Potential mechanism of Chai Gui Zexie Decoction for NSCLC treatment assessed using network pharmacology, bioinformatics, and molecular docking: An observational study.

To explore the potential mechanism of Chai Gui Zexie Decoction for non-small cell lung cancer (NSCLC) treatment using network pharmacology, bioinformatics, and molecular docking. The active ingredients of Chai Gui Zexie Decoction and the associated predicted targets were screened using the TCMSP database. NSCLC-related targets were obtained from GeneCards and OMIM. Potential action targets, which are intersecting drug-predicted targets and disease targets, were obtained from Venny 2.1. The protein-protein interaction network was constructed by importing potential action targets into the STRING database, and the core action targets and core ingredients were obtained via topological analysis. The core action targets were entered into the Metascape database, and Gene Ontology annotation analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were performed. Differentially expressed genes were screened using the Gene Expression Omnibus, and the key targets were obtained by validating the core action targets. The key targets were input into The Tumor IMmune Estimation Resource for immune cell infiltration analysis. Finally, the molecular docking of key targets and core ingredients was performed. We obtained 60 active ingredients, 251 drug prediction targets, and 2133 NSCLC-related targets. Meanwhile, 147 potential action targets were obtained, and 47 core action targets and 40 core ingredients were obtained via topological analysis. We detected 175 pathways related to NSCLC pharmaceutical therapy. In total, 1249 Gene Ontology items were evaluated. Additionally, 3102 differential genes were screened, and tumor protein P53, Jun proto-oncogene, interleukin-6, and mitogen-activated protein kinase 3 were identified as the key targets. The expression of these key targets in NSCLC was correlated with macrophage, CD4+ T, CD8+ T, dendritic cell, and neutrophil infiltration. The molecular docking results revealed that the core ingredients have a potent affinity for the key targets. Chai Gui Zexie Decoction might exert its therapeutic effect on NSCLC through multiple ingredients, targets, and signaling pathways.

The association between brominated flame retardants exposure with bone mineral density in US adults: A cross-sectional study of the national health and nutrition examination survey (NHANES) 2005-2014.

BACKGROUND AND AIMS: Exposure to brominated flame retardants (BFRs) has been widely confirmed to impair the normal functioning of the human body system. However, there is a paucity of study on the effects of serum BFRs on bone mineral density (BMD). This study aims to investigate the relationship between exposure to BFRs and BMD in a nationally representative sample of U.S. adults. METHODS: 3079 participants aged between 20 and 80 years with complete data were included in the study. Serum levels of BFRs were measured using automated liquid-liquid extraction and subsequent sample clean-up. The BMD of all participants were assessed by DXA examinations. Generalize linear model, Restricted cubic spline (RCS), subgroup, weighted quantile sum (WQS) and bayesian kernel machine regression (BKMR) were used to estimate the association between serum BFRs and BMD. RESULTS: Multivariate linear regression analyses revealed that, after adjusting for covariates, PBB153 was significantly associated with TF-BMD (ß = 0.0177, 95%CI: 0.0103-0.0252), FN-BMD (ß = 0.009, 95%CI: 0.0036-0.0145), TS-BMD (ß = 0.0081, 95%CI: 0.0013-0.015) and L1-BMD (ß = 0.0144, 95%CI: 0.0075-0.0213). However, the associations lose their statistical significance after further adjustment for sex. BFRs exhibited S-shaped or line-plateau dose-response curves with BMD. In subgroup analyses, BFRs were significantly associated with BMD in participants who were younger than 55 years, female, overweight (BMI >25 kg/m2), and less alcohol consumption. In WQS and BKMR analyses, the effects of BFRs mixtures on BMD differed by sex, and PBDE153, PBDE209 and PBB153 had the highest weights in the WQS regression model. CONCLUSION: This study showed that serum BFRs negatively predicted BMD in men, but not in women or the general population. PBDE153, PBDE209, and PBB153 were significant BMD factors, especially in younger, overweight, and less alcohol consumption individuals.

