FGF21 attenuates pulmonary arterial hypertension via downregulation of miR-130, which targets PPARγ.

The proliferation, migration and apoptotic resistance of pulmonary artery smooth muscle cells (PASMCs) are central to the progression of pulmonary arterial hypertension (PAH). Our previous study identified that fibroblast growth factor 21 (FGF21) regulates signalling pathway molecules, such as peroxisome proliferator-activated receptor gamma (PPARγ), to play an important role in PAH treatment. However, the biological roles of miRNAs in these effects are not yet clear. In this study, using miRNA sequencing and real-time PCR, we found that FGF21 treatment inhibited miR-130 elevation in hypoxia-induced PAH in vitro and in vivo. Dual luciferase reporter gene assays showed that miR-130 directly negatively regulates PPARγ expression. Inhibition of miR-130 expression suppressed abnormal proliferation, migration and apoptotic resistance in hypoxic PASMCs, and this effect was corrected upon PPARγ knockdown. Both the ameliorative effect of FGF21 on pulmonary vascular remodelling and the inhibitory effect on proliferation, migration and apoptotic resistance in PASMCs were observed following exogenous administration of miR-130 agomir. In conclusion, this study revealed the protective effect and mechanism of FGF21 on PAH through regulation of the miR-130/PPARγ axis, providing new ideas for the development of potential drugs for PAH based on FGF21.

Prognosis assessment model based on low serum calcium in patients with acute pulmonary thromboembolism.

BACKGROUND AND OBJECTIVE: The pulmonary embolism severity index (PESI) and simplified PESI (sPESI) are recommended to recognize patients with acute pulmonary thromboembolism (PTE) with low prognosis risk, which is of great significance for treatment. This study aims to verify the influence of hypocalcaemia on the prognosis of patients with PTE and to establish a new prognosis assessment model. METHODS: This is an observational, multicentre study enrolling patients with PTE from February 2010 to June 2020 across 12 Chinese hospitals. Variables in PESI, serum calcium levels and patient survival status as of 5 July 2020 were collected. The area under the curve of the receiver operating characteristic curve, sensitivity, specificity and Youden index were used to evaluate model performance. RESULTS: In the cohort of 4196 patients with PTE, independent associations existed between hypocalcaemia and mid- and long-term mortalities (p <0.05). By including hypocalcaemia, the new 30-day death risk prediction rule, Peking Union Medical College Hospital rule (PUMCH rule), showed significantly higher specificity (0.622 [0.582, 0.661]; p <0.001) than the PESI (0.514 [0.473, 0.554]) and sPESI (0.484 [0.444, 0.525]) and similar sensitivity (0.963 [0.810, 0.999]; p = 0.161) with PESI (0.889 [0.708, 0.976]) and sPESI (0.963 [0.810, 0.999]) in the internal validation cohort. Well-performing predictive validity was also verified on a constructed external validation cohort. CONCLUSION: Hypocalcaemia is independently associated with mid- and long-term PTE mortalities. The PUMCH rule showed significantly higher specificity than the PESI and sPESI and similar sensitivity, which may be used as a prognostic assessment tool for patients with acute PTE.

COVID-19 pneumonia: CD8+ T and NK cells are decreased in number but compensatory increased in cytotoxic potential.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is posing a huge threat to human health worldwide. We aim to investigate the immune status of CD8+ T and NK cells in COVID-19 patients. METHODS: The count and immune status of lymphocytes were detected by flow cytometry in 32 COVID-19 patients and 18 healthy individuals. RESULTS: As the disease progression in COVID-19 patients, CD8+ T and NK cells were significantly decreased in absolute number but highly activated. After patients' condition improved, the count and immune status of CD8+ T and NK cells restored to some extent. GrA+CD8+ T and perforin+ NK cells had good sensitivity and specificity for assisting diagnosis of COVID-19. CONCLUSIONS: As the disease progression, the declined lymphocytes in COVID-19 patients might lead to compensatory activation of CD8+ T and NK cells. GrA+CD8+ T and perforin+ NK cells might be used as meaningful indicators for assisting diagnosis of COVID-19.

