Hydrated [3+2] Cyclotelomerization of Butafulvenes to Create Multiple Contiguous Fully Substituted Carbon Centers.

The construction of multiple continuous fully substituted carbon centers, which serve as unique structural motif in natural products, is a challenging topic in organic synthesis. Herein, we report a hydrated [3+2] cyclotelomerization of butafulvenes to create contiguous fully substituted carbon backbone. In the presence of scandium triflate, all-carbon skeleton with spiro fused tricyclic ring can be constructed in high diastereoselectivity by utilizing butafulvene as the synthon. Mechanistic studies suggest that this atom-economic reaction probably proceeds through a synergistic process containing butafulvenes dimerization and nucleophilic attack by water. In addition, the tricyclic product can undergo a series of synthetic derivatizations, which highlights the potential applications of this strategy. The recyclability of Sc(OTf)3 has also been demonstrated to show its robust performance in this hydrated cyclotelomerization.

Decreasing the memory of the discontinuous Galerkin volume integral equation method for scattering from inhomogeneous dielectric objects.

A memory-efficient implementation scheme for the discontinuous Galerkin volume integral equation method (DGVIE) using Schaubert-Wilton-Glisson (SWG) basis functions is proposed to analyze electromagnetic scattering from inhomogeneous dielectric objects. For this proposed scheme, almost no half-SWG basis functions are needed for the elements separating nonconformal meshes, while these half-SWG basis functions are indispensable for the conventional DGVIE-SWG method. This is realized by applying the divergence-free condition of the electric displacement vector explicitly for nonconformal meshes separating neighboring subdomains of an inhomogeneous dielectric body. Therefore, the number of unknowns of the conventional DGVIE method can be further reduced. As a result, the memory of the proposed DGVIE method is only about half of the conventional one for inhomogeneous dielectric problems. Meanwhile, the total solution time has been reduced by the use of the proposed scheme. Particularly, the proposed DGVIE-SWG method is efficient in memory usage not only for inhomogeneous dielectric cases with high contrast ratio but also for cases with relatively low contrast ratio.

Exploring the Relationship between Perfectionism and Pain in Patients with Temporomandibular Disorders: A Cross-Sectional Study.

Objectives: The purpose of this cross-sectional study was to examine the relationship between perfectionism and pain in patients with temporomandibular disorders (TMDs). Methods: A total of 345 TMD patients were included. A questionnaire consisting of questions of demographic information, the 15-item short form of the Hewitt and Flett Multidimensional Perfectionism Scale, and the Patient Health Questionnaire-4 (PHQ-4) was distributed. According to the diagnostic criteria for TMDs, patients were categorized as pain-related (PT) and non-pain-related (NPT) groups, whereas PT patients were further divided into patients with pain-related TMDs only (OPT) and patients with combined pain-related and intra-articular TMDs (CPT). Data were analyzed using the chi-square test, Spearman's correlation, and logistic regression analysis with the significance level set at p < 0.05. Results: There were 68 patients in the NPT group, 80 in the OPT group, and 197 in the CPT group. PT patients had significantly higher perfectionism scores (63.58 ± 13.63) than NPT patients (56.32 ± 12.95, p < 0.001). The PHQ-4 score in the PT group was also higher. After adjusting the PHQ-4 scores, perfectionism scores of the PT group were 6.11 points higher than those in the NPT group (p < 0.001). There were no statistical differences in all parameters of OPT and CPT groups (p > 0.05). Perfectionism in total, other-oriented perfectionism (OOP), and socially prescribed perfectionism (SPP) showed significant but weak correlations with PHQ-4 scores (p < 0.001), while self-oriented perfectionism (SOP) was also significantly but very weakly correlated with PHQ-4 scores (p < 0.05). Conclusions: Pain-related TMD patients exhibited higher perfectionism scores than NPT patients, and neither their perfectionism nor pain scores were correlated with intra-articular diseases of TMJ. OOP and SOP presented weak correlations with psychological distress in TMD patients. It is suggested that pain-related TMD patients could be screened for perfectionism and perfectionism could be considered when proposing psychological treatment strategies to PT patients.