[Factors Affecting Nitrate Concentrations and Nitrogen and Oxygen Isotope Values of Effluents from Waste Water Treatment Plant].

Urban domestic sewage is one of the important nitrate (NO-3) sources for surface water; however, their NO-3 concentrations and nitrogen and oxygen isotope values (δ15N-NO-3 and δ18O-NO-3) remain unclear, and the factors affecting NO-3 concentrations and δ15N-NO-3 and δ18O-NO-3 values of effluents in the waste water treatment plant (WWTP) are still unknown. Water samples in the Jiaozuo WWTP were collected to illustrate this question. Influents, clarified water in the secondary sedimentation tank (SST), and effluents of the WWTP were sampled every 8 h. The ammonia (NH+4) concentrations, NO-3 concentrations, and δ15N-NO-3 and δ18O-NO-3 values were analyzed to elucidate the nitrogen transfers through different treatment sections and illustrate the factors affecting the effluent NO-3 concentrations and isotope ratios. The results indicated that ① the mean NH+4 concentration was (22.86±2.16) mg·L-1 in the influent and decreased to (3.78±1.98) mg·L-1 in the SST and continuously reduced to (2.70±1.98) mg·L-1 in the effluent of the WWTP. The median NO-3 concentration was 0.62 mg·L-1 in the influent, and the average NO-3 concentration increased to (33.48±3.10) mg·L-1 in the SST and gradually increased to (37.20±4.34) mg·L-1 in the effluent of the WWTP. ② The mean values of δ15N-NO-3 and δ18O-NO-3 were (17.1±10.7)‰ and (19.2±2.2)‰ in the influent of the WWTP, the median values of δ15N-NO-3 and δ18O-NO-3 were 11.9‰ and 6.4‰ in the SST, and the average values were (12.6±1.9)‰ and (5.7±0.8)‰ in the effluent of the WWTP. ③ The NH+4 concentrations of influent had significant differences compared to those in the SST and the effluent (P<0.05). The reduction of NH+4 concentrations in the SST was due to the above nitrification during the aerobic treatment process, which transferred NH+4 to NO-3. The NH+4 concentrations in the SST had no significant differences with that in the effluent of the WWTP (P>0.05). ④ The NO-3 concentrations in the influent had significant differences with those in the SST and the effluent (P<0.05), and minor NO-3 concentrations but relatively high δ15N-NO-3 and δ18O-NO-3 values in the influent were probably due to denitrification during the pipe sewage transportation. The obviously increased NO-3 concentrations (P<0.05) but decreased δ18O-NO-3 values (P<0.05) in the SST and the effluent resulted from water oxygen incorporation during the nitrification. The above results confirmed the impacts of aerobic and anaerobic treatment processes on NO-3 concentrations and isotope ratios of effluent from the WWTP and provided scientific basis for the identification of sewage contributions to surface water nitrate via average δ15N-NO-3 and δ18O-NO-3 values.

[Systematic Evaluation of Low-carbon Operation of Typical A2O Processes in Municipal Sewage Plant].

