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Pyroptosis is a host immune strategy to defend against Mycobacterium tuberculosis (Mtb) infection. S100A4, a calcium-binding protein that plays an important role in promoting cancer progression as well as the pathophysiological development of various non-tumor diseases, has not been explored in Mtb-infected hosts. In this study, transcriptome analysis of the peripheral blood of patients with pulmonary tuberculosis (PTB) revealed that S100A4 and GSDMD were significantly up-regulated in PTB patients' peripheral blood. Furthermore, there was a positive correlation between the expression of GSDMD and S100A4. KEGG pathway enrichment analysis showed that differentially expressed genes between PTB patients and healthy controls were significantly related to inflammation, such as the NOD-like receptor signaling pathway and NF-κB signaling pathway. To investigate the regulatory effects of S100A4 on macrophage pyroptosis, THP-1 macrophages infected with Bacillus Calmette-Guérin (BCG) were pre-treated with exogenous S100A4, S100A4 inhibitor or si-S100A4. This research study has shown that S100A4 promotes the pyroptosis of THP-1 macrophages caused by BCG infection and activates NLRP3 inflammasome and NF-κB signaling pathways, which can be inhibited by knockdown or inhibition of S100A4. In addition, inhibition of NF-κB or NLRP3 blocks the promotion effect of S100A4 on BCG-induced pyroptosis of THP-1 macrophages. In conclusion, S100A4 activates the NF-κB/NLRP3 inflammasome signaling pathway to promote macrophage pyroptosis induced by Mtb infection. These data provide new insights into how S100A4 affects Mtb-induced macrophage pyroptosis. [ABSTRACT FROM AUTHOR]

Background: Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is a nucleic acid‐binding protein. Reportedly, hnRNPK is overexpressed in many human tumors, and such overexpression is associated with poor prognosis, implicating the role of hnRNPK as an oncogene during tumorigenesis. In this study, hnRNPK expression in lung cancer tissues was investigated. Methods: Briefly, hnRNPK was knocked down in lung cancer cell lines, and effects of knockdown on the cell proliferation, migration, and cell cycle were assessed using a cell counting kit‐8 (CCK‐8) assay, colony formation assay, transwell assay and flow cytometry. The effects of hnRNPK knockdown on the p53‐dependent signaling pathway were examined using western blotting. Finally, the effect of hnRNPK knockdown on tumor growth was verified in vivo using a lung cancer xenograft mouse model. Results: hnRNPK knockdown inhibited the cell proliferation, migration and cell cycle. In addition to phenotypic changes, hnRNPK knockdown upregulated expressions of pCHK1, pCHK2, and p53，p21，cyclin D1, thereby mediating the DNA damage response (DDR). The regulatory function of hnRNPK during p53/p21/cyclin D1 signaling in hnRNPK‐knockdown A549 cells was confirmed by suppressed the protein expression of associated signaling pathways, which inhibited DDR. Conclusion: hnRNPK plays a crucial role in the progression of lung cancer, ultimately affecting survival rate. Inhibition of progression of lung cancer cells induced by hnRNPK‐knockdown is dependent on activation of p53 by the p53/p21/cyclin D1 pathway. [ABSTRACT FROM AUTHOR]

Summary: The Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays central roles in cancer cell growth and survival. Drug repurposing strategies have provided a valuable approach for developing antitumor drugs. Zelnorm (tegaserod maleate) was originally designed as an agonist of 5-hydroxytryptamine 4 receptor (5-HT4R) and approved by the FDA for treating irritable bowel syndrome with constipation (IBS-C). Through the use of a high-throughput drug screening system, Zelnorm was identified as a JAK/STAT3 signaling inhibitor. Moreover, the inhibition of STAT3 phosphorylation by Zelnorm was independent of its original target 5-HT4R. Zelnorm could cause G1 cell cycle arrest, induce cell apoptosis and inhibit the growth of a variety of cancer cells. The present study identifies Zelnorm as a novel JAK/STAT3 signaling inhibitor and reveals a new clinical application of Zelnorm upon market reintroduction. [ABSTRACT FROM AUTHOR]