Inulin-type oligosaccharides of Morinda officinalis exerted antidepressant effects by reducing hippocampal inflammation.

Neuroinflammation contributes to the pathogenesis of depression. Inulin-type oligosaccharides of Morinda officinalis (IOMO) exert antidepressant-like effects in rodents and patients with depression, while the underlying mechanisms remain unclear. This study used chronic restraint stress (CRS) and lipopolysaccharide (LPS) to induce depression-like behaviors in mice. Western blotting and ELISA analysis were used to investigate the effects of IOMO on inflammatory cytokine levels. Immunofluorescence analysis was used to investigate the effects of IOMO on hippocampal NLRP3 inflammasome and microglial cells. The results suggested that 6 weeks of CRS induced significant depression-like behaviors based on the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST), which were accompanied by increases in the expression of IL-6 and the activation of hippocampal microglial cells. Chronic treatment with IOMO (25 mg/kg, i.g.) for 28 days significantly reversed these depression-like behaviors and inhibited the activation of microglial cells. Furthermore, LPS (0.5 mg/kg, i.p.) also significantly induced depression-like behaviors in the TST, FST, and novelty-suppressed feeding test (NSFT), as well as increased the expression of IL-1ß and caspase-1, and activated the microglial cells and the NLRP3 inflammasome in the hippocampus. Treatment with IOMO for 9 days significantly reversed these depression-like behaviors and normalized the LPS-induced activation of the microglial cells and NLRP3 inflammasome. Taken together, these results suggested that IOMO exerted antidepressant-like effects via hippocampal microglial NLRP3 inflammasome mediation followed by caspase-1 inhibition and the production of IL-1ß. These findings provide a basis for developing new antidepressants targeting the microglial NLRP3 inflammasome.

Efficiency and Safety of Dextran-PAMAM/siMMP-9 Complexes for Decreasing Matrix Metalloproteinase-9 Expression and Promoting Wound Healing in Diabetic Rats.

Difficult healing of diabetic foot ulcers is associated with overexpression of matrix metalloproteinase 9 (MMP-9) in the local wound. Therefore, strategies aimed at downregulation of MMP-9 levels in ulcer sites may promote tissue regeneration and accelerate healing of diabetic foot ulcers (DFU). To fulfill this aim, we exploited dextran conjugated with poly(amidoamine) (Dextran-PAMAM) as a gene carrier to deliver MMP-9 targeted siRNA (siMMP-9). The prepared complexes could be efficiently endocytosed with low cytotoxicity to HaCat cells. Dextran-PAMAM could efficiently deliver siMMP-9 and significantly inhibit MMP-9 expression in vitro. Diabetic rats wound models showed that topical application of the Dextran-PAMAM/siMMP-9 complex effectively knocked down MMP-9 expression in skin wound tissue, thus accelerating wound healing. Taken together, this study demonstrates that the Dextran-PAMAM/siMMP-9 complex possesses high potential for wound healing and could serve as a promising regenerative platform for improving DFU healing.

Association between Stigma and Pain in Patients with Temporomandibular Disorders.