Under the "Carbon Peak, Carbon Neutral" goal, the systematic evaluation of the carbon emission equivalent (CO2eq) and its compositions of the typical A2O process has important guiding significance for the low-carbon operation of most municipal sewage plants in China. Based on the operational data on the first municipal sewage plant of Jiaozuo in 2020 and the methods presented in "2019 Refinement to the 2006 IPCC Guidelines for National Greenhouse Gas Inventories, " a systematic evaluation of the CO2eq of the typical A2O process was established, including direct emissions that were built on the Arrhenius model introducing the water temperature factor and indirect emissions from the three aspects of electricity consumption, agent addition, and sludge transportation. The results showed that the daily emission intensities of CH4 and N2O were (115±56) kg·d-1 and (30±18) kg·d-1, respectively. Additionally, indirect carbon emissions from electricity consumption and agent addition accounted for 48.4% and 51.3% in the biochemical treatment section, respectively. In 2020, CO2eq amounts of total research plant and per unit sewage were 2.17×104 t and (0.63±0.07) kg·m-3, respectively. The magnitude of the proportion of different carbon emission compositions was as follows:sewage electricity (36.5%)>sewage agent (26.6%)>N2O direct (15.4%)>sludge agent (9.6%)>sludge electricity (6.7%)>CH4 direct (4.9%)>sludge transportation (0.3%). System import/export fluxes of carbon and nitrogen elements were calculated, followed by the carbon to nitrogen mass ratio in the sewage plant. Direct carbon emission characteristics of CH4 and N2O and their influencing factors were discussed, respectively. Based on the balance theory of carbon and nitrogen elements in the system, it is proposed that the selective introduction of industrial wastewater may become an important reference measure for the low-carbon operation of municipal sewage plants in the future.

An alarm device for mechanical compression device displacement at femoral artery puncture sites.

OBJECTIVE: To develop an alarm device for the mechanical compression device displacement (MCD), and further evaluate its effectiveness in clinical use. MATERIAL AND METHODS: The alarm device is mainly composed of buzzer, indicator light, magnetic sheet. This is a prospective randomized and controlled study. Four hundred patients who met the inclusion/exclusion criteria were included and randomly assigned to two groups (MCD group vs alarm + MCD group). The primary outcome measures were the sensitivity and specificity of the alarm device to detect MCD displacement, time to hemostasis (TTH), time to ambulation (TTA), time to hospital discharge (TTHD), hospital costs (HC), complication rates, and patient satisfaction. RESULTS: The sensitivity and specificity of the alarm device in detecting MCD displacement were 94.44% and 88.46%, respectively. The study group achieved shorter TTH (p = .034), shorter TTA (p = .021), lower complication rates (p = .025), and better patients' satisfaction (p < .001) compared to the control group. However, no significant difference was observed in TTHD (p = .361) and HC (p = .583). CONCLUSION: The alarm device is highly sensitive in detecting MCD displacement, while achieving better clinical outcomes compared with artificial monitoring.

Spatio-temporal variations and drought of spring maize in Northeast China between 2002 and 2020.

A lot of spring maize is grown in Northeast China (Liaoning, Jilin, and Heilongjiang), an area that is highly susceptible to drought. Here, remote sensing indexes from 2002 to 2020 were studied using the 8-day surface reflectance and land surface temperature of Moderate-resolution Imaging Spectroradiometer data. Spring maize distribution was extracted using a decision tree classification, and the results were compared to the known distribution based on field investigation data and published statistics. The results showed that mixed pixels of spring maize and soybeans had limited influence on the study of spatio-temporal variations of spring maize, and the error was acceptable. The overall accuracy of verifying the spring maize distribution from 2018 to 2020 was above 85%. The stable, fluctuating, and low-frequency planting areas of spring maize accounted for 11.86%, 17.41%, and 34.86% of the study area, respectively. In 2015, the government directed a reduction of the planting area of spring maize in the "Liandaowan" region of Northeast China. The planting area of spring maize was characterized by a continuous increase before this change (2002-2014), exhibited changes and reductions in response to the change (2015-2017), and exhibited optimization and recovery after this change (2018-2020). Compared with the fluctuating and low-frequency planting areas, moderate and severe droughts were higher in stable planting areas. From 2002 to 2020, the most severe droughts occurred in the expanded planting areas. This rapid and large-scale monitoring of spatio-temporal variations and drought of spring maize provides a foundation for improving grain yield. This method could be easily applied to the study of other regions and combined with high-resolution and hyperspectral satellite data to improve monitoring accuracy.

RNA Sequencing Reveals the Potential Adaptation Mechanism to Different Hosts of Grapholita molesta.

