Mycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine.

Antimicrobial peptides (AMPs), ancient scavengers of bacteria, are very poorly induced in macrophages infected by Mycobacterium tuberculosis (M. tuberculosis), but the underlying mechanism remains unknown. Here, we report that L-alanine interacts with PRSS1 and unfreezes the inhibitory effect of PRSS1 on the activation of NF-κB pathway to induce the expression of AMPs, but mycobacterial alanine dehydrogenase (Ald) Rv2780 hydrolyzes L-alanine and reduces the level of L-alanine in macrophages, thereby suppressing the expression of AMPs to facilitate survival of mycobacteria. Mechanistically, PRSS1 associates with TAK1 and disruptes the formation of TAK1/TAB1 complex to inhibit TAK1-mediated activation of NF-κB pathway, but interaction of L-alanine with PRSS1, disables PRSS1-mediated impairment on TAK1/TAB1 complex formation, thereby triggering the activation of NF-κB pathway to induce expression of AMPs. Moreover, deletion of antimicrobial peptide gene ß-defensin 4 (Defb4) impairs the virulence by Rv2780 during infection in mice. Both L-alanine and the Rv2780 inhibitor, GWP-042, exhibits excellent inhibitory activity against M. tuberculosis infection in vivo. Our findings identify a previously unrecognized mechanism that M. tuberculosis uses its own alanine dehydrogenase to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.

Mycobacterium tuberculosis suppresses APLP2 expression to enhance its survival in macrophage.

Mycobacterium tuberculosis (M.tb), the most successful pathogen responsible for approximately 1.6 million deaths in 2021, employs various strategies to evade host antibacterial defenses, including mechanisms to counteract nitric oxide (NO) and certain cytokines. While Amyloid ß (A4) precursor-like protein 2 (Aplp2) has been implicated in various physiological and pathological processes, its role in tuberculosis (TB) pathogenesis remains largely uncharted. This study unveils a significant reduction in Aplp2 levels in TB patients, M.tb-infected macrophages, and mice. Intriguingly, Aplp2 mutation or knockdown results in diminished macrophage-mediated killing of M.tb, accompanied by decreased inducible nitric oxide synthase (iNOS) expression and reduced cytokine production, notably interleukin-1ß (Il-1ß). Notably, Aplp2 mutant mice exhibit heightened susceptibility to mycobacterial infection, evident through aggravated histopathological damage and increased lung bacterial loads, in contrast to Mycobacterium bovis BCG-infected wild-type (WT) mice. Mechanistically, the cleaved product of APLP2, AICD2, generated by γ-secretase, translocates to the nucleus, where it interacts with p65, culminating in enhanced the nuclear factor κB (NF-κB) transcriptional activity. This interaction triggers the upregulation of Il-1ß and iNOS expression. Collectively, our findings illuminate Aplp2's pivotal role in safeguarding against mycobacterial infections by promoting M.tb clearance through NO- or IL-1ß-mediated bactericidal effects. Therefore, we unveil a novel immune evasion strategy employed by M.tb, which could potentially serve as a target for innovative TB interventions.

Comparative interleukins and chemokines analysis of mice mesenchymal stromal cells infected with Mycobacterium tuberculosis H37Rv and H37Ra.

Inflammatory pathways involving Mesenchymal stromal cells (MSCs) play an important role in Mycobacterium tuberculosis (Mtb) infection. H37Rv (Rv) is a standard virulent strain, however, H37Ra (Ra) is a strain with reduced virulence. Interleukins and chemokines production are known to promote inflammation resistance in mammalian cells and is recently reported to regulate mycobacterial immunopathogenesis via inflammatory responses. MSCs are very important cells during Mtb infection. However, the different expressions of interleukins and chemokines in the process of Mtb-infected MSCs between Ra and Rv remain unclear. We used the techniques of RNA-Seq, qRT-PCR, ELISA, and Western Blotting. We have shown that Rv infection significantly increased mRNA expressions of Mndal, Gdap10, Bmp2, and Lif, thereby increasing more differentiation of MSCs compared with Ra infection in MSCs. Further investigation into the possible mechanisms, we found that Rv infection enhanced more inflammatory response (Mmp10, Mmp3, and Ptgs2) through more activation of the TLR2-MAP3K1-JNK pathway than did Ra infection in MSCs. Further action showed that Rv infection enhanced more Il1α, Il6, Il33, Cxcl2, Ccl3, and Ackr3 production than did Ra infection. Rv infection showed more expressions of Mmp10, Mmp3, Ptgs2, Il1α, Il6, Il33, Cxcl2, Ccl3, and Ackr3 possibly through more active TLR2-MAP3K1-JNK pathway than did Ra infection in MSCs. MSCs may therefore be a new candidate for the prevention and treatment of tuberculosis.

