[Prognostic Value of IGF2BP3 Gene Expression Levels in Patients with Acute Myeloid Leukemia].

OBJECTIVE: To investigate the relationship between IGF2BP3 gene expression and prognosis in patients with acute myeloid leukemia (AML). METHODS: High throughput transcriptome sequencing was performed on bone marrow primary leukemia cells from 27 patients with AML in our center, the relationship between IGF2BP3 expression levels and clinical characteristics were analyzed and verify the samples from patients with newly treated AML and refractory AML. The expression level of IGF2BP3 gene were analyzed in 20 healthy subjects and 26 patients with AML. The expression of IGF2BP3 in two anthracycline-resistant cell lines (HL60/ADR, K562/ADR) was detected by RT-qPCR and Western blot, and the expression difference of IGF2BP3 was compared with that in sensitive cells (HL60, K562). The relationship between the expression level of IGF2BP3 in patients with AML and prognostic were analyzed through data analysis of 746 patients with AML, and the prognostic value of IGF2BP3 in AML was analyzed by multivariate Cox regression analysis. RESULTS: In the bone marrow primary leukemia cells of 27 AML patients in our center, the expression level of IGF2BP3 in patients with refractory AML was significantly higher than that in chemotherapy sensitive patients (P =0.0343). The expression of IGF2BP3 in leukemia patients with extramedullary infiltration (EMI) was significantly higher than that in AML patients without extramedullary infiltration (P =0.0049). Compared with healthy subjects (n=20), IGF2BP3 expression in AML patients (n=26) was higher (P =0.0009). The expression of IGF2BP3 mRNA in the anthracycline resistant cell lines (HL60/ADR, K562/ADR) was significantly higher than that in the sensitive cell lines (K562/ADR vs K562,P =0.0430; HL60/ADR vs HL60, P =0.7369). Western blot results showed that the expression of IGF2BP3 protein in mycin resistant cells was significantly higher than that in sensitive cells (P < 0.001). qPCR results showed that the expression level of IGF2BP3 mRNA in refractory AML patients was significantly higher than that in patients with chemotherapy sensitive (P =0.002). High expression of IGF2BP3 was associated with poor prognosis in AML (P < 0.05) in 3 large sample cohorts of AML patients. Univariate and multivariate prognostic analyses demonstrated that high expression of IGF2BP3 was significantly associated with shorter event-free survival (EFS, HR=1.887, P =0.024) and overall survival (OS, HR=1.619, P =0.016). CONCLUSION: The high expression of IGF2BP3 gene may be an important factor in the poor prognosis of AML, suggesting that IGF2BP3 gene may be a new molecular marker for the clinical prognosis evaluation and treatment strategy of AML.

Bcat2-Mediated Branched-Chain Amino Acid Catabolism Is Linked to the Aggravated Inflammation in Obese with Psoriasis Mice.

SCOPE: The global prevalence of obesity has significantly increased, presenting a major health challenge. High-fat diet (HFD)-induced obesity is closely related to the disease severity of psoriasis, but the mechanism is not fully understood. METHODS AND RESULTS: The study utilizes the HFD-induced obesity model along with an imiquimod (IMQ)-induced psoriasis-like mouse model (HFD-IMQ) to conduct transcriptomics and metabolomic analyses. HFD-induced obese mice exhibits more severe psoriasis-like lesions compared to normal diet (ND)-IMQ mice. The expression of genes of the IL-17 signaling pathway (IL-17A, IL-17F, S100A9, CCL20, CXCL1) is significantly upregulated, leading to an accumulation of T cells and neutrophils in the skin. Moreover, the study finds that there is an inhibition of the branched-chain amino acids (BCAAs) catabolism pathway, and the key gene branched-chain amino transferase 2 (Bcat2) is significantly downregulated, and the levels of leucine, isoleucine, and valine are elevated in the HFD-IMQ mice. Furthermore, the study finds that the peroxisome proliferator-activated receptor gamma (PPAR γ) is inhibited, while STAT3 activity is promoted in HFD-IMQ mice. CONCLUSION: HFD-induced obesity significantly amplifies IL-17 signaling and exacerbates psoriasis, with a potential role played by Bcat2-mediated BCAAs metabolism. The study suggests that BCAA catabolism and PPAR γ-STAT3 exacerbate inflammation in psoriasis with obesity.

