MicroRNA-99b Regulates Bacillus Calmette-Guerin-Infected Immature Dendritic Cell-Induced CD4+ T Cell Differentiation by Targeting mTOR Signaling.

This study aimed to elucidate the mechanisms by which microRNA-99b (miR-99b) regulates CD4+ T cell differentiation induced by Bacillus Calmette-Guerin (BCG)-infected immature dendritic cells (imDCs). Levels of miR-99b, interferon-gamma (IFN-γ), Foxp3, interleukin (IL)-10, IL-17, IL-23, and ROR-γt were assessed. Effects of miR-99b inhibition and mechanistic target of rapamycin (mTOR) agonist on Th17/Treg cell ratio and cytokine levels (IL-6, IL-17, IL-23) were studied. Expression of mTOR, S6K1, and 4E-BP1 related to miR-99b was analyzed. BCG-infected imDCs led to CD4+ T cell differentiation and altered levels of IFN-γ, Foxp3, IL-10, miR-99b, IL-17, IL-23, and ROR-γt. Inhibition of miR-99b increased the Th17/Treg cell ratio in CD4+ T cells co-cultured with BCG-infected imDCs, and this effect was further enhanced by the mTOR agonist. Additionally, the miR-99b inhibitor elevated the levels of IL-6, IL-17, and IL-23 when CD4+ T cells were co-cultured with BCG-infected imDCs, and the mTOR agonist further amplified this increase. Notably, miR-99b negatively regulated mTOR signaling, as the miR-99b inhibitor upregulated the expression levels of mTOR, S6K1, and 4E-BP1 while decreasing miR-99b. It was concluded that miR-99b modulates CD4+ T cell differentiation via mTOR pathway in response to BCG-infected im-DCs. Inhibiting miR-99b affects Th17/Treg ratio and pro-inflammatory cytokines, potentially impacting tuberculosis immunotherapies.

Identification of the key genes of tuberculosis and construction of a diagnostic model via weighted gene co-expression network analysis.

BACKGROUND: Tuberculosis (TB) is an infectious disease with high mortality, and mining key genes for TB diagnosis is vital to raise the survival rate of patients. METHODS: The whole microarray datasets GSE83456 (training set) and GSE19444 (validation set) of TB patients were downloaded from the Gene Expression Omnibus (GEO) database. Differential expression was conducted on genes between TB and normal samples (unconfirmed TB) in GSE83456 to yield TB-related differentially expressed genes (DEGs). DEGs were subjected to weighted gene co-expression network analysis (WGCNA) and clustered to form distinct gene modules. The immune scores of 25 kinds of immune cells were obtained by single-sample gene set enrichment analysis (ssGSEA) of TB samples, and Pearson correlation analysis was carried out between the 25 immune scores and diverse gene modules. The gene modules significantly associated with immune cells were retained as Target modules. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the genes in the modules (p-value <0.05). The protein-protein interaction (PPI) network was established utilizing the STRING database for genes in the Target module, and the selected key genes were intersected with immune-related genes in the ImmPort database. The obtained immune-related module genes were used for subsequent least absolute shrinkage and selection operator (LASSO) regression analysis and diagnostic models were constructed. Finally, the receiver operating characteristic (ROC) curve was utilized to validate the diagnostic model. RESULTS: The turquoise and yellow modules had a high correlation with macrophages. LASSO regression analysis of immune-related genes in TB was carried on to finally construct a 5-gene diagnostic model composed of C5, GRN, IL1B, IL23A, and TYMP. As demonstrated by the ROC curves, the diagnostic efficiency of this diagnostic model was 0.957 and 0.944 in the training and validation sets, respectively. Therefore, the immune-related 5-gene model had a good diagnostic function for TB. CONCLUSION: We identified 5 immune-related diagnostic markers that may play an important role in TB, and verified that this immune-related key gene model had a good diagnostic performance.

Interleukin 4 gene polymorphisms and the risk of tuberculosis: A meta-analysis.

BACKGROUND: Interleukin-4 (IL-4) is implicated in the progression of tuberculosis (TB); however, these results remain controversial. OBJECTIVES: This meta-analysis examined the relationship between IL and 4 polymorphisms (-589C/T, +4221C > A, and -33C/T) and the risk of TB. METHODS: A retrospective database analysis was conducted using the CNKI and PubMed databases. Using fixed- and random-effects models, we calculated the combined odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We identified 14 articles related to this topic, and theresultsshowed that the IL-4 -589C/T polymorphism didnotinfluencethe risk of TB. However,in subgroupanalyses we found that the IL-4 -589C/T polymorphism was associated with the risk of TB inCaucasians (recessive modelOR = 2.54, 95% CI = 1.30-4.96). In our study, the IL-4--33C/T polymorphism was not associated with the risk of TB. The IL-4 + 4221C > A polymorphism was associated with the risk of TB (recessive model: OR = 1.40, 95% CI = 1.07-1.83). CONCLUSION: This meta-analysis showed that the IL-4 -589C/T polymorphism was associated with TB risk in Caucasian populations, and the IL-4 + 4221C > A polymorphism is associated with TB risk.

