Th17 Cell-Derived Amphiregulin Promotes Colitis-Associated Intestinal Fibrosis Through Activation of mTOR and MEK in Intestinal Myofibroblasts.

BACKGROUND & AIMS: Intestinal fibrosis is a significant complication of Crohn's disease (CD). Gut microbiota reactive Th17 cells are crucial in the pathogenesis of CD; however, how Th17 cells induce intestinal fibrosis is still not completely understood. METHODS: In this study, T-cell transfer model with wild-type (WT) and Areg-/- Th17 cells and dextran sulfate sodium (DSS)-induced chronic colitis model in WT and Areg-/- mice were used. CD4+ T-cell expression of AREG was determined by quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of AREG on proliferation/migration/collagen expression in human intestinal myofibroblasts was determined. AREG expression was assessed in healthy controls and patients with CD with or without intestinal fibrosis. RESULTS: Although Th1 and Th17 cells induced intestinal inflammation at similar levels when transferred into Tcrßxδ-/- mice, Th17 cells induced more severe intestinal fibrosis. Th17 cells expressed higher levels of AREG than Th1 cells. Areg-/- mice developed less severe intestinal fibrosis compared with WT mice on DSS insults. Transfer of Areg-/- Th17 cells induced less severe fibrosis in Tcrßxδ-/- mice compared with WT Th17 cells. Interleukin (IL)6 and IL21 promoted AREG expression in Th17 cells by activating Stat3. Stat3 inhibitor suppressed Th17-induced intestinal fibrosis. AREG promoted human intestinal myofibroblast proliferation, motility, and collagen I expression, which was mediated by activating mammalian target of rapamycin and MEK. AREG expression was increased in intestinal CD4+ T cells in fibrotic sites compared with nonfibrotic sites from patients with CD. CONCLUSIONS: These findings reveal that Th17-derived AREG promotes intestinal fibrotic responses in experimental colitis and human patients with CD. Thereby, AREG might serve as a potential therapeutic target for fibrosis in CD.

Coronavirus Porcine Epidemic Diarrhea Virus Utilizes Chemokine Interleukin-8 to Facilitate Viral Replication by Regulating Ca2+ Flux.

Chemokine production by epithelial cells is crucial for neutrophil recruitment to sites of inflammation during viral infection. However, the effect of chemokine on epithelia and how chemokine is involved in coronavirus infection remains to be fully understood. Here, we identified an inducible chemokine interleukin-8 (CXCL8/IL-8), which could promote coronavirus porcine epidemic diarrhea virus (PEDV) infection in African green monkey kidney epithelial cells (Vero) and Lilly Laboratories cell-porcine kidney 1 epithelial cells (LLC-PK1). IL-8 deletion restrained cytosolic calcium (Ca2+), whereas IL-8 stimulation improved cytosolic Ca2+. The consumption of Ca2+ restricted PEDV infection. PEDV internalization and budding were obvious reductions when cytosolic Ca2+ was abolished in the presence of Ca2+ chelators. Further study revealed that the upregulated cytosolic Ca2+ redistributes intracellular Ca2+. Finally, we identified that G protein-coupled receptor (GPCR)-phospholipase C (PLC)-inositol trisphosphate receptor (IP3R)-store-operated Ca2+ (SOC) signaling was crucial for enhancive cytosolic Ca2+ and PEDV infection. To our knowledge, this study is the first to uncover the function of chemokine IL-8 during coronavirus PEDV infection in epithelia. PEDV induces IL-8 expression to elevate cytosolic Ca2+, promoting its infection. Our findings reveal a novel role of IL-8 in PEDV infection and suggest that targeting IL-8 could be a new approach to controlling PEDV infection. IMPORTANCE Coronavirus porcine epidemic diarrhea virus (PEDV) is a highly contagious enteric coronavirus that caused severe economic losses worldwide, and more effort is needed to develop economical and efficient vaccines to control or eliminate this disease. The chemokine interleukin-8 (CXCL8/IL-8) is indispensable for the activation and trafficking of inflammatory mediators and tumor progression and metastasis. This study evaluated the effect of IL-8 on PEDV infection in epithelia. We found that IL-8 expression improved cytosolic Ca2+ in epithelia, facilitating PEDV rapid internalization and egress. G protein-coupled receptor (GPCR)-phospholipase C (PLC)-inositol trisphosphate receptor (IP3R)-SOC signaling was activated by IL-8, releasing the intracellular Ca2+ stores from endoplasmic reticulum (ER). These findings provide a better understanding of the role of IL-8 in PEDV-induced immune responses, which will help develop small-molecule drugs for coronavirus cure.