T. marneffei infection complications in an HIV-negative patient with pre-existing pulmonary sarcoidosis: a rare case report.

BACKGROUND: Talaromyces marneffei (T. marneffei) is a thermal dimorphic pathogenic fungus that often causes fatal opportunistic infections in human immunodeficiency virus (HIV)-infected patients. Although T. marneffei-infected cases have been increasingly reported among non-HIV-infected patients in recent years, no cases of T. marneffei infection have been reported in pulmonary sarcoidosis patients. In this case, we describe a T. marneffei infection in an HIV-negative patient diagnosed with pulmonary sarcoidosis. CASE PRESENTATION: A 41-year-old Chinese man who had pre-existing pulmonary sarcoidosis presented with daily hyperpyrexia and cough. Following a fungal culture from bronchoalveolar lavage (BAL), the patient was diagnosed with T. marneffei infection. A high-resolution computed tomography (HRCT) chest scan revealed bilateral lung diffuse miliary nodules, multiple patchy exudative shadows in the bilateral superior lobes and right inferior lobes, air bronchogram in the consolidation of the right superior lobe, multiple hilar and mediastinal lymphadenopathies and local pleural thickening. After 3 mos of antifungal therapy, the patient's pulmonary symptoms rapidly disappeared, and the physical condition improved markedly. A subsequent CT re-examination demonstrated that foci were absorbed remarkably after treatment. The patient is receiving follow-up therapy and assessment for a cure. CONCLUSION: This case suggested that clinicians should pay more attention to non-HIV-related lung infections in patients with pulmonary sarcoidosis. Early diagnosis and treatment with antifungal therapy can improve the prognosis of T. marneffei infection.

Baicalin attenuates bleomycin-induced pulmonary fibrosis via adenosine A2a receptor related TGF-ß1-induced ERK1/2 signaling pathway.

BACKGROUND: Baicalin has been reported to have anti-fibrosis effect; however, its mechanism still remains to be elucidated. Adenosine A2a receptor (A2aR) is a novel inflammation regulator, and transforming growth factor-ß1 (TGF-ß1)-induced extracellular signal regulated kinase1/2 (ERK1/2) signaling pathway plays an important role in idiopathic pulmonary fibrosis (IPF). This study was to explore the relationship of A2aR and TGF-ß1-induced ERK1/2 in bleomycin (BLM)-induced pulmonary fibrosis in mice, and to investigate whether A2aR mediate the anti-fibrosis effect of Baicalin on BLM-induced pulmonary fibrosis. METHODS: The A2aR-/- and A2aR+/+ mice were respectively divided into three groups: control group, model group, baicalin group. Pulmonary fibrosis was induced in mice of model groups by intratracheal instillation of bleomycin, and baicalin was administered in mice of baicalin groups daily for 28 days. Histopathological and ultrastructural changes of lung tissues were evaluated. Lung coefficient and the levels of hydroxyproline (HYP) in lung tissues were measured at the same time. The levels of serum TGF-ß1 were measured by ELISA. The expression of TGF-ß1, ERK1/2, p-ERK1/2 and A2aR were detected by western blot and immunohistochemical staining techniques. RESULTS: Severe lung fibrosis was observed in the bleomycin-treated mice on day 28. The histopathological findings and collagen content of lung tissues were much severer/higher in A2aR-/- mice than in A2aR+/+ mice. We also showed that TGF-ß1 and p-ERK1/2 were upregulated in bleomycin-treated mice and expressed higher in A2aR-/- mice compared to A2aR+/+ mice. Besides, bleomycin-treated A2aR+/+ mice had increased A2aR level in lungs. However, long-term treatment with baicalin in A2aR-/- and A2aR+/+ mice significantly ameliorated the histopathological changes in lungs. Moreover, Increased TGF-ß1 and p-ERK1/2 expressions in bleomycin-treated A2aR-/- and A2aR+/+ mice were obviously diminished by baicalin. The baicalin-treated A2aR-/- mice had severer lung fibrosis and higher expressions of TGF-ß1 and p-ERK1/2 than A2aR+/+ mice. Baicalin has also upregulated the expression of A2aR in A2aR+/+ mice. CONCLUSIONS: Genetic inactivation of A2aR exacerbated the pathological processes of bleomycin-induced pulmonary fibrosis. Together, baicalin could inhibit BLM-induced pulmonary fibrosis by upregulating A2aR, suggesting A2aR as a therapeutic target of baicalin for the treatment of pulmonary fibrosis.

