Talaromyces marneffei and nontuberculous mycobacteria co-infection in HIV-negative patients.

To describe the clinical features and the risk factors for nontuberculous mycobacteria (NTM) and Talaromyces marneffei (TM) co-infections in HIV-negative patients. A multicenter retrospective study in 13 hospitals, and a systematic literature review were performed of original articles published in English related to TM/NTM co-infections. HIV-negative patients with TM and NTM co-infections comprised Group 1; TM-only infection Group 2; NTM-only infection Group 3; and healthy volunteers Group 4. Univariate logistic analysis was used to estimate the potential risk factors of TM/NTM co-infections. A total of 22 cases of TM and NTM co-infections were enrolled. Of these, 17 patients (77.3%) had a missed diagnosis of one of the TM or NTM pathogens. The anti-IFN-γ autoantibodies (AIGAs) titer, white blood cell (WBC), neutrophil counts (N), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), globulin, and immunoglobulin G (IgG) levels of Group 1 were higher than those of the other groups, whereas the levels of CD4+T cells was lower than those of other groups. There was a significant negative correlation between the AIGA titers and the number of CD4+T cells (P < 0.05). Factors including the ratio of the actual values to the cut-off values of AIGAs, WBC, N, HGB, CD4+T cells, IgG, IgM, IgA, serum globulin, ESR, and CRP were taken as potential risk factors for TM and NTM co-infection. Most patients with TM and NTM co-infection had a missed diagnosis of one of the TM or NTM pathogens. The levels of AIGAs, WBC, N, ESR, and CRP in TM and NTM co-infections were remarkably higher than in mono-infection. High-titer AIGAs may be a potential risk factor and susceptibility factor for co-infection of TM and NTM in HIV-negative hosts.

Differential DAMP release was observed in the sputum of COPD, asthma and asthma-COPD overlap (ACO) patients.

Asthma-COPD overlap (ACO) has been under intensive focus; however, the levels of damage-associated molecular patterns (DAMPs) that can activate the innate and adaptive immune responses of ACO are unknown. The present study aimed to examine the levels of some DAMPs in asthma, COPD, and ACO and to identify the associations between clinical characteristics and DAMPs in ACO. Sputum from subjects with asthma (n = 87) or COPD (n = 73) and ACO (n = 68) or from smokers (n = 62) and never-smokers (n = 62) was analyzed for high mobility group protein B1 (HMGB1), heat shock protein 70 (HSP70), LL-37, S100A8, and galectin-3 (Gal-3). The concentration of HMGB1, HSP70, LL-37, and S100A8 proteins in sputum from ACO patients was significantly elevated, whereas that of Gal-3 was reduced, compared to that of smokers and never-smokers. The levels of HMGB1 and Gal-3 proteins in ACO patients were elevated compared to those in asthma patients. The sputum from ACO patients showed an increase in the levels of LL-37 and S100A8 proteins compared to that of asthma patients, whereas the levels decreased compared to those of COPD patients. The concentrations of HMGB1, HSP70, LL-37, and S100A8 proteins in the sputum of 352 participants were negatively correlated, whereas the levels of Gal-3 were positively correlated, with FEV1, FEV1%pred, and FEV1/FVC. Sputum HMGB1 had a high AUC of the ROC curve while distinguishing ACO patients from asthma patients. Meanwhile, sputum LL-37 had a high AUC of the ROC curve in differentiating asthma and COPD. The release of sputum DAMPs in ACO may be involved in chronic airway inflammation in ACO; the sputum HMGB1 level might serve as a valuable biomarker for distinguishing ACO from asthma, and the sputum LL-37 level might be a biomarker for differentiating asthma and COPD.

High mobility group protein B1 (HMGB1) interacts with receptor for advanced glycation end products (RAGE) to promote airway smooth muscle cell proliferation through ERK and NF-κB pathways.

