Various investigations have expanded the views that tuberculosis is an important risk factor for lung cancer occurrence. Lung cancer originates from chronic inflammation and infection. It is becoming clearer that Mycobacterium tuberculosis (M.tb) in tuberculosis patients meticulously schemes multiple mechanisms to induce tumor formation and is indispensable to participate in the occurrence of lung cancer. In addition, some additional factors such as age, sex and smoking, accelerate the development of lung cancer after Mycobacterium tuberculosis infection. The clarification of these insights is fostering new diagnoses and therapeutic approaches to prevention of the patients developing from tuberculosis into lung cancer.

Introduction: Sepsis is characterized by an endotoxin tolerance phenotype that occurs in the stage of infection. Persistent bacterial infection can lead to immune cell exhaustion. Triad3A, an E3 ubiquitin ligase, negatively regulates its activation by TLR4. However, the effect of Triad3A on endotoxin tolerance and bactericidal ability in the state of endotoxin tolerance remains unclear.Methods: Using single dose LPS and repeated LPS stimulated macrophage cell lines at indicated times, we investigated miR‐191, Tirad3A, TRAF3, TLR4, p‐P65, TNF‐α, IL‐1β, and iNOS expression, the effect of miR‐191 on Triad3A and TRAF3, gene loss‐of‐function analyses, the effect of Triad3A on TLR4, p‐P65, cytokine, and mycobactericidal activity in endotoxin tolerant cells infected with Mycobacterium marinum.Results: Here we found that Triad3A is involved in regulating endotoxin tolerance. Our result also displayed that miR‐191 expression is downregulated in macrophages in the state of endotoxin tolerance. miR‐191 can directly bind to Triad3A and TRAF3. Additionally, knockdown of Triad3A can reverse the effect of decreasing TNF‐α and IL‐1β in endotoxin tolerant macrophages. Furthermore, we demonstrated that the TLR4‐NF‐κB‐NO pathway was associated with Triad3A and responsible for the killing of intracellular mycobacteria in a tuberculosis sepsis model.Conclusions: These results provide new insight into the mechanisms of Triad3A induced tolerogenic phenotype in macrophages, which can help the better comprehension of the pathogenesis involved in septic shock with infection of Mycobacterium tuberculosis, and suggest that Triad3A may be a potential drug target for the treatment of severe septic tuberculosis.

Hepatic stellate cell (HSC) activation is the key step in liver fibrogenesis characterized by excessive extracellular matrix (ECM) accumulation, which is based on fibrogenic factors-induced changes in gene expression in HSCs. The post-transcriptional gene-expression regulation plays a crucial role in regulation of gene expression by controlling mRNA fate through RNA binding proteins (RBPs), RBPs are essentially involved in the process of HSC activation and liver fibrogenesis. Since the activated HSCs possess the characteristics of neuron and the roles of multifunctional polypyrimidine tract binding protein 1 (PTBP1), a key RBP in inhibiting neuron differentiation, in HSC activation and liver fibrosis are elusive, this research aimed to investigate the effects of PTBP1 on HSC activation and liver fibrosis. The study employed RNA sequencing, targeted over-expression of Ptbp1, Ptbp1 gene-knockdown mice, different mouse model of liver fibrosis, and liver samples from clinical patients. Ptbp1 silencing in HSCs in vitro led to an increase in the expression of many pro-fibrotic genes, including at least the most potent fibrogenic factors, fibrogenic factor receptors, signal transducer, and ECM, but caused a decrease in the expression of pro-apoptotic genes and transcriptional factor Srebp1c, a key one to inhibiting HSC activation. Ptbp1 knockdown in mouse upregulated the expression of pro-fibrotic genes and enhanced HSC activation as well as liver fibrosis. Targeted over-expression of Ptbp1 in HSCs in the model of liver fibrosis further confirmed the effects of PTBP1 on the pro- and anti-fibrotic gene expression in HSCs, HSC activation, and liver fibrosis. Ptbp1 could bind to Srebp1c mRNA, thus inhibiting its degradation. PTBP1 also blocked PI3K/Akt pathway in HSCs. Its levels were reduced in the activated HSCs in livers from mice and clinical patients. This research demonstrated a previously unrecognized inhibitory effect of the multifunctional PTBP1 on HSC activation and liver fibrogenesis and the underlying mechanisms were involved in PTBP1 regulation of the important pro- or anti-fibrotic genes. Given that PTBP1 targeted lots of important pro- and anti-fibrotic genes, PTBP1 may serve as a potential therapeutic strategy for treatment of liver fibrosis.

Background: Unlike smear-positive tuberculosis (TB) which is more easily diagnosed due to the presence of Mycobacterium tuberculosis (MTB) in sputum, smear-negative pulmonary tuberculosis (SN-TB) poses a diagnostic challenge that can lead to delayed treatment hence new molecular diagnostic markers are urgently needed. The aim of this study was to analyze the expression of CD101 in peripheral blood mononuclear cells (PBMCs), T cells and natural killer (NK) cells of patients with SN-TB through a case-control study and to assess the value of CD101 alone or combined with other cytokines in the auxiliary diagnosis of SN-TB. Methods: Sixty-three newly treated patients with TB and negative smear results diagnosis by clinicians were included as the SN-TB group, while 59 healthy individuals [healthy control (HC)] were included as the control group. The expression of CD101 in PBMCs of the two groups was detected via real-time quantitative polymerase chain reaction (RT-qPCR). The expression of CD101 on T cells and NK cells, as well as the expression of T helper (Th) 1/2/17-related cytokines was detected by flow cytometry. Spearman analysis was used to analyze the correlation between CD101 expression, cytokines and clinical indicators in patients with SN-TB. Receiver operating characteristic (ROC) curve analysis was used to analyze the sensitivity and specificity of CD101 alone or in combination with other cytokines in diagnosing SN-TB. Results: Compared with the control group, the experimental group showed high CD101 expression in PBMCs and CD4⁺ T cells but not in CD8⁺ T cells or NK cells. Th1/Th2-related cytokines interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) were highly expressed in patients with SN-TB, but there was no significant difference in the expression of the Th17-related cytokine (IL-17A). The expression of CD101 on CD4⁺ T cells in patients with SN-TB was positively correlated with cytokines IL-2 and IFN-γ and the clinical indicators of ESR and CRP. CD101 on CD4⁺ T cells could well distinguish patients with SN-TB from HC, with a sensitivity of 71.43%, a specificity of 71.19% and an area under the curve (AUC) of 0.7604. The sensitivity of CD101⁺CD4⁺ (%) combined with IL-2 was 73.25%, the specificity was 68.25% and the AUC was 0.7893. The sensitivity of CD101⁺CD4⁺ (%) combined with IFN-γ was 72.88%, the specificity was 66.67% and the AUC was 0.7678. The sensitivity of CD101⁺CD4⁺ (%) combined with IFN-γ and IL-2 was 74.58%, the specificity was 74.60% and the AUC was 0.7899. Conclusions: The expression of CD101 on CD4⁺ T cells could distinguish patients with SN-TB from healthy individuals and was correlated with key TB infection cytokines, including IL-2 and IFN-γ, as well as with ESR and CRP. CD101 demonstrated good diagnostic efficacy in combination with cytokines. It might thus be an indicator for laboratory-assisted diagnosis of SN-TB.