Elevated urine albumin-to-creatinine ratio increases the risk of new-onset heart failure in patients with type 2 diabetes.

BACKGROUND: Although albuminuria has been linked to heart failure in the general population, the relationship between urine albumin-to-creatinine ratio (uACR) and heart failure in type 2 diabetes patients is not well understood. We aimed to investigate the relationship between uACR and new-onset heart failure (HF) in type 2 diabetics. METHODS: We included 9287 Chinese participants with type 2 diabetes (T2D) but no heart failure (HF) who were assessed with uACR between 2014 and 2016. The participants were divided into three groups based on their baseline uACR: normal (< 3 mg/mmol), microalbuminuria (3-30 mg/mmol), and macroalbuminuria (≥ 30 mg/mmol). The relationship between uACR and new-onset HF was studied using Cox proportional hazard models and restricted cubic spline. The area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to see if incorporating uACR into existing models could improve performance. RESULTS: 216 new-onset HF cases (2.33%) were recorded after a median follow-up of 4.05 years. When compared to normal uACR, elevated uACR was associated with a progressively increased risk of new-onset HF, ranging from microalbuminuria (adjusted HR, 2.21; 95% CI 1.59-3.06) to macroalbuminuria (adjusted HR, 6.02; 95% CI 4.11-8.80), and 1 standard deviation (SD) in ln (uACR) (adjusted HR, 1.89; 95% CI 1.68-2.13). The results were consistent across sex, estimated glomerular filtration rate, systolic blood pressure, and glycosylated hemoglobin subgroups. The addition of uACR to established HF risk models improved the HF risk prediction efficacy. CONCLUSIONS: Increasing uACR, even below the normal range, is an independent risk factor for new-onset HF in a type 2 diabetic population. Furthermore, uACR may improve HF risk prediction in community-based T2D patients.

Hsa_circ_0001204 modulates inflammatory response of macrophages infected by Mycobacterium tuberculosis via TLR4/NF-κB signalling pathway.

Circular RNAs (circRNAs) play a vital role in the regulation of Mycobacterium tuberculosis (M.tb) by macrophages. In this project, the potential role of hsa_circ_0001204 in M.tb-infected macrophages is explored. Hsa_circ_0001204 was determined in the patients with tuberculosis (TB) and M.tb-infected macrophages. Its effect on the survival of M.tb and the apoptosis and inflammation of M.tb-infected macrophages was evaluated. Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signalling was detected by western blotting and immunofluorescence. TB patients and M.tb-infected THP-1 cells showed the significant downregulation of hsa_circ_0001204. Upregulating hsa_circ_0001204 reduced M.tb survival and suppressed the apoptosis and inflammatory response of THP-1 cells. The TLR4/NF-κB signalling pathway could be inhibited by hsa_circ_0001204 overexpression, which was activated by M.tb-infection. Hsa_circ_0001204 confers protective effects in M.tb-infected THP-1 cells, at least partly via the inhibition of TLR4/NF-κB signalling pathway.

Performance evaluation and clinical validation of optimized nucleotide MALDI-TOF-MS for mycobacterial identification.

Objective: To evaluate the performance and validate the diagnostic value of a nucleotide matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS) with the analysis process optimized in identification of mycobacterium species. Methods: The optimized analysis process was used for mycobacterial identification in the nucleic MALDI-TOF-MS. 108 samples were used for assessing the performance of nucleic MALDI-TOF-MS, including 25 reference standards, 37 clinical isolates, 37 BALF, and 9 plasmids. The BALF of 38 patients suspected of pulmonary mycobacterial infection was collected for validation. Clinical etiological diagnosis was used as the gold standard to evaluate the diagnostic value of nucleotide MALDI-TOF-MS. Results: The sensitivity, specificity, and accuracy of the nucleotide MALDI-TOF-MS in mycobacterial identification were 96.91%, 100% and 97.22%, respectively, and the limit of detection for mycobacterium tuberculosis (MTB) was 50 bacteria/mL. Among 38 patients suspected of pulmonary mycobacterial infection, 33 were diagnosed with pulmonary tuberculosis infection, and 5 with non-mycobacterial infection. In clinical validation, the positive rates of MALDI-TOF-MS, Xpert MTB/RIF, culture and AFS in BALF of patients diagnosed with tuberculosis infection were 72.7%, 63.6%, 54.5% and 27.3%, respectively. The sensitivity/specificity of MALDI-TOF-MS, Xpert, culture and AFS in diagnosing MTB were 72.7%/100%, 63.6%/100%, 54.5%/100%, 27.3%/100%, with the areas under the curve of 0.864, 0.818, 0.773, and 0.636, respectively. Conclusion: Optimized nucleotide MALDI-TOF-MS has satisfactory sensitivity, specificity and low LOD in the identification of mycobacteria, which may serve as a potential assay for mycobacterial identification.