Electroacupuncture on Baihui (DU20) and Xuehai (SP10) acupoints alleviates psoriatic inflammation by regulating neurotransmitter substance P- Neurokinin-1 receptor signaling.

Background: At present, acupuncture-related practices have been widely used to treat psoriasis. In our study, we investigated the effect and explored the mechanism of electroacupuncture (EA) on acupoints Baihui (DU20) and Xuehai (SP10) for the treatment of psoriasis. Methods: Imiquimod-induced psoriasis-like mouse model was used in this study. Mice were treated with electroacupuncture at DU20 and SP10 (depth of 2-3 mm, frequency of 2/15 Hz, intensity of 0.5-1.0 mA, 10 min/day). The severity of psoriasis-like lesions for each group was assessed. In addition, histological analysis of the lesions were performed. The levels of inflammatory cytokines were determined using Elisa. The expression levels of Substance P (SP) and NK1R were measured using Western blotting. In addition, NK1R inhibitor was administrated to evaluate the target of electroacupuncture in our mouse model. Results: Electroacupuncture significantly alleviated IMQ-induced skin lesions and epidermal thickness, accompanied with reduced keratinocyte proliferation, CD3+, CD4+, and CD8+ T cells infiltration. The reduced levels of inflammatory cytokines was observed after electroacupuncture treatment. In addition, electroacupuncture inhibited the expression levels of SP and NK1R. NK1R inhibitor could ameliorate lesional symptoms and suppress epidermal thickening and CD3+, CD4+, and CD8 + T cell infiltration. Conclusions: Electroacupuncture relieved psoriasis-like inflammation and T cell infiltration. This therapeutic action was likely mediated by the modulation of Substance P and its receptor NK1R.

Jianpi-Yangxue-Jiedu decoction improves the energy metabolism of psoriasis mice by regulating the electron transfer of oxidative phosphorylation.

ETHNOPHARMACOLOGICAL RELEVANCE: The inflammatory skin condition psoriasis is immune-related. The decoction of Jianpi-Yangxue-Jiiedu (JPYX) is a useful medication for psoriasis. However, the underlying mechanics of JPYX have not yet been clarified. AIM OF THE STUDY: The objective of this study was to investigate the mechanism underlying the efficacy of JPYX in the treatment of psoriasis in the context of a high-fat diet. MATERIALS AND METHODS: This work generated a high-fat feeding model of imiquimod (IMQ)-induced psoriasis-like lesion mice. The blood composition of JPYX was examined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The mechanism of JPYX decoction for treating psoriasis was predicted using methods of network pharmacology, metabolomics, and transcriptomics. RESULTS: JPYX prevented the release of inflammatory cytokines, decreased keratinocyte proliferation, enhanced the percentage of Treg cells in the skin, lymph nodes, and thymus, and greatly alleviated psoriatic lesions. Network pharmacology predicted that IL-1ß, TNF, STAT3, and EGFR may be potential targets, and KEGG results showed that PI3K-AKT-mTOR may be a potential mechanism of action. Verification of experimental data demonstrated that the JPYX decoction dramatically decreased mTOR and AKT phosphorylation. According to metabolomics analysis, amino acids and their metabolites, benzene and its substitutes, aldehyde ketone esters, heterocyclic compounds, etc. were the primary metabolites regulated by JPYX. KEGG enrichment analysis of differential metabolites was performed. Fatty acid biosynthesis, Type I polyketide structures, Steroid hormone biosynthesis, Biosynthesis of unsaturated fatty acid, etc. Transcriptomic results showed that JPYX significantly regulated skin development, keratinocyte differentiation, and oxidative phosphorylation. Further experimental data verification showed that JPYX decoction significantly reduced the mRNA levels of mt-Nd4, mt-Nd5, mt-Nd1, Ifi205, Ifi211, and mt-Atp8. CONCLUSIONS: JPYX may improve psoriasis by regulating the metabolic pathways of fatty acids and electron transport of oxidative phosphorylation.

Gut microbiota and risk of lower respiratory tract infections: a bidirectional two-sample Mendelian randomization study.