Rapid detection of physiological changes of neuropeptides is of great importance as they are involved in a wide range of physiological processes and behaviors. Abnormalities in their expression level are correlated with various neurological diseases. However, current methods such as radioimmunoassay, enzyme-linked immunosorbent assays and liquid chromatography tandem mass spectrometry relied on cumbersome operation steps and could not rapidly provide the information of their concentration fluctuations. Thus motivated, we developed a target-driven DNA-based molecular machine that could be triggered only in the presence of a specific target neuropeptide. Using arginine-vasopressin (AVP) as a model neuropeptide, we integrated the DNA-based molecular machine with fluorescence signal transduction and amplification technology. The assay was rapid and homogeneous, which offered a linear range of 75–700 pM and a limit-of-detection as low as 75 pM. It holds great potential for further applications in real-time monitoring of the variations of the AVP level in biological samples. [ABSTRACT FROM AUTHOR]

Smad ubiquitination regulatory factor 1 (Smurf1) is a HECT-type E3 ubiquitin ligase that regulates several important signaling pathways, including the bone morphogenetic protein pathway and the transforming growth factor-beta ( TGF-β) signaling pathway. However, the function of Smurf1 in cell cycle progression remains unclear. Here, we demonstrate that silencing of Smurf1 results in S phase arrest, confirming that Smurf1 is required for S phase progression. Furthermore, we demonstrate that Smurf1-mediated S phase progression is largely dependent on the ubiquitination-dependent degradation of Wee1. This study defines a novel role for Smurf1 in controlling S phase progression by promoting Wee1 degradation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Schisandrol A is a bioactive lignan of Schisandrae Chinensis Fructus. • Schisandrol A plays critical roles in drug-induced liver injury by acetaminophen. • The mechanism is that TNF signaling pathway is regulated. • The oxidative stress, inflammation, P450 enzymes' activities are inhibited. Schisandrae Chinensis Fructus (SCF) was a Traditional Chinese Medicine for protecting liver. However, underlying therapeutic mechanisms of these bioactive lignans from SCF similar hepatoprotective effects against drug-induced liver injury (DILI) by acetaminophen (APAP) are still unclear. This study aims to discover the potential regulation mechanisms of Schisandrol A in the treatment of DILI by APAP. The integrated UPLC-Q-TOF/MS, pharmacodynamic study, histopathological combination with network pharmacology and molecular docking technology were used to explore the potential mechanisms. The results showed that Schisandrol A reduced the level of AST, ALT, MDA, PNP, TNF-α and IL-1β, increased the levels of the GSH against acute liver failure. Additionally, Schisandrol A could improve the morphological characteristics of DILI by APAP in mice with liver tissue. Molecular docking results had showed that Schisandrol A with high scores when docking with COX-2, ALOX5, CYP2E1, CYP2C9, CYP2C19, EGFR SRC, Nrf2, MAPK14 and MAPK8. The study demonstrated that Schisandrol A could play critical roles in DILI by APAP via regulating TNF signaling pathway, inhibiting oxidative stress, inflammation and inhibiting the activities of cytochrome P450 enzymes, which contributed to searching for leading compounds and the development of new drugs for DILI by APAP. [ABSTRACT FROM AUTHOR]

