Systems pharmacology approach to explore the mechanisms of shufeng Jiedu Capsule on treating H1N1 infection.

BACKGROUND: Influenza caused by the H1N1 virus still affects human health. There is currently no effective strategy against H1N1 virus infection. The present study is to evaluate the mechanism of Shufeng Jiedu Capsule (SFJDC) in the treatment of H1N1 infection using an integrated systems pharmacology approach and experimental validation. SFJDC is recommended for the treatment of H1N1 infection in traditional Chinese medicine (TCM), whose mechanism of action is not precise. METHODS: We systematically analyzed SFJDC using a systematic pharmacology and ADME screening model, and predicted effective targets using systematic drug targeting (SysDT) algorithm. Subsequently, the network of interactions between compounds and targets was built to help in the discovery of new drugs. In addition, the pathway of molecular action was determined by using enrichment analysis from the predicted targets. what is more, molecular docking also applied to predict the specific binding sites and binding capacity of active compounds and related targets, which validated the results of the compounds-targets network (C-T network). Finally, the mechanism of SFJDC effect on autophagy and virus replication in H1N1 virus-infected RAW264.7 mouse macrophage cells was experimentally verified. RESULTS: The systematic pharmacology results suggested that 68 candidate compounds were obtained from SFJDC, which interacted with 74 different targets related to inflammation and the immune system. The CCK-8 results showed that different concentrations of SFJDC serum had no significant inhibitory effect on the viability of RAW264.7 cells. LC3-II was significantly increased after virus infection compared to the control group, while it was inhibited by different concentrations of SFJDC serum. H1N1 virus nucleocapsid protein (NP protein) was significantly reduced in the high concentration group, Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α), and viral M1 gene were significantly reduced compared to the H1N1 group. CONCLUSIONS: The integrated systemic pharmacological approach and experimental validation not only provide a precise explanation of the molecular mechanism of SFJDC in the treatment of H1N1 infection but also provide valuable clues for the development of novel drug strategies to control the H1N1 infection.

Enrichment of Circulating Tumor Cells of Lung Cancer and Correlation With Serum Leukomonocyte and Tumor Biomarkers: A Retrospective Study.

STUDY DESIGN: Circulating tumor cells is important in the clinical diagnosis of cancer and there are a number of circulating tumor cell detection systems associated with different isolation strategies being validated. There is a novel platform, the CytoBot 2000, which utilizes a combination of physical and immunological technologies to isolate and capture circulating tumor cells. METHODS: In this retrospective study, 39 lung cancer patients and 11 normal healthy individuals were enrolled and performed circulating tumor cell tests and immunofluorescence staining with CytoBot 2000. The performance of this device was assessed by receiver operating characteristic curve. The clinical relevance of circulating tumor cells was assessed by Chi-square. The correlations between circulating tumor cell number and blood lymphocytes and tumor biomarkers were analyzed by Pearson correlation coefficient. RESULTS: The number of circulating tumor cell is significantly increased in lung cancer patients (3.74 > 0.45, P < .0001). The CytoBot 2000 presented a 100% (39/39) circulating tumor cell detection rate in lung cancer patients and 36% (4/11) in healthy individual blood samples, the sensitivity and specificity were 89.7% and 90.9%, respectively, and with the area under curve of 0.966. Further, there was a positive correlation between circulating tumor cell count and carcinoembryonic antigen 211 (R2 = 0.125, P = .027), but not blood lymphocytes (P = .089). CONCLUSIONS: This automatic platform showed excellent performance of circulating tumor cell detection by clinical sample. The tumor biomarkers increased with the number of circulating tumor cell in the lung cancer patients.

PLZF promotes the development of asthma tolerance via affecting memory phenotypes of immune cells.