Introduction: Observational studies have reported the association between gut microbiota and the risk of lower respiratory tract infections (LRTIs). However, whether the association reflects a causal relationship remains obscure. Methods: A bidirectional twosample Mendelian randomization (MR) analysis was conducted by assessing genome-wide association study (GWAS) summary statistics for gut microbiota taxa and five common LRTIs. MR methods including inverse-variance-weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode were used to analyze the causality. Gene pleiotropy was tested using MR-Egger regression and MR-PRESSO methods. Cochran's Q test was used to check for heterogeneity. Leave-one-out analysis was used to assess the stability of effect sizes. Detected significant associations were validated by using an independent LRTI GWAS summary statistics dataset. An optional MR method of causal analysis using summary effect estimates (CAUSE) was further performed as a validation to avoid potential false-positive results. Results: According to the MR-Egger estimates in forward MR analysis, a causal effect of gut Blautia on increased odds of bronchiectasis and pneumonia was suggested. MR-Egger regression pleiotropy intercept methods detected no significant horizontal pleiotropy between the instrumental variables of these associations. MR-PRESSO global test examined no potential horizontal pleiotropy. Cochran's Q test showed that no heterogeneity biased the results. The leave-one-out sensitivity analyses suggested robust causality results. These associations with consistent effect direction were successfully replicated in IVW analysis by using the validation GWAS dataset. However, these evidence of causality did not survive after applying strict Bonferroni correction or CAUSE analysis. The reverse MR analysis failed to achieve consistent results in the effect of LRTIs on gut microbiota through comprehensive discovery and validation processes. Discussion: This study established no strong causality between genetically predicted gut microbiome and the risk of lower respiratory tract infections. However, specific subtypes of microbial genera, such as Blautia, were identified as potential influencers and require further investigation, particularly at the species or strain levels.

Dexmedetomidine modulates neuronal activity of horizontal limbs of diagonal band via α2 adrenergic receptor in mice.

BACKGROUND AND OBJECTIVES: Dexmedetomidine (DEX) is widely used in clinical sedation which has little effect on cardiopulmonary inhibition, however the mechanism remains to be elucidated. The basal forebrain (BF) is a key nucleus that controls sleep-wake cycle. The horizontal limbs of diagonal bundle (HDB) is one subregions of the BF. The purpose of this study was to examine whether the possible mechanism of DEX is through the α2 adrenergic receptor of BF (HDB). METHODS: In this study, we investigated the effects of DEX on the BF (HDB) by using whole cell patch clamp recordings. The threshold stimulus intensity, the inter-spike-intervals (ISIs) and the frequency of action potential firing in the BF (HDB) neurons were recorded by application of DEX (2 µM) and co-application of a α2 adrenergic receptor antagonist phentolamine (PHEN) (10 µM). RESULTS: DEX (2 µM) increased the threshold stimulus intensity, inhibited the frequency of action potential firing and enlarged the inter-spike-interval (ISI) in the BF (HDB) neurons. These effects were reversed by co-application of PHEN (10 µM). CONCLUSION: Taken together, our findings revealed DEX decreased the discharge activity of BF (HDB) neuron via α2 adrenergic receptors.

Resveratrol Ameliorates Imiquimod-Induced Psoriasis-Like Mouse Model via Reducing Macrophage Infiltration and Inhibiting Glycolysis.

Purpose: Resveratrol (Res) is a natural polyphenol with anti-inflammatory and immunomodulatory effects. Alterations in metabolic pathways have been studied in psoriasis. This study is aimed to further explore the potential molecular mechanism of psoriasis improvement by Res. Patients and Methods: Imiquimod (IMQ)-induced psoriasis-like mouse model was established to observe the effects of Res. NanoString nCounter Metabolic Pathways Panel was used to analyze the changed mRNA and qRT-PCR was used for validation. Flow cytometry was used to analyze immune cell subsets in skin lesions. In vitro, we observed the effects of Res on R848-stimulated macrophages glycolysis and inflammation. Results: Res reduced the proliferation of keratinocytes and the secretion of inflammatory cytokines in IMQ-induced psoriasis-like mouse model. Psoriasis model skin lesions were in a state of hypoxia, with upregulated glycolysis and downregulated AMPK activity. Res inhibited the levels of hypoxia-related genes (hif1α, hif3α) and glycolysis-related genes (hk1, ldha), meanwhile increased the levels of AMPK genes (prkaa1, prkaa2). Flow cytometry analysis revealed that Res decreased the infiltration of macrophages in psoriasis-like lesions. In addition, Res decreased the secretion of macrophage-associated pro-inflammatory cytokines (IL-23, TNF-α, IL-1ß). In vitro, Res diminished the secretion of IL-23, TNF-α, IL-1ß, and lactate by R848-stimulated macrophages and activated AMPK. Conclusion: This study suggested that Res diminished psoriasis symptoms by inhibiting macrophages infiltration and inhibiting glycolysis, which providing novel insights into the underlying mechanisms of therapeutic action of Res in the treatment of psoriasis.

