Geniposide effectively safeguards HT22 cells against Aß-induced damage by activating mitophagy via the PINK1/Parkin signaling pathway.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the significant involvement of amyloid-beta (Aß) peptide in its pathogenesis. Geniposide, derived from the versatile medicinal of Gardenia jasminoides, is one of the active compounds studied extensively. The objective was to explore the impact of geniposide on Aß25-35-induced damage in HT22 cells, specifically focusing on its modulation of PINK1/Parkin-mediated mitophagy. In our investigation, geniposide exhibited remarkable restorative effects by enhancing cell viability and preserving the mitochondrial membrane potential. Moreover, it effectively reduced and mitigated the oxidative stress and apoptosis rates induced by Aß25-35. Notably, geniposide exhibited the capacity to enhance autophagic flux, upregulate LC3II and Beclin-1 expression, and downregulate the expression of p62. Furthermore, geniposide positively influenced the expression of PINK1 and Parkin proteins, with molecular docking substantiating a strong interaction between geniposide and PINK1/Parkin proteins. Intriguingly, the beneficial outcomes of geniposide on alleviating the pronounced apoptosis rates, the overproduction of reactive oxygen species, and diminished the PINK1 and Parkin expression induced by Aß25-35 were compromised by the mitophagy inhibitor cyclosporine A (CsA). Collectively, these findings suggested that geniposide potentially shields HT22 cells against neurodegenerative damage triggered by Aß25-35 through the activation of mitophagy. The insights contribute valuable references to the defensive consequences against neurological damage of geniposide, thereby highlighting its potential as a therapeutic intervention in AD.

Determination of soil phenanthrene degradation through a fungal-bacterial consortium.

Fungal-bacterial consortia enhance organic pollutant removal, but the underlying mechanisms are unclear. We used stable isotope probing (SIP) to explore the mechanism of bioaugmentation involved in polycyclic aromatic hydrocarbon (PAH) biodegradation in petroleum-contaminated soil by introducing the indigenous fungal strain Aspergillus sp. LJD-29 and the bacterial strain Pseudomonas XH-1. While each strain alone increased phenanthrene (PHE) degradation, the simultaneous addition of both strains showed no significant enhancement compared to treatment with XH-1 alone. Nonetheless, the assimilation effect of microorganisms on PHE was significantly enhanced. SIP revealed a role of XH-1 in PHE degradation, while the absence of LJD-29 in 13C-DNA indicated a supporting role. The correlations between fungal abundance, degradation efficiency, and soil extracellular enzyme activity indicated that LJD-29, while not directly involved in PHE assimilation, played a crucial role in the breakdown of PHE through extracellular enzymes, facilitating the assimilation of metabolites by bacteria. This observation was substantiated by the results of metabolite analysis. Furthermore, the combination of fungus and bacterium significantly influenced the diversity of PHE degraders. Taken together, this study highlighted the synergistic effects of fungi and bacteria in PAH degradation, revealed a new fungal-bacterial bioaugmentation mechanism and diversity of PAH-degrading microorganisms, and provided insights for in situ bioremediation of PAH-contaminated soil.IMPORTANCEThis study was performed to explore the mechanism of bioaugmentation by a fungal-bacterial consortium for phenanthrene (PHE) degradation in petroleum-contaminated soil. Using the indigenous fungal strain Aspergillus sp. LJD-29 and bacterial strain Pseudomonas XH-1, we performed stable isotope probing (SIP) to trace active PHE-degrading microorganisms. While inoculation of either organism alone significantly enhanced PHE degradation, the simultaneous addition of both strains revealed complex interactions. The efficiency plateaued, highlighting the nuanced microbial interactions. SIP identified XH-1 as the primary contributor to in situ PHE degradation, in contrast to the limited role of LJD-29. Correlations between fungal abundance, degradation efficiency, and extracellular enzyme activity underscored the pivotal role of LJD-29 in enzymatically facilitating PHE breakdown and enriching bacterial assimilation. Metabolite analysis validated this synergy, unveiling distinct biodegradation mechanisms. Furthermore, this fungal-bacterial alliance significantly impacted PHE-degrading microorganism diversity. These findings advance our understanding of fungal-bacterial bioaugmentation and microorganism diversity in polycyclic aromatic hydrocarbon (PAH) degradation as well as providing insights for theoretical guidance in the in situ bioremediation of PAH-contaminated soil.