Objective: This study aims to explore the association between stigma and pain in patients with temporomandibular disorders (TMDs). Methods: Two hundred and twenty-five patients with TMDs were recruited, and they completed the questionnaires including the Visual Analogue Scale of Pain (VAS), Generalized Anxiety Disorder 7-Item (GAD-7), the Patient Health Questionnaire 9-item (PHQ-9), Jaw Functional Limitation Scale 8-item (JFLS-8), the Stigma Scale for Chronic Illness 8-item (SSCI-8), and other demographic and disease-related information. The total score of SSCI-8 indicated overall stigma, which could be classified into 2 subdomains, felt stigma and enacted stigma, according to their representative items, respectively. Then, the patients were divided into 2 groups in each subdomain of stigma according to their scores: stigma group (score ≥ 1) and no stigma group (score = 0). Results: Patients with overall stigma and enacted stigma presented significantly higher scores in VAS, GAD-7, PHQ-9, and JFLS-8 than those without overall stigma and those without enacted stigma, respectively. Significant differences between patients with and without felt stigma were only observed in GAD-7, PHQ-9, and JFLS-8. Patients with overall stigma and enacted stigma mainly suffered from pain-related TMDs (PTs) and combined TMDs (CTs). Overall stigma and enacted stigma rather than felt stigma were significantly associated with both PTs and CTs. Stigma, including overall stigma, enacted stigma, and felt stigma, was more associated with anxiety and depression and less related to jaw functional limitation of the patients with TMDs. Conclusion: Stigma, specifically enacted stigma, was correlated to pain in patients with TMDs. Stigma was more related to psychological problems than jaw functional limitation.

Involvement of regulation of the excitation:inhibition functional balance in the mPFC in the antidepressant-anxiolytic effect of YL-IPA08, a novel TSPO ligand.

TSPO, an 18 kDa translocator protein, has received increased attention due to its antidepressant-anxiolytic effects. The balance between glutamatergic and GABAergic (E: I) in the medial prefrontal cortex (mPFC) is crucial for antidepressant-anxiolytic effects. However, no evidence is available to clarify the relationship between TSPO and E:I balance. In the present study, we used the TSPO global-knockout (KO) and TSPO wild-type (WT) mice to assess the effects of TSPO on antidepressant-anxiolytic effects of YL-IPA08 (a novel TSPO ligand) and the underlying neurobiological mechanism. Additionally, a multichannel electrophysiological technique was used to explore the effects of YL-IPA08 on pyramidal neurons and interneurons in mPFC. Open field test (OFT) and elevated plus maze (EPM) test revealed that a single dose of YL-IPA08 (0.3 mg/kg, i.p.) exhibited significant anxiolytic actions in WT mice except in KO mice. In only WT mice, significant antidepressant effects were observed in tail suspension test (TST) and forced swim test (FST). The multichannel electrophysiological technique demonstrated that YL-IPA08 significantly increased the firing rates of pyramidal neurons and decreased those of interneurons. Further studies illustrated that the firing rates of glutamatergic might be antagonized by PK11195 (a classic TSPO antagonist). Our results suggest that YL-IPA08 might regulate the E:I balance in mPFC, mediated by TSPO. In summary, TSPO regulates E:I functional balance in mPFC, play a critical role in antidepressant-anxiolytic effects of YL-IPA08, and provide a potential target site for the development of antidepressant and anxiolytic drugs.

Synthesis of W-Phos Ligand and Its Application in the Copper-Catalyzed Enantioselective Addition of Linear Grignard Reagents to Ketones.

The asymmetric catalytic addition of linear Grignard reagents to ketones has been a long-standing challenge in organic synthesis. Herein, a novel family of PNP ligands (W-Phos) was designed and applied in copper-catalyzed asymmetric addition of linear Grignard reagents to aryl alkyl ketones, allowing facile access to versatile chiral tertiary alcohols in good to high yields with excellent enantioselectivities (up to 94 % yield, 96 % ee). The process can also be used to synthesize chiral allylic tertiary alcohols from more challenging α,ß-unsaturated ketones. Notably, the potential utility of this method is demonstrated in the gram-scale synthesis and modification of various densely functionalized medicinally relevant molecules.

[Mortality and cause of death of hospitalized neonates in Weifang, China: a multicenter study]. / æ½åŠå¸‚ä½é™¢æ–°ç”Ÿå„¿ç— æ­»çŽ‡åŠæ­»äº¡åŽŸå› çš„å¤šä¸­å¿ƒç ”ç©¶.