Salidroside attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A2a receptor related mitochondria-dependent apoptosis pathway.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial remodeling mainly due to excess cellular proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Salidroside, an active ingredient isolated from Rhodiola rosea is proposed to exert protective effects against PAH. However, the function of salidroside in PAH has not been investigated systematically and the underlying mechanisms are not clear. To investigate the effects of salidroside on PAH, the mice in chronic hypoxia model of PAH were given by an increasing concentration of salidroside (0, 16 mg/kg, 32 mg/kg, and 64 mg/kg). After salidroside treatment, the chronic hypoxia-induced right ventricular hypertrophy and pulmonary arterial remodeling were attenuated, suggesting a protective role played by salidroside in PAH. To explore the potential mechanisms, the apoptosis of PASMCs after salidroside treatment under hypoxia conditions were determined in vivo and in vitro, and also the mitochondria-dependent apoptosis factors, Bax, Bcl-2, cytochrome C, and caspase 9 were examined. The results revealed that salidroside reversed hypoxia-induced cell apoptosis resistance at least partially via a mitochondria-dependent pathway. In addition, salidroside upregulated the expression of adenosine A2a receptor (A2aR) in lung tissues of mice and in PASMCs in vitro after hypoxia exposure. Combined the evidence above, we conclude that salidroside can attenuate chronic hypoxia-induced PAH by promoting PASMCs apoptosis via an A2aR related mitochondria dependent pathway.

Identification of inflammatory response-related molecular mechanisms based on the ATM/ATR/p53 pathway in tumor cells.

Inflammatory response is a crucial factor that affects prognosis and therapeutic effect in tumor cells. Although some studies have shown that inflammation could make DNA more vulnerable to external attacks, resulting in serious DNA damage, the underlying mechanism remains unknown. Then, using tumor necrosis factor α (TNF-α) and lipopolysaccharide (LPS), this research elevated the level of inflammation in cancer cells, and hydrogen peroxide (H2O2) and ultraviolet (UV) were utilized as common reactive oxygen species (ROS)-induced DNA damage agents. We show that either H2O2 or UV achieved a more substantial antiproliferative effect in the inflammation environment compared with H2O2 or UV treatment alone. The inflammation environment enhanced H2O2- or UV-induced cell apoptosis and ROS production. Although the phenomenon that inflammation itself could trigger ROS-dependent DNA damage was well known, the underlying mechanism for the sensitization of inflammation to trigger intense DNA damage via ROS in cancer cells remains unclear. In this study, the inflammation-related genes and the corresponding expression information were obtained from the TCGA and fetched genes associated with inflammatory factors. Screening of thirteen inflammatory-related, including ATM, and prognostic genes. In addition, KEGG analysis of prognostic genes shows that biological processes such as DNA replication. ATM and ATR, which belong to the PI3/PI4-kinase family, can activate p53. Inflammation promotes the vulnerability of DNA by activating the ATM/ATR/p53 pathway, while not affecting the DNA damage repair pathway. In brief, this research suggested that inflammation made DNA vulnerable due to the amplifying H2O2- or UV-induced ROS production and the motoring ATM/ATR/p53 pathway. In addition, our findings revealed that inflammation's motoring of the ATM/ATR/p53 pathway plays a crucial role in DNA damage. Therefore, exploring the mechanism between inflammation and ROS-dependent DNA damage would be extremely valuable and innovative. This study would somewhat establish a better understanding of inflammation, DNA damage, and cancer.

Comprehensive analysis of cuproptosis-related genes in immune infiltration and prognosis in lung adenocarcinoma.