Construction of Oxygen Vacancy-Rich TiO2 Nanocrystals for Boosting the Ammonolysis of Caprolactam to 6-Aminocapronitrile.

Hexamethylene diamine, an important chemical intermediate for polyamides, can be synthesized through the two-step route of caprolactam (CPL) ammonolysis to 6-aminocapronitrile (ACN), followed by hydrogenation. This method has received increasing attention from academia and industry. However, studies on the catalyst structure-performance correlation in CPL ammonolysis are still sporadic. In this work, a series of anatase TiO2 with different oxygen vacancy concentrations was prepared by chemical reduction using NaBH4. The oxygen vacancy on TiO2 surface, presented as Ti3+ sites, substantially enhances the adsorption and activation of NH3, which are demonstrated as the key steps in ammonolysis. Owing to the synergistic effect of Ti3+ and Ti4+ species, the CPL conversion rate and ACN selectivity of 85 and 97%, respectively, are achieved within 250 h. Density functional theory calculations showed that the intermediates on oxygen vacancy-rich TiO2 had a more favorable adsorption energy compared to those on intact TiO2, which is in good agreement with the experimental results.

Unveiling the synergistic mechanism of autochthonous fungal bioaugmentation and ammonium nitrogen biostimulation for enhanced phenanthrene degradation in oil-contaminated soils.

Autochthonous bioaugmentation and nutrient biostimulation are promising bioremediation methods for polycyclic aromatic hydrocarbons (PAHs) in contaminated agricultural soils, but little is known about their combined working mechanism. In this study, a microcosm trial was conducted to explore the combined mechanism of autochthonous fungal bioaugmentation and ammonium nitrogen biostimulation, using DNA stable-isotope-probing (DNA-SIP) and microbial network analysis. Both treatments significantly improved phenanthrene (PHE) removal, with their combined application producing the best results. The microbial community composition was notably altered by all bioremediation treatments, particularly the PHE-degrading bacterial and fungal taxa. Fungal bioaugmentation removed PAHs through extracellular enzyme secretion but reduced soil microbial diversity and ecological stability, while nitrogen biostimulation promoted PAH dissipation by stimulating indigenous soil degrading microbes, including fungi and key bacteria in the soil co-occurrence networks, ensuring the ecological diversity of soil microorganisms. The combination of both approaches proved to be the most effective strategy, maintaining a high degradation efficiency and relatively stable soil biodiversity through the secretion of lignin hydrolytic enzymes by fungi, and stimulating the reproduction of soil native degrading microbes, especially the key degraders in the co-occurrence networks. Our findings provide a fresh perspective of the synergy between fungal bioaugmentation and nitrogen biostimulation, highlighting the potential of this combined bioremediation approach for in situ PAH-contaminated soils.

Protective effect of canagliflozin on post-resuscitation myocardial function in a rat model of cardiac arrest.