OBJECTIVES: To study the changes in the mortality rate and cause of death of hospitalized neonates in grade A tertiary hospitals in Weifang City of Shandong Province during a 10-year period. METHODS: A retrospective analysis was performed on 461 neonates who died in three grade A tertiary hospitals in Weifang City of Shandong Province from January 1, 2012 to December 31, 2021. The related clinical data were collected to examine the changes of neonatal mortality with time, gestational age (GA) and birth weight (BW). The main causes of death of the neonates were compared between the first 5 years (2012-2016) and the last 5 years (2017-2021) in the period. RESULTS: A total of 43 037 neonates were admitted from 2012 to 2021, among whom 461 died, resulting in a mortality rate of 1.07%. The mortality rate in the last 5 years was significantly lower than that in the first 5 years [0.96% (211/22 059 vs 1.19% (250/20 978); P<0.05]. The mortality rate of neonates decreased with the increases in GA and BW (P<0.05). In the first 5 years, the top three main causes of neonatal death were respiratory distress syndrome (RDS), sepsis, and pneumorrhagia, while in the last 5 years, the top three causes were sepsis, pneumorrhagia, and RDS. The leading cause of death was severe asphyxia for the neonates with a GA of <26 weeks and a BW of <750 g in both the first and last 5 years. For the neonates with a GA of 26-<28 weeks, the leading cause of death changed from RDS in the first 5 years to pneumorrhagia in the last 5 years. For the neonates with a BW of 750-<1 000 g, the leading cause of death changed from pneumorrhagia in the first 5 years to RDS in the last 5 years. For the neonates with a GA of 28-<32 weeks and a BW of 1 000-<1 500 g, the leading cause of death was RDS in both the first and last 5 years. For the neonates with a GA of 32-<37 weeks and a BW of 1 500-<2 500 g, the leading cause of death changed from RDS in the first 5 years to sepsis in the last 5 years. The leading cause of death was sepsis for the neonates with a GA of 37-<42 weeks and a BW of 2 500-<4 000 g in both the first and last 5 years. CONCLUSIONS: The mortality rate of neonates in the grade A tertiary hospitals in Weifang City of Shandong Province has been decreasing in the past 10 years, and it decreases with the increases in GA and BW. Sepsis, RDS, and pneumorrhagia are the leading causes of neonatal death. The mortality rate caused by RDS decreases from the first 5 years to the last 5 years, while the mortality rate caused by sepsis or pneumorrhagia increases from the first 5 years to the last 5 years. Therefore, reducing the incidence rates of sepsis, RDS, and pneumorrhagia is the key to reducing neonatal mortality.

Direct solution of the volume integral equation for electromagnetic scattering from dielectric objects with negative permittivity.

In this paper, electromagnetic scattering from dielectric objects with negative permittivity is solved by the volume integral equation (VIE)-hierarchical matrix (H-matrix)-based fast direct solver. To improve solution efficiency, a coarsening algorithm for the H-matrix is used, and the key parameter for the admissible condition is optimized through numerical experiments. Finally, the discontinuous Galerkin (DG) VIE (DGVIE) method is developed for the fast direct solver. It is shown that scattering from inhomogeneous dielectric objects with negative permittivity and with multiscale structure can be analyzed efficiently by the DGVIE-H-matrix-based fast direct solver.

Cationic porphyrins with large side arm substituents as resonance light scattering ratiometric probes for specific recognition of nucleic acid G-quadruplexes.