Clarifying the pathogenesis of asthma and/or identifying the specific pathway underlying oral asthma tolerance (OT) would be of great significance. In our previous study, promyelocytic leukemia zinc finger (PLZF), which reportedly regulates memory phenotypes, was found to promote ovalbumin (OVA)-induced OT. Therefore, this study aimed to explore the regulatory effects of PLZF on memory phenotypes in asthma and OT mouse models. We found that Zbtb16 (encoding PLZF) and PLZF+ cells were highly increased in OT lungs compared with asthmatic lungs. PLZF was co-expressed with GATA3, and IL-4+PLZF+ cells were significantly lower in OT lungs than in asthmatic lungs. Notably, memory cells were decreased in OT mice, and these mice had PLZF+ cells that expressed lower levels of CD44 than those of asthmatic mice. When Zbtb16 was overexpressed in splenic lymphocytes, the number of CD44+ cells decreased. There were increased memory cells in splenic lymphocytes after treatment with the supernatant of OVA-treated airway epithelial cells; however, this was reversed by Zbtb16 overexpression. Early respiratory syncytial virus infection increased memory cells and reduced PLZF+ cells in the OT mice. Collectively, these results indicate that PLZF may reduce the proportion of memory cells, thereby, promoting the establishment of OT.

Oral antibiotics relieve allergic asthma in post-weaning mice via reducing iNKT cells and function of ADRB2.

The role of normal gut microbiota in asthma or ovalbumin (OVA)-induced asthma tolerance (OT) remains unclear. Here, we established mouse models of asthma and OT followed by 2 weeks of antibiotic treatment, to clear the gut microbiota. Antibiotic treatment was found to alleviate allergic asthma accompanied with a reduction of invariant natural killer (iNKT) cells. By RNA-seq analysis, we found that ß-adrenergic receptor (ADRB) genes, including Adrb1, Adrb2, and Adrb3, were downregulated in asthmatic lungs, but these changes were reversed in OT lungs. Moreover, Adrb2 and Adrb3 were significantly upregulated in asthmatic lungs after antibiotic treatment. Surprisingly, blocking ADRB with propranolol relieved allergic asthma while reducing T helper 2 (Th2) and Treg cell numbers. Further analyses using flow cytometry and immunofluorescence showed that the protein expression level of ADRB2 was higher in asthmatic lungs than that in the control and OT lungs. Notably, dendritic cells (DCs), especially the ADRB2+ DCs, were increased in asthmatic lungs compared to that in the control and OT lungs. In addition, ADRB2+ DCs were significantly reduced following the administration of the ADRB2-specific antagonist ICI118551. Our findings suggest that antibiotic treatment can alleviate OVA-induced allergic asthma via reducing the frequency of iNKT cells and function of ADRB2.

Pulmonary resident memory T cells in respiratory virus infection and their inspiration on therapeutic strategies.

The immune system generates memory cells on infection with a virus for the first time. These memory cells play an essential role in protection against reinfection. Tissue-resident memory T (TRM) cells can be generated in situ once attacked by pathogens. TRM cells dominate the defense mechanism during early stages of reinfection and have gradually become one of the most popular focuses in recent years. Here, we mainly reviewed the development and regulation of various TRM cell signaling pathways in the respiratory tract. Moreover, we explored the protective roles of TRM cells in immune response against various respiratory viruses, such as Respiratory Syncytial Virus (RSV) and influenza. The complex roles of TRM cells against SARS-CoV-2 infection are also discussed. Current evidence supports the therapeutic strategies targeting TRM cells, providing more possibilities for treatment. Rational utilization of TRM cells for therapeutics is vital for defense against respiratory viruses.

Delta Variant: Partially Sensitive To Vaccination, but Still Worth Global Attention.

The pandemic coronavirus disease 2019 (COVID-19) has rapidly spread to all countries worldwide. The emergence of its variants has exacerbated this problem. To date, many variants have been identified across the viral genome; the variants of concern are the focus of attention due to their higher transmissibility and resistance to vaccines, especially the delta variant. The delta variant has become the dominant severe acute respiratory syndrome novel coronavirus (SARS-CoV-2) variant worldwide, causing severe panic as it is highly infectious. A better understanding of these variants may help in the development of possible treatments and save more lives. In this study, we summarize the characteristics of the variants of concern. More importantly, we summarize the results of previous studies on the delta variant. The delta variant has a high transmissibility rate and increases the risk of hospitalization and death. However, it is partially sensitive to vaccines. In addition, nonpharmaceutical interventions are valuable during epidemics. These interventions can be used against the delta variant, but managing this variant should still be taken seriously.