Modified Xiaoyao San (MXYS), a clinical empirical modified formula based on famous traditional Chinese herbal prescription Xiaoyao San, according to the "yu syndrome" theory of traditional Chinese medicine. MXYS has been shown to be an excellent effective therapy for depression patients in clinic, but the antidepressant mechanisms remain unclear. A growing body of evidence indicates the microglia autophagy and M1 polarized microglia (proinflammatory phenotype)-mediated neuroinflammation act critical roles in the pathogenesis of depression. This study aimed to investigate whether MXYS exerts antidepressant efficacy through inhibition of M1 polarized microglia-mediated neuroinflammation and modulation of autophagy involved in PI3K/Akt/mTOR pathway. In present research, the lipopolysaccharide (LPS)-induced depressive mice and LPS-stimulated N9 microglia cell line were utilized. Behavioral tests (sucrose preference, tail suspension and open field tests) were carried out to evaluate the antidepressant effect of MXYS. The neuronal damage was measured by Nissl's staining in LPS-treated mice. The proinflammatory cytokine levels, the autophagic markers, microglia M1 polarization as well as the PI3K/Akt/mTOR pathway related proteins of MXYS treatment were analyzed by ELISA kits, Western blot and immunofluorescence staining in vivo and vitro. Finally, the influence of autophagy antagonist (3-MA) on the protective effect of MXYS-containing serum in the LPS-stimulated N9 microglia was investigated. Treatment of LPS-induced depressive mice with MXYS significantly reversed depression-like behaviors, accompanied by reduction of proinflammatory cytokine levels (TNF-α, IL-1β) and amelioration of neuronal damage in prefrontal cortex. MXYS suppressed microglia M1 polarization and promoted autophagy in prefrontal cortex and LPS-stimulated N9 cells. Importantly, the remarkable inhibitory effect of the MXYS-medicated serum on microglia M1 polarization was blocked by autophagy antagonist 3-MA in LPS-stimulated N9 cells. Meanwhile, the MXYS treatment exhibited an excellent inhibition effect of PI3K/Akt/mTOR pathway in vivo and vitro. Our research suggests that the antidepressant effect of MXYS in LPS-induced depressive mice may be related to alleviate neuroinflammation through suppression of microglia M1 polarization via enhancing autophagy involved in inactivation of the PI3K/Akt/mTOR pathway. [Display omitted] • MXYS reverses depression-like behaviors by inhibiting neuroinflammation. • MXYS inhibits microglial M1 polarization via promoting autophagy. • MXYS enhances autophagy by inhibiting the activation of PI3K/Akt/mTOR pathway. [ABSTRACT FROM AUTHOR]

