[Efficacy and safety of dust mite subcutaneous immunotherapy in children with allergic asthma： a prospective randomized controlled study]. / å°˜èž¨çš®ä¸‹å ç–«æ²»ç–—åº”ç”¨äºŽå„¿ç«¥è¿‡æ•æ€§å“®å–˜ç–—æ•ˆä¸Žå®‰å ¨æ€§çš„å‰çž»æ€§éšæœºå¯¹ç §ç ”ç©¶.

OBJECTIVES: To investigate the efficacy and safety of subcutaneous immunotherapy (SCIT) using dust mites in children with allergic asthma. METHODS: In a prospective randomized controlled study, 98 children with dust mite-induced allergic asthma were randomly divided into a control group (n=49) and an SCIT group (n=49). The control group received inhaled corticosteroid treatment, while the SCIT group additionally received a standardized three-year SCIT regimen. The two groups were compared based on peripheral blood eosinophil percentage, visual analogue score (VAS), total medication score, Asthma Control Test/Childhood Asthma Control Test scores, fractional exhaled nitric oxide (FeNO), and lung function before treatment, and at 6 months, 1 year, 2 years, and 3 years after treatment. Adverse reactions were recorded post-injection to evaluate the safety of SCIT. RESULTS: Compared with pre-treatment levels, the SCIT group showed a significant reduction in the percentage of peripheral blood eosinophils, VAS, total medication score, and FeNO, while lung function significantly improved, and asthma control levels were better 3 years after treatment (P<0.05). Compared with the control group, the SCIT group showed more significant improvement in all evaluated indicators 3 years after treatment (P<0.05). A total of 2 744 injections were administered, resulting in 157 cases (5.72%) of local adverse reactions and 4 cases (0.15%) of systemic adverse reactions, with no severe systemic adverse events. CONCLUSIONS: SCIT is an effective and safe treatment for allergic asthma in children.

Unraveling the pharmacodynamic substances and possible mechanism of Trichosanthis Pericarpium in the treatment of coronary heart disease based on plasma pharmacochemistry, network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Coronary heart disease (CHD) is a chronic disease that seriously threatens people's health and even their lives. Currently, there is no ideal drug without side effects for the treatment of CHD. Trichosanthis Pericarpium (TP) has been used for several years in the treatment of diseases associated with CHD. However, there is still a need for systematic research to unravel the pharmacodynamic substances and possible mechanism of TP in the treatment of coronary heart. AIM OF THE STUDY: The purpose of current study was to explore the pharmacodynamic substances and potential mechanisms of TP in the treatment of CHD via integrating network pharmacology with plasma pharmacochemistry and experimental validation. MATERIALS AND METHODS: The effect of TP intervention in CHD was firstly assessed on high-fat diet combined with isoprenaline-induced CHD rats and H2O2-induced H9c2 cells, respectively. Then, the LC-MS was utilized to identify the absorbed components of TP in the plasma of CHD rats, and this was used to develop a network pharmacology prediction to obtain the possible active components and mechanisms of action. Molecular docking and immunohistochemistry were used to explore the interaction between TP and key targets. Subsequently, the efficacy of the active ingredients was investigated by in vitro cellular experiments, and their metabolic pathways in CHD rats were further analyzed. RESULTS: The effects of TP on amelioration of CHD were verified by in vivo and in vitro experiments. Plasma pharmacochemistry and network pharmacology screened six active components in plasma including apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin. The interaction of these compounds with potential key targets AKT1, IL-1ß, IL-6, TNF-α and VEGFA were preliminarily verified by molecular docking. And immunohistochemical results showed that TP reduced the expression of AKT1, IL-1ß, IL-6, TNF-α and VEGFA in CHD rat hearts. Then cellular experiments confirmed that apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin were able to reduce the ROS level in H2O2-induced HUVEC cells and promote the migration and tubule formation of HUVEC cells, indicating the pharmacodynamic effects of the active components. Meanwhile, the metabolites of TP in CHD rats suggested that the pharmacological effects of TP might be the result of the combined effects of the active ingredients and their metabolites. CONCLUSION: Our study found that TP intervention in CHD is characterized by multi-component and multi-target regulation. Apigenin, phenylalanine, linoleic acid, quercetin, luteolin, and tangeretin are the main active components of TP. TP could reduce inflammatory response and endothelial damage by regulating AKT1, IL-1ß, IL-6, TNF-α and VEGFA, reduce ROS level to alleviate the oxidative stress situation and improve heart disease by promoting angiogenesis to regulate endothelial function. This study also provides an experimental and scientific basis for the clinical application and rational development of TP.