B(C6F5)3/CPA-Catalyzed Aza-Diels-Alder Reaction of 3,3-Difluoro-2-Aryl-3H-indoles and Unactivated Dienes.

Here we report B(C6F5)3/CPA-catalyzed enantioselective aza-Diels-Alder reaction of 3,3-difluoro-2-Aryl-3H-indoles with unactivated dienes to access chiral 10,10-difluoro-tetrahydropyrido[1,2-a]indoles. This protocol allows the formation of pyrazole-based C2-quaternary indolin-3-ones with high enantioselectivities and regioselectivities. Moreover, gram-scale synthesis of the 10,10-difluoro-tetrahydropyrido[1,2-a]indole skeleton was successfully achieved without any reduction in both yield and enantioselectivity.

Impact of army morale on suicidal ideation: The mediating role of grit and the moderating role of social support in a Chinese Navy population.

This study constructed a moderated mediation model to examine whether increased army morale could reduce suicidal ideation. The mediating role of grit and the moderating role of social support were also examined. A total of 1029 male navy cadets in China were recruited to complete the survey. The measures used in the study included the Army Morale Scale, Grit Scale, Social Support Scale, and Self-rated Idea of Suicide Scale. The results indicated that: increased army morale could significantly reduce suicidal ideation; the impact of army morale on suicidal ideation could be partially mediated by grit; and social support moderated the impact of army morale on suicidal ideation. Specifically, relatively higher levels of social support could reduce suicidal ideation among individuals with lower levels of army morale, but the effect is not significant when the morale is at a high level. The study revealed that increased army morale could reduce suicidal ideation. Moreover, the mediating role of grit and the moderating role of social support were also revealed.

GPR120 Inhibits Colitis Through Regulation of CD4+ T Cell Interleukin 10 Production.

BACKGROUND & AIMS: G protein-coupled receptor (GPR) 120 has been implicated in regulating metabolic syndromes with anti-inflammatory function. However, the role of GPR120 in intestinal inflammation is unknown. Here, we investigated whether and how GPR120 regulates CD4+ T cell function to inhibit colitis development. METHODS: Dextran sodium sulfate (DSS)-induced colitis model, Citrobacter rodentium infection model, and CD4+ T cell adoptive transfer model were used to analyze the role of GPR120 in regulating colitis development. The effect of GPR120 on CD4+ T cell functions was analyzed by RNA sequencing, flow cytometry, and Seahorse metabolic assays. Mice were administered GPR120 agonist for investigating the potential of GPR120 agonist in preventing and treating colitis. RESULTS: Deficiency of GPR120 in CD4+ T cells resulted in more severe colitis in mice upon dextran sodium sulfate insult and enteric infection. Transfer of GPR120-deficient CD4+CD45Rbhi T cells induced more severe colitis in Rag-/- mice with lower intestinal interleukin (IL) 10+CD4+ T cells. Treatment with the GPR120 agonist CpdA promoted CD4+ T cell production of IL10 by up-regulating Blimp1 and enhancing glycolysis, which was regulated by mTOR. GPR120 agonist-treated wild-type, but not IL10-deficient and Blimp1-deficient, T helper 1 cells induced less severe colitis. Furthermore, oral administration of GPR120 agonist protected mice from intestinal inflammation in both prevention and treatment schemes. Gpr120 expression was positively correlated with Il10 expression in the human colonic mucosa, including patients with inflammatory bowel diseases. CONCLUSIONS: Our findings show the role of GPR120 in regulating intestinal CD4+ T cell production of IL10 to inhibit colitis development, which identifies GPR120 as a potential therapeutic target for treating inflammatory bowel diseases.

