Randomized control study of the use of faropenem for treating patients with pulmonary tuberculosis.

OBJECTIVES: Faropenem has antituberculosis activity in vitro but its utility in treating patients with tuberculosis (TB) is unclear. METHODS: We conducted an open-label, randomized trial in China, involving newly diagnosed, drug-susceptible pulmonary TB. The control group was treated with the standard 6-month regimen. The experimental group replaced ethambutol with faropenem for 2 months. The primary outcome was the treatment success rate after 6 months of treatment. Noninferiority was confirmed if the lower limit of a 95% one-sided confidence interval (CI) of the difference was greater than -10%. RESULTS: A total of 227 patients eligible for the study were enrolled in the trial group and the control group in a ratio of 1:1. Baseline characteristics of participants were similar in both groups. In the modified intention-to-treat population, 88.18% of patients in the faropenem group achieved treatment success, and 85.98% of those in the control group were successfully treated, with a difference of 2.2% (95% CI, -6.73-11.13). In the per-protocol population, treatment success was 96.04% in the faropenem group and 95.83% in the control group, with a difference of 2.1% (95% CI, -5.31-5.72). The faropenem group showed noninferiority to the control group in the 6-month treatment success rates. The faropenem group had significantly fewer adverse events (P <0.01). CONCLUSIONS: Our study proved that oral faropenem regimen can be used for the treatment of TB, with fewer adverse events. (Chinese Clinical Trial Registry, ChiCTR1800015959).

Long noncoding RNA SNHG16 targets miR-146a-5p/CCL5 to regulate LPS-induced WI-38 cell apoptosis and inflammation in acute pneumonia.

AIMS: Aberrant expression of the lncRNA small nucleolar RNA host gene 16 (SNHG16) has been researched in multiple cancers and inflammatory diseases. This study was intended to investigate the effect of SNHG16 in vitro model of pneumonia and explore the potential mechanism. MAIN METHODS: The LPS-induced pulmonary injury model was established in WI-38 human lung fibroblasts cells. SNHG16 and miR-146a-5p expression levels were altered by transfection assay and were evaluated by qRT-PCR. Cell viability and apoptosis were respectively assessed by CCK-8 assay and flow cytometry analysis. The combination of miR-146a-5p and SNHG16 were demonstrated by luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull-down assay. Associated inflammatory factors expression levels and productions were determined by qRT-PCR, western blotting and Enzyme-linked immunosorbent (ELISA) assay, respectively. Main proteins related apoptosis, c-Jun N-terminal kinase (JNK) pathway and nuclear factor (NF)-κB pathway were also analyzed by western blotting. KEY FINDINGS: SNHG16 was highly expressed in serum of acute stage pneumonia patients. SNHG16 was up-regulated in LPS-treated WI-38 cell model and SNHG16 knockdown obviously mitigated LPS-induced cell injury by promoting viability, restraining apoptosis and production of inflammatory cytokines. SNHG16 functioned as a competitive endogenous RNA (ceRNA) by efficaciously binding to miR-146a-5p and then restoring CC motif chemokine ligand 5 (CCL5) expression. Besides, miR-146a-5p inhibitor abolished the function of SNHG16 knockdown on cell injury, JNK and NF-κB pathways. SIGNIFICANCE: SNHG16 regulated LPS-induced inflammation injury in WI-38 cells through competitively binding miR-146a-5p with CCL5 further mediating JNK and NF-κB pathways, which sheds novel light on diagnostics and therapeutics in pneumonia.

Knockdown XIST alleviates LPS-induced WI-38 cell apoptosis and inflammation injury via targeting miR-370-3p/TLR4 in acute pneumonia.