Tai Chi as a complementary exercise for pulmonary rehabilitation in chronic obstructive pulmonary disease: A randomised controlled trial.

OBJECTIVES: With the characteristics of mindfulness and breathing techniques, Tai Chi has been recommended with therapeutic values in chronic obstructive pulmonary disease (COPD). However, its strengths as a complementary exercise for conventional pulmonary rehabilitation (PR) remain unclear. DESIGN AND SETTING: This single-blinded randomised controlled trial recruited patients with mild to severe stable COPD. Eligible participants were randomly assigned to the group with usual care (control), total body recumbent stepper (TBRS) exercise, Tai Chi (TC), or combined TBRS exercise and Tai Chi (TBRS-TC). Patients received a two-month hospital-based supervised exercise, followed by a ten-month community- or home-based rehabilitation program. RESULTS: A total of 120 participants were recruited, and 102 were included in the per-protocol analysis. The mean changes in St George's Respiratory Questionnaire (SGRQ) total score from baseline to the post-hospital exercise in the control group, TBRS group, TC group, and TBRS-TC group was 2.62 (95 % CI -8.99 to 8.99), -9.28 (95 % CI -13.96 to -4.60), -10.19 (95 % CI -13.72 to -6.67), and -16.75 (95 % CI -20.25 to -13.24), respectively, with a statistically significant difference between groups in favor of the TBRS-TC exercise (P < 0.001). The remarkable effect of TBRS-TC exercise in improving the quality of life maintained until the end of the community- or home-based rehabilitation training (P < 0.001). Besides, a statistically better effect with the TBRS-TC exercise was also observed in the outcomes regarding exercise capacity, pulmonary function, symptom burden, and systemic inflammation after the whole process of 12-month integrative PR exercise programme. CONCLUSIONS: Based on the results, a novel integrated exercise modality combining Tai Chi and conventional pulmonary rehabilitation was developed. It might contribute to more positive effects in patients with stable COPD. REGISTRATION: The study was registered with the Chinese Clinical Trial Registry (ChiCTR-IOR-15006874) prior to commencing recruitment.

Efficacy and safety of antifibrotic agents in the treatment of CTD-ILD and RA-ILD: A systematic review and meta-analysis.

OBJECTIVE: The clinical spectrum of connective tissue disease-associated interstitial lung disease (CTD-ILD) and rheumatoid arthritis-associated interstitial lung disease (RA-ILD) ranges from asymptomatic findings on radiographic imaging to a rapidly progressive illness leading to respiratory failure and death. The treatment is always challenging due to the paucity of proven effective treatments. Nintedanib and pirfenidone are recently approved antifibrotics in idiopathic pulmonary fibrosis. This study aimed to investigate the efficacy and safety of antifibrotic agents in the treatment of CTD-ILD and RA-ILD. METHODS: Relevant databases were searched for randomized controlled trials that compared pirfenidone or nintedanib with placebo in patients with CTD-ILD and RA-ILD. The primary outcome was the change in forced vital capacity (FVC). The odds ratio or risk ratio with 95% confidence interval (CI) was estimated for categorical data, and the mean difference with 95% CI was estimated for continuous data. The I2 statistic was used to assess heterogeneity, and meta-analysis was performed when possible. RESULTS: Ten studies with a total of 880 participants met the inclusion criteria. Of these, four studies were included in the meta-analysis. According to the pooled result, the annual decline of FVC was significantly decreased in the antifibrotic agent arm compared to that in the placebo arm (MD 70.58 mL/yr, 95% CI 40.55 to 100.61). CONCLUSION: This review suggests a potential benefit and safety of antifibrotic treatment in slowing the decline of FVC in patients with CTD-ILD and RA-ILD. Further large-sample, random-controlled, high-quality trials are needed to provide more evidence in the decision-making regarding the use of antifibrotics in this group of patients. CLINICAL TRIAL REGISTRATION: PROSPERO; No: CRD42022369112; URL: https://www.crd.york.ac.uk/prospero/.