Asymmetric aza-Friedel-Crafts Reaction of Cyclic Ketimines with 5-Aminopyrazole Derivatives: Expedient Access to Pyrazole-Based C2-quaternary Indolin-3-Ones.

A chiral phosphoric acid-catalyzed enantioselective aza-Friedel-Crafts reaction of 5-aminopyrazole derivatives with cyclic ketimines attached to a neutral functional group is reported. This protocol allows the formation of pyrazole-based C2-quaternary indolin-3-ones with high enantioselectivities and regioselectivities. Moreover, gram-scale synthesis of the 5-aminopyrazole-based C2-quaternary indolin-3-ones was performed, with no decrease in the yield and enantioselectivity.

Luteolin ameliorates cornea stromal collagen degradation and inflammatory damage in rats with corneal alkali burn.

Corneal alkali burn (AB) is a blindness-causing ocular trauma commonly seen in clinics. An excessive inflammatory reaction and stromal collagen degradation contribute to corneal pathological damage. Luteolin (LUT) has been studied for its anti-inflammatory effects. In this study, the effect of LUT on cornea stromal collagen degradation and inflammatory damage in rats with corneal alkali burn was investigated. After corneal alkali burn, rats were randomly assigned to the AB group and AB + LUT group and received an injection of saline and LUT (200 mg/kg) once daily. Subsequently, corneal opacity, epithelial defects, inflammation and neovascularization (NV) were observed and recorded on Days 1, 2, 3, 7 and 14 post-injury. The concentration of LUT in ocular surface tissues and anterior chamber, as well as the levels of collagen degradation, inflammatory cytokines, matrix metalloproteinases (MMPs) and their activity in the cornea were detected. Human corneal fibroblasts (HCFs) were co-cultured with interleukin (IL)-1ß and LUT. Cell proliferation and apoptosis were assessed by CCK-8 assay and flow cytometry respectively. Measurement of hydroxyproline (HYP) in culture supernatants was used to quantify the amount of collagen degradation. Plasmin activity was also assessed. ELISA or real-time PCR was used to detect the production of matrix metalloproteinases (MMPs), IL-8, IL-6 and monocyte chemotactic protein (MCP)-1. Furthermore, the immunoblot method was used to assess the phosphorylation of mitogen-activated protein kinases (MAPKs), transforming growth factor-ß-activated kinase (TAK)-1, activator protein-1 (AP-1) and inhibitory protein IκB-α. At last, immunofluorescence staining helped to develop nuclear factor (NF)-κB. LUT was detectable in ocular tissues and anterior chamber after intraperitoneal injection. An intraperitoneal injection of LUT ameliorated alkali burn-elicited corneal opacity, corneal epithelial defects, collagen degradation, NV, and the infiltration of inflammatory cells. The mRNA expressions of IL-1ß, IL-6, MCP-1, vascular endothelial growth factor (VEGF)-A, and MMPs in corneal tissue were downregulated by LUT intervention. And its administration reduced the protein levels of IL-1ß, collagenases, and MMP activity. Furthermore, in vitro study showed that LUT inhibited IL-1ß-induced type I collagen degradation and the release of inflammatory cytokines and chemokines by corneal stromal fibroblasts. LUT also inhibited the IL-1ß-induced activation of TAK-1, mitogen-activated protein kinase (MAPK), c-Jun, and NF-κB signaling pathways in these cells. Our results demonstrate that LUT inhibited alkali burn-stimulated collagen breakdown and corneal inflammation, most likely by attenuating the IL-1ß signaling pathway. LUT may therefore prove to be of clinical value for treating corneal alkali burns.