BACKGROUND: Currently, most patients with cardiac arrest (CA) show reversible myocardial dysfunction, hemodynamic instability, systemic inflammation and other pathophysiological state in early stage of resuscitation, some patients may eventually progress to multiple organ failure. There is evidence that heart failure is the terminal stage in the development of various cardiovascular diseases. Although the cardio-protective effect of canagliflozin (CANA) has been confirmed in large clinical studies and recommended in domestic and international heart failure-related guidelines, the effectiveness of CANA after resuscitation remains unclear. In this study, we constructed a modified CA/CPR rat model to investigate whether CANA administered on post-resuscitation improves myocardial function. METHODS: Twenty-fourth healthy male Sprague-Dawley rats were randomized into four groups: (1) Sham + placebo group, (2) Sham + CANA group, (3) CPR + placebo group, and (4) CPR + CANA group. Ventricular fibrillation was induced by transcutaneous electrical stimulation on epicardium. After 6 min untreated ventricular fibrillation, chest compressions was initiated. The rats were received an injection of placebo or canagliflozin (3 ug/kg) randomly 15 min after restore of spontaneous circulation (ROSC). Electrocardiogram (ECG) and blood pressure were continuously detected in each group throughout the experiment. The rats were killed 6 h after ROSC to collected the arterial serum and myocardial tissue. Myocardial injury was estimated with concentrations of inflammatory factors, oxidative stress indexes and, apoptosis index, myocardial injury markers, echocardiography and myocardial pathological slices. RESULTS: After resuscitation, mean arterial pressure (MAP) were significantly increased after cardiopulmonary resuscitation in CANA group rats when compared with placebo group. Heart rate, body lactate returned and left ventricular ejection fraction (LVEF) to normal levels in a shorter time and the myocardial injury was obviously attenuated in CPR + CANA group. Inflammatory factors (IL-6, TNF-α) and oxidative stress indexes (MAD, SOD, CAT) were dramatically decreased with the administration of CANA. The expression of apoptosis index (BAX, caspase-3) were higher in CPR + placebo group and the expression of anti-apoptosis index (Bcl-2) was lower (P < 0.05). CONCLUSIONS: The administration of CANA effectively reduces myocardial ischaemia/reperfusion (I/R) injury after cardiac arrest and cardiopulmonary resuscitation (CPR), and the underlying mechanism may be related to anti-inflammation, oxidative stress and apoptosis.

Protective effects of berberine against ß-amyloid-induced neurotoxicity in HT22 cells via the Nrf2/HO-1 pathway.

Neuronal apoptosis has been found to have a pivotal role in the course of Alzheimer's disease (AD). Berberine (BBR), a potent antioxidant, occurs in plants such as Berberis, Phellodendron chinense, and Hydrastis canadensis. In this study, a neuronal apoptotic model was established in vitro using HT22 cells induced by Aß25-35 to explore whether BBR contributes to protecting neurons against Aß25-35-induced neurotoxicity, as well as its potential mechanisms. BBR was applied to HT22 cells for 1 h prior to exposing the cells to Aß25-35 for 24 h. A CCK-8 assay was utilized to assess cell viability, and Annexin V - fluorescein isothiocyanate (FITC)/propidium iodide and Hoechst 33342 fluorescence staining were used to measure the rate of cell apoptosis. Existing scientific literature was also reviewed to further determine the effects of BBR on ROS production and mitochondrial function in HT22 cells. Furthermore, the expressions of proteins, including cytochrome C, cleaved caspase-3, p-p65, p65, and Nrf2/HO-1 antioxidant axis were assessed by Western blotting. The data indicated that BBR markedly improved cell viability, inhibited apoptosis and intracellular ROS levels, improved mitochondrial membrane potentials, decreased the rate of p-p65/p65, cytochrome C, and cleaved caspase-3, and intensified the activity of Nrf2/HO-1 antioxidants in HT22 cells. Overall, the findings indicated that BBR provides a certain level of neuroprotectiveness in HT22 cells exposed to Aß25-35 via relieving oxidative stress, as well as by restraining the mitochondrial pathway of cellular apoptosis. In addition, the restraint of NF-κB activity and sensitization of the Nrf2/HO-1 antioxidant axis, which together are intimately involved in the neuroprotection of BBR, may be possible mechanisms accounting for its effectiveness against Aß25-35in vitro.

Emerging applications of metabolomics in food science and future trends.

Metabolomics is a relatively new component in systems biology that focuses on the high-throughput characterization of small molecular metabolites in biological systems. It is widely used in several scientific fields, particularly in that of food. Due to its excellent detection and prediction capacities, metabolomics well suited to analyze such complex matrix. This review emphasizes the most commonly used food metabolomics analytical technologies with a focus on novel approaches that have emerged in recent years, highlighting their suitability for food samples analysis as aided by chemometric data visualization. A comparison is presented among different metabolomics platforms and their prioritization for which metabolite classes in food. Application of metabolomics are presented in the context of food composition analysis, food quality safety, and food traceability. Furthermore, the constraints and limitations of actual metabolomics applications are explored, bringing novel insights into metabolomics use in food science to maximize its application potential in that major industrial sector.

Advances in fucoxanthin chemistry and management of neurodegenerative diseases.

