Aberrant LYZ expression in tumor cells serves as the potential biomarker and target for HCC and promotes tumor progression via csGRP78.

Hepatocellular carcinoma (HCC) takes the predominant malignancy of hepatocytes with bleak outcomes owing to high heterogeneity among patients. Personalized treatments based on molecular profiles will better improve patients' prognosis. Lysozyme (LYZ), a secretory protein with antibacterial function generally expressed in monocytes/macrophages, has been observed for the prognostic implications in different types of tumors. However, studies about the explicit applicative scenarios and mechanisms for tumor progression are still quite limited, especially for HCC. Here, based on the proteomic molecular classification data of early-stage HCC, we revealed that the LYZ level was elevated significantly in the most malignant HCC subtype and could serve as an independent prognostic predictor for HCC patients. Molecular profiles of LYZ-high HCCs were typical of those for the most malignant HCC subtype, with impaired metabolism, along with promoted proliferation and metastasis characteristics. Further studies demonstrated that LYZ tended to be aberrantly expressed in poorly differentiated HCC cells, which was regulated by STAT3 activation. LYZ promoted HCC proliferation and migration in both autocrine and paracrine manners independent of the muramidase activity through the activation of downstream protumoral signaling pathways via cell surface GRP78. Subcutaneous and orthotopic xenograft tumor models indicated that targeting LYZ inhibited HCC growth markedly in NOD/SCID mice. These results propose LYZ as a prognostic biomarker and therapeutic target for the subclass of HCC with an aggressive phenotype.

MEK/ERK signaling pathway is required for enterovirus 71 replication in immature dendritic cells.

BACKGROUND: The mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase (MEK/ERK) signaling pathway is involved in viral life cycle. However, the effect of MEK/ERK pathway in enterovirus 71(EV71)-infected immature dendritic cells (iDCs) is still unclear. METHODS: Human peripheral blood mononuclear cells (PBMCs) were isolated and induced to generate iDCs. Unifected iDCs and EV71-infected iDCs with a multiplicity of infection (MOI = 5) were analyzed by flow cytometry. Differential gene expressions of MEK/ERK signaling pathway molecules in EV71-infected iDCs were performed by PCR arrays. The phosphorylation of MEK/ERK pathway molecules in EV71-infected iDCs preincubated without or with U0126 (20 µM) at indicated times was detected by Western blot. The concentrations of IL-1α, IL-2, IL-6, IL-12, TNF-α, IFN-α1, IFN-ß and IFN-γ in culture supernatant were analyzed by the luminex fluorescent technique. RESULTS: When iDCs were infected with EV71 for 24 h, the percentage of CD80, CD83, CD86 and HLA-DR expressed on iDCs significantly increased. PCR arrays showed that gene expressions of molecules in MEK/ERK signaling pathway were remarkably upregulated in EV71-infected iDCs. EV71 infection activated both MEK1/2 and ERK1/2, which phosphorylated their downstream transcription factor c-Fos, c-Jun, c-myc and Elk1. Importantly, the treatment of U0126 significantly inhibited MEK/ERK signaling pathway molecules and severely impaired virus replication., Additionally, EV71 infection promoted the expression of son of sevenless (SOS1) and increased the secretion of IL-1α, IL-2, IL-6, IL-12, TNF-α,IFN-ß and IFN-γ. Furthermore,the release of IL-1α, IL-2,IL-6 and TNF-α could be effectively suppressed by inhibitor U0126. CONCLUSIONS: Our data suggest that the MEK/ERK signaling pathway plays an important role in EV71-infected iDCs and these molecules may be potential targets for the development of new anti-EV71 drugs.

Clinical effects of nonconvulsive electrotherapy combined with mindfulness-based stress reduction and changes of serum inflammatory factors in depression.