Specific G-quadruplex-probing is crucial for both biological sciences and biosensing applications. Most reported probes are focused on fluorescent or colorimetric recognition of G-quadruplexes. Herein, for the first time, we reported a new specific G-quadruplex-probing technique-resonance light scattering (RLS)-based ratiometric recognition. To achieve the RLS probing of G-quadruplexes in the important physiological pH range of 7.4-6.0, four water soluble cationic porphyrin derivatives, including an unreported octa-cationic porphyrin, with large side arm substituents were synthesized and developed as RLS probes. These RLS probes were demonstrated to work well for ratiometric recognition of G-quadruplexes with high specificity against single- and double-stranded DNAs, including long double-stranded ones. The working mechanism was speculated to be based on the RLS signal changes caused by porphyrin protonation that was promoted by the end-stacking of porphyrins on G-quadruplexes. This work adds an important member in G-quadruplex probe family, thus providing a useful tool for studies on G-quadruplex-related events concerning G-quadruplex formation, destruction and changes in size, shape and aggregation. As a proof-of-concept example of applications, the RLS probes were demonstrated to work well for label-free and sequence-specific sensing of microRNA. This work also provides a simple and useful way for the preparation of cationic porphyrins with high charges.

Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene.

Paroxysmal kinesigenic dyskinesia (PKD) is a heterogeneous movement disorder characterized by recurrent dyskinesia attacks triggered by sudden movement. PRRT2 has been identified as the first causative gene of PKD. However, it is only responsible for approximately half of affected individuals, indicating that other loci are most likely involved in the etiology of this disorder. To explore the underlying causative gene of PRRT2-negative PKD, we used a combination strategy including linkage analysis, whole-exome sequencing and copy number variations analysis to detect the genetic variants within a family with PKD. We identified a linkage locus on chromosome 12 (12p13.32-12p12.3) and detected a novel heterozygous mutation c.956 T>G (p.319 L>R) in the potassium voltage-gated channel subfamily A member 1, KCNA1. Whole-exome sequencing in another 58 Chinese patients with PKD who lacked mutations in PRRT2 revealed another novel mutation in the KCNA1 gene [c.765 C>A (p.255 N>K)] within another family. Biochemical analysis revealed that the L319R mutant accelerated protein degradation via the proteasome pathway and disrupted membrane expression of the Kv1.1 channel. Electrophysiological examinations in transfected HEK293 cells showed that both the L319R and N255K mutants resulted in reduced potassium currents and respective altered gating properties, with a dominant negative effect on the Kv1.1 wild-type channel. Our study suggests that these mutations in KCNA1 cause the Kv1.1 channel dysfunction, which leads to familial PKD. The current study further extended the genotypic spectrum of this disorder, indicating that Kv1.1 channel dysfunction maybe one of the underlying defects in PKD.

Onboard absolute radiometric calibration and validation of the satellite calibration spectrometer on HY-1C.

As the reference radiometric calibration standard of sensors on the Haiyang-1C (HY-1C) satellite platform, the satellite calibration spectrometer (SCS) is equipped with an onboard calibration system composed of double solar diffusers and an erbium-doped diffuser to monitor the postlaunch radiometric response change. Herein, through onboard calibration data analysis, the calibration diffuser performance remains stable without degradation, and the Moderate Resolution Imaging Spectroradiometer (MODIS) on Terra is adopted as a reference to repeatedly verify onboard radiometric calibration results by selecting different dates and reflectance scenes. The SCS equivalent reflectance is obtained by combining the mean digital number (DN) of the SCS crossing area image with the radiometric calibration coefficient. The spectral reflectance is obtained via interpolation and iteration, which is adopted as the actual MODIS incident pupil spectral reflectance because the small imaging time interval can be ignored and almost vertically observed, and it is convoluted with the MODIS spectral response function to obtain the predicted equivalent reflectance. Validation is completed by comparing the predicted MODIS equivalent reflectance to the measured value based on the onboard calibration coefficient. The results show that (1) the difference between the measured and predicted MODIS band equivalent reflectance is between -0.00466 and 0.0039, and (2) the percentage difference between the measured and predicted MODIS band equivalent reflectance ranges from 4.17% and 1.24%, indicating that the calibration system carried on HY-1C can perform high-precision SCS radiometric calibration, meeting the cross-calibration accuracy requirements of other loads on the same platform.

A neutral polysaccharide from green tea: Structure, effect on α-amylase activity and hydrolysis property.

