebral infarction. The retrieval time was from the time of database establishment to January 2021. After two researchers independently screened out the literature and extracted the data, AMSTAR-2 scale was used to evaluate the methodological quality of the included systematic reviews, GRADE system was used to grade the quality of evidences of the outcome indicators, and the efficacy evaluation was summarized. A total of 5 systematic reviews were included. AMSTAR-2 evaluation results showed that 3 items were relatively complete, while 4 items had a poor overall quality. P. notoginseng saponins combined with conventional Western medicine therapy was superior to single conventional therapy in the recovery of neurological function, enhancement of the total effective rate in clinic, and improvement of activities of daily living. GRADE evaluation results showed that the quality of evidence was from low quality to very low quality. In conclusion, in the treatment of acute cerebral infarction, P. notoginseng saponins can improve the clinical efficacy, with a good safety but a not high methodological quality and a low evidence quality. It is suggested that high-quality clinical studies shall be further carried out to provide evidence-based basis for the application of P. notoginseng saponins in the treatment of acute cerebral infarction.

Hypoxia-induced autophagy activation through NF-κB pathway regulates cell proliferation and migration to induce pulmonary vascular remodeling.

OBJECTIVES: This study aimed to investigate whether autophagy mediated cell proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) under hypoxia and to validate the underlying mechanism. METHODS: The rat model of chronic hypoxia-induced pulmonary vascular remodeling was established. Rat primary PASMCs were isolated and cultured in vitro in hypoxia or normoxia to explore the underlying mechanism. RESULTS: Hypoxia exposure for 21 days induced pulmonary vascular remodeling in rats, accompanied by enhanced proliferation and decreased apoptosis, as well as induced expression of autophagic marker LC3II in their lungs. Furthermore, in vitro assays revealed that hypoxia exposure significantly promoted cell proliferation and migration, but inhibited apoptosis of PASMCs compared with normoxia treatment. Besides, hypoxia exposure led to an increase of cell fractions in S phase and a decrease in G0/G1 of PASMCs, whereas had no significant effect on cell population in G2/M phase. Moreover, the autophagy inhibitor 3-MA significantly decreased the hypoxia-induced upregulated expression of LC3II in PASMCs and abrogated the effect of hypoxia on cell proliferation, cell apoptosis, cell cycle, and cell migration of PASMCs. Additionally, inhibition of NF-κB pathway by PDTC suppressed the hypoxia-induced upregulation of NF-κB activity, LC3II, and cell cycle regulators (cyclin D1, CDK4, and CDK6) in PASMCs, and abolished the hypoxia-mediated regulation of cell proliferation, apoptosis, cycle, and migration of PASMCs. CONCLUSION: In summary, hypoxia could induce autophagy activation through NF-κB pathway, and thereby regulate cell proliferation and migration to induce pulmonary vascular remodeling.

A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use.

Food intake increases the activity of hepatic de novo lipogenesis, which mediates the conversion of glucose to fats for storage or use. In mice, this program follows a circadian rhythm that peaks with nocturnal feeding and is repressed by Rev-erbα/ß and an HDAC3-containing complex during the day. The transcriptional activators controlling rhythmic lipid synthesis in the dark cycle remain poorly defined. Disturbances in hepatic lipogenesis are also associated with systemic metabolic phenotypes, suggesting that lipogenesis in the liver communicates with peripheral tissues to control energy substrate homeostasis. Here we identify a PPARδ-dependent de novo lipogenic pathway in the liver that modulates fat use by muscle via a circulating lipid. The nuclear receptor PPARδ controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific PPARδ activation increases, whereas hepatocyte-Ppard deletion reduces, muscle fatty acid uptake. Unbiased metabolite profiling identifies phosphatidylcholine 18:0/18:1 (PC(18:0/18:1) as a serum lipid regulated by diurnal hepatic PPARδ activity. PC(18:0/18:1) reduces postprandial lipid levels and increases fatty acid use through muscle PPARα. High-fat feeding diminishes rhythmic production of PC(18:0/18:1), whereas PC(18:0/18:1) administration in db/db mice (also known as Lepr(-/-)) improves metabolic homeostasis. These findings reveal an integrated regulatory circuit coupling lipid synthesis in the liver to energy use in muscle by coordinating the activity of two closely related nuclear receptors. These data implicate alterations in diurnal hepatic PPARδ-PC(18:0/18:1) signalling in metabolic disorders, including obesity.