BACKGROUND: High-mobility graoup box protein 1 (HMGB1) has been shown to mediate a wide range of pathologic responses by interacting with RAGE (receptor for advanced glycation endproducts) and TLRs (Toll-like receptors). Our previous study showed that HMGB1 has been involved in pathogenesis of airway remodeling in an allergen-induced chronic mice asthma model. Increased airway smooth muscle (ASM) mass is a vital feature of airway remodeling. OBJECTIVE: To evaluate the effect of HMGB1 on proliferation of ASMs and the underlying mechanisms. METHODS: Rat airway smooth muscle cells (RASMs) were obtained by primary explant techniques. We investigated the effect of HMGB1 on the proliferation of RASMs. To identify which receptors and signaling pathways be involved in proliferation of RASMs, we performed western blot and CCK-8 assay by specific receptor blockade and inhibition of MAPK (p38, JNK and ERK) and NF-κB signaling pathways. RESULTS: HMGB1 stimulated RASMs proliferation in a dose- and time-dependent manner and also increased proliferating cell nuclear antigen (PCNA) and RAGE expression of RASMs. The inhibitor of RAGE, but not TLR2 and TLR4, reversed HMGB1-induced RASM proliferation and PCNA expression. Incubation of RASMs with HMGB1 caused a rapid increase in P65 and ERK phosphorylation. RASM proliferation and PCNA expression toward HMGB1 were significantly inhibited by the inhibitors of ERK and NF-κB. CONCLUSION: HMGB1 induces proliferation of RASMs through a RAGE-dependent activation of ERK and NF-κB signaling pathways.

Elevated S100A4 in asthmatics and an allergen-induced mouse asthma model.

The elevated S100A4 level has been found in some inflammatory diseases. However, the expression and role of S100A4 in asthma is unknown. The expression of S100A4 in induced sputum and plasma from healthy control and asthmatics were assessed by ELISA. Then an allergen-induced asthma mouse model treatment with anti-S100A4 antibody was used to explore the role of S100A4 in the pathogenesis of asthma. The S100A4 levels in sputum not in plasma in asthmatics were significantly increased than those of healthy controls and were negatively correlated with some lung function parameters and were positively correlated with sputum eosinophilia and lymphocyte. The expression of S100A4 in the lung as well as in BALF were also significantly higher in the asthma mouse model and treatment with anti-S100A4 antibody exhibited reductions in inflammatory cell accumulation, inflammatory mediators, and airway hyper-responsiveness. We further showed that LY294002, a specific inhibitor of PI3K, markedly decreased S100A4 expression in lung and S100A4 secretion in BALF in asthmatic mice. In conclusion, these data demonstrated that S100A4 may be involved in the pathogenesis of airway inflammation in asthma.

Rosiglitazone reduces fatty acid translocase and increases AMPK in skeletal muscle in aged rats: a possible mechanism to prevent high-fat-induced insulin resistance.

BACKGROUND: As an agonist of peroxisome proliferator-activated receptor-gamma (PPARγ), rosiglitazone can prevent acute fatty acid-induced insulin resistance in rats, however, the precise mechanisms by which rosiglitazone alleviates insulin resistance induced by high-fat diet need to be further investigated. METHODS: Wistar rats aged 23-24 weeks were divided into three groups: (1) aged control group (OC), (2) high-fat diet (HF) group and (3) high-fat diet plus rosiglitazone maleate tablets (HF + Rosi) treatment group (n = 20 in each group). Insulin sensitivity was evaluated by conscious hyperinsulinemic-euglycemic clamp technique. mRNA levels of fatty acid translocase (FAT/CD36), AMP-activated protein kinase α1 (AMPKα1), AMPKα2 and acetyl CoA carboxylase (ACC) of rat skeletal muscle were determined using real-time PCR, while muscle carnitine palmitoyltransferase-1 (CPT-1ß) was determined using semi-quantitative PCR. Protein expression levels of FAT/CD36, AMPK phosphorylation (reflecting AMPK activity), P-ACC (inversely related with ACC activity) and muscle CPT-1M in rat skeletal muscles were measured using Western blotting. RESULTS: Aged rats fed by diet rich in fat for more than 8 weeks led to significant increases of plasma lipids, skeletal muscle intramuscular triglyceride and long-chain fatty acyl-CoA (LCACoA) compared to aged rats fed by normal chow diet (OC) (P < 0.05), which might correlate with the lower (reduced by 42.4%) whole body insulin sensitivity in HF rats. FAT/CD36 protein concentrations and mRNA levels increased in untreated HF aged rats (P < 0.01) and high-fat diet induced a significant decrease in P-AMPK, P-ACC, CPT-1M protein concentrations and AMPKα2 and CPT-1ß mRNA levels in rat skeletal muscles (P < 0.05). No change in AMPKα1 mRNA levels was observed in the HF group. CONCLUSION: High-fat diet in aged rats results in a lipid accumulation and subsequent insulin resistance, while rosiglitazone can alleviate the insulin resistance by reducing fatty acid uptake as well as enhancing lipometabolism.