BACKGROUND: Neurodegenerative diseases are chronic, currently incurable, diseases of the elderly, which are characterized by protein misfolding and neuronal damage. Fucoxanthin, derived from marine brown algae, presents a promising candidate for the development of effective therapeutic strategies. HYPOTHESIS AND PURPOSE: The relationship between neurodegenerative disease management and fucoxanthin has not yet been clarified. This study focuses on the fundamental mechanisms and targets of fucoxanthin in Alzheimer's and Parkinson's disease management, showing that communication between the brain and the gut contributes to neurodegenerative diseases and early diagnosis of ophthalmic diseases. This paper also presents, new insights for future therapeutic directions based on the integrated application of artificial intelligence. CONCLUSION: Fucoxanthin primarily binds to amyloid fibrils with spreading properties such as Aß, tau, and α-synuclein to reduce their accumulation levels, alleviate inflammatory factors, and restore mitochondrial membranes to prevent oxidative stress via Nrf2 and Akt signaling pathways, involving reduction of specific secretases. In addition, fucoxanthin may serve as a preventive diagnosis for neurodegenerative diseases through ophthalmic disorders. It can modulate gut microbes and has potential for the alleviation and treatment of neurodegenerative diseases.

AIM2 Promotes Gastric Cancer Cell Proliferation via the MAPK Signaling Pathway.

Background: Gastric cancer (GC) is a highly prevalent tumor type. The dysregulated expression of melanoma deficiency factor 2 (AIM2) has been observed in a range of tumor types. Herein, we explore the role of AIM2 in the regulation of GC progression. Methods: Gastric cancer cells BGC-823 and MGC-803 in logarithmic growth phase were divided into blank group (control), Control group (NC) and SH-AIM2 group, respectively. Control group and SH-AIM2 group were transfected with AIM2 NC and SH-AIM2, respectively. Nude mice were divided into blank group (control) and SH-AIM2 group, and the treatment methods were the same as above. Differential AIM2 expression in GC tissues was assessed via bioinformatics analyses, after which western blotting was used for analyzing the AIM2 levels in tumor and paracancerous tissues from five stomach cancer patients. In addition, qPCR and protein imprinting were used to assess AIM2 expression levels in GC cells, and AIM2 knockdown was conducted in MGC-803 and BGC-823cells, after which colony formation and EdU incorporation assay were utilized to assess cell proliferation. The oncogenic role of AIM2 was then assessed in mice and validated through immunohistochemical analyses. Results: GC tissues and cell lines exhibited marked AIM2 overexpression. AIM2 knockdown significantly impaired GC cell proliferation and migration, as confirmed through in vitro assays. In vivo experiments showed that both the increment ability and invasion and migration ability of AIM2 knockdown group were significantly lower than that of control and NC the change of AIM2 protein level would affect the change of MAPK pathway related protein level. Conclusions: AIM2 knockdown markedly suppresses the proliferation, migration, as well as invasion of GC cells via the inhibition of MAPK signaling, thereby slowing tumor progression. Overall, these results suggest that further analyses of AIM2 may offer clinically valuable insights that can aid in the treatment of human GC.