Copper-dependent cell death, called cuproptosis, is connected to tumor development, prognosis, and the immune response. Nevertheless, the function of cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD) remains unknown. This work used R software packages to classify the raw data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases of LUAD patients. Afterward, the connections of the various subgroups, clinical pathological traits, and immune infiltration (IMIF) features with the TME mutation status were explored. Ultimately, a nomogram and calibration curve were developed, aiming at enhancing the clinical application of CRG scores and estimating the survival probability of patients. Moreover, the relationships between cuproptosis and the molecular traits, immune cell infiltration of tumor tissue, prognosis, and clinical treatment of patients were investigated in this work. Subsequently, the CRG score was established to predict overall survival (OS), and its credible predictive ability in LUAD patients was identified. Afterward, a highly credible nomogram was created to contribute to the clinical viability of the CRG score. Furthermore, as demonstrated, gene signatures could be applied in assessing tumor immune cell infiltration, clinical traits, and prognosis. In addition, high tumor mutation burden, immunological activity, and significant survival probability were characterized by low CRG scores, and high CRG scores were related to immunosuppression and stromal pathway activation. The current work also discovered a predictive CRG-related signature for LUAD patients, probably contributing to TME trait clarification and more potent immunotherapy strategy exploration.

Baicalin alleviates bleomycin-induced early pulmonary fibrosis in mice via the mitoKATP signaling pathway.

Bleomycin (BLM), a frequently employed chemotherapeutic agent, exhibits restricted clinical utility owing to its pulmonary toxicity. Meanwhile, baicalin (BA)-an active ingredient extracted from the roots of Scutellaria baicalensis Georgi -has been shown to alleviate BLM-induced pulmonary fibrosis (PF). Hence, the objective of this study was to examine the protective effects of BA in the context of BLM-induced early PF in mice and elucidate the underlying mechanism(s). We established an in vivo BLM (3.5 mg/kg)-induced PF murine model and in vitro BLM (35 µM)-damaged MLE-12 cell model. On Day 14 of treatment, the levels of fibrosis and apoptosis were evaluated in mouse lungs via hydroxyproline analysis, western blotting (COL1A1, TGF-ß, Bax, Bcl-2, cleaved caspase-3), and Masson, immunohistochemical (α-SMA, AIF, Cyto C), and TUNEL staining. Additionally, in vitro, apoptosis was assessed in MLE-12 cells exposed to BLM for 24 h using the Annexin V/PI assay and western blotting (Bax, Bcl-2, cleaved caspase-3, AIF, Cyto C). To elucidate the role of the mitochondrial ATP-sensitive potassium channel (mitoKATP) in the protective effect of BA, we utilised diazoxide (DZX)-a mitoKATP agonist-and 5-hydroxydecanoate sodium (5-HD)-a mitoKATP inhibitor. Results revealed the involvement of mitoKATP in the protective effect of BA in BLM-induced PF. More specifically, mitoKATP activation can attenuate BLM-induced PF progression and mitigate alveolar epithelial type II cell death by reducing mitochondrial ROS, maintaining the mitochondrial membrane potential, and impeding the mitochondrial apoptotic pathway. Collectively, the findings offer pharmacological support to use BA for the treatment or prevention of BLM-induced PF and suggest that mitoKATP might serve as an effective therapeutic target for this condition.

Global, regional, and national burden of chronic respiratory diseases and associated risk factors, 1990-2019: Results from the Global Burden of Disease Study 2019.