Pharmacological boosting of cGAS activation sensitizes chemotherapy by enhancing antitumor immunity.

Enhancing chemosensitivity is one of the largest unmet medical needs in cancer therapy. Cyclic GMP-AMP synthase (cGAS) connects genome instability caused by platinum-based chemotherapeutics to type I interferon (IFN) response. Here, by using a high-throughput small-molecule microarray-based screening of cGAS interacting compounds, we identify brivanib, known as a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor, as a cGAS modulator. Brivanib markedly enhances cGAS-mediated type I IFN response in tumor cells treated with platinum. Mechanistically, brivanib directly targets cGAS and enhances its DNA binding affinity. Importantly, brivanib synergizes with cisplatin in tumor control by boosting CD8+ T cell response in a tumor-intrinsic cGAS-dependent manner, which is further validated by a patient-derived tumor-like cell clusters model. Taken together, our findings identify cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.

Multiscale Crystalline Structure of Confined Polypeptoid Films: The Effect of Alkyl Side Chain Branching.

We report the effect of alkyl side chain branching on melt-recrystallization of nanoconfined polypeptoid films using poly(N-octyl glycine) (PNOG) and poly(N-2-ethyl-1-hexyl glycine) (PNEHG) as model systems. Upon cooling from the isotropic melt, confined PNOG molecules recrystallize into a near-perfect orthorhombic crystal structure with the board-like molecules stacked face-to-face in the substrate-parallel direction, resulting in long-range ordered wormlike lamellae that occupy the entire film. By contrast, rod-like PNEHG molecules bearing branched N-2-ethyl-1-hexyl side chains stack into a columnar hexagonal mesophase with their backbones oriented parallel to the substrates, forming micron-sized sheaf-like superstructures under confinement, exposing large areas of empty spaces in the film. These findings highlight the effect of alkyl side chain branching on the packing motif and multiscale crystalline structure of polypeptoids under a nanoconfined geometry.

CDK inhibitor Palbociclib targets STING to alleviate autoinflammation.

Aberrant activation of stimulator of interferon genes (STING) is tightly associated with multiple types of disease, including cancer, infection, and autoimmune diseases. However, the development of STING modulators for the therapy of STING-related diseases is still an unmet clinical need. We employed a high-throughput screening approach based on the interaction of small-molecule chemical compounds with recombinant STING protein to identify functional STING modulators. Intriguingly, the cyclin-dependent protein kinase (CDK) inhibitor Palbociclib was found to directly bind STING and inhibit its activation in both mouse and human cells. Mechanistically, Palbociclib targets Y167 of STING to block its dimerization, its binding with cyclic dinucleotides, and its trafficking. Importantly, Palbociclib alleviates autoimmune disease features induced by dextran sulphate sodium or genetic ablation of three prime repair exonuclease 1 (Trex1) in mice in a STING-dependent manner. Our work identifies Palbociclib as a novel pharmacological inhibitor of STING that abrogates its homodimerization and provides a basis for the fast repurposing of this Food and Drug Administration-approved drug for the therapy of autoinflammatory diseases.

Interception of host fatty acid metabolism by mycobacteria under hypoxia to suppress anti-TB immunity.

Pathogenic mycobacteria induce the formation of hypoxic granulomas during latent tuberculosis (TB) infection, in which the immune system contains, but fails to eliminate the mycobacteria. Fatty acid metabolism-related genes are relatively overrepresented in the mycobacterial genome and mycobacteria favor host-derived fatty acids as nutrient sources. However, whether and how mycobacteria modulate host fatty acid metabolism to drive granuloma progression remains unknown. Here, we report that mycobacteria under hypoxia markedly secrete the protein Rv0859/MMAR_4677 (Fatty-acid degradation A, FadA), which is also enriched in tuberculous granulomas. FadA acts as an acetyltransferase that converts host acetyl-CoA to acetoacetyl-CoA. The reduced acetyl-CoA level suppresses H3K9Ac-mediated expression of the host proinflammatory cytokine Il6, thus promoting granuloma progression. Moreover, supplementation of acetate increases the level of acetyl-CoA and inhibits the formation of granulomas. Our findings suggest an unexpected mechanism of a hypoxia-induced mycobacterial protein suppressing host immunity via modulation of host fatty acid metabolism and raise the possibility of a novel therapeutic strategy for TB infection.