Integrative network pharmacology and experimental verification to reveal the anti-inflammatory mechanism of ginsenoside Rh4.

Inflammation is an innate immune response to infection, and it is the main factor causing bodily injury and other complications in the pathological process. Ginsenoside Rh4 (G-Rh4), a minor ginsenoside of Panax ginseng C. A. Meyer and Panax notoginseng, has excellent pharmacological properties. However, many of its major pharmacological mechanisms, including anti-inflammatory actions, remain unrevealed. In this study, network pharmacology and an experimental approach were employed to elucidate the drug target and pathways of G-Rh4 in treating inflammation. The potential targets of G-Rh4 were selected from the multi-source databases, and 58 overlapping gene symbols related to G-Rh4 and inflammation were obtained for generating a protein-protein interaction (PPI) network. Molecular docking revealed the high affinities between key proteins and G-Rh4. Gene ontology (GO) and pathway enrichment analyses were used to analyze the screened core targets and explore the target-pathway networks. It was found that the JAK-STAT signaling pathway, TNF signaling pathway, NF-κB signaling pathway, and PI3K-Akt signaling pathway may be the key and main pathways of G-Rh4 to treat inflammation. Additionally, the potential molecular mechanisms of G-Rh4 predicted from network pharmacology analysis were validated in RAW264.7 cells. RT-PCR, Western blot, and ELISA analysis indicated that G-Rh4 significantly inhibited the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1ß, as well as inflammation-related enzymes in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Moreover, in vitro experiments evaluated that Ginsenoside Rh4 exerts anti-inflammatory effects via the NF-κB and STAT3 signaling pathways. It is believed that our study will provide the basic scientific evidence that G-Rh4 has potential anti-inflammatory effects for further clinical studies.

Midterm outcomes of penetrating keratoplasty following allogeneic cultivated limbal epithelial transplantation in patients with bilateral limbal stem cell deficiency.

AIM: To evaluate the midterm outcomes of penetrating keratoplasty (PK) following allogeneic cultivated limbal epithelial transplantation (CLET) for bilateral total limbal stem cell deficiency (LSCD). METHODS: Ten patients (10 eyes) with bilateral LSCD were enrolled in this prospective noncomparative case series study. Each participant underwent PK approximately 6mo after a CLET. Topical tacrolimus, topical and systemic steroids, and oral ciclosporin were administered postoperatively. Best-corrected visual acuity (BCVA), intraocular pressure (IOP), ocular surface grading scores (OSS), corneal graft epithelial rehabilitation, persistent epithelial defect (PED), immunological rejection, and graft survival rate were assessed. RESULTS: The time interval between PK and allogeneic CLET was 6.90±1.29 (6-10)mo. BCVA improved from 2.46±0.32 logMAR preoperatively to 0.77±0.55 logMAR post-PK (P<0.001). Kaplan-Meier analysis of mean graft survival revealed graft survival rates of 100% at 12 and 24mo and 80.0% at 36mo. PEDs appeared in 5 eyes at different periods post-PK, and graft rejection occurred in 4 eyes. The total OSS decreased from 12.4±4.4 before allogeneic CLET to 1.4±1.51 after PK. CONCLUSION: A sequential therapy design of PK following allogeneic CLET can maintain a stable ocular surface with improved BCVA despite the relatively high graft rejection rate.

Identification of Potential Hub Genes of Atherosclerosis Through Bioinformatic Analysis.