Background: The burden of chronic respiratory diseases has changed over the three decades. This study aims to describe the spatiotemporal trends of prevalence, mortality, and disability-adjusted life years (DALY) due to chronic respiratory diseases (CRDs) worldwide during 1990-2019 using data from the Global Burden of Disease Study 2019 (GBD 2019). Methods: The prevalence, mortality, and DALY attributable to CRDs and risk factors from 1990 to 2019 were estimated. We also assessed the driving factors and potentiality for improvement with decomposition and frontier analyses, respectively. Results: In 2019, 454.56 [95% uncertainty interval (UI): 417.35-499.14] million individuals worldwide had a CRD, showing a 39·8% increase compared with 1990. Deaths due to CRDs were 3.97 (95%UI: 3.58-4.30) million, and DALY in 2019 was 103.53 (95%UI: 94.79-112.27) million. Declines by average annual percent change (AAPC) were observed in age-standardized prevalence rates (ASPR) (0.64% decrease), age-standardized mortality rates (ASMR) (1.92%), and age-standardized DALY rates (ASDR) (1.72%) globally and in 5 socio-demographic index (SDI) regions. Decomposition analyses represented that the increase in overall CRDs DALY was driven by aging and population growth. However, chronic obstructive pulmonary disease (COPD) was the leading driver of increased DALY worldwide. Frontier analyses witnessed significant improvement opportunities at all levels of the development spectrum. Smoking remained a leading risk factor (RF) for mortality and DALY, although it showed a downward trend. Air pollution, a growing factor especially in relatively low SDI regions, deserves our attention. Conclusion: Our study clarified that CRDs remain the leading causes of prevalence, mortality, and DALY worldwide, with growth in absolute numbers but declines in several age-standardized estimators since 1990. The estimated contribution of risk factors to mortality and DALY demands the need for urgent measures to improve them. Systematic review registration: http://ghdx.healthdata.org/gbd-results-tool.

Inhibition of pulmonary artery smooth muscle cells via the delivery of curcuminoid WZ35 by Cu-based metal organic frameworks.

Hypoxic pulmonary hypertension (HPH) is a life-threatening disease that occurs due to a lack of oxygen in the lungs, leading to an increase in pulmonary vascular resistance, right ventricular failure, and ultimately death. HPH is a multifactorial disorder that involves multiple molecular pathways, making it a challenge for clinicians to identify effective therapies. Pulmonary artery smooth muscle cells (PASMCs) play a crucial role in HPH pathogenesis by proliferating, resisting apoptosis, and promoting vascular remodelling. Curcumin, a natural polyphenolic compound, has shown potential as a therapeutic agent for HPH by reducing pulmonary vascular resistance, inhibiting vascular remodelling, and promoting apoptosis of PASMCs. Regulation of PASMCs could significantly inhibits HPH. However, curcumin has the disadvantages of poor solubility and low bioavailability, and its derivative WZ35 has better biosafety. Here, Cu-based metal organic frameworks (MOFCu ) was fabricated to encapsulate the curcumin analogue WZ35 (MOFCu @WZ35) for the inhibition of PASMCs proliferation. The authors found that the MOFCu @WZ35 could promote the death of PASMCs. Furthermore, the authors believed that this drug delivery system will effectively alleviate the HPH.

Effects of SASH1 on lung cancer cell proliferation, apoptosis, and invasion in vitro.

The purposes of this study were to investigate the effects of the SASH1 gene on the growth, proliferation, apoptosis, invasiveness, and metastatic potential of lung cancer cells and explore the potential use of SASH1 for the treatment of human lung cancer. The SASH1 gene was cloned into the pcDNA3.1 eukaryotic expression vector, and SASH1 shRNA were designed and constructed. The resulting constructs were transfected into A549 human lung cancer cells, and the changes in the relevant biological characteristics of the cells overexpressing SASH1 and cells with downregulated expression of SASH1 were analyzed using the MTT assay, transwell invasion assay, and flow cytometry. The effects of the SASH1 gene on the expression of cyclin D1, Bcl-2, and MMP-2/9 were also concurrently examined. In the A549 cells from the pcDNA3.1-SASH1 transfected group, cell viability, proliferation, and migration were significantly reduced compared to the control cells (p = 0.039, p = 0.013), and a cell cycle arrest in G1 was observed. The A549 cells transfected with the SASH1 shRNA demonstrated significantly higher cell viabilities, proliferation, and migration compared to the control cells (p = 0.012, p = 0.045). Additionally, the percentage of A549 cells undergoing apoptosis was significantly higher in the pcDNA3.1-SASH1 transfected cells and significantly lower in the SASH1 shRNA transfected cells compared to the control cells (p = 0.010, p = 0.000). The cyclin D1, Bcl-2, and MMP-9/2 protein expression levels were significantly lower in the pcDNA3.1-SASH1-transfected cells and were significantly higher in the SASH1 shRNA-transfected cells than that in the control cells. The SASH1 gene may inhibit A549 cell growth and proliferation as well as promote cellular apoptosis. The overexpression of the SASH1 gene may also be related to the decreased migration of A549 human lung cancer cells.