Organocatalyzed Enantioselective Aza-Morita-Baylis-Hillman Reaction of Cyclic Ketimine with α,ß-Unsaturated γ-Butyrolactam.

The enantioselective aza-MBH reaction is an efficient strategy for constructing novel carbon-carbon bonds, providing access to multitudinous chiral densely functionalized MBH products. However, the enantioselective aza-MBH reaction of cyclic-ketimines that would generate a versatile synthon is still missing and challenging. Herein, we developed a challenging direct organocatalytic asymmetric aza-MBH reaction involving cyclic ketimines attached to a neutral functional group. Moreover, the α,ß-unsaturated γ-butyrolactam was utilized as a rare nucleophile alkene in this work. The reactions provide enantiomerically enriched 2-alkenyl-2-phenyl-1,2-dihydro-3H-indol-3-ones, bearing with a tetra-substituted stereogenic center. Moreover, this reaction features high α-selectivities, high enantioselectivities (up to 99% ee), and good yields (up to 80%).

Chiral phosphoric acid-catalyzed enantioselective aza-Friedel-Crafts reaction of naphthols and electron-rich phenols with 2-aryl-3H-indol-3-ones.

The enantioselective aza-Friedel-Crafts reaction is one of the most straightforward and efficient strategies for constructing a new carbon-carbon bond bearing quaternary stereocenter in organic synthesis, but the catalytic asymmetric aza-Friedel-Crafts reaction of naphthols/phenols with cyclic-ketimines attached to a neutral functional group remains still relatively unexplored. Herein, a highly enantioselective aza-Friedel-Crafts reaction of cyclic-ketimines and naphthols/phenols has been realized using a chiral phosphoric acid catalyst. A variety of chiral aminonaphthols (chiral indolin-3-ones) containing a quaternary stereocenter at the C2 position were obtained with excellent outcomes (up to 97% yield, 98% ee). Moreover, the synthetic utility of the enantiomerically enriched chiral aminonaphthols was demonstrated in some efficient transformations. According to the experimental results, a possible transition state model has been proposed to rationalize the origin of asymmetric induction.

B(C6F5)3-catalyzed ß-C(sp3)-H alkylation of tertiary amines with 2-aryl-3H-indol-3-ones.

The ß-C-H functionalization of amines is one of the most powerful tools for the synthesis of saturated nitrogen-containing heterocycles in organic synthesis. However, the ß-C-H functionalization of amines via redox-neutral addition with cyclic-ketimines is still unprecedented. Herein, the ß-C-H functionalization of tertiary amines is described, providing the corresponding 1,3-diamines containing the indolin-3-one moiety in high yields via the B(C6F5)3-catalyzed borrowing hydrogen strategy. According to the experimental results, a possible catalytic cycle has been proposed to rationalize the process of this reaction. Notably, the ß-C-H alkylation of amines is external oxidant- and transition-metal-free, which makes a significant contribution to promoting economical chemical synthesis.

Inhibition of phase transition from δ-MnO2 to α-MnO2 by Mo-doping and the application of Mo-doped MnO2 in aqueous zinc-ion batteries.

MnO2 is an oxide with many crystalline phases and is often used as a cathode material for aqueous zinc-ion batteries. However, its poor electrical conductivity and structural instability limit its further application. In the present work, Mo-doped MnO2 microflowers are successfully prepared by a facile hydrothermal method. Interestingly, it is found that the doping of Mo inhibits the phase transition from δ-MnO2 to α-MnO2, which may be related to the low crystallinity of Mo doped MnO2. Compared with undoped MnO2, Mo-doped MnO2 maintains two-dimensional morphology with a large specific surface area and mesoporous structure. In addition, the electronic conductivity and reversibility of Zn2+ insertion/extraction are improved in Mo doped MnO2. Therefore, Mo-doped MnO2 exhibits high reversible capacity and long cycling stability. For example, a high reversible capacity of 72.6 mA h g-1 can be achieved at a current density of 2000 mA g-1 after 2500 cycles.