Cardiovascular and cerebrovascular diseases, which mainly consist of atherosclerosis (AS), are major causes of death. A great deal of research has been carried out to clarify the molecular mechanisms of AS. However, the etiology of AS remains poorly understood. To screen the potential genes of AS occurrence and development, GSE43292 and GSE57691 were obtained from the Gene Expression Omnibus (GEO) database in this study for bioinformatic analysis. First, GEO2R was used to identify differentially expressed genes (DEGs) and the functional annotation of DEGs was performed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The Search Tool for the Retrieval of Interacting Genes (STRING) tool was used to construct the protein-protein interaction network and the most important modules and core genes were mined. The results show that a total of 211 DEGs are identified. The functional changes of DEGs are mainly associated with the cellular process, catalytic activity, and protein binding. Eighteen genes were identified as core genes. Bioinformatic analysis showed that the core genes are mainly enriched in numerous processes related to actin. In conclusion, the DEGs and hub genes identified in this study may help us understand the potential etiology of the occurrence and development of AS.

Higher neutrophil-lymphocyte ratio is associated with better prognosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide; its morbidity and mortality have both recently increased. Lately, the role played by the neutrophil-lymphocyte ratio (NLR) in the development of HCC has attracted attention. However, the exact relationship is not fully understood.A total of 538 participants diagnosed with HCC were recruited between 2010 and 2018. Their relevant routine blood parameters were measured, including NLR. Pearson Chi-Squared test, Spearman Rho test, and logistic regression analysis were performed to explore any correlations between NLR and HCC. A receiver operating characteristic (ROC) curve analysis was performed to determine the usefulness of NLR for predicting HCC. Univariate and multivariate Cox regression analysis for relevant routine blood parameters and any relationships with overall survival (OS) were performed. The Kaplan-Meier method was used to explore any further relationships with OS.NLR was significantly correlated with HCC tumor size by Pearson Chi-Squared test (P = .008). Furthermore, Spearman correlation coefficient showed that HCC tumor size was significantly correlated with NLR (P = .115, P = .008). NLR could sensitively and specifically predict HCC tumor size (area under the curve [AUC], 0.605; 95% confidence interval [CI], 0.429-0.743; P = .000). Higher NLR in patients with HCC was correlated with better OS (hazard ratio [HR] = 0.584; P = .000).A close correlation existed between increased NLR and HCC; NLR could sensitively and specifically predict HCC. High NLR might be an independent protective factor in the prognosis of patients with HCC.

Progress in the correlation between PTPN12 gene expression and human tumors.

BACKGROUND: The global morbidity of cancer is rising rapidly. Despite advances in molecular biology, immunology, and cytotoxic and immune-anticancer therapies, cancer remains a major cause of death worldwide. Protein tyrosine phosphatase non-receptor type 12 (PTPN12) is a new member of the cytoplasmic protein tyrosine phosphatase family, isolated from a cDNA library of adult colon tissue. Thus far, no studies have reviewed the correlation between PTPN12 gene expression and human tumors. METHODS: This article summarizes the latest domestic and international research developments on how the expression of PTPN12 relates to human tumors. The extensive search in Web of Science and PubMed with the keywords including PTPN12, tumor, renal cell carcinoma, proto-oncogenes, tumor suppressor genes was undertaken. RESULTS: More and more studies have shown that a tumor is essentially a genetic disease, arising from a broken antagonistic function between proto-oncogenes and tumor suppressor genes. When their antagonistic effect is out of balance, it may cause uncontrolled growth of cells and lead to the occurrence of tumors. PTPN12 is a tumor suppressor gene, so inhibiting its activity will lead directly or indirectly to the occurrence of tumors. CONCLUSION: The etiology, prevention, and treatment of tumors have become the focus of research around the world. PTPN12 is a tumor suppressor gene. In the future, PTPN12 might serve as a novel molecular marker to benefit patients, and even the development of tumor suppressor gene activation agents can form a practical research direction.

Elevated Circulating Interleukin-17 Levels in Patients with Systemic Lupus Erythematosus: A Meta-analysis.