Sirt1 activation negatively regulates overt apoptosis in Mtb-infected macrophage through Bax.

Apoptotic pathways play an important role in Mycobacterium tuberculosis-infected macrophages. Sirt1 is a member of the deacetylase family that is known to promote apoptosis resistance in many mammalian cells. However, the apoptotic role of Sirt1 in the process of M. tuberculosis infection remains unclear. With the help of mouse macrophage samples, 129/Sv background mice, and PBMCs-derived macrophages from healthy controls and patients with tuberculosis, we have shown that M. tuberculosis infection reduced Sirt1 mRNA and protein expression, however, increased Bax mRNA and protein expression. Further, we found that resveratrol, a Sirt1 activator, inhibited M. tuberculosis-induced Bax expression. Thus, it seems that Sirt1 acts as a novel regulator of apoptosis signaling in M. tuberculosis infection via its effects on Bax. Sirt1 activation may therefore be a new candidate for the prevention and treatment of tuberculosis.

Sirtuin inhibits M. tuberculosis -induced apoptosis in macrophage through glycogen synthase kinase-3ß.

Apoptotic and inflammatory pathways play important roles in Mycobacterium tuberculosis-infected macrophages. Sirt1 is a member of the deacetylase family that is known to promote apoptosis resistance in mammalian cells and was recently reported to regulate mycobacterial immunopathogenesis via inflammatory responses. However, the apoptotic role of Sirt1 in the process of M. tuberculosis infection remains unclear. With the help of mouse peritoneal macrophage samples, we have shown that resveratrol, a Sirt1 activator, inhibited M. tuberculosis-induced apoptosis in peritoneal macrophages. Further, we found that Sirt1 activation prompted M. tuberculosis induced GSK3ß phosphorylation. Further investigation into the possible mechanisms of action showed that Sirt1 directly interacted with GSK3ß and enhanced GSK3ß phosphorylation by promoting its deacetylation. Sirt1 activation inhibited M. tuberculosis growth. Thus, it seemed that Sirt1 acted as a novel regulator of apoptosis signaling in M. tuberculosis infection via its direct effects on GSK3ß. Sirt1 may therefore be a new candidate for the prevention and treatment of tuberculosis.

The possible regulatory effect of the PD-1/PD-L1 signaling pathway on Tregs in ovarian cancer.

Aim of this study was to investigate the possible regulatory effect of the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) signaling pathway on Tregs in ovarian cancer. Immunohistochemistry was used to detect the expression of PD-L1 and PD-1 and the presence of FOXP3+ Tregs in ovarian cancer. Then, ovarian cancer HO8910 cells were subjected to transfection with PD-L1 siRNA in vitro. CCK-8, Transwell and wound healing assays were performed to detect the biological behaviors of ovarian cancer cells. Human T-cells isolated from human peripheral blood were cocultured with HO8910 cells, which were divided into the Control, TGF-ß, and TGF-ß+ anti-PD-L1 groups. The proportion of differentiated Tregs was detected by flow cytometry. Mouse models of ovarian cancer were established, and PD-L1 antibody therapy was administered. Tumor growth and Treg recruitment were observed. PD-L1, PD-1 and FOXP3+ Tregs were found in ovarian cancer tissue. Patients with tumors with an advanced stage and low differentiation and lymph node metastasis had significantly higher levels of PD-1, PD-L1 and FOXP3+ Tregs. After transfection with PD-L1 siRNA, HO8910 cells showed a significant reduction in PD-L1 expression, proliferation, migration and invasion. After T-cells were cocultured with ovarian cancer cells, the TGF-ß+ anti-PD-L1 group showed a substantial decline in the differentiation of T-cells into Tregs compared with the TGF-ß group. Moreover, mice in the anti-PD-L1 group had significantly reduced tumor growth rates, Treg proportions in the tumor microenvironment, and FOXP3 expression.

Cyclic Topology Enhancing Structural Ordering and Stability of Comb-Shaped Polypeptoid Thin Films against Melt-Induced Dewetting.