Ultrasound Guidance Combined with C-Arm Fluoroscopy in Selective Semilunar Ganglion Radiofrequency Thermocoagulation Through the Foramen Ovale for Trigeminal Neuralgia: A Randomized Controlled Trial.

OBJECTIVE: To explore the clinical value of ultrasound guidance combined with C-arm guidance during selective semilunar ganglion radiofrequency thermocoagulation via the foramen ovale for trigeminal neuralgia. METHODS: This study enrolled 48 patients diagnosed with trigeminal neuralgia between January 2021 and December 2021 in the Department of Pain Management at Xuanwu Hospital. Patients were randomly and equally divided into a C-arm-only group and an ultrasound-combined-with-C-arm (ultrasound+C-arm) group, according to a random number table. After exclusions, 42 patients were analyzed. Of these, 21 patients underwent selective semilunar ganglion radiofrequency thermocoagulation via the foramen ovale guided by the C-arm alone, whereas 21 patients underwent the same procedure guided by ultrasound combined with C-arm. The number of punctures, the amount of time elapsed until the target area of the semilunar ganglion was punctured, the cumulative dose of radiation exposure, and puncture-related complications were recorded during the operation. Numerical rating scale scores and radiofrequency thermocoagulation-related complications were evaluated preoperatively and at 1 day, 3 days, 7 days, 1 month, and 3 months after surgery. RESULTS: The number of punctures, the amount of time elapsed until the target area of the semilunar ganglion was punctured, and the cumulative dose of radiation exposure were all lower in the ultrasound+C-arm group than in the C-arm-only group (all P < 0.05). No significant differences were found in numerical rating scale scores and radiofrequency thermocoagulation-related complications between the two groups (P > 0.05). No puncture-related complications occurred in either of the groups. CONCLUSION: Ultrasound guidance combined with C-arm guidance could be safely used for puncturing the semilunar ganglion via the foramen ovale, with more efficiency and less radiation exposure than C-arm guidance alone.

Changes in blood pressure, oxygen saturation, hemoglobin concentration, and heart rate among low-altitude migrants living at high altitude (5380 m) for 360 days.

BACKGROUND: This article aimed to study the adjustment and adaptation of resting systolic blood pressure (SBP), diastolic blood pressure (DPB), oxygen saturation (SpO2 ), hemoglobin concentration ([Hb]), and heart rate (HR) in low-altitude migrants during a 1-year stay at high altitude. MATERIALS AND METHODS: Our study enrolled 35 young migrants who were exposed to a hypoxia environment at 5380 m altitude on the Qinghai Tibetan Plateau between June 21, 2017, and June 16, 2018. We set 14-time points (the 1st-10th, 20th, 30th, 180th, and 360th day after arriving at 5380 m) for obtaining the measurements of resting SBP, DBP, HR, SpO2, and [Hb] and compared them with the control values recorded prior to migration. Variables with continuous data were summarized as means (SD). One-way repeated measures ANOVA without assuming sphericity was carried out to test whether the mean values (SBP, DBP, HR, SpO2 , and [Hb]) on different days were different significantly. Furthermore, Dunnett's multiple comparisons test was carried out to determine the time points whose values were significantly different from the control values. RESULTS: SBP and DBP were continually increasing within d1-3 and peaked on the 3rd day, then steadily declined from d3 to d30. SBP fell back to the control values on d10 (p > 0.05), and DBP fell back to the control values on d20 (p > 0.05). A significant decline occurred on d180 (p < 0.05). Both SBP and DBP were lower than the control values on d180 (p < 0.05), and this trend was maintained to d360. There were similar characteristics of HR and BP in the time course at HA. HR on d1-3 was increasing (p < 0.05) compared to the control values, after which it fell back to the control values on d180 (p > 0.05), and this trend was maintained to d360. SpO2 was the lowest on d1 and lower than the control value throughout the study at HA (p < 0.05). [Hb] increased after long-term exposure (180 and 360 days) to HA (p < 0.05). CONCLUSIONS: Our study continuously monitored lowlanders at 5380 m in Tibet, and is perhaps the only longitudinal study of migrants conducted at an altitude above 5000 m during a 1-year period. Our study provides new information on the adjustment and adaptation of [Hb], SpO2 , SBP, DBP, and HR in high-altitude plateau migrants during a 360-day stay at an altitude of 5380 m.