A neutral tea polysaccharide (TPSN) was isolated from green tea. Gas chromatography analysis showed that TPSN was composed of d-glucose, l-arabinose and d-galactose residues at a molar ratio of 90.0: 9.1: 0.9. The weight-averaged molecular weight of TPSN was determined as about 2.0 × 105 g mol-1 using static light scattering analysis. The result of nuclear magnetic resonance (NMR) spectroscopy indicated that TPSN and water-soluble starch had similar structures. TPSN exhibited inhibitory activity towards α-amylase through the noncompetitive inhibition mechanism, but the tertiary structure of α-amylase related to enzymatic activity, analyzed using circular dichroism spectroscopy, was not affected by TPSN. Meanwhile, TPSN exhibited hydrolysis properties catalyzed by α-amylase. Molecular docking analysis revealed that the various behaviors of TPSN to α-amylase could be attributed to that the different chain segments of TPSN combined with different amino acid residues of α-amylase.

Emergency tracheal intubation in 202 patients with COVID-19 in Wuhan, China: lessons learnt and international expert recommendations.

Tracheal intubation in coronavirus disease 2019 (COVID-19) patients creates a risk to physiologically compromised patients and to attending healthcare providers. Clinical information on airway management and expert recommendations in these patients are urgently needed. By analysing a two-centre retrospective observational case series from Wuhan, China, a panel of international airway management experts discussed the results and formulated consensus recommendations for the management of tracheal intubation in COVID-19 patients. Of 202 COVID-19 patients undergoing emergency tracheal intubation, most were males (n=136; 67.3%) and aged 65 yr or more (n=128; 63.4%). Most patients (n=152; 75.2%) were hypoxaemic (Sao2 <90%) before intubation. Personal protective equipment was worn by all intubating healthcare workers. Rapid sequence induction (RSI) or modified RSI was used with an intubation success rate of 89.1% on the first attempt and 100% overall. Hypoxaemia (Sao2 <90%) was common during intubation (n=148; 73.3%). Hypotension (arterial pressure <90/60 mm Hg) occurred in 36 (17.8%) patients during and 45 (22.3%) after intubation with cardiac arrest in four (2.0%). Pneumothorax occurred in 12 (5.9%) patients and death within 24 h in 21 (10.4%). Up to 14 days post-procedure, there was no evidence of cross infection in the anaesthesiologists who intubated the COVID-19 patients. Based on clinical information and expert recommendation, we propose detailed planning, strategy, and methods for tracheal intubation in COVID-19 patients.

Neutralization of IL-18 by IL-18 binding protein ameliorates bleomycin-induced pulmonary fibrosis via inhibition of epithelial-mesenchymal transition.

Idiopathic pulmonary fibrosis (IPF) is a fatal parenchymal lung disease with limited effective therapies. Interleukin (IL)-18 belongs to a rather large IL-1 gene family and is a proinflammatory cytokine, which acts in both acquired and innate immunity. We have previously reported that IL-18 play an important role in lipopolysaccharide-induced acute lung injury in mice. Persistent inflammation often drives fibrotic progression in the bleomycin (BLM) injury model. However, the role of IL-18 in pulmonary fibrosis (PF) is still unknown. IL-18 binding protein (IL-18BP) is able to neutralize IL-18 biological activity and has a protective effect against renal fibrosis. The aim of this study was to investigate the effects of IL-18BP on BLM-induced PF. In the present study, we found that IL-18 was upregulated in lungs of BLM-injured mice. Neutralization of IL-18 by IL-18BP improved the survival rate and ameliorated BLM-induced PF in mice, which was associated with attenuated pathological changes, reduced collagen deposition, and decreased content of transforming growth factor-ß1 (TGF-ß1). We further demonstrated that IL-18BP treatment suppressed the BLM-induced epithelial mesenchymal transition (EMT), characterized by decreased α-smooth muscle actin (α-SMA) and increased E-cadherin (E-cad) in vivo. In addition, we provided in vitro evidence demonstrating that IL-18 promoted EMT through upregulation of Snail-1 in A549 cells. In conclusion, our findings raise the possibility that the increase of IL-18 is involved in the development of BLM-induced PF through modulating EMT in a Snail-1-dependent manner. IL-18BP may be a worthwhile candidate option for PF therapy.