Detection of pulmonary embolism severity using clinical characteristics, hematological indices, and machine learning techniques.

Introduction: Pulmonary embolism (PE) is a cardiopulmonary condition that can be fatal. PE can lead to sudden cardiovascular collapse and is potentially life-threatening, necessitating risk classification to modify therapy following the diagnosis of PE. We collected clinical characteristics, routine blood data, and arterial blood gas analysis data from all 139 patients. Methods: Combining these data, this paper proposes a PE risk stratified prediction framework based on machine learning technology. An improved algorithm is proposed by adding sobol sequence and black hole mechanism to the cuckoo search algorithm (CS), called SBCS. Based on the coupling of the enhanced algorithm and the kernel extreme learning machine (KELM), a prediction framework is also proposed. Results: To confirm the overall performance of SBCS, we run benchmark function experiments in this work. The results demonstrate that SBCS has great convergence accuracy and speed. Then, tests based on seven open data sets are carried out in this study to verify the performance of SBCS on the feature selection problem. To further demonstrate the usefulness and applicability of the SBCS-KELM framework, this paper conducts aided diagnosis experiments on PE data collected from the hospital. Discussion: The experiment findings show that the indicators chosen, such as syncope, systolic blood pressure (SBP), oxygen saturation (SaO2%), white blood cell (WBC), neutrophil percentage (NEUT%), and others, are crucial for the feature selection approach presented in this study to assess the severity of PE. The classification results reveal that the prediction model's accuracy is 99.26% and its sensitivity is 98.57%. It is expected to become a new and accurate method to distinguish the severity of PE.

A new machine learning model for predicting severity prognosis in patients with pulmonary embolism: Study protocol from Wenzhou, China.

Introduction: Pulmonary embolism (PE) is a common thrombotic disease and potentially deadly cardiovascular disorder. The ratio of clinical misdiagnosis and missed diagnosis of PE is very large because patients with PE are asymptomatic or non-specific. Methods: Using the clinical data from the First Affiliated Hospital of Wenzhou Medical University (Wenzhou, China), we proposed a swarm intelligence algorithm-based kernel extreme learning machine model (SSACS-KELM) to recognize and discriminate the severity of the PE by patient's basic information and serum biomarkers. First, an enhanced method (SSACS) is presented by combining the salp swarm algorithm (SSA) with the cuckoo search (CS). Then, the SSACS algorithm is introduced into the KELM classifier to propose the SSACS-KELM model to improve the accuracy and stability of the traditional classifier. Results: In the experiments, the benchmark optimization performance of SSACS is confirmed by comparing SSACS with five original classical methods and five high-performance improved algorithms through benchmark function experiments. Then, the overall adaptability and accuracy of the SSACS-KELM model are tested using eight public data sets. Further, to highlight the superiority of SSACS-KELM on PE datasets, this paper conducts comparison experiments with other classical classifiers, swarm intelligence algorithms, and feature selection approaches. Discussion: The experimental results show that high D-dimer concentration, hypoalbuminemia, and other indicators are important for the diagnosis of PE. The classification results showed that the accuracy of the prediction model was 99.33%. It is expected to be a new and accurate method to distinguish the severity of PE.

Detection of COVID-19 severity using blood gas analysis parameters and Harris hawks optimized extreme learning machine.