Grapholita molesta is an important fruit tree worldwide pest which feeds on hosts extensively and does serious harm. In this paper, the growth and development parameters and protease activities of G. molesta fed on different hosts were compared. Using Illumina RNA sequencing technology, 18 midgut samples from five different hosts (apple, pear, plum, peach and peach shoots) and artificial diet were sequenced and compared with the reference genome, resulting in 15269 genes and 2785 predicted new genes. From 15 comparative combinations, DEGs were found from 286 to 4187 in each group, with up-regulated genes from 107 to 2395 and down-regulated genes from 83 to 2665. KEGG pathway analysis showed that DEGs were associated with amino acid metabolism, starch and sucrose metabolism, carbohydrate metabolism, and hydrolase activity. A total of 31 co-expression gene modules of different hosts were identified by WGCNA. qRT-PCR showed that the expression pattern of the trypsin gene was consistent with RNA sequencing. In this study, growth and development parameters, protease activity, DEGs, enrichment analysis and qRT-PCR were combined to reveal the adaptation process to different hosts of G. molesta in many aspects. The results of this study provide a basis for further exploration of the molecular mechanism of host adaptation of G. molesta.

Path of Regional Economic Transformation and Upgrading Based on Recurrent Neural Network.

At present, the development of the regional economy is very rapid and widespread. However, due to increasingly prominent problems such as the low level of technological innovation and the unreasonable industrial structure, the economic growth rate has declined. Therefore, it is particularly important to use the circular economy network to study the transformation and upgrading of the regional economy. It clarifies the stakeholders in the process of transformation and upgrading of manufacturing enterprises. Its benefits in the network are given, and symptoms and mobilization methods and the obstacles and solutions to the development of mobilization among various subjects are drawn. In addition, it also emphasizes the equivalence between intelligent products and human subjects in this network. Because of the intelligence carried by products under the current background, diversified connotations and functions are becoming more and more abundant. The empirical results show that the pulling coefficients of residents' consumption level, the development of modern service industry, and urbanization rate to economic growth are 0.1812, 0.7165, and 0.1635, respectively, while the pulling coefficient of Gini coefficient to economic growth is -0.1785.

The Contributions of Language Skills and Comprehension Monitoring to Chinese Reading Comprehension: A Longitudinal Investigation.

This study examined how vocabulary, syntactic knowledge, and orthographic knowledge are related to comprehension monitoring and whether comprehension monitoring mediates the relations between these language skills and reading comprehension. Eighty-nine Chinese children were assessed on their vocabulary, syntactic knowledge, orthographic knowledge, and comprehension monitoring in Grade 1. Their reading comprehension skills were assessed in Grade 1 and Grade 3. Results showed that in Grade 1, comprehension monitoring mediated the relations between vocabulary and syntactic knowledge and reading comprehension. For Grade 3 reading comprehension, syntactic knowledge in Grade 1 was the only significant predictor. These findings indicate that multiple language skills make direct and indirect contributions via comprehension monitoring to Chinese reading comprehension, and the relations would change as children's reading skills develop.

Clinical characteristics, rates of blindness, and geographic features of PACD in China.

OBJECTIVE: To analyze the rates of blindness with the demographics and clinical characteristics of patients with primary angle-closure disease (PACD) to provide a comprehensive epidemiologic reference in China. METHODS: A retrospective analysis was conducted in the Chinese Glaucoma Study Consortium database, which is a national multicenter glaucoma research alliance of 111 hospitals participating between December 21, 2015 and September 9, 2018. The diagnosis of PACD was made by qualified physicians through examination. Comparison of sex, age, family history, subtypes of PACD, and blindness were analyzed. RESULTS: A total of 5762 glaucoma patients were included, of which 4588 (79.6%) had PACD. Of PACD patients, 72.1% were female with the sex ratio (F/M) of 2.6, and the average age of patients was 63.8±9.3 years with the majority between 60 and 70 years. Additionally, 30% of these patients had low vision in one eye, 8.8% had low vision in both eyes, 1.7% had blindness in one eye, and 0.3% had blindness in both eyes. There were statistical differences with regards to age between male and female patients with PACD, with male patients being older on average. Primary angle-closure glaucoma was more commonly diagnosed in males (60%) compared to females (35.9%), whereas acute primary angle closure (APAC) was more commonly diagnosed in females (54.3%) compared to males (37.7%). The visual acuity in APAC patients was lower and the rate of low vision and blindness was higher than other subtypes. CONCLUSION: PACD was the major type of glaucoma in Chinese hospitals. There were more female patients with PACD, mostly between 60 and 70 years old, with higher rates of APAC in women. APAC resulted in the worst visual outcomes of all PACD subtypes.