The faster-onset antidepressant effects of hypidone hydrochloride (YL-0919).

Hypidone hydrochloride (YL-0919), is a novel structural antidepressant candidate as a triple selective serotonin re-uptake inhibitor (SSRI), 5-HT1A partial agonist and 5-HT6 agonist. Here, we investigated the rapid onset antidepressant-like effects of YL-0919 and the possible mechanism in rats exposed to a chronic unpredictable stress (CUS) paradigm. In the CUS rats, it was found that fluoxetine (FLX, 10 mg/kg) treatment exerted antidepressant actions on 20-22d, while YL-0919 or vilazodone (VLZ, a dual 5-HT1A partial agonist and SSRI) administrated once daily exerted faster antidepressant-like behaviors [4 days in the sucrose preference test (SPT) and 6 days in the novelty suppressed feeding test (NSF)]. Thereafter, the serum corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels were reversed by treatment with YL-0919 for 7 days. Furthermore, YL-0919 treatment for 5 days reversed the brain derived neurotrophic factor (BDNF)-mammalian target of rapamycin (mTOR) signaling and the key synaptic proteins, such as post-synaptic density (PSD95), GluR1 and presynaptic protein synapsin1. Meanwhile, the dendritic complexity of pyramidal neurons in prefrontal cortex (PFC) were also increased in the CUS rats. These data suggest that YL-0919 exerts a faster antidepressant-like effect on behaviors and this effect maybe at least partially mediated by the BDNF-mTOR signaling related dendritic complexity increase in the PFC.

Interleukin-18 binding protein attenuates lipopolysaccharide-induced acute lung injury in mice via suppression NF-κB and activation Nrf2 pathway.

Interleukin (IL)-18 belongs to a rather large IL-1 gene family and is a proinflammatory cytokine. IL-18 plays important roles in lung injury. IL-18 binding protein (IL-18BP), a natural antagonist of IL-18, binds IL-18 with high affinity. IL-18BP is able to neutralize IL-18 biological activity and has a protective effect against renal fibrosis. The aim of this study was to evaluate the potential protective effect of IL-18BP on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and to illuminate the underlying mechanisms. Results indicated that pretreatment with IL-18BP significantly attenuated LPS-induced pulmonary pathological injury. Meanwhile, IL-18BP pretreatment markedly inhibited infiltration of inflammatory cell and release of inflammatory factor in ALI mice in vivo and in primary macrophages after LPS insult in vitro. IL-18BP treatment dramatically reduced oxidative stress through increasing superoxide dismutase (SOD) and glutathione (GSH) contents, and decreasing the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in LPS-induced ALI mice and primary macrophages. Additionally, IL-18BP was also observed to markedly decreased the activation of nuclear factor-kappa B (NF-κB) and upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2). Taken together, IL-18BP possessed protective effect against LPS-induced ALI, which might be associated with its regulation of NF-κB and Nrf2 activities. The results rendered IL-18BP worthy of further development into a pharmaceutical drug for the treatment of ALI.

Ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cord.