BACKGROUND: Previous studies concerning the circulating interleukin-17 (IL-17) in systemic lupus erythematosus (SLE) were contradictory. AIMS: To further precisely investigate circulating IL-17 in SLE and evaluate its influential factors by meta-analysis. METHODS: EMBASE, PubMed and Cochrane Library were comprehensively searched to obtain studies on circulating IL-17 in SLE patients by November 22, 2018. The results were illustrated by pooled standard mean difference (SMD) with corresponding 95% confidence interval (CI) using random-effects model as there was significant heterogeneity, which was estimated using Cochran Q and I2 statistics. Subgroup analyses and sensitivity analyses were also conducted. RESULTS: Overall, 1872 articles were reviewed and 20 studies involving 1067 subjects with SLE and 721 healthy controls (HCs) were enrolled in the final analysis according to inclusion criteria. Compared with HCs, circulating IL-17 levels in SLE patients were elevated (SMD: 1.183, 95% CI: 0.763-1.603; P < .001). Moreover, in comparison to HCs, European and Asian SLE patients, age <30 years, disease duration ≥5 years, NOS scores <7 and using ELISA showed increased circulating IL-17 status, whereas no significant change was observed in other subgroups. There was no significant publication bias. Sensitivity analyses demonstrated that the results of our meta-analysis were robust. CONCLUSIONS: SLE patients have higher circulating IL-17 levels, which is influenced by ethnic, age and disease duration, literature quality and measurements.

Advances in research on the interaction between inflammation and cancer.

Inflammation is the body's response to cell damage. Cancer is a general term that describes all malignant tumours. There are no confirmed data on cancer-related inflammation, but some research suggests that up to 50% of cancers may be linked to inflammation, which has led to the concept of 'cancer-associated inflammation'. Although some cancer patients do not appear to have a chronic inflammatory background, there might be inflammatory cell infiltration in their cancer tissues. The continuation of the inflammatory response plays an important role in the initiation, promotion, malignant transformation, invasion and metastasis of cancer. Anti-inflammatory therapy has been shown to have some effects on the prevention and treatment of cancer, which supports a pathogenic relationship between inflammation and cancer. This review describes the interaction between inflammation and tumour development and the main mechanism of regulation of the inflammatory response during tumour development.

Synergetic iridium and amine catalysis enables asymmetric [4+2] cycloadditions of vinyl aminoalcohols with carbonyls.

Catalytic asymmetric cycloadditions via transition-metal-containing dipolar intermediates are a powerful tool for synthesizing chiral heterocycles. However, within the field of palladium catalysis, compared with the well-developed normal electron-demand cycloadditions with electrophilic dipolarophiles, a general strategy for inverse electron-demand ones with nucleophilic dipolarophiles remains elusive, due to the inherent linear selectivity in the key palladium-catalyzed intermolecular allylations. Herein, based on the switched regioselectivity of iridium-catalyzed allylations, we achieved two asymmetric [4+2] cycloadditions of vinyl aminoalcohols with aldehydes and ß,γ-unsaturated ketones through synergetic iridium and amine catalysis. The activation of vinyl aminoalcohols by iridium catalysts and carbonyls by amine catalysts provide a foundation for the subsequent asymmetric [4+2] cycloadditions of the resulting iridium-containing 1,4-dipoles and (di)enamine dipolarophiles. The former provides a straightforward route to a diverse set of enantio-enriched hydroquinolines bearing chiral quaternary stereocenters, and the later represent an enantio- and diastereodivergent synthesis of chiral hydroquinolines.

Transcriptomic Sequencing of Airway Epithelial Cell NCI-H292 Induced by Synthetic Cationic Polypeptides.