IL-25 Treatment Improves Metabolic Syndrome in High-Fat Diet and Genetic Models of Obesity.

INTRODUCTION: Endemic obesity is considered the driving force for the dramatic increase in incidence of type 2 diabetes (T2D). There is mounting evidence that chronic, low-grade inflammation driven by Th1/Th17 cells and M1 macrophages, is a critical link between obesity and insulin resistance. IL-25 promotes development of a Th2 immune response and M2 macrophages that counteract the inflammation associated with obesity and T2D. METHODS: Mice were fed a high-fat diet (HFD) for 16 weeks and then treated with IL-25 or BSA as a control for 21 days. Body weight, blood glucose levels, intraperitoneal glucose tolerance, and gene expression were evaluated in mice treated with BSA or IL-25. Ob/ob mice fed a normal control diet were also treated with BSA or IL-25 and body weight and blood glucose levels were measured. Transepithelial electrical resistance and sodium-linked glucose absorption were determined in muscle-free small intestinal tissue and glucose absorption assessed in vitro in intestinal epithelial and skeletal muscle cell lines. RESULTS: Administration of IL-25 to HFD fed mice reversed glucose intolerance, an effect mediated in part by reduction in SGLT-1 activity and Glut2 expression. Importantly, the improved glucose tolerance in HFD mice treated with IL-25 was maintained for several weeks post-treatment indicating long-term changes in glucose metabolism in obese mice. Glucose intolerance was also reversed by IL-25 treatment in genetically obese ob/ob mice without inducing weight loss. In vitro studies demonstrated that glucose absorption was inhibited by IL-25 treatment in the epithelial IPEC-1 cells but increased glucose absorption in the L6 skeletal muscle cells. This supports a direct cell-specific effect of IL-25 on glucose metabolism. CONCLUSION: These results suggest that the IL-25 pathway may be a useful target for the treatment of metabolic syndrome.

The Chinese Glaucoma Study Consortium for Patients With Glaucoma: Design, Rationale and Baseline Patient Characteristics.

PRECIS: Chinese Glaucoma Study Consortium (CGSC) as the first nationwide glaucoma registry in China, we describe its design, rationale, the geographic distribution of the hospitals, and baseline patient characteristics. AIM: As a leading cause of blindness in China, glaucoma affects 2% to 4% of adults over the age of 40 and will become increasingly prevalent as the population ages. At the national level, there are few reports on the current medical practice for glaucoma patients. CGSC will be considered as the first nationwide glaucoma registry in China. Here we describe its design, rationale, the geographic distribution of the hospitals, and baseline patient characteristics. METHODS: From December 21, 2015 to September 9, 2018, CGSC recruited patients with the diagnoses of primary angle-closure suspect, primary angle-closure, primary angle-closure glaucoma, acute primary angle closure, primary open-angle glaucoma (POAG), pigmentary glaucoma (PG), and pseudoexfoliative glaucoma (PXG) from 111 hospitals covering 67 cities from 22 provinces, 4 municipalities, and 5 autonomous regions in mainland China. Clinical data were collected using an Electronic Data Capture System designed by Tongren hospital and Gauss informed Ltd. Blood samples were collected from every patient for further genetic analysis. RESULTS: Medical records of 10,892 patients were collected, of which 5762 patients have complete information. The average age of those with complete information (n=5762) was 62.05±11.26 years old, and 35.25% were males. Primary angle-closure disease, including primary angle-closure suspect/primary angle-closure/primary angle-closure glaucoma/acute primary angle closure, was predominant (4588, 79.63%), and the distribution for others is as follows: POAG (1116, 19.37%), PXG (41, 0.71%) and PG (17, 0.30%). A total of 16,684 blood samples were collected, of which 9917 (82.68%) were primary angle-closure disease, 1987 (16.57%) were POAG, 69 (0.58%) were PXG, 22 (0.18%) were PG, and 4689 were normal controls. CONCLUSIONS: The CGSC is the first national-level glaucoma registry study in China. Clinical data and blood samples will provide the opportunity to study the epidemiology of glaucoma in Chinese hospitals, to evaluate the level of medical diagnosis and treatment of glaucoma in China, and to identify the susceptibility loci for glaucoma.