Effectiveness of Proton-Pump Inhibitors in Chronic Obstructive Pulmonary Disease: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Although several randomized controlled trials (RCTs) have been published in recent years, the role of proton-pump inhibitors (PPI) in patients with chronic obstructive pulmonary disease (COPD) remains controversial. This preliminary meta-analysis was conducted to evaluate the clinical efficacy of PPI in patients with COPD. METHODS: RCTs related to PPI in the treatment of patients with a definite diagnosis of COPD were enrolled in this meta-analysis. PubMed, Embase, Cochrane Library, CNKI, Wanfang and VIP databases were retrieved to identify eligible studies from database establishment to September 22, 2021. Two researchers independently screened the articles, extracted the data and evaluated the risk of bias in the included studies independently. The study complied with PRISMA 2020 guideline for this study. The meta-analysis was performed using RevMan 5.3. Heterogeneity among studies was tested using the I 2 test. The results were presented as risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS: A total of 15 RCTs, including 1,684 patients, were enrolled. The meta-analysis revealed that PPI plus conventional treatment was superior to conventional treatment with respect to the case fatality rate (RR = 0.30; 95% CI, 0.18-0.52; P < 0.001), the incidence of gastrointestinal bleeding (RR = 0.23; 95% CI, 0.14-0.38; P < 0.001), the incidence of other adverse reactions (RR = 0.33; 95% CI, 0.28-0.39; P < 0.001) and the number of acute exacerbations [mean difference (MD) = -1.17; 95% CI, 1.75 to -0.60: P < 0.001] in patients with COPD. No significant differences were found in clinical efficacy (RR = 1.08; 95% CI, 0.95-1.22; P = 0.25), FEV1/FVC (MD = 3.94; 95% CI, -8.70 to 16.58; P = 0.54) and nosocomial infection rate (RR = 1.31; 95% CI, 0.57-3.00; P = 0.52) between the two groups. DISCUSSION: This comprehensive meta-analysis suggested that PPI treatment for COPD may reduce the case fatality rate, incidence of gastrointestinal bleeding and other adverse reactions and number of acute exacerbations. However, the present meta-analysis also has some limitations of the evidence, such as the high risk of bias of the included studies, and predominance of included studies from China, which may result in publication bias. Therefore, further large-scale RCTs are needed to confirm our findings. SYSTEMATIC TRIAL REGISTRATION: Identifier: CRD42022301304.

Hematological characteristics of patients with novel coronavirus pneumonia in intensive care unit.

BACKGROUND: Toward the end of December 2019, a novel type of coronavirus (2019-nCoV) broke out in Wuhan, China. Here, the hematological characteristics of patients with severe and critical 2019-nCoV pneumonia in intensive care unit (ICU) were investigated, which may provide the necessary basis for its diagnosis and treatment. METHODS: We collected data on patients with confirmed 2019-nCoV pneumonia in the ICU of Leishenshan Hospital in Wuhan from February 25 to April 2, 2020. Real-time reverse-transcription polymerase chain reaction was used to confirm the presence of 2019-nCoV, and various hematological characteristics were analyzed. RESULTS: All patients tested positive for 2019-nCoV using nasopharyngeal swabs or sputum after admission, and interstitial pneumonia findings were noted on chest computed tomography. Sex, age and comorbidities were not significantly different between the severe and critical groups. In terms of prognosis, the survival rate of patients in the severe group reached 100%, whereas that of patients in the critical group was only 13.33% after positive treatment. Furthermore, lymphocyte percentage, blood urea nitrogen, calcium, D-dimer, myohemoglobin, procalcitonin, and IL-6 levels were high-risk factors for disease progression in critical patients. Finally, lymphocyte percentage and blood urea nitrogen, calcium, myohemoglobin, and IL-6 levels were closely associated with patient prognosis. CONCLUSIONS: 2019-nCoV pneumonia should be considered a systemic disease. Patients with more complications were more likely to develop critical disease. Lymphocyte percentage and blood urea nitrogen, calcium, myohemoglobin, and IL-6 levels can be monitored to prevent progression critical disease.

Research on the Potential Mechanism of Gentiopicroside Against Gastric Cancer Based on Network Pharmacology.

BACKGROUND: Gastric cancer was still one of the commonly diagnosed cancer types and the third-most common cause of cancer-related death in the world. Gentiopicroside, which is extracted from the Gentianella acuta, is commonly used in both traditional treatment and modern clinical care; therefore, its anticancer effects have been attracted more attention. However, the systematic analysis of action mechanism of Gentiopicroside on gastric cancer (GC) has not yet been carried out. AIM: A network pharmacology-based strategy combined with molecular docking studies and in vitro validation was employed to investigate potential targets and molecular mechanism of Gentiopicroside against GC. MATERIALS AND METHODS: Potential targets of Gentiopicroside, as well as related genes of GC, were acquired from public databases. Potential targets, and signaling pathways were determined through bioinformatic analysis, including protein-protein interaction (PPI), the Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, molecular docking and cell experiments were performed to further verify the above findings. RESULTS: Our findings revealed that the anticancer activity of Gentiopicroside potentially involves 53 putative identified target genes. In addition, GO, KEGG, and network analyses revealed that these targets were associated with cell proliferation, metabolic process, and other physiological processes. Furthermore, we have proved that critical compound affected the expression of CCND1, CCNE1, p-AKT and p-P38 at protein levels. These findings provide an overview of the anticancer action of Gentiopicroside from a network perspective; meanwhile, it might also set an example for future studies of other materials used in traditional Chinese medicine (TCM). CONCLUSION: This study comprehensively illuminated the potential targets and molecular mechanism of Gentiopicroside against GC. It also provided a promising approach to uncover the scientific basis and therapeutic mechanism of TCM treating for disease.