Chemical Vapor Deposition of Superconducting FeTe1-xSex Nanosheets.

FeTe1-xSex, a promising layered material used to realize Majorana zero modes, has attracted enormous attention in recent years. Pulsed laser deposition (PLD) and molecular-beam epitaxy (MBE) are the routine growth methods used to prepare FeTe1-xSex thin films. However, both methods require high-vacuum conditions and polished crystalline substrates, which hinder the exploration of the topological superconductivity and related nanodevices of this material. Here we demonstrate the growth of the ultrathin FeTe1-xSex superconductor by a facile, atmospheric pressure chemical vapor deposition (CVD) method. The composition and thickness of the two-dimensional (2D) FeTe1-xSex nanosheets are well controlled by tuning the experimental conditions. The as-prepared FeTe0.8Se0.2 nanosheet exhibits an onset superconducting transition temperature of 12.4 K, proving its high quality. Our work offers an effective strategy for preparing the ultrathin FeTe1-xSex superconductor, which could become a promising platform for further study of the unconventional superconductivity in the FeTe1-xSex system.

Th17/Treg cell imbalance plays an important role in respiratory syncytial virus infection compromising asthma tolerance in mice.

Mucosal tolerance is induced early in life and is an important mechanism of protection from diseases, such as asthma. Respiratory syncytial virus (RSV) is a main cause of bronchiolitis and pneumonia in infants. Clinical studies have found that there is a strong association between RSV infection in infancy and later development of asthma, but the underlying mechanisms are unclear. A mouse model of immune tolerance induced by oral feeding of ovalbumin(OVA) was successfully established in our previous studies. We found that RSV infection could break the oral immune tolerance state.RSV infection increased the mRNA expression of IL-17A and IL-17A/Foxp3(the transcription factor forkhead box P3) in OT mice, but the mRNA expression of IL-4 and other T helper(Th)2 cytokines did not change significantly. As detected by flow cytometry analysis, RSV infection elevated Th17 cell levels and correspondingly decreased Regulatory T(Treg) cell levels in the hilar lymph nodes (HLNs) and mesenteric lymph nodes (MLNs), but there were no significant differences in the spleen or peripheral blood.We hypothesized that an imbalance in Th cells played an important role in RSV infection compromising asthma tolerance.RSV infection disrupted asthma tolerance by increasing the Th17/Treg ratio rather than the Th1/Th2 ratio'.Therefore, altering the Th17/Treg ratio has been identified as a potential therapeutic target in asthma caused by RSV or another virus.

Astragaloside IV attenuates IL-1ß secretion by enhancing autophagy in H1N1 infection.

Excessive secretion of inflammatory factors (cytokine storm) plays a significant role in H1N1-induced acute pneumonia, and autophagy acts as a cell-intrinsic mechanism to regulate inflammation. Astragaloside IV (AS-IV), originating from the astragalus root, possesses multiple pharmacological activities, such as anti-inflammation. However, the influences of AS-IV on H1N1-induced autophagy and inflammation have remained elusive. It has been reported that H1N1 infection leads to the accumulation of autophagosomes but obstructs autophagosomes incorporating into lysosomes, whereas the present study showed that AS-IV enhanced autophagy activation in H1N1 infection. Furthermore, we found that AS-IV promoted H1N1-triggered formation of autophagosomes and autolysosomes. Additionally, it was noted that AS-IV did not affect viral replication, mRNA level of interleukin-1 beta (IL-1ß) and pro-IL-1ß protein level, but significantly decreased secretion of IL-1ß, and chloroquine (CQ, as an inhibitor of autophagy) increased secretion of IL-1ß in H1N1 infection. In conclusion, AS-IV stimulates the formation of autophagosomes and the fusion of autophagosomes and lysosomes in H1N1 infection and may lead to decreased IL-1ß secretion.

LncRNA SNHG3 is activated by E2F1 and promotes proliferation and migration of non-small-cell lung cancer cells through activating TGF-ß pathway and IL-6/JAK2/STAT3 pathway.