We investigated the effect of cyclic chain topology on the molecular ordering and thermal stability of comb-shaped polypeptoid thin films on silicon (Si) substrates. Cyclic and linear poly(N-decylglycine) (PNDG) bearing long n-decyl side chains were synthesized by ring-opening polymerization of N-decylglycine-derived N-carboxyanhydrides. When the spin-coated thin films were subjected to thermal annealing at temperatures above the melting temperature (T > T m), the cyclic PNDG films exhibited significantly enhanced stability against melt-induced dewetting than the linear counterparts (l-PNDG). When recrystallized at temperatures below the crystallization temperature (T < T c), the homogeneous c-PNDG films exhibit enhanced crystalline ordering relative to the macroscopically dewetted l-PNDG films. Both cyclic and linear PNDG molecules adopt cis-amide conformations in the crystalline film, which transition into trans-amide conformations upon melting. A top-down solvent leaching treatment of both l/c-PNDG films revealed the formation of an irreversibly physisorbed monolayer with similar thickness (ca. 3 nm) on the Si substrate. The physisorbed monolayers are more disordered relative to the respective thicker crystalline films for both cyclic and linear PNDGs. Upon heating above T m, the adsorbed c-PNDG chains adopt trans-amide backbone conformation identical with the free c-PNDG molecules in the molten film. By contrast, the backbone conformations of l-PNDG chains in the adsorbed layers are notably different from those of the free chains in the molten film. We postulate that the conformational disparity between the chains in the physically adsorbed layers versus the free chains in the molten film is an important factor to account for the difference in the thermal stability of PNDG thin films. These findings highlight the use of cyclic chain topology to suppress the melt-induced dewetting in polymer thin films.

Host-mediated ubiquitination of a mycobacterial protein suppresses immunity.

Mycobacterium tuberculosis is an intracellular pathogen that uses several strategies to interfere with the signalling functions of host immune molecules. Many other bacterial pathogens exploit the host ubiquitination system to promote pathogenesis1,2, but whether this same system modulates the ubiquitination of M. tuberculosis proteins is unknown. Here we report that the host E3 ubiquitin ligase ANAPC2-a core subunit of the anaphase-promoting complex/cyclosome-interacts with the mycobacterial protein Rv0222 and promotes the attachment of lysine-11-linked ubiquitin chains to lysine 76 of Rv0222 in order to suppress the expression of proinflammatory cytokines. Inhibition of ANAPC2 by specific short hairpin RNA abolishes the inhibitory effect of Rv0222 on proinflammatory responses. Moreover, mutation of the ubiquitination site on Rv0222 impairs the inhibition of proinflammatory cytokines by Rv0222 and reduces virulence during infection in mice. Mechanistically, lysine-11-linked ubiquitination of Rv0222 by ANAPC2 facilitates the recruitment of the protein tyrosine phosphatase SHP1 to the adaptor protein TRAF6, preventing the lysine-63-linked ubiquitination and activation of TRAF6. Our findings identify a previously unrecognized mechanism that M. tuberculosis uses to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.

miR-509-5p Downregulation Is Associated With Male Infertility And Acts As A Suppressor In Testicular Germ Cell Tumor Cells Through Targeting MDM2.

BACKGROUND: The dysregulation of microRNAs (miRNAs) has been linked with male infertility. miR-509-5p is highly expressed in testis and exerts suppressive effects on multiple types of human cancers. OBJECTIVES: Yet, whether miR-509-5p is connected with male infertility and plays a role in testicular germ cell tumor (TGCT) have not been explored. MATERIALS AND METHODS: This study detected miR-509-5p expression in germ cells from MA patients, and further characterize its functional roles in the proliferation and apoptosis of TGCT cells in vitro. RESULTS: We report that miR-509-5p is downregulated in germ cells from infertile men with maturation arrest (MA), which implies an inverse association between miR-509-5p level and male infertility. In addition, miR-509-5p suppresses proliferation and induces apoptosis of TGCT cells in vitro, suggesting that it exhibits tumor-suppressive effects on TGCT. Mechanistically, miR-509-5p targets the mouse double minute 2 (MDM2), an oncogenic factor in TGCT, and moreover, restored expression of MDM2 rescues miR-509-5p suppressive effects on TGCT cells, demonstrating that miR-509-5p suppresses TGCT cells through targeting MDM2. CONCLUSION: Collectively, these results implicate that miR-509-5p may participate in the pathogenesis of male infertility and TGCT through regulating proliferation and apoptosis, two critical cellular activities for spermatogenesis and TGCT tumorigenesis.

Design of a Targeted Sequencing Assay to Detect Rare Mutations in Circulating Tumor DNA.