The mechanisms to dispose of misfolded proteins in the endoplasmic reticulum of adipocytes.

Endoplasmic reticulum (ER)-associated degradation (ERAD) and ER-phagy are two principal degradative mechanisms for ER proteins and aggregates, respectively; however, the crosstalk between these two pathways under physiological settings remains unexplored. Using adipocytes as a model system, here we report that SEL1L-HRD1 protein complex of ERAD degrades misfolded ER proteins and limits ER-phagy and that, only when SEL1L-HRD1 ERAD is impaired, the ER becomes fragmented and cleared by ER-phagy. When both are compromised, ER fragments containing misfolded proteins spatially coalesce into a distinct architecture termed Coalescence of ER Fragments (CERFs), consisted of lipoprotein lipase (LPL, a key lipolytic enzyme and an endogenous SEL1L-HRD1 substrate) and certain ER chaperones. CERFs enlarge and become increasingly insoluble with age. Finally, we reconstitute the CERFs through LPL and BiP phase separation in vitro, a process influenced by both redox environment and C-terminal tryptophan loop of LPL. Hence, our findings demonstrate a sequence of events centered around SEL1L-HRD1 ERAD to dispose of misfolded proteins in the ER of adipocytes, highlighting the profound cellular adaptability to misfolded proteins in the ER in vivo.

Combining network pharmacology, RNA-seq, and metabolomics strategies to reveal the mechanism of Cimicifugae Rhizoma - Smilax glabra Roxb herb pair for the treatment of psoriasis.

BACKGROUND: Psoriasis is a prevalent chronic inflammatory skin condition marked by immune cell infiltration and keratinocyte abnormal proliferation. Cimicifugae Rhizoma - Smilax glabra Roxb (CS) herb pair, the main component of Shengma Detoxification Decoction, has been proven effective for the treatment of psoriasis. However, the mechanism is yet to be deciphered. PURPOSE: To explore the mechanism of CS for the treatment of psoriasis. METHODS: The imiquimod-induced psoriasis-like lesion mouse model was used to identify the targets and the molecular mechanisms of CS. Network pharmacology combined with RNA-seq strategy was employed to predict the targets and mechanisms of CS for psoriasis. Metabolomics approaches were used to demonstrate the complexity of CS for the treatment of psoriasis. Finally, a compound-response-enzyme-gene network was constructed based on the multi-omics results to elucidate potential connections. RESULTS: The CS herb pair could significantly improve psoriatic lesions and reduce the inflammatory cell infiltration and proliferation of keratinocytes in skin lesions. Network pharmacology predicted that TNF, JNK, IL-6, and IL-1ß could be potential targets. RNA-seq data revealed that CS could significantly regulate genes and signaling pathways associated with Th17 responses, such as IL-36, IL-1ß, CCl2, CXCL16, keratin 14, keratin 5, and antimicrobial peptides S100A8 and S100A9 well as MAPK, mTOR, and other signaling pathways. Further experimental data validated that CS treatment remarkably reduced the expression of inflammatory cytokines and factors, such as CCL2, CCL7, IL1F6, IL-17, IL-23, IL-1ß, TNF-α, and IL-6, and inhibited the phosphorylation of p38 and ERK1/2. This indicated that CS exerts its therapeutic effect by inhibiting the MAPK signaling pathways. In addition, metabolomic analyses demonstrated that CS treatment improved seven metabolic pathways, these included phenylalanine, tyrosine, pyruvate metabolism, carnitine metabolism, etc. Four key metabolites (L-Arginine, L-Phenylalanine, L-Carnitine, O-Acetylcarnitine) and nine differential genes (CMA1, PCBD2, TPSAB1, TPSB2, etc.) were identified that affected amino acid metabolism, carnitine metabolism, and other pathways contributing to the infiltration of Th17 cells in psoriatic lesions. CONCLUSION: CS could alleviate IMQ-induced psoriasis-like dermatitis by reducing the expression of cytokines and chemokines mediated by the MAPK pathway, and improved amino acid and carnitine metabolism in vivo. Our study is the first to demonstrate the complex mechanism of CS for the treatment of psoriasis and provides a new paradigm to elucidate the pharmacological effects of Traditional Chinese Medicine (TCM) drugs for psoriasis from multiple perspectives.