NLRP3 regulates macrophage M2 polarization through up-regulation of IL-4 in asthma.

Activation of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome received substantial attention recently in inflammatory diseases. Macrophages contribute to allergic inflammation in asthma. The present study was aimed to investigate the effect of NLRP3 inflammasome on the polarization of macrophages. We utilized human primary monocytes and monocyte-derived macrophages to study the expression of NLRP3 inflammasome components (NLRP3, apoptosis-associated specklike protein, and caspase-1) and its downstream cytokine interleukin-1ß (IL-1ß). By gain- or loss-of-function assays, we next explored the effects of NLRP3 inflammasome on M1/M2 polarization and secretion of IL-4, interferon-γ, tumor necrosis factor-α, and IL-1ß. The results showed increased numbers of M2 cells in asthma. And NLRP3 inflammasome was activated and involved in the inflammation of asthma. Furthermore, silence of NLRP3 down-regulated IL-4 secretion and up-regulated M1/M2. In contrast, overexpression of NLRP3 increased IL-4 and decreased M1/M2. As expected, IL-4 was involved in NLRP3-mediated down-regulation of Ml/M2 ratio. Moreover, NLRP3 interacted with IRF4 and was required for optimal IRF4-dependent IL-4 transcription. Subsequently, deficiency of NLRP3 in ovalbumin-induced allergic asthmatic mice impaired lung inflammation and up-regulated M1/M2, and diminished IL-4 in bronchoalveolar lavage fluid. Collectively, we demonstrated here that activation of NLRP3 was engaged in the promotion of asthma. NLRP3, but not the inflammasome adaptor ASC or caspase-1, promoted the polarization of M2 macrophages through up-regulating the expression of IL-4, thereby contributing to its regulation of asthma.

Thymic Stromal Lymphopoietin Signaling Pathway Inhibition Attenuates Airway Inflammation and Remodeling in Rats with Asthma.

BACKGROUND/AIMS: Thymic stromal lymphopoietin (TSLP) is a cytokine that plays diverse roles in the regulation of immune responses. However, a detailed understanding of the TSLP signaling pathway in asthma remains elusive. In this study, we aimed to investigate the role of the TSLP signaling pathway in asthma and its effect on airway inflammation and remodeling. METHODS: Forty Sprague Dawley (SD) rats were evenly classified into control, asthma, IgG2a mAb and anti-TSLP mAb groups. Ovalbumin (OVA)-induced asthma models were successfully established. Blood, bronchoalveolar lavage fluid (BALF) and lung tissue samples were prepared. Total BALF leukocytes were counted, and the proportions of different leukocyte types were determined. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry were performed to determine the mRNA and protein levels of TSLP, OX40L, α-smooth muscle actin (α-SMA, a marker of airway remodeling in asthma) and collagen I in the plasma. Enzyme-linked immunosorbent assay (ELISA) was carried out to measure the concentrations of TSLP, OX40L, and other inflammatory factors, such as interferon (IFN)-γ, interleukin (IL)-4, IL-5 and IL-13, in the plasma. RESULTS: Compared with the control group, there were more leukocytes, increased EOS and LYM proportions, higher Underwood and PAS scores, increased WTt, WTm, WAt/A0, WAm/WAt, WTt/R0, WTm/WTt, TSLP, OX40L, a-SMA and collagen I mRNA and protein levels, and higher SLP, OX40L, IL-4, IL-5 and IL-13 levels, but lower MON proportions and IFN-γ levels in the asthma and IgG2a mAb groups. Compared with the asthma and IgG2a mAb groups, there were less leukocytes, decreased EOS and LYM proportions, lower Underwood and PAS scores, decreased WTt, WTm, WAt/A0, WAm/WAt, WTt/R0, WTm/WTt, TSLP, OX40L, a-SMA and Collagen I mRNA and protein levels, and lower levels of SLP, OX40L, IL-4, IL-5 and IL-13, but higher MON proportions and IFN-γ levels in the anti-TSLP mAb group. WTm and WTt were positively associated with the TSLP, OX40L, α-SMA and collagen-I levels in the rat lung tissues. CONCLUSION: The results indicate that TSLP may be an important contributor for asthma development as TSLP signaling blockade attenuates airway inflammation and remodeling in asthmatic rats.

Knockdown of LncRNA MALAT1 contributes to the suppression of inflammatory responses by up-regulating miR-146a in LPS-induced acute lung injury.