Densely Connected Networks with Multiple Features for Classifying Sound Signals with Reverberation.

In indoor environments, reverberation can distort the signalseceived by active noise cancelation devices, posing a challenge to sound classification. Therefore, we combined three speech spectral features based on different frequency scales into a densely connected network (DenseNet) to accomplish sound classification with reverberation effects. We adopted the DenseNet structure to make the model lightweight A dataset was created based on experimental and simulation methods, andhe classification goal was to distinguish between music signals, song signals, and speech signals. Using this framework, effectivexperiments were conducted. It was shown that the classification accuracy of the approach based on DenseNet and fused features reached 95.90%, betterhan the results based on other convolutional neural networks (CNNs). The size of the optimized DenseNet model is only 3.09 MB, which is only 7.76% of the size before optimization. We migrated the model to the Android platform. The modified model can discriminate sound clips faster on Android thanhe network before the modification. This shows that the approach based on DenseNet and fused features can dealith sound classification tasks in different indoor scenes, and the lightweight model can be deployed on embedded devices.

Estimation of Target Motion Parameters from the Tonal Signals with a Single Hydrophone.

In the shallow-water waveguide environment, the tonal signals radiated by moving targets carry modal interference and Doppler shift information. The modal interference can be used to obtain the time of the closest point of approach (tCPA) and the ratio of the range at the closest point of approach to the velocity of the source (rCPA/v). However, parameters rCPA and v cannot be solved separately. When tCPA is known, the rCPA and the v of the target can be obtained theoretically by using the Doppler information. However, when the Doppler frequency shift is small or at a low signal-to-noise ratio, there will be a strong parametric coupling between rCPA and v. In order to solve the above parameter coupling problem, a target motion parameter estimation method from tonal signals with a single hydrophone is proposed in this paper. The method uses the Doppler and modal interference information carried by the tonal signals to obtain two different parametric coupling curves. Then, the parametric coupling curves can be used to estimate the two motion parameters. Simulation experiments verified the rationality of this method. The proposed method was applied to the SWellEx-96 and speedboat experiments, and the estimation errors of the motion parameters were within 10%, which shows the method is effective in its practical applications.

Myxobolus dumerilii sp. n. (Myxozoa: Myxobolidae) infecting the brain of Chinese longsnout catfish Tachysurus dumerili (Bleeker) in China.

During an investigation of Myxobolus diversity in the Chinese longsnout catfish Tachysurus dumerili (Bleeker), a new species infecting the intracranial epidermis of the host was discovered. Upon opening the cranial cavity, several round whitish plasmodia measuring 0.55-0.80 mm in diameter were observed. Fresh spores (n= 50) were pyriform in the frontal view and fusiform in the sutural view, with a length of 15.4±0.6 (13.9-16.5) µm, width of 9.1±0.4 (8.3-9.8) µm, and thickness of 7.0±0.4 (6.3-7.9) µm. The spores had smooth shell surfaces and transparent membrane sheaths in the posterior. No folds, intercapsular appendix, and caudal appendages were observed. Two equal polar capsules were pyriform and measured 7.5±0.5 (6.7-8.7) µm in length and 3.2±0.3 (2.5-3.6) µm in width. The polar filaments were coiled with five to six turns and perpendicular to the polar capsule length. A BLAST search indicated M. dumerilii sp. n. was closely related to five Myxobolus species (with sequences similarities ranging from 90.54% to 96.52%) found in different organs of yellow catfish Tachysurus fulvidraco (Richardson), rather than the T. dumerili-infecting species M. branchiola Dong and Zhao, 2014 (with 90.5% sequence similarity). Phylogenetic analysis showed that M. dumerilii sp. n. didn't form sister clade with brain-infecting Myxobolus spp, but clustered with M. jianlinensis Gao et Zhao, 2020 and M. voremkhai Akhmerov, 1960 within the Siluriformes-clade with highly supported values, indicating that the host specificity may play a stronger signal than site infections during the evolution of Myxobolus species. Based on the morphological, ecological, and molecular differences observed between the newly discovered species and other available Myxobolus species, M. dumerilii sp. n., is proposed and described in this study.