BACKGROUND: Qualitative and quantitative detection of circulating tumor DNA (ctDNA) is a liquid biopsy technology used for early cancer diagnosis. However, the plasma ctDNA content is extremely low, so it is difficult to detect somatic mutations of tumors using conventional sequencing methods. Target region sequencing (TRS) technology, through enrichment of the target genomic region followed by next generation sequencing, overcomes this challenge and has been widely used in ctDNA sequencing. METHODS: We designed a ctDNA sequencing panel to capture 128 tumor genes, and tested the performance of the panel by running TRS for ctDNA of a clear cell renal cell carcinoma (ccRCC) patient and 12 breast cancer patients. RESULTS: TRS using the new ctDNA panel at more than 500 × coverage depth achieved almost the same accuracy as traditional whole-exome sequencing (WES). PBRM1 p.L641V was detected in the plasma sample of the ccRCC patient with an allele frequency of 0.2%. The ctDNA of 12 breast cancer patients was sequenced at a depth of 500-fold, achieving 99.89% coverage; 34 genes were detected with mutations, including the drug target genes BRCA2, PTEN, TP53, APC, KDR, and NOTCH2. CONCLUSIONS: This TRS new ctDNA panel can be used to detect mutations in cell-free DNA from multiple types of cancer.

Nuclear E-Cadherin Acetylation Promotes Colorectal Tumorigenesis via Enhancing ß-Catenin Activity.

The E-cadherin/ß-catenin signaling pathway plays a critical role in the maintenance of epithelial architecture and regulation of tumor progression. Normally, E-cadherin locates on the cell surface with its cytosolic domain linking to the actin cytoskeleton through interaction with catenins. Although the nuclear localization of E-cadherin has been frequently observed in various types of cancers, little is known regarding the functional consequences of its nuclear translocation. Here, we showed that in colorectal cancer samples and cell lines, E-cadherin localized in the nucleus; and the nuclear localization was mediated through protein interaction with CTNND1. In the nucleus, E-cadherin was acetylated by CREB-binding protein at Lysine870 and Lysine871 in its ß-catenin-binding domain, and the acetylation can be reversed by SIRT2. Acetylation of nuclear E-cadherin attenuated its interaction with ß-catenin, which therefore released ß-catenin from the complex, resulting in increased expression of its downstream genes and accelerated tumor growth and migration. Further study showed that acetylation level of nuclear E-cadherin had high prognostic significance in clinical colorectal samples. Taken together, our findings reveal a novel mechanism of tumor progression through posttranslational modification of E-cadherin, which may serve as a potential drug target of tumor therapy. IMPLICATIONS: This finding that acetylation of nuclear E-cadherin regulates ß-catenin activity expands our understanding of the acetylation of E-cadherin promotes colorectal cancer cell growth and suggests novel therapeutic approaches of targeting acetylation in tumors.

Nuclear cGAS suppresses DNA repair and promotes tumorigenesis.

Accurate repair of DNA double-stranded breaks by homologous recombination preserves genome integrity and inhibits tumorigenesis. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that activates innate immunity by initiating the STING-IRF3-type I IFN signalling cascade1,2. Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response3,4, but the potential involvement of cGAS in DNA repair remains unknown. Here we demonstrate that cGAS inhibits homologous recombination in mouse and human models. DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS. In the nucleus, cGAS is recruited to double-stranded breaks and interacts with PARP1 via poly(ADP-ribose). The cGAS-PARP1 interaction impedes the formation of the PARP1-Timeless complex, and thereby suppresses homologous recombination. We show that knockdown of cGAS suppresses DNA damage and inhibits tumour growth both in vitro and in vivo. We conclude that nuclear cGAS suppresses homologous-recombination-mediated repair and promotes tumour growth, and that cGAS therefore represents a potential target for cancer prevention and therapy.

2-aminopurine suppresses the TGF-ß1-induced epithelial-mesenchymal transition and attenuates bleomycin-induced pulmonary fibrosis.

The epithelial-mesenchymal transition (EMT) is a multifunctional cell process involved in the pathogenesis of numerous conditions, including fibrosis and cancer. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by fibroblast accumulation and collagen deposition in the lungs. The fibroblasts involved in this process partially originate from lung epithelial cells via the EMT. Evidence suggests that the EMT contributes to progression, invasion, and metastasis of various types of cancer. We screened a series of 80 compounds for the ability to interfere with the EMT and potentially be applied as a therapeutic for IPF and/or lung cancer. We identified 2-aminopurine (2-AP), a fluorescent analog of guanosine and adenosine, as a candidate in this screen. Herein, we demonstrate that 2-AP can restore E-cadherin expression and inhibit fibronectin and vimentin expression in TGF-ß1-treated A549 lung cancer cells. Moreover, 2-AP can inhibit TGF-ß1-induced metastasis of A549 cells. This compound significantly attenuated bleomycin (BLM)-induced pulmonary inflammation, the EMT, and fibrosis. In addition, 2-AP treatment significantly decreased mortality in a mouse model of pulmonary fibrosis. Collectively, we determined that 2-AP could inhibit metastasis in vitro by suppressing the TGF-ß1-induced EMT and could attenuate BLM-induced pulmonary fibrosis in vivo. Results of this study suggest that 2-AP may have utility as a treatment for lung cancer and pulmonary fibrosis.