BACKGROUND: Acute lung injury (ALI) is a type of severe pulmonary inflammatory disease with high rates of morbidity and mortality. Now, an increasing number of studies suggest that lncRNAs may act as key regulators of the inflammatory response and play a crucial role in the pathogenesis of many inflammatory diseases. Our study firstly explored the function and underlying mechanism of lncRNA metastasis-associated lung adenocarcinoma transcription 1 (MALAT1) in regulating the inflammatory response of lipopolysaccharide (LPS)-induced ALI in rats. METHODS: The ALI rats were constructed by intratracheal instillation with LPS. Hematoxylin and eosin (HE) for histological examination were performed to detect histopathological changes in the lung tissues. Enzyme-linked immunosorbent assay (ELISA) was used to determine the concentrations of cytokines TNF-α, IL-6, and IL-1ß in the supernatants of the bronchoalveolar lavage fluid (BALF). Quantitative real-time PCR (qRT-PCR) analysis was employed to assess the expression of MALAT1, miR-146a, TNF-α, IL-6, and IL-1ß in lung tissues. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to detect the relationship between MALAT1 and miR-146a. RESULTS: The results revealed that MALAT1 knockdown played a protective role in the LPS-induced ALI rat model. In addition, knockdown of MALAT1 in vitro inhibited LPS-induced inflammatory response in murine alveolar macrophages cell line MH-S and murine alveolar epithelial cell line MLE-12. This study found that MALAT1 acts as a molecular sponge for miR-146a and MALAT1 negatively regulated miR-146a expression. Mechanistically, MALAT1 overexpression alleviated the inhibitory effect of miR-146a on LPS-induced inflammatory response in MH-S. CONCLUSIONS: Together, our study provided the first evidence that MALAT1 knockdown could suppress inflammatory response by up-regulating miR-146a in LPS-induced ALI, which provided a potential therapeutic target for the treatment of ALI.

Magnetite Triggering Enhanced Direct Interspecies Electron Transfer: A Scavenger for the Blockage of Electron Transfer in Anaerobic Digestion of High-Solids Sewage Sludge.

At present, high-solids anaerobic digestion of sewage sludge has drawn great attention due to the superiority of its small land area footprint and low energy consumption. However, a high organic loading rate may cause acids accumulation and ammonia inhibition, thus leading to an inhibited pseudo-steady state in which electron transfer through interspecies hydrogen transfer (IHT) between acetogens and methanogens is blocked. In this study, adding 50 mg/g TS (total solid) magnetite clearly reduced the accumulation of short-chain fatty acids and accelerated methane production by 26.6%. As demonstrated, the individual processes of anaerobic digestion could not be improved by magnetite when methanogenesis was interrupted. Analyzing stable carbon isotopes and investigating the methanogenesis pathways using acetate and H2/CO2 as substrates together proved that direct interspecies electron transfer (DIET) was enhanced by magnetite. Metatranscriptomic analysis and determination of key enzymes showed that IHT could be partially substituted by enhanced DIET, and acetate-dependent methanogenesis was improved after the blockage of electron transfer was scavenged. Additionally, the expression of both pili and c-type cytochromes was found to decrease, indicating that magnetite could replace their roles for efficient electron transfer between acetogens and methanogens; thus, a robust chain of electron transfer was established.

Anaerobic digestion of sludge differing in inorganic solids content: performance comparison and the effect of inorganic suspended solids content on degradation.

High inorganic suspended solids (ISS) content of sludge in many areas (especially with combined sewage systems) results in low VS/TS (volatile solids, VS; total solids, TS) levels and raises concerns about its effect on anaerobic digestion. The performances of sludge anaerobic digestion with different feeding VS/TS levels as well as the effect of ISS content on the anaerobic degradation process were investigated in completely stirred tank reactors by semi-continuous and batch experiments. In semi-continuous experiment with sludge at VS/TS of 61.4%, 45.0, 30.0% and 15.0%, biogas yield, VS reduction and methane content decreased logarithmically with the feeding VS/TS decreasing; slightly higher volatile fatty acid concentration was observed at VS/TS 15%. Results of the batch experiments suggested that acetogenesis and methanogenesis are obviously affected by high ISS addition, while hydrolysis is less affected. The retardment of substrate conversion rate is probably attributed to decreased mass transfer efficiency at high ISS content.