IL-18 polymorphisms and tuberculosis susceptibility: a meta-analysis.

OBJECTIVE: To investigate the association between IL-18 polymorphisms and Tuberculosis(TB). MATERIALS AND METHODS: We searched PubMed and Embase databases, and conducted a meta-analysis using 4 models. Data were extracted from the studies by two independent reviewers. Statistical analysis was performed using STATA 12.0 software. RESULTS: Five qualified studies with a total of 1293 TB patients and 1724 controls were included. There was no significant association between the IL-18 -607C>A polymorphism and TB risk in the total population(AA vs CC: OR=1.27,95% CI=0.82-1.96;-CA vs CC:OR=1.06,95% CI=0.89-1.26; Dominant model: OR =1.09, 95% CI =0.83-1.43; Recessive model:OR=1.23, 95% CI=0.92-1.65). For IL-18 -137G>C polymorphism, lack of an association was also found(GG vs CC: OR=1.42,95% CI=0.78-2.58;GC vs CC:OR=1.16,95% CI=0.62-2.16; Dominant model: OR =1.34,95% CI=0.74-2.43;Recessive model:OR=0.96,95%-CI=0.26-3.56). CONCLUSION: The present meta-analysis found no evidence for IL-18 -607C>A and -137G>C polymorphisms as risk factors for TB. Further large-scale and well-designed articles are still needed to validate this result.

A randomized study of prourokinase during primary percutaneous coronary intervention in acute ST-segment elevation myocardial infarction.

OBJECTIVES: To evaluate the efficacy and safety of intracoronary administration of prourokinase via balloon catheter during primary percutaneous coronary interventions (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI). METHODS: Acute STEMI patients underwent primary PCI were randomly divided into two groups: intracoronary prourokinase (IP) group (n = 118) and control group (n = 112). During primary PCI, prourokinase or saline were injected to the distal end of the culprit lesion via balloon catheter after balloon catheter dilatation. Demographic and clinical characteristics, infarct size, myocardial reperfusion, and cardiac functions were evaluated and compared between two groups. Hemorrhagic complications and MACE occurred in the 6-months follow up were recorded. RESULTS: No significant differences were observed between two groups with respect to baseline demographic, clinical, and angiographic characteristics (P > 0.05). In IP group, more patients had complete ST segment resolution (>70%) compared with control group (P < 0.05). Patients in IP group showed lower levels of serum CK, CK-MB and TnI, and a much higher myocardial blood flow (MBF) than those in control group (P < 0.05). No significant differences of TIMI major or minor bleeding complications were observed between the two groups (P > 0.05). At 6-months follow-up, there was a trend that patients in the IP group had a less chance to have MACE, though it was not statistically different (8.5% vs 12.5%, P > 0.05). CONCLUSIONS: Intracoronary administration of prourokinase via balloon catheter during primary PCI effectively improved myocardial perfusion in STEMI patients.

[Effects of electroacupuncture of low frequency on heroin-seeking behavior and FosB protein expression in relative brain regions].

OBJECTIVE: To observe effects of electroacupuncture (EA) of low frequency on heroin-seeking behavior and FosB protein expression in relative brain regions so as to explore the mechanism of EA. METHODS: Rat model of relapsing into heroin was established with progressive fixed ratio program, and model rats were randomly divided into 3 groups: a "Sanyinjiao" needle-retention control group, a low frequency and weak EA group, and a low frequency and strong EA group. Heroin-seeking behavior was elicited by conditional clue and small dose of heroin; FosB protein expression was investigated with immunohistochemical technique. RESULTS: After treatment, the heroin-seeking behavior induced by conditional clue decreased in the needle-retention control group and the weak EA group, and the heroin-seeking behavior induced by small dose of heroin in the weak EA group significantly reduced as compared with the control group, and FosB protein expression in the nucleus accumbens septi, globus pallidus, basolateral amygdaloid nucleus significantly decreased in the weak EA group, and did not significantly change in the strong EA group; the activity induced by heroin increased as compared with those in the control group and the weak EA group. CONCLUSION: EA of low frequency and low intensity can cure the heroin-seeking behavior, which is correlated with regulating nervous adaptation of nucleus accumbens septi, basolateral amygdaloid nucleus, etc..