Eosinophil asthma is characterized by the infiltration of eosinophils to the bronchial epithelium. The toxic cationic protein released by eosinophils, mainly major basic protein (MBP), is one of the most important causative factors of epithelium damage. Poly-L-Arginine (PLA) is a kind of synthetic cationic polypeptides, which is widely used to mimic the effects of MBP on epithelial cells in vitro. However, little is known about the changes of differentially expressed genes (DEGs) and transcriptome profiles in cationic protein stimulated epithelial cells. In this study, we compared the expression of DEGs and transcriptome profiles between PLA-treated airway epithelial cells NCI-H292 and control. The results showed that there were a total of 230 DEGs, of which 86 were upregulated and 144 were downregulated. These DEGs were further analyzed using gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The results showed that the upregulated DEGs were involved in cholesterol synthesis, protein binding, and composition of cellular membranes, mainly enriched in metabolic and biosynthesis pathways. While downregulated DEGs were implicated in cell adhesion, extracellular matrix (ECM) composition and cytoskeleton and were enriched in ECM pathway. In conclusion, our research provided the mechanism of the cationic polypeptides acting on the airway epithelial cells on the basis of transcriptomic profile, and this could be regarded as important indications in unveiling the pathologic role of natural cationic proteins in the damage to epithelial cells of asthmatics.

Inverse-Electron-Demand Palladium-Catalyzed Asymmetric [4+2] Cycloadditions Enabled by Chiral P,S-Ligand and Hydrogen Bonding.

Catalytic asymmetric cycloadditions of ambident Pd-containing dipolar species with nucleophilic dipolarophiles, namely, inverse-electron-demand cycloadditions, are challenging and underdeveloped. Possibly, the inherent linear selectivity of Pd-catalyzed intermolecular allylations and the lack of efficient chiral ligands are responsible for this limitation. Herein, two cycloadditions of such intermediates with deconjugated butenolides and azlactones were accomplished by using a novel chiral hybrid P,S-ligand and hydrogen bonding. By doing so, highly functionalized, optically active dihydroquinol-2-ones were produced with generally high reaction efficiencies and selectivities. Preliminary DFT calculations were performed to explain the high enantio- and diastereoselectivities.

The Association Between Sleep Disorders and the Risk of Colorectal Cancer in Patients: A Population-based Nested Case-Control Study.

AIM: To investigate the risk of colorectal cancer in patients with sleep disorders. MATERIALS AND METHODS: We identified 7,355 participants with colorectal cancer between January 1, 2000, and December 31, 2013, from the Longitudinal Health Insurance Database 2005 of the Taiwan National Health Insurance Research Database; 29,420 controls were also identified from the same database based on frequency matching on age, sex, and index date of the cases. Diagnoses of sleep disorders by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) in the cases and controls prior to the index date were assessed. The risk of colorectal cancer in patients with sleep disorders was estimated with multivariate logistic regression analyses. RESULTS: The mean age of the 36,775 patients was 63.05 years, and 56% of them were males. The risk of colorectal cancer was higher in patients with sleep disorders compared to those without [adjusted odds ratio (OR)=1.29, 95% confidence interval (CI)=1.13-1.47]. The risk of colorectal cancer was higher in patients having sleep disorders with depression compared to those without the condition (adjusted OR=5.69, 95% CI=4.01-6.98). CONCLUSION: The risk of colorectal cancer in patients with sleep disorders was found to be significantly higher by case-control study and particularly pronounced among those with sleep disorders with depression, exhibiting a joint effect on colorectal cancer risk.

Expression of visual system homeobox 1 in human keratoconus.

AIM: To investigate the expression of visual system homeobox 1 (VSX1) and myofibroblast marker alpha smooth muscle actin (α-SMA) in keratoconus (KC). METHODS: Thirty corneal tissue were collected from KC patients after corneal transplantation and 15 normal donor corneas were obtained. All corneal tissues divided into 4 parts for different detections. Scanning electron microscopy was used to observe the ultrastructure of the specimens. VSX1 and α-SMA localization in cornea tissues was detected using immunofluorescence histochemistry. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot were performed to analyze the expression level of VSX1 and α-SMA. RESULTS: Compared to normal cornea tissue, the collagen fibers in KC stroma were distortional and attenuated and keratocytes were abnormally changed. VSX1 and α-SMA located in the corneal stroma. The mRNA and protein expression level of VSX1 in KC were about 3 times as high as that of normal tissue (P<0.001). α-SMA was hardly expressed in the normal corneas, however, its expression in the KC was about 1.5 times higher than that of the normal corneas (P<0.0001). CONCLUSION: Compared with normal corneal the expression of VSX1 and α-SMA in KC both increased. VSX1 is related to the activation of keratocytes and involved in the pathogenesis of keratoconus.