Pneumonia is an inflammatory disease that occurs in the lungs associated with pathogens or other factors. It has been well established that long noncoding RNA X inactivate-specific transcript (XIST) is involved in several cancers. The present study focused on the effect and detailed mechanism of XIST in lipopolysaccharide (LPS)-induced injury in pneumonia. Here, XIST was silenced by transfection with XIST-targeted siRNA, and then, mRNA expression, cell viability, apoptosis, and protein expression were, respectively, assessed by qRT-PCR, CCK-8, flow cytometry, and Western blotting. Luciferase reporter, RIP, and RNA pull-down assays were used to detect the combination of miR-370-3p and XIST. Besides, the tested proinflammatory factors were analysed by qRT-PCR and Western blot, and their productions were quantified by ELISA. The results showed that XIST expression was robustly increased in serum of patients with acute-stage pneumonia and LPS-induced WI-38 human lung fibroblasts cells. Functional analyses demonstrated that knockdown of XIST remarkably alleviated LPS-induced cell injury through increasing cell viability and inhibiting apoptosis and inflammatory cytokine levels. Mechanistically, XIST functioned as a competitive endogenous RNA (ceRNA) by effectively binding to miR-370-3p and then restoring TLR4 expression. More importantly, miR-370-3p inhibitor abolished the function of XIST knockdown on cell injury and JAK/STAT and NF-κB pathways. Taken together, XIST may be involved in progression of cell inflammatory response, and XIST/miR-370-3p/TLR4 axis thus may shed light on the development of novel therapeutics to the treatment of acute stage of pneumonia. SIGNIFICANCE OF THE STUDY: Our study demonstrated that XIST was highly expressed in patients with acute stage of pneumonia. Knockdown of XIST remarkably alleviated LPS-induced cell injury through increasing cell viability and inhibiting apoptosis and inflammatory cytokine levels through regulating JAK/STAT and NF-κB pathways.

Suppression of cyclooxygenase 2 increases chemosensitivity to sesamin through the Akt­PI3K signaling pathway in lung cancer cells.

Safe, affordable and efficacious agents are urgently required for cancer prevention. Sesamin, a lipid­soluble lignan from sesame (Sesamum indicum) displays anticancer activities through an unknown mechanism. In the present study, the anticancer activity of sesamin via cyclooxygenase 2 (COX2) was investigated in lung cancer. Quantitative polymerase chain reaction was performed to determine the mRNA expression levels of COX2 in cells, while western blot analysis was used to determine its protein expression levels. Cell proliferation was evaluated by Cell Counting Kit­8 assay, while apoptosis and cell cycle analyses were conducted by flow cytometry. The results indicated that COX2 expression was upregulated in lung cancer cell lines compared with human normal lung epithelial cell line BEAS­2B and sesamin was demonstrated to decrease the levels of COX2, inhibit the proliferation of lung cancer cells and promote their apoptosis in a concentration­dependent manner. Furthermore, decreased COX2 expression potentiated sesamin­induced apoptosis and G1­phase arrest, which was correlated with the suppression of gene products associated with cell apoptosis (Bcl­2 and Bax) and the cell cycle (cyclin E1). In addition, cotreatment with the COX2 inhibitor CAY10404 and sesamin downregulated the expression of downstream molecules of COX2 [including interleukin (IL)1ß, IL6 and tumor necrosis factor α] compared with CAY10404 or sesamin alone. Furthermore, cotreatment with sesamin and CAY10404 markedly reduced the levels of phosphorylated protein kinase B (pAkt) and phosoinositide 3 kinase (PI3K) in three lung cancer cell lines. PI3K expression was observed to be under the control of COX2, possibly forming a negative feedback loop. In addition, PI3K depletion induced apoptosis and G1­phase arrest in A549 cells. These results suggested that sesamin blocked the pAkt­PI3K signaling pathway by downregulating the expression of COX2, therefore resulting in cell cycle arrest and increased apoptosis in vitro. In conclusion, inhibition of COX2 increased the sensitivity of lung cancer cells to sesamin by modulating pAkt­PI3K signaling. These results may aid the development of more selective agents to overcome cancer.

Vitamin D3 as adjunctive therapy in the treatment of depression in tuberculosis patients: a short-term pilot randomized double-blind controlled study.