Asymmetric Intramolecular Hydroalkylation of Internal Olefin with Cycloalkanone to Directly Access Polycyclic Systems.

An asymmetric intramolecular hydroalkylation of unactivated internal olefins with tethered cyclic ketones was realized by the cooperative catalysis of a newly designed chiral amine (SPD-NH2 ) and PdII complex, providing straightforward access to either bridged or fused bicyclic systems containing three stereogenic centers with excellent enantioselectivity (up to 99 % ee) and diastereoselectivity (up to >20 : 1 dr). Notably, the bicyclic products could be conveniently transformed into a diverse range of key structures frequently found in bioactive terpenes, such as Δ6 -protoilludene, cracroson D, and vulgarisins. The steric hindrance between the Ar group of the SPD-NH2 catalyst and the branched chain of the substrate, hydrogen-bonding interactions between the N-H of the enamine motif and the C=O of the directing group MQ, and the counterion of the PdII complex were identified as key factors for excellent stereoinduction in this dual catalytic process by density functional theory calculations.

α7 nicotinic acetylcholine receptor agonist GTS-21 attenuates DSS-induced intestinal colitis by improving intestinal mucosal barrier function.

BACKGROUND AND AIMS: Cholinergic output, which could modulate innate immune responses through stimulation of α7 nicotinic acetylcholine receptor (α7nAChR), might be a target to minimize tissue damage in autoimmune disease. GTS-21, a selective α7nAChR agonist, has previously demonstrated to inhibit synovium inflammation in rheumatoid arthritis. In this study, we investigated the effect of GTS-21 on dextran sulfate sodium (DSS)-induced colitis model and its potential mechanism. METHODS: Male BABL/c mice (n = 32) were randomly divided into four groups: normal control group, DSS-induced colitis group, GTS-21 treatment with or without α7nAChR antagonist α-BGT treatment group. Disease activity index (DAI), histological activity index (HAI) and colonic macroscopic damage were evaluated. Fluorescein isothiocyanate (FITC)-dextran assay was applied to measure intestinal permeability. The expressions of tight junction (TJ) proteins and NF-κB associated proteins were detected by Western blot. RESULTS: GTS-21 could decrease DAI scores, HAI scores, intestinal permeability and reduce the intestinal bacterial translocation in DSS-induced colitis group, whereas α7nAChR antagonist α-BGT could impair this protective influence. The expressions of TJ proteins were increased with administration of GTS-21 both in vivo and in vitro. Furthermore, GTS-21 also inhibited the NF-қB activation in intestinal epithelial cells and colitis model, while α-BGT reversed the inhibitory effect. CONCLUSION: The α7nAChR agonist GTS-21 attenuated DSS-induced colitis through increasing expressions of TJ proteins in colon tissues and improved intestinal barrier function, which might be due to  modulating NF-қB activation in intestinal epithelial cells.

Evaluation of log odds of positive lymph nodes in predicting the survival of patients with non-small cell lung cancer treated with neoadjuvant therapy and surgery: a SEER cohort-based study.