Recently, long noncoding RNAs (lncRNAs) have been widely reported to play pivotal roles in the regulation of human cancers. Although the oncogenic property of lncRNA small nucleolar RNA host gene 3 (SNHG3) has been revealed in a variety of cancers, functions and regulatory mechanism of SNHG3 in non-small-cell lung cancer (NSCLC) remain to be investigated. In this study, we detected the upregulated expression of SNHG3 in NSCLC tissues as well as cells through quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis. Using Kaplan-Meier analysis, we determined that a high-level of SNHG3 was associated with a low overall survival rate of patients with NSCLC. Through gain and loss of function experiments, we demonstrated that SNHG3 had a significantly positive effect on NSCLC cell proliferation and migration. Mechanistic investigations revealed that SNHG3 was a predicted direct transcriptional target of E2F1. We observed that the transcriptional activation of SNHG3 could be induced by E2F1. To explore the mechanism, rescue experiments were carried out, which revealed that the cotreatment with SB-431542, JSI-124, or JSI-124 + SB-431542 rescued the effects brought by the overexpression of SNHG3 on NSCLC cell proliferation, migration, and epithelial-mesenchymal transition process. Our results suggested that E2F1 activated SNHG3 and promoted cell proliferation and migration in NSCLC via transforming growth factor-ß pathway and interleukin-6/janus-activated kinase 2/signal transducer and activator of transcription 3 pathway, which implied that SNHG3 may be a biomarker for the treatment of patients with NSCLC.

Analysis of viral infection and biomarkers in patients with acute exacerbation of chronic obstructive pulmonary disease.

OBJECTIVE: To investigate viral infection in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in Shanghai, and to analyze the clinical characteristics and biomarkers in viral infection. METHODS: This study included all consecutive patients who were admitted for a diagnosis of AECOPD during June 2013 to May 2015. Thirty-one stable COPD patients and 31 healthy controls were also recruited. Oropharyngeal samples were assessed, PCR for respiratory viruses were performed. Patients were divided into AECOPD virus-positive (+) group and AECOPD virus-negative (-) group according to viral detection. Luminex was used to detect the concentrations of inflammatory cytokines in the serum. RESULTS: A total of 264 patients were included with a mean age of 75 ± 0.5 years. There were 72 patients (27.3%) identified with viral positive, of whom two patients were detected with double viral infections (FluA + FluB and RSVA + HRV, respectively). The rate of viral detection was associated with season, highest in winter. Comparisons of clinical characteristics showed no significant differences between AECOPD virus+ group and AECOPD virus- group. However, serum concentrations of interferon-inducible protein-10 (IP-10) and interferon-gamma (IFN-γ) in virus+ AECOPD patients were significantly higher than those in the virus- AECOPD, stable COPD and healthy control groups (P < .05). CONCLUSION: Viral infection was an important pathogen in AECOPD patients; the most common viruses included FluA, HRV and FluB. It was very difficult to diagnose the viral infection according to clinical characteristics. The increased of serum IP-10 and IFN-γ levels might be value to indicate viral infection in AECOPD.

Respiratory Syncytial virus infection compromises asthma tolerance by recruiting interleukin-17A-producing cells via CCR6-CCL20 signaling.

Asthma tolerance can be induced by breast-feeding or oral feeding with ovalbumin (OVA). Anergy or deletion of specific T cells and generation of T regulatory cells might contribute to this process. However, whether respiratory syncytial virus (RSV) infection would affect asthma tolerance is not very clear. Here, we first established asthma and oral tolerance mouse models and then analyzed airway hypersensitivity and asthma-related genes in the lung, CCR6-expressing IL-17A+ cells in the lungs, hilar or mesenteric lymph nodes (HLN or MLN) among control, asthmatic, tolerized, RSV infection, and RSV-infected asthmatic and tolerized groups. We also administrated CCL20 or IL-17A neutralizing antibody to RSV-infected tolerized mice to test whether RSV infection would mobilize CCR6-expressing IL-17A+ cells from MLN to the infected lungs. We found that tolerized mice infected with RSV developed asthma-like responses manifested by increasing airway hypersensitivity, exacerbating peribronchial inflammation, elevating lung asthma-related genes (Il17a, Mu5ac, and Gob5), accumulating CCR6-expressing IL-17A+ cells in the lungs and HLN with a reduction of this cell population in MLN. CCL20-CCR6 co-expression in RSV-infected tolerized MLN was reduced. Neutralization of CCL20 reduced CD3+CD4+CCR6+ cells in the RSV-infected tolerized HLN. Neutralization of IL-17A mitigated the compromising effects of RSV infection on asthma tolerance. Taken together, RSV infection impairs asthma tolerance by recruiting IL-17A-producing cells via CCR6-CCL20 signaling. The findings provide novel insight into exacerbation and therapeutic strategy of asthma under RSV infection.