Coronavirus disease-2019 (COVID-19) has made the world more cautious about widespread viruses, and a tragic pandemic that was caused by a novel coronavirus has harmed human beings in recent years. The new coronavirus pneumonia outbreak is spreading rapidly worldwide. We collect arterial blood samples from 51 patients with a COVID-19 diagnosis. Blood gas analysis is performed using a Siemens RAPID Point 500 blood gas analyzer. To accurately determine the factors that play a decisive role in the early recognition and discrimination of COVID-19 severity, a prediction framework that is based on an improved binary Harris hawk optimization (HHO) algorithm in combination with a kernel extreme learning machine is proposed in this paper. This method uses specular reflection learning to improve the original HHO algorithm and is referred to as HHOSRL. The experimental results show that the selected indicators, such as age, partial pressure of oxygen, oxygen saturation, sodium ion concentration, and lactic acid, are essential for the early accurate assessment of COVID-19 severity by the proposed feature selection method. The simulation results show that the established methodlogy can achieve promising performance. We believe that our proposed model provides an effective strategy for accurate early assessment of COVID-19 and distinguishing disease severity. The codes of HHO will be updated in https://aliasgharheidari.com/HHO.html.

Erratum: Astaxanthin prevents against lipopolysaccharide-induced acute lung injury and sepsis via inhibiting activation of MAPK/NF-κB.

[This corrects the article on p. 1884 in vol. 11, PMID: 30972212.].

Multifunctional T cell response in active pulmonary tuberculosis patients.

BACKGROUND: Tuberculosis still threatens human health. We aimed to investigate the T cell immune status and the role of multifunctional T cells in pulmonary tuberculosis patients. METHODS: Thirty active pulmonary tuberculosis (APTB) patients, 30 latent tuberculosis infection (LTBI) patients, 25 cured pulmonary tuberculosis (CPTB) patients and 25 healthy controls (HCs) enrolled in this study. Flow cytometer for detecting T cell phenotype and function. CBA Flex Set was used to measure chemokine. RESULTS: Compared with HCs and LTBI patients, APTB patients had fewer CD4+ T and CD8+ T cells, but the expression of granzyme A, granzyme B and perforin on CD8+ T cells increased. Compared to LTBI and CPTB patients, Mycobacterium tuberculosis-specific CD8+ T cells in APTB patients appeared to be more differentiated CD45RA-CCR7- cells, and there were more multifunctional CD4+ T and CD8+ T cells. Importantly, the frequency of multifunctional CD4+ T cells in the pleural fluid of APTB patients was higher than that of peripheral blood. And the proportion of multifunctional CD4+ T cells expressing the migration receptor CXCR3 in the peripheral blood of APTB patients decreased, while the concentrations of its ligands, chemokine MIG, IP-10 and I-TAC increased significantly in plasma, especially in pleural fluid. CONCLUSIONS: Decreased T lymphocytes in APTB patients may cause compensatory activation of CD8+ T cells. Multifunctional CD4+ T cells in peripheral blood could migrate to the lungs under the action of CXCR3 and associated chemokine. Multifunctional CD4+ T cells and Multifunctional CD8+ T cells were of great significance in monitoring disease treatment.

Investigation of Alpha-Fetoprotein Antibody Modified Fluorescent Magnetic Probe on HepG2 Cell and Cancer Model Mouse.

To construct a dual-targeting (magnetic targeting and antibody targeting) multi-functional magnetic fluorescent liposome probe with a good biocompatibility and high specificity for early liver cancerdiagnosis. 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine-N-[amino(polyethylene glycol)] (DSPE-PEG2000-NH2) and Cyanine7 N-hydroxysuccinimide ester (Cy7-NHS) were measured and reacted for forming DSPE-PEG2000-Cy7. Egg yolk lecithin, cholesterol, DSPE-PEG2000-Cy7 and Fe3O4 were added in orderly into the reaction solution for synthesis of fluorescent ferroferric oxide (Fe3O4) liposome. The Magnetic liposome (MLP) was coupled with Alpha-Fetoprotein (AFP) polyclonal antibody and the ending AFP antibody modified magnetic liposome was analyzed and studied on human hepatoma cell HepG2 and cancer model mouse. The fluorescent ferroferric oxide liposome appeared as a sphericalmorphology and they were about 150 nm in mean hydrodynamic diameter with negative charge. The fluorescent magnetic probe had a little toxic effect on hepG2 cells and increased the specificity liver cancer diagnosis by AFP antibody target imaging in model mouse of liver cancer. In brief, the AFP antibody conjugated fluorescent magnetic probe is a promising multi-functional tool with good biocompatibility and high sensitivity and specificity for clinical cancer diagnosis and therapy.