BACKGROUND: Log odds of positive lymph nodes (LODDS) is a novel lymph node (LN) descriptor that demonstrates promising prognostic value in many tumors. However, there is limited information regarding LODDS in patients with non-small cell lung cancer (NSCLC), especially those receiving neoadjuvant therapy followed by lung surgery. METHODS: A total of 2059 patients with NSCLC who received neoadjuvant therapy and surgery were identified from the Surveillance, Epidemiology, and End Results (SEER) database. We used the X-tile software to calculate the LODDS cutoff value. Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curve analysis were performed to compare predictive values of the American Joint Committee on Cancer (AJCC) N staging descriptor and LODDS. Univariate and multivariate Cox regression and inverse probability of treatment weighting (IPTW) analyses were conducted to construct a model for predicting prognosis. RESULTS: According to the survival analysis, LODDS had better differentiating ability than the N staging descriptor (log-rank test, P < 0.0001 vs. P = 0.031). The ROC curve demonstrated that the AUC of LODDS was significantly higher than that of the N staging descriptor in the 1-, 3-, and 5-year survival analyses (all P < 0.05). Univariate and multivariate Cox regression analyses showed that LODDS was an independent risk factor for patients with NSCLC receiving neoadjuvant therapy followed by surgery both before and after IPTW (all P < 0.001). A clinicopathological model with LODDS, age, sex, T stage, and radiotherapy could better predict prognosis. CONCLUSIONS: Compared with the AJCC N staging descriptor, LODDS exhibited better predictive ability for patients with NSCLC receiving neoadjuvant therapy followed by surgery. A multivariate clinicopathological model with LODDS demonstrated a sound performance in predicting prognosis.

Sulforaphane inhibits cytokine-stimulated chemokine and adhesion molecule expressions in human corneal fibroblasts: Involvement of the MAPK, STAT, and NF-κB signaling pathways.

Chemokines and adhesion molecules are major inflammatory mediators of chronic and recurrent vernal keratoconjunctivitis (VKC). Sulforaphane (SFN) is a natural plant extract that is known to have anti-inflammatory and antioxidant properties. SFN is demonstrated to be effective against a variety of human diseases. The current investigation examines the effects and the molecular mechanisms of SFN on cytokine-induced human corneal fibroblasts (HCFs) expression of adhesion molecules and chemokines. HCFs were exposed to both interleukin (IL)-4 and tumor necrosis factor (TNF)-α in the absence or presence of SFN treatment. The levels of thymus- and activation-regulated chemokine (TARC) and eotaxin-1 in culture supernatants were evaluated using enzyme-linked immunosorbent assay (ELISA). Reverse transcription-polymerase chain reaction analysis (RT-PCR) enabled quantification of mRNA levels of vascular cell adhesion molecule (VCAM)-1, eotaxin-1, and TARC along with cytokine receptors. An immunoblotting assay was used to evaluate the activities of VCAM-1, nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs), signal transducer and activator of transcription factor (STAT)6 pathways, along with the expression of the cytokine receptors including IL-4 receptor (R)α, IL-13Rα1, TNFRI, as well as TNFRII. SFN inhibited TARC and eotaxin-1 release in HCFs stimulated by TNF-α and IL-4 in a manner dependent on dose and time. SFN suppressed transcriptions of TARC, eotaxin-1, and VCAM-1. Furthermore, the mRNA and protein expression levels of IL-4Rα, TNFRI, and TNFRII were also attenuated by SFN exposure, however, those of IL-13Rα1 remained unaffected. In addition, SFN downregulated the expression of VCAM-1 and the phosphorylation of MAPKs, IκBα, and STAT6. These results suggest that SFN inhibited cytokine-stimulated TARC, eotaxin-1 secretion as well as VCAM-1 expression in HCFs, with these effects likely occurring as a result of cytokine receptor inhibition and attenuation of MAPK, NF-κB, and STAT6 signaling. SFN may therefore have therapeutic potential in VKC treatment.