Urinary metabonomics of rats with ketamine-induced cystitis using GC-MS spectroscopy.

Ketamine abuse has dramatically increased in recently years. With the widely application of ketamine, its side effects, especially cystitis induced by long-term use, have attracted more and more attention from the public. In the present study, we aimed to explore the potential generative mechanism of ketamine-induced cystitis by determining the endogenous metabolites at different time points after ketamine treatment. Body weight, bladder/body coefficient, urinary frequency, urinary potassium, serum IL-6, and TNF-α were determined at different time points after ketamine treatment. H&E staining was used to observe the changes of histopathology. Metabonomics was performed to determine the changes of endogenous metabolites. After 12 weeks of treatment, obvious inflammatory reaction was noticed in the KET group; the body weight and urinary potassium of the KET group were significantly lower than the NS group (P < 0.05) and other factors, such as urinary frequency, bladder/body coefficient, serum TNF-α and IL-6 were higher than the NS group (P < 0.05). A total of 30, 28, and 32 significantly changed metabolites were identified at the 1st week, 4th week and 12th week, respectively. Metabolic pathway analysis showed that different metabolic pathways were affected during the treatment process. Linoleic acid metabolism, beta-alanine metabolism, glyoxylate and dicarboxylate metabolism were only affected following long-term administration of ketamine. Those metabolic pathways may have a close relationship with cystitis induced by ketamine.

Notch4 Negatively Regulates the Inflammatory Response to Mycobacterium tuberculosis Infection by Inhibiting TAK1 Activation.

Tuberculosis, caused by Mycobacterium tuberculosis infection, remains a global threat to human health, but knowledge of the molecular mechanisms underlying the pathogenesis of tuberculosis is still limited. Although Notch4, a member of the Notch receptor family, is involved in the initiation of mammary tumors, its function in M. tuberculosis infection remains unclear. In this study, we found that Notch4-deficient mice were more resistant to M. tuberculosis infection, with a much lower bacterial burden and fewer pathological changes in the lungs. Notch4 inhibited M. tuberculosis-induced production of proinflammatory cytokines by interaction with TAK1 and inhibition of its activation. Furthermore, we found that Notch intracellular domain 4 prevented TRAF6 autoubiquitination and suppressed TRAF6-mediated TAK1 polyubiquitination. Finally, Notch inhibitors made mice more resistant to M. tuberculosis infection. These results suggest that Notch4 is a negative regulator of M. tuberculosis-induced inflammatory response, and treatment with a Notch inhibitor could serve as a new therapeutic strategy for tuberculosis.

Predictive value of microRNA-143 in evaluating the prognosis of patients with hepatocellular carcinoma.

OBJECTIVE: The study aims to evaluate the predictive value of microRNA-143 (miR-143) for the prognosis of patients with hepatocellular carcinoma (HCC). METHODS: Between October 2010 and October 2012, 131 HCC patients were selected as a case group; meanwhile, 122 healthy controls were enrolled as a control group. The miR-143 expression in serum was detected by quantitative real-time polymerase chain reaction (qRT-PCR). These HCC patients were divided into the high miR-143 expression group and the low miR-143 expression group based on the threshold of receiver operating characteristic (ROC) curve. Kaplan-Meier method was applied to analyze the prognosis of HCC patients. RESULTS: MiR-143 exhibited decreased expression in the case group significantly compared to the control group. The areas under the ROC curve (AUC), sensitivity value and specificity value of the miR-143 expression for the diagnosis of HCC were 0.831, 80.30% and 82.40%, respectively. The miR-143 expression was negatively correlated with vascular invasion, TNM staging, tumor recurrence, metastasis and survival of HCC patients. CONCLUSIONS: Our study provides evidence that miR-143 may be negatively correlated with the prognosis of HCC and provides a promising strategy for HCC treatment and prognosis improvement.