Non-Bonding Interactions Enable the Selective Formation of Branched Products in Palladium-Catalyzed Allylic Substitution Reactions.

Palladium-catalyzed allylic substitution reactions have become established as an important tool for the construction of carbon-carbon and carbon-heteroatom bonds in modern organic synthesis. However, controlling the regioselectivity of this type of transformation to afford chiral branched products, in addition to controlling the enantioselectivity, is a significant challenge. Excitingly, controlling nonbonding interactions between the substituents on the π-allyl-palladium intermediate and the nucleophile or palladium catalyst has been shown to be effective in achieving this goal. This Focus Review highlights representative advances in this field, according to the mode of non-bonding interaction, including hydrogen-bonding, electrostatic, and coordination interactions.

Poly-L-Arginine Induces Apoptosis of NCI-H292 Cells via ERK1/2 Signaling Pathway.

Cationic protein is a cytotoxic protein secreted by eosinophils and takes part in the damage of airway epithelium in asthma. Poly-L-arginine (PLA), a synthetic cationic protein, is widely used to mimic the biological function of the natural cationic protein in vitro. Previous studies demonstrated the damage of the airway epithelial cells by cationic protein, but the molecular mechanism is unclear. The purpose of this study aimed at exploring whether PLA could induce apoptosis of human airway epithelial cells (NCI-H292) and the underlying mechanism. Methods. The morphology of apoptotic cells was observed by transmission electron microscopy. The rate of apoptosis was analyzed by flow cytometry (FCM). The expressions of the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), Bcl-2/Bax, and cleaved caspase-3 were assessed by western blot. Results. PLA can induce apoptosis in NCI-H292 cells in a concentration-dependent manner. Moreover, the phosphorylation of the ERK1/2 and the unbalance of Bcl2/Bax, as well as the activation of caspase-3, were involved in the PLA-induced apoptosis. Conclusions. PLA can induce the apoptosis in NCI-H292 cells, and this process at least involved the ERK1/2 and mitochondrial pathway. The results could have some indications in revealing the apoptotic damage of the airway epithelial cells. Besides, inhibition of cationic protein-induced apoptotic death in airway epithelial cells could be considered as a potential target of anti-injury or antiremodeling in asthmatics.

Copper-catalyzed decarboxylative cyclization via tandem C-P and C-N bond formation: access to 2-phosphorylmethyl indoles.

A novel copper-catalyzed decarboxylative cyclization of ethynyl benzoxazinanones with P(O)H compounds has been developed. This protocol leads to a series of 2-phosphorylmethyl indoles with high efficiency and selectivity (up to 99% yield) through tandem C-P/C-N bond formation under mild conditions.

Synthesis of Polysubstituted Pyrroles through a Formal [4 + 1] Cycloaddition/E1cb Elimination/Aromatization Sequence of Sulfur Ylides and α,ß-Unsaturated Imines.

A reaction sequence comprising a formal [4 + 1] cycloaddition, an E1cb elimination, and an aromatization process is described in this work. By doing so, polysubstituted pyrroles were achieved from easily available chemicals, sulfur ylides, and α,ß-unsaturated imines. This protocol features mild conditions, high efficiency, and wide substrate scopes.

Divergent Synthesis of Polycyclic Indolines: Copper-Catalyzed Cascade Reactions of Propargylic Carbamates and Indoles.

Polycyclic indolines are the common and core structural motif of many indole alkaloids that usually exhibit biological activities. Here, we describe two copper-catalyzed cascade reactions between propargylic carbamates and indoles. By doing so, one-step and divergent synthesis of structurally distinct polycyclic indolines, quinoline-fused indolines, C(3a)-indolyl furoindolines, and pyrroloindolines was achieved in high synthetic efficiency and selectivity.