An MKP-MAPK protein phosphorylation cascade controls vascular immunity in plants.

Global crop production is greatly reduced by vascular diseases. These diseases include bacterial blight of rice and crucifer black rot caused by Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas campestris pv. campestris (Xcc). The molecular mechanisms that activate vascular defense against such pathogens remains underexplored. Here, we show that an Arabidopsis MAPK phosphatase 1 (MKP1) mutant has increased host susceptibility to the adapted pathogen Xcc and is compromised in nonhost resistance to the rice pathogen Xoo. MKP1 regulates MAPK-mediated phosphorylation of the transcription factor MYB4 that negatively regulates vascular lignification through inhibiting lignin biosynthesis. Induction of lignin biosynthesis is, therefore, an important part of vascular-specific immunity. The role of MKP-MAPK-MYB signaling in lignin biosynthesis and vascular resistance to Xoo is conserved in rice, indicating that these factors form a tissue-specific defense regulatory network. Our study likely reveals a major vascular immune mechanism that underlies tissue-specific disease resistance against bacterial pathogens in plants.

Eosinopenia as a biomarker for antibiotic use in COPD exacerbations: protocol for a retrospective hospital-based cohort study.

INTRODUCTION: The acute exacerbation of chronic obstructive pulmonary disease (AECOPD) has a seriously negative impact on patients' healths condition and disease progression. Bacterial infection is closely related to AECOPD, and antibiotics are frequently used in clinical practice. The lack of specific biomarkers for rational antibiotics use always leads to antibiotics abuse in chronic obstructive pulmonary disease (COPD) flare-ups. Eosinopenia has been considered to be related to increased bacterial load of potentially pathogenic organisms at the onset of COPD exacerbations. Therefore, this study aims to investigate whether eosinopenia could be used as a reference for the use of antibiotics in AECOPD. METHODS AND ANALYSIS: In this study, a hospital-based retrospective cohort design will be adopted to analyse the clinical data of inpatients who are primarily diagnosed with AECOPD in West China Hospital of Sichuan University from 1 January 2010 to 31 December 2020. Relevant data will be extracted from the Clinical Big Data Platform for Scientific Research in West China Hospital, including demographic characteristics, blood eosinophil count, procalcitonin, C reactive protein, microbial cultivation, antibiotics use, length of hospital stay, non-invasive ventilation use, intensive care unit transfer and mortality, etc. The collected data will be described and inferred by corresponding statistical methods according to the data type and their distributions. Multiple binary logistic regression models will be used to analyse the relationship between blood eosinophil count and bacterial infection. The antibiotics use, and patient morbidity and mortality will be compared between patients with or without eosinopenia. ETHICS AND DISSEMINATION: This study has been approved by the Biomedical Ethics Review Board of West China Hospital of Sichuan University (Approval No. 2020-1056). And the research results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ChiCTR2000039379.

MAIT Cell Activation and Functions.

Mucosal associated invariant T (MAIT) cells are striking in their abundance and their strict conservation across 150 million years of mammalian evolution, implying they must fulfill critical immunological function(s). MAIT cells are defined by their expression of a semi-invariant αß TCR which recognizes biosynthetic derivatives of riboflavin synthesis presented on MR1. Initial studies focused on their role in detecting predominantly intracellular bacterial and mycobacterial infections. However, it is now recognized that there are several modes of MAIT cell activation and these are related to activation of distinct transcriptional programmes, each associated with distinct functional roles. In this minireview, we summarize current knowledge from human and animal studies of MAIT cell activation induced (1) in an MR1-TCR dependent manner in the context of inflammatory danger signals and associated with antibacterial host defense; (2) in an MR1-TCR independent manner by the cytokines interleukin(IL)-12/-15/-18 and type I interferon, which is associated with antiviral responses; and (3) a recently-described TCR-dependent "tissue repair" programme which is associated with accelerated wound healing in the context of commensal microbiota. Because of this capability for diverse functional responses in diverse immunological contexts, these intriguing cells now appear to be multifunctional effectors central to the interface of innate and adaptive immunity.