OBJECTIVE: We aimed to evaluate whether high-dose cholecalciferol has beneficial effects on depression in pulmonary tuberculosis (PTB) patients. METHODS: This pilot, randomized, and double-blind trial enrolled 123 recurrent PTB patients (aged ≥18 years) meeting Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria of major depressive disorder from four hospitals in Southeast China. Patients were randomly assigned to 8-week oral treatment with 100,000 IU/week cholecalciferol (Vit D group) or a matching placebo (control group). The primary outcome was treatment response, defined as a 50% reduction in symptoms and change in scores of the Chinese version of Beck Depression Inventory (BDI) from baseline to 8 weeks. Relative risks of depression were estimated using multivariable logistic regression. RESULTS: Finally, 120 patients were enrolled, including 56 test patients and 64 controls. After 8 weeks, the treatment response or BDI scores did not differ significantly between groups. Multivariate logistic regression showed that BDI scores were not significantly improved in the Vit D group after adjustment for age, time to first negative smear, or 25-hydroxyvitamin D level. CONCLUSION: The use of high-dose Vit D3 supplementation may not be warranted for reducing depressive symptoms in the PTB population. Nevertheless, this finding should be validated by further large-scale studies according to different kinds of depression or Vit D receptor polymorphism genotype.

Short-course Regimen for Subsequent Treatment of Pulmonary Tuberculosis: A Prospective, Randomized, Controlled Multicenter Clinical Trial in China.

PURPOSE: We designed a prospective, multicenter, randomized, controlled study to assess a 5-month regimen compared with the standard regimen on previously treated patients with pulmonary tuberculosis (TB). METHODS: We enrolled 917 sputum smear-positive patients undergoing additional treatment in 27 major tuberculosis hospitals in China. Patients were randomly assigned to a test group (n = 626)treated with a 5-month regimen of moxifloxacin, pasiniazid, rifabutin, ethambutol, and pyrazinamide or a reference group (n = 291) treated with an 8-month regimen of isoniazid, rifampicin, and streptomycin. All patients with a favorable response were followed up for 5 years after the end of treatment. FINDINGS: Of the study patients, 61 in the test group and 19 in the reference group had multidrug-resistant (MDR) TB. The treatment success rate in the study group was 74.12%, which was significantly higher than the 67.70% in the reference group (P = 0.04), whereas the treatment success rate of patients with MDR-TB was not significantly different between the test and reference groups (70.5% vs 63.1%, P =0.79). The adverse effects rates in the test and reference groups were 7.4% and 3.1%, respectively (P = .01). The difference in the TB recurrence rates between the group arm (9.6%) and the reference group (21.8%) was statistically significant (P < 0.001). IMPLICATIONS: The moxifloxacin, pasiniazid, rifabutin, ethambutol, and pyrazinamide test regimen yielded higher success and lower recurrence rates than the currently recommended isoniazid, rifampicin, and streptomycin regimen, but the rate of adverse effects was higher. ClinicalTrials.gov identifier: NCT02331823.

[Analysis of pathogen distribution and drug resistance in coal workers' pneumoconiosis associated with pneumonia].

OBJECTIVE: To investigate the pathogen distribution and drug resistance in coal workers' pneumoconiosis associated with pneumonia and to provide a scientific basis for early guidance for rational clinical application of antibacterial agents. METHODS: Seventy-six patients with coal workers' pneumoconiosis associated with pneumonia who were admitted to our hospital from June 2011 to June 2014 were enrolled as subjects. The sputum specimens were aseptically collected for bacterial culture and drug sensitivity tests. RESULTS: In 245 sputum specimens collected from 76 patients, a total of 218 strains of pathogens, including 163 strains of Gram-negative bacilli (74.77%), 39 strains of Gram-positive cocci (17.89%), and 16 strains of fungi (7.34%) were isolated by bacteriological tests. The main Gram-negative bacilli had high rates of resistance to amoxicillin/clavulanic acid, ampicillin, cotrimoxazole, cefotaxime, and aztreonam, and were sensitive to amikacin, imipenem, and meropenem. The main Gram-positive cocci had high rates of resistance to penicillin, erythromycin, amoxicillin/clavulanic acid, ampicillin, cefotaxime, and clindamycin, and were sensitive to vancomycin and teicoplanin. CONCLUSION: The main pathogens in these patients with coal workers' pneumoconiosis associated with pneumonia are Gram-negative bacilli, which are highly resistant to common clinically used antibacterial agents. The pathogen distribution and drug resistance should be well understood, and the antibacterial agents should be rationally selected according to the results of drug sensitivity tests.