BACKGROUND: Diabetic neuropathic pain (DNP) is a common and distressing complication in patients with diabetes, and the underlying mechanism remains unclear. Tricyclic antidepressants (TCAs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are recommended as first-line drugs for DNP. Ammoxetine is a novel and potent SNRI that exhibited a strong analgesic effect on models of neuropathic pain, fibromyalgia-related pain, and inflammatory pain in our primary study. The present study was undertaken to investigate the chronic treatment properties of ammoxetine on DNP and the underlying mechanisms for its effects. METHODS: The rat model of DNP was established by a single streptozocin (STZ) injection (60 mg/kg). Two weeks after STZ injection, the DNP rats were treated with ammoxetine (2.5, 5, and 10 mg/kg/day) for 4 weeks. The mechanical allodynia and locomotor activity were assayed to evaluate the therapeutic effect of ammoxetine. In mechanism study, the activation of microglia, astrocytes, the protein levels of pro-inflammatory cytokines, the mitogen-activated protein kinases (MAPK), and NF-κB were evaluated. Also, microglia culture was used to assess the direct effects of ammoxetine on microglial activation and the signal transduction mechanism. RESULTS: Treatment with ammoxetine for 4 weeks significantly relieved the mechanical allodynia and ameliorated depressive-like behavior in DNP rats. In addition, DNP rats displayed increased activation of microglia in the spinal cord, but not astrocytes. Ammoxetine reduced the microglial activation, accumulation of pro-inflammatory cytokines, and activation of p38 and c-Jun N-terminal kinase (JNK) in the spinal cord of DNP rats. Furthermore, ammoxetine displayed anti-inflammatory effects upon challenge with LPS in BV-2 microglia cells. CONCLUSION: Our results suggest that ammoxetine may be an effective treatment for relieving DNP symptoms. Moreover, a reduction in microglial activation and pro-inflammatory release by inhibiting the p-p38 and p-JNK pathways is involved in the mechanism.

Mechanical ventilation enhances extrapulmonary sepsis-induced lung injury: role of WISP1-αvß5 integrin pathway in TLR4-mediated inflammation and injury.

BACKGROUND: High tidal volume ventilation of healthy lungs or exacerbation of existing acute lung injury (ALI) by more moderate mechanical ventilation (MTV) produces ventilator-induced lung injury. It is less clear whether extrapulmonary sepsis sensitizes the lung to MTV. METHODS: We used a two-hit model of cecal ligation and puncture (CLP) followed 12 h later by MTV (10 ml/kg; 6 h) to determine whether otherwise noninjurious MTV enhances CLP-induced ALI by contrasting wildtype and TLR4-/- mice with respect to: alveolar-capillary permeability, histopathology and intrapulmonary levels of WNT-inducible secreted protein 1 (WISP1) and integrin ß5; plasma levels of cytokines and chemokines (TNF-α, IL-6, MIP-2, MCP-1) and intrapulmonary neutrophil infiltration; and other inflammatory signaling via intrapulmonary activation of JNK, p38 and ERK. A separate cohort of mice was pretreated with intratracheal neutralizing antibodies to WISP1, integrin ß5 or IgG as control and the presented phenotyping repeated in a two-hit model; there were 10 mice per group in these first three experiments. Also, isolated peritoneal macrophages (PM) from wildtype and TLR4-/-, MyD88-/- and TRIF-/- mice were used to identify a WISP1-TLR4-integrin ß5 pathway; and the requisite role of integrin ß5 in WISP1-induced cytokine and chemokine production in LPS-primed PM was examined by siRNA treatment. RESULTS: MTV, that in itself did not cause ALI, exacerbated increases in alveolar-capillary permeability, histopathologic scoring and indices of pulmonary inflammation in mice that previously underwent CLP; the effects of this two-hit model were abrogated in TLR4-/- mice. Attendant with these findings was a significant increase in intrapulmonary WISP1 and integrin ß5 in the two-hit model. Anti-WISP1 or anti-integrin ß5 antibodies partially inhibited the two-hit phenotype. In PM, activation of TLR4 led to an increase in integrin ß5 expression that was MyD88 and NF-κB dependent. Recombinant WISP1 increased LPS-induced cytokine release in PM that was inhibited by silencing either TLR4 or integrin ß5. CONCLUSIONS: These data show for the first time that otherwise noninjurious mechanical ventilation can exacerbate ALI due to extrapulmonary sepsis underscoring a potential interactive contribution of common events (sepsis and mechanical ventilation) in critical care, and that a WISP1-TLR4-integrin ß5 pathway contributes to this phenomenon.