Formation of Enamines via Catalytic Dehydrogenation by Pincer-Iridium Complexes.

Di-isopropylphosphino-substituted pincer-ligated iridium catalysts are found to be significantly more effective for the dehydrogenation of simple tertiary amines to give enamines than the previously reported di-t-butylphosphino-substituted species. It is also found that the di-isopropylphosphino-substituted complexes catalyze dehydrogenation of several ß-functionalized tertiary amines to give the corresponding 1,2-difunctionalized olefins. The di-t-butylphosphino-substituted species are ineffective for such substrates; presumably, the marked difference is attributable to the lesser crowding of the di-isopropylphosphino-substituted catalysts. Experimentally determined kinetic isotope effects in conjunction with DFT-based analysis support a dehydrogenation mechanism involving initial pre-equilibrium oxidative addition of the amine α-C-H bond followed by rate-determining elimination of the ß-C-H bond.

Systems pharmacology-based study of Tanreqing injection in airway mucus hypersecretion.

ETHNOPHARMACOLOGICAL RELEVANCE: Mucus hypersecretion (MH) is recognized as a key pathophysiological and clinical feature of many airway inflammatory diseases. MUC5AC is a major component of airway mucus. Tanreqing injection (TRQ) is a widely used herbal formula for the treatment of respiratory inflammations for years in China. However, a holistic network pharmacology approach to understanding its therapeutic mechanisms against MH has not been pursued. AIM OF THE STUDY: This study aimed to explore the systems-level potential active compounds and therapeutic mechanisms of TRQ in the treatment of MH. MATERIALS AND METHODS: We established systems pharmacology-based strategies comprising compound screenings, target predictions, and pathway identifications to speculate the potential active compounds and therapeutic targets of TRQ. We also applied compound-target and target-disease network analyses to evaluate the possible action mechanisms of TRQ. Then, lipopolysaccharide (LPS)-induced Sprague-Dawley (SD) rat model was constructed to assess the effect of TRQ in the treatment of MH and to validate the possible molecular mechanisms as predicted in systems pharmacology approach. RESULTS: The comprehensive compound collection successfully generated 55 compound candidates from TRQ. Among them, 11 compounds with high relevance to the potential targets were defined as representative and potential active ingredients in TRQ formula. Target identification revealed 172 potential targets, including pro-inflammatory cytokines of tumor necrosis factor α (TNF-α), interleukin (IL)-6, and IL-8. Pathway analyses uncovered the possible action of TRQ in the regulation of IL-17 signaling pathway and its downstream protein MUC5AC. Then in vivo experiment indicated that TRQ could significantly inhibit LPS stimulated MUC5AC over-production as well as the expression of TNF-α, IL-6, IL-8, and IL-17A, in both protein and mRNA levels. CONCLUSIONS: Based on the systems pharmacology method and in vivo experiment, our work provided a general knowledge on the potential active compounds and possible therapeutic targets of TRQ formula in its anti-MH process. This work might suggest directions for further research on TRQ and provide more insight into better understanding the chemical and pharmacological mechanisms of complex herbal prescriptions in a network perspective.

Dissection of Pharmacological Mechanism of Chinese Herbal Medicine Yihuo Huatan Formula on Chronic Obstructive Pulmonary Disease: A Systems Pharmacology-Based Study.

Chronic obstructive pulmonary disease (COPD) is one of the most common respiratory diseases. Yihuo Huatan Formula (YHF), as a proven Chinese Herbal Medicine (CHM), has been verified to be effective in the treatment of stable COPD through years' of practice. Nevertheless, its working mechanism is still unclear. We sought to systematically decipher the mechanism of YHF for treating stable COPD using systems pharmacology-based method that integrates pharmacokinetic screening, target prediction, network analyses, GO and KEGG enrichment analyses. Firstly, a total of 1267 chemicals out of 15 herbal components were included in YHF chemical database. Among them, 180 potential active molecules were screened out through pharmacokinetic evaluation. Then 258 targets of the active molecules were predicted, of which 84 were chosen for further analyses. Finally, the network analyses and GO and KEGG enrichment methods suggested a therapeutic effect of YHF on the alleviation of airway inflammation, decrease of mucus secretion, maintenance of immune homeostasis and benefit of COPD comorbidities, by regulating multiple targets and pathways. The systems pharmacology-based approach helps to understand the underlying working mechanism of YHF in stable COPD from a holistic perspective, and offers an exemplification for systematically uncovering the action mechanisms of CHM.