Inhibitory Effect of Protease Inhibitors on Larval Midgut Protease Activities and the Performance of Plutella xylostella (Lepidoptera: Plutellidae).

Plutella xylostella L. (diamondback moth) is a pest of cruciferous plants. To understand the relationship among protease inhibitors, protease activities and the growth and development of this insect, the activities of midgut proteases of P. xylostella larvae were determined in this study. Protease samples were extracted from the midguts of P. xylostella larvae, and the protease activities were determined using enzyme specific substrates. The results showed that CaCl2, EDTA, and EGTA inhibited only the trypsin. Among the common protease inhibitors, phenylmethyl sulfonyl fluorine (PMSF), Nα-p-methyl sulfonyl-L-lysine chloromethylketone (TLCK), Nα-methyl sulfonyl-L- phenylalanine chloromethyl ketone (TPCK), soybean trypsin inhibitor (STI), and PMSF inhibited the total protease, high-alkaline trypsin (a trypsin subtype with highly alkaline pH optimum), low-alkaline trypsin (another trypsin subtype with slightly alkaline pH optimum), and chymotrypsin; TLCK inhibited the total protease and high-alkaline trypsin, whereas TPCK only activated the high-alkaline trypsin activities. STI had an inhibitory effect on all the proteases. These results showed that protease inhibitors had a certain extent inhibition to protease activities in the larval midgut of P. xylostella and that STI can potentially be used for effective pest control. The development of P. xylostella was delayed in the presence of different inhibitors. These effects were also related to the concentration of the inhibitor. A higher STI concentration showed a longer lasting effect but lower effect in this study compared to that of TLCK. The protease inhibitors had some inhibitory effect on the synthesis and secretion of proteases, and interfered with the protease activity, thereby inhibiting the absorption of nutrients and delaying the growth and development of P. xylostella and reducing their ability to reproduce. These findings should provide the baseline information about using for effective pest management in the future.

Bone marrow PD-1 positive T cells reflect tumor mass and prognosis in multiple myeloma.

Programmed cell death protein 1 (PD-1) negatively regulates T cell effector mechanisms and contributes to tumor cell escape from immune surveillance. To evaluate potential clinical significance of PD-1 in multiple myeloma (MM), we quantified PD-1 expressing T cells in bone marrow (BM) of MM patients using flow cytometry. Our results showed that PD-1 positive T cells in BM from relapsed/refractory patients were significantly higher than those in the newly diagnosed, partial/complete remission MM, and controls, respectively. Additionally, high-risk MM patients had more PD-1 positive T cells in BM than low-risk patients. Moreover, PD-1 positive T cells in relapsed/refractory MM patients were positively associated with myeloma cell counts in BM and clinical stages. PD-1 positive T cells in BM of all MM and relapsed/refractory MM patients were positively correlated with their serum ß2-microglobulin concentrations. Our results strongly suggest that PD-1 expressing T cells in BM may be applied as a biomarker to reflect tumor mass and prognosis.

Burden of vision loss associated with eye disease in China 1990-2020: findings from the Global Burden of Disease Study 2015.