IL-17A and IL-17F single nucleotide polymorphisms associated with lung cancer in Chinese population.

BACKGROUND AND AIMS: Genetic predisposition and environmental factors impact the development of lung cancer. The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) of the IL-17A and IL-17F genes with lung cancer risk in Chinese Han population. METHODS: A total of 678 subjects were enrolled, including 320 lung cancer patients and 358 healthy controls. Six SNPs of IL-17A (rs2275913, rs3748067 and rs3819025) and IL-17F (rs763780, rs1266828 and rs12203582) were genotyped using the polymerase chain reaction (PCR) and ligase detection reaction (LDR). RESULTS: The distribution of IL-17A alleles and A and AA genotype for rs2275913 had a significant association with lung cancer risk (OR: 1.26, 95% confidence interval = 1.01-1.56 and OR: 2.08, 95% confidence interval = 1.311-3.31, respectively). In the subgroup analysis, people carrying homozygous variants of rs2275913 and rs12203582 were more likely to develop lung cancer both in adenocarcinoma (OR: 2.33, 95% confidence interval = 1.34-4.05; OR: 1.84, 95% confidence interval = 1.04-3.25) and advanced (OR: 2.35, 95% confidence interval = 1.46-3.80; OR: 1.74, 95% confidence interval = 1.06-2.87) groups. Although no interaction was found between variants of rs2275913 and rs12203582 and tobacco smoking (P > 0.05), smokers carrying homozygous variants of rs2275913 and rs12203582 are at high risk of lung cancer, while no relationship were found among non-smokers. No significant associations between rs3748067, rs3819025, rs763780 and rs1266828 polymorphisms and lung cancer risk were observed. CONCLUSIONS: Polymorphisms of both IL-17A and IL-17F may increase lung cancer risk in Chinese population, and are associated differently with subtypes of clinical-pathologic features and tobacco smoking history of lung cancer patients. SNPs of IL-17A and IL-17F predict lung cancer risk.

Association between genetic polymorphisms in XPD and XRCC1 genes and risks of non-small cell lung cancer in East Chinese Han population.

BACKGROUND AND AIMS: Lung cancer is a multifactorial disease. Xeroderma pigmentosum group D (XPD) and X-ray repair cross-complementing 1 (XRCC1) genes are 2 important susceptibility genes related to lung cancer. In this study, we explored the correlation between genetic polymorphisms in XPD and XRCC1 and the risk of non-small cell lung cancer (NSCLC) in the East Chinese Han population. We also investigated risk factors associated with non-small cell lung cancer in this population. METHODS: We conducted a case control study in 120 NSCLC patients and 120 healthy controls. The NSCLC patients were further divided into three subgroups, squamous carcinoma, adenocarcinoma and other type of cancer, according to tumor histology. No patients had undergone any treatment. Polymerase chain reaction and restriction fragment length polymorphism technologies were applied to detect the distribution of XPD-751, XRCC1-194 and XRCC1-399 genes in all patients. RESULTS: The results showed significant gene frequency differences for all three genes between patients with NSCLC and control patients. Significantly different frequencies of XPD-751-Gln, XRCC-194-Trp and XRCC1-399-Gln mutant alleles were observed between the two groups. XPD-751SNP and XRCC1-194SNP frequencies varied among the three lung cancer groups, while the frequency of XRCC1-399SNP did not differ significantly. CONCLUSIONS: The results suggested that genetic polymorphisms in XPD-751, XRCC1-194 and XRCC1-399 were related to the risk of NSCLC, among which XPD-751SNP was responsible for adenocarcinoma, while XRCC1-194SNP was closely linked to squamous carcinoma. Smoking and XRCC1-194SNP were risk factors of NSCLC.