Effect of eugenol fumigation treatment on chilling injury and CBF gene expression in eggplant fruit during cold storage.

The effect of eugenol (EUG) on chilling injury (CI) to eggplant fruit (Solanum melongena L.) was investigated. Eggplant fruit were pre-treated with 25 µL/L EUG, and then stored at 4 °C for 12 days. Results showed that EUG fumigation treatment effectively retarded the CI development, reduced pulp browning, weight loss, and malondialdehyde (MDA) content, and sustained soluble solids content (SSC) and proline content. Moreover, the activities of polyphenol oxidase (PPO) and peroxidase (POD) were inhibited by EUG. C-repeat/dehydration-responsive element binding factors (CBF) genes are transcription factors playing a critical role in cold acclimation. To illuminate the molecular regulation of EUG on chilling tolerance in eggplant fruit, a 1151 bp SmCBF gene was identified and the effect of EUG on SmCBF expression was determined by RT-qPCR. EUG resulted in a higher SmCBF expression. These findings suggested that EUG treatment had potential effect on alleviating CI in eggplant fruit.

Geniposide attenuates Aß25-35-induced neurotoxicity via the TLR4/NF-κB pathway in HT22 cells.

Alzheimer's disease (AD), a neurodegenerative disorder, is marked by the accumulation of amyloid-ß (Aß) and neuroinflammation which promote the development of AD. Geniposide, the main ingredient isolated from Chinese herbal medicine Gardenia jasminoides Ellis, has a variety of pharmacological functions such as anti-apoptosis and anti-inflammatory activity. Hence, we estimated the inflammatory cytotoxicity caused by Aß25-35 and the neuroprotective effects of geniposide in HT22 cells. In this research, following incubation with Aß25-35 (40 µM, 24 h) in HT22 cells, the methylthiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) release assays showed that the cell survival rate was significantly decreased. In contrast, the reactive oxygen species (ROS) assay indicated that Aß25-35 enhanced ROS accumulation and apoptosis showed in both hoechst 33342 staining and annexin V-FITC/PI double staining. And then, immunofluorescence test revealed that Aß25-35 promoted p65 to transfer into the nucleus indicating p65 was activated by Aß25-35. Moreover, western blot analysis proved that Aß25-35 increased the expression of nitric oxide species (iNOS), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and interleukin-1ß (IL-1ß). Simultaneously, Aß25-35 also promoted the expression of toll-like receptor 4 (TLR4), p-p65 and p-IκB-α accompanied with the increase in the level of beta-secretase 1 (BACE1) and caspase-3 which further supported Aß25-35 induced apoptosis and inflammation. Fortunately, this up-regulation was reversed by geniposide. In conclusion, our data suggest that geniposide can alleviate Aß25-35-induced inflammatory response to protect neurons, which is possibly involved with the inhibition of the TLR4/NF-κB pathway in HT22 cells. Geniposide may be the latent treatment for AD induced by neuroinflammation and apoptosis.

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.

Association between fractional exhaled nitric oxide (FeNO) cutoff values (25 ppb) and risk factors of cough.