AIMS: To assess the burden of vision loss due to eye disease in China between 1990 and 2015, and to predict the burden in 2020. METHODS: Data from the GBD 2015 (Global Burden of Diseases, Injuries, and Risk Factors Study 2015) were used. The main outcome measures were prevalence and years lived with disability (YLDs) for vision loss due to cataract, glaucoma, macular degeneration, other vision loss, refraction and accommodation disorders and trachoma. RESULTS: Prevalence for eye diseases increased steadily from 1990 to 2015, and will increase until 2020. From 1990 to 2015, the most common eye disorder was refraction and accommodation disorders. From 1990 to 2015, the vision loss burden due to eye disease decreased for those aged 0-14 years, and increased for those aged 15 years and above, with the most notable increases occurring among those aged 50 years and above. China ranked 10th when comparing YLDs for vision loss due to eye disease with the other members of the G20 (Group of Twenty, an international forum for the governments from 20 major economies) . Age-standardised YLD rates for vision loss due to eye disease declined in all 19 countries, except for China. The burden from vision loss due to eye disease ranked 12th and 11th among all causes of health loss in China in 1990 and 2015, respectively. CONCLUSION: Alone among major economies, China has experienced an increase in the burden of age-standardised vision loss from eye disease over the last two decades. In the future, China may expect a growing burden of vision loss due to population growth and ageing.

IL-25 stimulates M2 macrophage polarization and thereby promotes mitochondrial respiratory capacity and lipolysis in adipose tissues against obesity.

Obesity and associated metabolic diseases are characterized by a chronic low-grade inflammatory state with the infiltration of many inflammatory cells, especially macrophages. Immune molecules, including some cytokines, have a close relationship with metabolism. Interleukin (IL)-25 is a member of the IL-17 cytokine family that can regulate macrophages and alleviate some metabolic dysfunction; however, its role and mechanisms in lipid metabolism remain to be extensively clarified. Human serum and liver biopsy specimens, high-fat diet-induced obesity mice and DB/DB (Lepr-/-) animal models were used to examine IL-25 expression in obesity and nonalcoholic fatty liver diseases (NAFLD). To observe the role of IL-25 in lipid metabolism, model mice were administered with IL-25 or adoptively transferred with IL-25-educated macrophages in vivo, whereas bone marrow-derived macrophages, the macrophage cell line RAW264.7 and adipocytes differentiated from 3T3-L1 were used in vitro. IL-25 was decreased in NAFLD patients and obese mice. In addition, IL-25 reduced body weight gain and lipid accumulation, enhanced lipid uptake by macrophages and increased the expression of lipolysis and ß-oxidation enzymes via alternatively activating macrophages. IL-25 also promoted lipolysis and suppressed lipogenesis in adipocytes co-cultured with the IL-25-educated macrophages. Furthermore, IL-25 improved the mitochondrial respiratory capacity and oxygen consumption rate of macrophages and produced more NAD+/NADH and ATP. In conclusion, IL-25 can stimulate M2 macrophage polarization and thereby promote lipolysis and mitochondrial respiratory capacity, highlighting the potential for IL-25 to be used as a therapeutic agent against obesity and associated metabolic syndromes.

Critical Role for Interleukin-25 in Host Protective Th2 Memory Response against Heligmosomoides polygyrus bakeri.