MicroRNA-141 promotes the proliferation of non-small cell lung cancer cells by regulating expression of PHLPP1 and PHLPP2.

The dysregulation of microRNAs (miRNAs) is crucially implicated in the development of various cancers. In this study, we explored the biological role of miR-141 in non-small cell lung cancer (NSCLC). miR-141 expression was significantly up-regulated in NSCLC tissues, and its overexpression accelerated NSCLC cell proliferation in vitro and tumor growth in vivo. We subsequently identified the antagonists of PI3K/AKT signaling, PH domain leucine-rich-repeats protein phosphatase 1 (PHLPP1) and PHLPP2, as direct targets of miR-141. Re-introduction of PHLPP1 and PHLPP2 abrogated miR-141-induced proliferation of NSCLC cells. Together, the results of this study suggest that miR-141 and its targets PHLPP1 and PHLPP2 play critical roles in NSCLC tumorigenesis, and provide potential therapeutic targets for NSCLC treatment.

Full-Genome Analysis of Influenza A(H7N9) Virus from Shanghai, China, 2014.

We analyzed the complete genome sequence of the A/Shanghai/01/2014 (H7N9) strain, which will provide a better understanding of the evolution of influenza A(H7N9) virus.

A detailed epidemiological and clinical description of 6 human cases of avian-origin influenza A (H7N9) virus infection in Shanghai.

BACKGROUND: The world's first reported patient infected with avian influenza H7N9 was treated at the Fifth People's Hospital of Shanghai. Shortly thereafter, several other cases emerged in the local area. Here, we describe the detailed epidemiological and clinical data of 6 cases of avian influenza H7N9. METHODS AND FINDINGS: We analyzed the epidemiologic and clinical data from clustered patients infected with H7N9 in the Minhang District of Shanghai during a 2-week period. Of the 6 patients, 2 were from a single family. In addition, 3 patients had a history of contact with poultry; however, all 6 patients lived in the proximity of 2 food markets where the H7N9 virus was detected in chickens and pigeons. The main symptoms were fever, cough, and hemoptysis. At onset, a decreased lymphocyte count and elevated creatine kinase, lactate dehydrogenase, procalcitonin, and C-reactive protein levels were observed. As the disease progressed, most patients developed dyspnea and hypoxemia. Imaging studies revealed lung consolidation and multiple ground-glass opacities in the early stage, rapidly extending bilaterally. All patients were treated with oseltamivir tablets beginning on days 3-8 after onset. The main complications were as follows: acute respiratory distress syndrome (ARDS; 83.3%), secondary bacterial infection (66.7%), pleural effusion (50%), left ventricular failure (33.3%), neuropsychiatric symptoms (33.3%), and rhabdomyolysis (16.7%). Of the 6 patients, 4 died of ARDS, with 2 patients recovering from the infection. CONCLUSIONS: An outbreak of H7N9 infection occurred in the Minhang District of Shanghai that easily progressed to acute respiratory distress syndrome. Two cases showed family aggregation, which led us to identify the H7N9 virus and indicated that human transmission may be involved in the spread of this infection.

The first patient recovered from avian influenza A H7N9 viral infection: A case report and review of the literature.

In March 2013, a novel avian-origin influenza A (H7N9) virus was isolated from throat swabs of 2 patients at the Fifth People's Hospital of Shanghai, China. Subsequently, 4 more patients infected by H7N9 were identified. Of the 6 patients, 4 died of acute respiratory distress syndrome. Here, we report the first case of a patient who recovered from pneumonia induced by H7N9 infection. The patient presented with fever, cough, and blood in sputum. Laboratory tests showed a low level of leukocytes, hypoxaemia, and increased levels of creatine kinase and lactate dehydrogenase. Imaging showed multiple areas of segmental ground-glass opacity in the right lung. Oseltamivir and antibiotics were administered. Supplemental oxygen helped relieve symptoms. Approximately 2 weeks after treatment, the patient finally recovered. A follow-up chest computed tomography scan taken 8 weeks later revealed that the ground-glass opacity was clearly absorbed. Therefore, timely intervention with oseltamivir and supplemental oxygen may be very important in the treatment of H7N9 infection.