Continuous tracking of COVID-19 patients' immune status.

BACKGROUND: COVID-19 is threating human health worldwide. We aim to investigate the dynamic changes of immune status in COVID-19 patients with clinical evolution. METHODS: Sixty-one COVID-19 patients (42 mild cases and 19 severe cases, 51 cases without secondary infection as non-infection group and 10 cases with secondary bacterial/fungal infection as infection group) and 52 healthy controls (HCs) were enrolled from our hospital. Leucocyte classification, lymphocyte subsets and cytokines were detected by full-automatic blood cell analyzer and flow cytometer, respectively. RESULTS: Upon admission, eosinophils and lymphocyte subsets decreased significantly, while neutrophils, monocytes, basophils, IL-2, IL-6, IL-10 and IFN-γ increased significantly in COVID-19 patients compared to HCs. CD3+ T and DN (CD3+CD4-CD8-) cells appeared sustained decline, leucocytes, neutrophils and IL-10 showed sustained increase in severe group compared to mild group. Compared with the non-infection group, we observed a depletion of eosinophils, CD3+ T and CD4+ T cells, but leucocytes, neutrophils, IL-6 and IL-10 on the contrary in the infection group. Besides, in severe group of COVID-19 patients, DN cells were negatively correlated with IL-10, and DP (CD3+CD4+CD8+) cells were negatively correlated with IL-6. Lymphocytes, eosinophils, CD3+ T cells, CD4+ T cells, IL-6 and IL-10 all had great diagnostic efficacy (AUC, 0.905-0.975) for COVID-19. The laboratory indicators of COVID-19 patients with improved condition also showed a recovery trend with time. CONCLUSIONS: The immune status of COVID-19 patients is different in each stage, and dynamic monitoring of related indicators can help predict the disease and may avoid cytokine storms.

Astaxanthin prevents against lipopolysaccharide-induced acute lung injury and sepsis via inhibiting activation of MAPK/NF-κB.

BACKGROUND: Endotoxin-induced acute inflammatory diseases such as sepsis, mediated by excessive production of various pro-inflammatory cytokines remain the leading cause of mortality in critically ill patients. Lipopolysaccharide (LPS), the characteristic endotoxin found in the outer membrane of Gram-negative bacteria, can induce the innate immunity system and through Mitogen activated protein kinase (MAPK) and Nuclear Factor-κB (NF-κB), increase the production of inflammatory mediators. Astaxanthin (ASX), a xanthophyll carotenoid, exerts beneficial effects against oxidation, inflammation, and cancer. But poor evidence has been reported that whether it has protective effects on LPS-induced injury. This study aims to investigate the effects of ASX on LPS-induced sepsis and acute lung injury and to demonstrate its mechanisms. METHODS: Mouse prime macrophage (MPM) challenged with LPS were used for in vitro pharmacological activity and mechanistic studies. Inflammatory facors (tumor necrosis factor-alpha and interleukin-6 levels) in MPM were determined. The mouse models of LPS-induced sepsis and acute lung injury administrated with or without the compound were used for in vivo studies. RESULTS: Pre-treatment of MPM with ASX inhibited MAPK/NF-κB signaling pathway, and attenuated LPS-increased inflammatory factors in vitro. In animal models of LPS-induced sepsis and acute lung injury, administration of ASX significantly improved survival and protected lung injury. Subsequently, ASX was shown to suppress LPS-induced inflammatory factors increase, MAPK phosphorylation, and NF-κB activation in vivo. CONCLUSIONS: ASX exerts impressively protective effects on LPS-induced injury in vitro and in vivo. Taken together, it might be used as a potential candidate for clinical sepsis.