Infection with parasitic nematodes, especially gastrointestinal geohelminths, affects hundreds of millions of people worldwide and thus poses a major risk to global health. The host mechanism of defense against enteric nematode infection remains to be fully understood, but it involves a polarized type 2 immunity leading to alterations in intestinal function that facilitate worm expulsion. We investigated the role of interleukin-25 (IL-25) in host protection against Heligmosomoides polygyrus bakeri infection in mice. Our results showed that Il25 and its receptor subunit, Il17rb, were upregulated during a primary infection and a secondary challenge infection with H. polygyrus bakeri Genetic deletion of IL-25 (IL-25-/-) led to an attenuated type 2 cytokine response and increased worm fecundity in mice with a primary H. polygyrus bakeri infection. In addition, the full spectrum of the host memory response against a secondary infection with H. polygyrus bakeri was severely impaired in IL-25-/- mice, including delayed type 2 cytokine responses, an attenuated functional response of the intestinal smooth muscle and epithelium, diminished intestinal smooth muscle hypertrophy/hyperplasia, and impaired worm expulsion. Furthermore, exogenous administration of IL-25 restored the host protective memory response against H. polygyrus bakeri infection in IL-25-/- mice. These data demonstrate that IL-25 is critical for host protective immunity against H. polygyrus bakeri infection, highlighting its potential application as a therapeutic agent against parasitic nematode infection worldwide.

Mechanisms Involved in the Development of the Chronic Gastrointestinal Syndrome in Nonhuman Primates after Total-Body Irradiation with Bone Marrow Shielding.

In this study, nonhuman primates (NHPs) exposed to lethal doses of total body irradiation (TBI) within the gastrointestinal (GI) acute radiation syndrome range, sparing ∼5% of bone marrow (TBI-BM5), were used to evaluate the mechanisms involved in development of the chronic GI syndrome. TBI increased mucosal permeability in the jejunum (12-14 Gy) and proximal colon (13-14 Gy). TBI-BM5 also impaired mucosal barrier function at doses ranging from 10-12.5 Gy in both small intestine and colon. Timed necropsies of NHPs at 6-180 days after 10 Gy TBI-BM5 showed that changes in small intestine preceded those in the colon. Chronic GI syndrome in NHPs is characterized by continued weight loss and intermittent GI syndrome symptoms. There was a long-lasting decrease in jejunal glucose absorption coincident with reduced expression of the sodium-linked glucose transporter. The small intestine and colon showed a modest upregulation of several different pro-inflammatory mediators such as NOS-2. The persistent inflammation in the post-TBI-BM5 period was associated with a long-lasting impairment of mucosal restitution and a reduced expression of intestinal and serum levels of alkaline phosphatase (ALP). Mucosal healing in the postirradiation period is dependent on sparing of stem cell crypts and maturation of crypt cells into appropriate phenotypes. At 30 days after 10 Gy TBI-BM5, there was a significant downregulation in the gene and protein expression of the stem cell marker Lgr5 but no change in the gene expression of enterocyte or enteroendocrine lineage markers. These data indicate that even a threshold dose of 10 Gy TBI-BM5 induces a persistent impairment of both mucosal barrier function and restitution in the GI tract and that ALP may serve as a biomarker for these events. These findings have important therapeutic implications for the design of medical countermeasures.

Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of Nippostrongylus brasiliensis through induction of TH2 cytokines.

Despite increased appreciation for the role of nicotinic receptors in the modulation of and response to inflammation, the contribution of muscarinic receptors to mucosal homeostasis, clearance of enteric pathogens, and modulation of immune cell function remains relatively undefined. Uninfected and Nippostrongylus brasiliensis-infected wild-type and type 3 muscarinic receptor (M3R)-deficient (Chrm3(-/-)) mice were studied to determine the contribution of M3R to mucosal homeostasis as well as host defense against the TH2-eliciting enteric nematode N. brasiliensis Intestinal permeability and expression of TH1/TH17 cytokines were increased in uninfected Chrm3(-/-) small intestine. Notably, in Chrm3(-/-) mice infected with N. brasiliensis, small intestinal upregulation of TH2 cytokines was attenuated and nematode clearance was delayed. In Chrm3(-/-) mice, TH2-dependent changes in small intestinal function including smooth muscle hypercontractility, increased epithelial permeability, decreased epithelial secretion and absorption, and goblet cell expansion were absent despite N. brasiliensis infection. These findings identify an important role for M3R in host defense and clearance of N. brasiliensis, and support the expanding role of cholinergic muscarinic receptors in maintaining mucosal homeostasis.