T-2 toxin is part of the most toxic fungal secondary metabolites contaminating different kinds of grains. Previous studies have demonstrated that T-2 toxin can influence the survival of chondrocytes and extracellular matrix (ECM) composition. MiR-214-3p is essential for the homeostasis of chondrocytes and ECM. However, the molecular machinery underlying T-2 toxin-induced chondrocyte apoptosis and ECM degradation remain to be elucidated. The present study aimed to investigate the mechanism of miR-214-3p's involvement in T-2 toxin-induced chondrocyte apoptosis and ECM degradation. Meanwhile, the role of the NF-κB signaling pathway was scrutinized. C28/I2 chondrocytes were treated with 8 ng/ml of T-2 toxin for 24 h, after the pretreatment of miR-214-3p interfering RNAs for 6 h. Gene and protein levels involved in chondrocyte apoptosis and ECM degradation were assessed through RT-PCR and Western blotting. The apoptosis rate of chondrocyte was measured by flow cytometry. Results and data indicated that miR-214-3p was decreased in a dose-dependent manner at different concentrations of T-2 toxin. The enhancement of miR-214-3p could alleviate chondrocyte apoptosis and ECM degradation due to T-2 toxin exposure. The upregulation of miR-214-3p was associated with the decreased expression of apoptosis-promoting genes such as Bax and Cleaved-caspase3/caspase3 as well as the increased expression of anti-apoptotic genes such as Bcl2 and Survivin. Furthermore, miR-214-3p stimulated the relative protein expression of collagen Ⅱ but inhibited the expression of MMP13. Overexpressing miR-214-3p could suppress the relative protein expression of IKKβ and phospho-p65/p65, thus blocking the activation of the NF-κB signaling pathway. The study suggested that the miR-214-3p attenuates T-2 toxin-induced chondrocyte apoptosis and ECM degradation through a potential NF-κB signaling pathway. [Display omitted] • MiR-214-3p involved in T-2 toxin-induced chondrocyte apoptosis and ECM degradation. • Overexpressing miR-214-3p can alleviate T-2 toxin-induced chondrocyte apoptosis and ECM degradation. • Inhibiting miR-214-3p can aggravate T-2 toxin-induced chondrocyte apoptosis and ECM degradation. • Overexpressing miR-214-3p can inhibit the NF-κB signaling pathway. • Inhibiting miR-214-3p can activate the NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is a toxic metal and also a well-known reproductive toxicant. Cd could induce germ cells apoptosis in mouse testes, however, the mechanism remains unclear. This study designed in vitro using GC-1 spermatogonial (spg) cells to explore the cytotoxicity and the molecular mechanisms induced by cadmium chloride(CdCl 2). As expected, CdCl 2 elevated the levels of reactive oxygen species (ROS) and induced the release of AIF and Cyt-c from the mitochondria to the cytosol in spermatogonia. Correspondingly, CdCl 2 apparently increased the apoptotic rate in spermatogonia. Further researches found that CdCl 2 could activate IP 3 R-MCU pathway, trigger Ca2+ transfer from endoplasmic reticulum to mitochondria, and cause mitochondrial Ca2+ overload. BAPTA acetoxymethyl ester (BAPTA-AM), a calcium chelator, almost completely attenuated IP 3 R phosphorylation, inhibited the mRNA and protein expression levels of VDAC1, MCU and MCUR1 upregulated by CdCl 2 , reduced the calcium ion content in the mitochondria. Moreover, BAPTA-AM could decrease the level of ROS, antagonize CdCl 2 -induced release of AIF and Cyt-c from the mitochondria to the cytosol and alleviate CdCl 2 -induced apoptosis in spermatogonia. As above, these results provided the evidence that CdCl 2 might induce apoptosis of spermatogonia via mitochondrial Ca2+ overload mediated by IP 3 R-MCU signal pathway. • Cd induced spermatogonia apoptosis. • Cd caused mitochondrial Ca2+ overload. • Cd activated IP 3 R-MCU calcium regulation axis. [ABSTRACT FROM AUTHOR]

Autophagy functions as a critical process that can suppress the proliferation of Mycobacterium tuberculosis (Mtb) within infected host cells. Wnt5a is a secreted protein that plays a range of physiological functions, activating several signaling pathways and thereby controlling cellular responses to particular stimuli. The importance of Wnt5a as a regulator of protection against Mtb infection, however, has yet to be fully characterized. Here, changes in murine pulmonary epithelial-like TC-1 cell morphology, autophagy, the Wnt/Ca2+ signaling pathway, and the mTOR autophagy pathway were analyzed following infection with the Mtb model pathogen Bacille Calmette-Guerin (BCG) in order to understand the regulatory role of Wnt5a in this context. These experiments revealed that Wnt5a was upregulated and autophagy was enhanced in TC-1 cells infected with BCG, and Wnt5a overexpression was found to drive BCG-induced autophagy in these cells upon infection, whereas the inhibition or knockdown of Wnt5a yielded the opposite effect. At the mechanistic level, Wnt5a was found to mediate non-canonical Wnt/Ca2+ signaling and thereby inhibit mTOR-dependent pathway activation, promoting autophagic induction within BCG-infected TC-1 cells. These data offer new insight regarding how Wnt5a influences Mtb- induced autophagy within pulmonary epithelial cells, providing a foundation for further research exploring the immunological control of this infection through the modulation of autophagy. • BCG infection promotes autophagy and high expression of Wnt5a in PECs. • Wnt5a positively regulates BCG induced autophagy in PECs. • Wnt5a mediated noncanonical Wnt/Ca2+ pathway positively regulates BCG induced autophagy in PECs. • Wnt5a regulated BCG-induced PECs autophagy via the Wnt/Ca2+ pathway through mechanisms dependent on the PI3K/AKT/mTOR pathway. [ABSTRACT FROM AUTHOR]