INTRODUCTION: Cough is among the most common symptoms for patients to seek medical attention. OBJECTIVES: The purpose of this study is to evaluate the association between fractional exhaled nitric oxide (FeNO) cutoff values (25 ppb) and risk factors related to cough, hoping to evaluate the feasibility of the FeNO cut point values (25 ppb) for clinical prediction of cough in etiology. METHODS: In 107 adult patients with acute, subacute, or chronic cough, the FeNO, forced expiratory volume for 1 second (FEV1), forced vital capacity (FVC), blood routine (white blood cell and neutrophil), immunoglobulin E (IgE), lymphocyte eosinophils, and hemoglobin were measured. The Student's t-test was used to test the differences of FeNO levels compared with FEV1/FVC, lymphocyte, and hemoglobin level. For evaluating the correlation of FeNO levels with IgE, eosinophil, blood routine, pulmonary infection, and smoking status, the chi-square test was performed. RESULTS: FeNO cutoff value (25 ppb) significantly correlated with serum IgE (P < .0001) between ≥200 IU/mL and <200 IU/mL level, eosinophil (P = .039) between ≥5% and <5% level, lymphocyte percentage (P = .032) and the ratio of FEV1/FVC (P = .032), while weakly correlated with pulmonary infection, blood routine (white blood cell and neutrophil), hemoglobin, and smoking. CONCLUSION: The cutoff values of FeNO (≥25 ppb or <25 ppb) are useful for etiological detection of cough with high sensitivity.

Targeting CD73 in the tumor microenvironment with MEDI9447.

MEDI9447 is a human monoclonal antibody that is specific for the ectoenzyme CD73 and currently undergoing Phase I clinical trials. Here we show that MEDI9447 is a potent inhibitor of CD73 ectonucleotidase activity, with wide ranging immune regulatory consequences. MEDI9447 results in relief from adenosine monophosphate (AMP)-mediated lymphocyte suppression in vitro and inhibition of mouse syngeneic tumor growth in vivo. In contrast with other cancer immunotherapy agents such as checkpoint inhibitors or T-cell agonists, MEDI9447 drives changes in both myeloid and lymphoid infiltrating leukocyte populations within the tumor microenvironment of mouse models. Changes include significant alterations in a number of tumor micro-environmental subpopulations including increases in CD8(+) effector cells and activated macrophages. Furthermore, these changes correlate directly with responder and non-responder subpopulations within animal studies using syngeneic tumors. Combination data showing additive activity between MEDI9447 and anti-PD-1 antibodies using human cells in vitro and mouse tumor models further demonstrate the potential value of relieving adenosine-mediated immunosuppression. Based on these data, a Phase I study to test the safety, tolerability, and clinical activity of MEDI9447 in cancer patients was initiated (NCT02503774).

Co-inhibition of CD73 and A2AR Adenosine Signaling Improves Anti-tumor Immune Responses.

Preclinical studies targeting the adenosinergic pathway have gained much attention for their clinical potential in overcoming tumor-induced immunosuppression. Here, we have identified that co-blockade of the ectonucleotidase that generates adenosine CD73 and the A2A adenosine receptor (A2AR) that mediates adenosine signaling in leuokocytes, by using compound gene-targeted mice or therapeutics that target these molecules, limits tumor initiation, growth, and metastasis. This tumor control requires effector lymphocytes and interferon-γ, while antibodies targeting CD73 promote an optimal therapeutic response in vivo when engaging activating Fc receptors. In a two-way mixed leukocyte reaction using a fully human anti-CD73, we demonstrated that Fc receptor binding augmented the production of proinflammatory cytokines.

Biodistribution Analyses of a Near-Infrared, Fluorescently Labeled, Bispecific Monoclonal Antibody Using Optical Imaging.

In recent years, biodistribution analyses of pharmaceutical compounds in preclinical animal models have become an integral part of drug development. Here we report on the use of optical imaging biodistribution analyses in a mouse xenograft model to identify tissues that nonspecifically retained a bispecific antibody under development. Although our bispecific antibody bound both the epidermal growth factor receptor and insulin growth factor 1 receptor are expressed on H358, nonsmall-cell lung carcinoma cells, the fluorescence from labeled bispecific antibody was less intense than expected in xenografted tumors. Imaging analyses of live mice and major organs revealed that the majority of the Alexa Fluor 750 labeled bispecific antibody was sequestered in the liver within 2 h of injection. However, results varied depending on which near-infrared fluorophore was used, and fluorescence from the livers of mice injected with bispecific antibody labeled with Alexa Fluor 680 was less pronounced than those labeled with Alexa Fluor 750. The tissue distribution of control antibodies remained unaffected by label and suggests that the retention of fluorophores in the liver may differ. Given these precautions, these results support the incorporation of optical imaging biodistribution analyses in biotherapeutic development strategies.