A Temperature-Sensitive Misfolded bri1-301 Receptor Requires Its Kinase Activity to Promote Growth.

BRASSINOSTEROID-INSENSITIVE1 (BRI1) is a leucine-rich-repeat receptor-like kinase that functions as the cell surface receptor for brassinosteroids (BRs). Previous studies showed that BRI1 requires its kinase activity to transduce the extracellular BR signal into the nucleus. Among the many reported mutant bri1 alleles, bri1-301 is unique, as its glycine-989-to-isoleucine mutation completely inhibits its kinase activity in vitro but only gives rise to a weak dwarf phenotype compared with strong or null bri1 alleles, raising the question of whether kinase activity is essential for the biological function of BRI1. Here, we show that the Arabidopsis (Arabidopsis thaliana) bri1-301 mutant receptor exhibits weak BR-triggered phosphorylation in vivo and absolutely requires its kinase activity for the limited growth that occurs in the bri1-301 mutant. We also show that bri1-301 is a temperature-sensitive misfolded protein that is rapidly degraded in the endoplasmic reticulum and at the plasma membrane by yet unknown mechanisms. A temperature increase from 22°C to 29°C reduced the protein stability and biochemical activity of bri1-301, likely due to temperature-enhanced protein misfolding. The bri1-301 protein could be used as a model to study the degradation machinery for misfolded membrane proteins with cytosolic structural lesions and the plasma membrane-associated protein quality-control mechanism.

Chinese Herbal Medicine for Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Chinese herbal medicine (CHM) has been widely used in the treatment of advanced non-small-cell lung cancer (NSCLC), but their efficacy and safety remain controversial. We sought to comprehensively aggregate and evaluate the available evidence on the efficacy and safety of the combination treatment with CHM and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in NSCLC patients. Our exhausted and systematical searching strategy yielded 64 related randomized controlled trials involving 4384 patients. Compared with EGFR-TKIs therapy alone, meta-analysis showed significant differences favoring the combination treatment in progression-free survival ([Formula: see text]), median survival time ([Formula: see text]), one-year survival rate ([Formula: see text]), two-year survival rate ([Formula: see text]), probability of severe toxicities ([Formula: see text]), objective response rate ([Formula: see text]), Karnofsky performance status ([Formula: see text]), and improvement in percentage of CD3[Formula: see text] T lymphocyte ([Formula: see text]) and CD4[Formula: see text] T lymphocyte ([Formula: see text]). Though these results require further confirmation, they are prone to show a potential therapeutic value of CHM in improving the clinical effect, overcoming the drug resistance and toxicities as an adjunctive therapy to EGFR-TKIs.

Dihydrogen/dihydride or tetrahydride? An experimental and computational investigation of pincer iridium polyhydrides.

The iridium pincer complexes (PCP)IrH(4) (1; PCP = [kappa(3)-1,3-(CH(2)P(t)Bu(2))(2)C(6)H(3)]) and (POCOP)IrH(4) (2; POCOP = [kappa(3)-1,3-(OP(t)Bu(2))(2)C(6)H(3)]) have proven to be effective catalyst precursors for dehydrogenation of alkanes. The complex (POCOP)IrH(2) has also been applied successfully as a catalyst for release of H(2) from ammonia borane. Investigation of the "tetrahydride" forms of these complexes by solution NMR methods suggests their formulation as dihydrogen/dihydride species. This is in contrast to the solid state structure of 1, determined by neutron diffraction (at 100 K), which indicates a compressed tetrahydride structure with only weak H-H interactions. Complex 1 (C(24)H(47)IrP(2)) crystallizes in the space group P4(2), tetragonal, (Z = 2) with a = 11.7006 (19) A, c = 9.7008(27) A, and V = 1328.1(5) A(3). Electronic structure calculations on 1 and 2 indicate that the global minima on the potential energy surfaces in the gas phase are tetrahydride structures; however, the dihydrogen/dihydride forms are only slightly higher in energy (1-3 kcal/mol). A dihydrogen/dihydride species is calculated to be the global minimum for 2 when in solution. The barriers to interconversion between the tetrahydride and dihydrogen/dihydride species are almost negligible.