BACKGROUND: Depression is a common and serious psychological condition, which seriously affects individual well-being and functional ability. Traditional treatment methods include drug therapy and psychological counseling; however, these methods have different degrees of side effects and limitations. In recent years, nonconvulsive electrotherapy (NET) has attracted increasing attention as a noninvasive treatment method. However, the clinical efficacy and potential mechanism of NET on depression are still unclear. We hypothesized that NET has a positive clinical effect in the treatment of depression, and may have a regulatory effect on serum inflammatory factors during treatment. AIM: To assess the effects of NET on depression and analyze changes in serum inflammatory factors. METHODS: This retrospective study enrolled 140 patients undergoing treatment for depression between May 2017 and June 2022, the observation group that received a combination of mindfulness-based stress reduction (MBSR) and NET treatment (n = 70) and the control group that only received MBSR therapy (n = 70). The clinical effectiveness of the treatment was evaluated by assessing various factors, including the Hamilton Depression Scale (HAMD)-17, self-rating idea of suicide scale (SSIOS), Pittsburgh Sleep Quality Index (PSQI), and levels of serum inflammatory factors before and after 8 wk of treatment. The quality of life scores between the two groups were compared. Comparisons were made using t and χ2 tests. RESULTS: After 8 wk of treatment, the observation group exhibited a 91.43% overall effectiveness rate which was higher than that of the control group which was 74.29% (64 vs 52, χ2 = 7.241; P < 0.05). The HAMD, SSIOS, and PSQI scores showed a significant decrease in both groups. Moreover, the observation group had lower scores than the control group (10.37 ± 2.04 vs 14.02 ± 2.16, t = 10.280; 1.67 ±0.28 vs 0.87 ± 0.12, t = 21.970; 5.29 ± 1.33 vs 7.94 ± 1.35, t = 11.700; P both < 0.001). Additionally, there was a notable decrease in the IL-2, IL-1ß, and IL-6 in both groups after treatment. Furthermore, the observation group exhibited superior serum inflammatory factors compared to the control group (70.12 ± 10.32 vs 102.24 ± 20.21, t = 11.840; 19.35 ± 2.46 vs 22.27 ± 2.13, t = 7.508; 32.25 ± 4.6 vs 39.42 ± 4.23, t = 9.565; P both < 0.001). Moreover, the observation group exhibited significantly improved quality of life scores compared to the control group (Social function: 19.25 ± 2.76 vs 16.23 ± 2.34; Emotions: 18.54 ± 2.83 vs 12.28 ± 2.16; Environment: 18.49 ± 2.48 vs 16.56 ± 3.44; Physical health: 19.53 ± 2.39 vs 16.62 ± 3.46; P both < 0.001) after treatment. CONCLUSION: MBSR combined with NET effectively alleviates depression, lowers inflammation (IL-2, IL-1ß, and IL-6), reduces suicidal thoughts, enhances sleep, and improves the quality of life of individuals with depression.

Genome-wide RNA-sequencing dataset reveals AC096751.1 sever as a novel prognostic long non-coding RNA and its potential molecular mechanisms in patients with colon adenocarcinoma.

Objective: Through data analysis, we observed that AC096751.1 is markedly imbalance between colon adenocarcinoma (COAD) cancer and paracancerous tissues. However, the prognostic value and potential molecular mechanism of AC096751.1 in COAD are still unclear. Methods: Whole genome RNA-sequencing datasets of The Cancer Genome Atlas (TCGA) COAD cohort were collected into current study, comprehensive survival analysis and bioinformatics function enrichment analysis approaches were apply to explore the clinical outcome and molecular mechanisms of AC096751.1 in COAD. Results: In current study, we found that AC096751.1 is markedly down-regulated in COAD cancer tissues (log2 fold change =2.303, P<0.0001, false discovery rate <0.0001), and can be serve as a biomarker to distinguish COAD cancer and paracancerous tissues [area under curve=0.9518, 95% confidence interval (CI)=0.9261-0.9776]. Survival analysis suggests that low expression of AC096751.1 is connected with poor clinical outcome of COAD, and can serve as a novel prognostic indicator (log-rank P=0.016, adjusted P=0.005, hazard ratio=0.548, 95% CI=0.360-0.836). Bioinformatics function enrichment analysis suggests that the molecular mechanism of AC096751.1 in COAD may include participation in cell adhesion, cell proliferation, mitogen-activated protein kinase kinase (MAPKK), MAPK, janus-activated kinase-singal transducers and activators of transcriprion cascade, Erk1 and Erk 2 cascade, and nuclear factor-kappa B pathway. Tumor microenvironment and immune infiltration analysis indicates that COAD patients with different AC096751.1 expression have significant variation in tumor immune background. Conclusion: The present study found that AC096751.1 is significantly differentially expressed in COAD and can be serve as a novel prognostic biomarker.

Correlation Between Serum High-Sensitivity C-Reactive Protein, Tumor Necrosis Factor-Alpha, Serum Interleukin-6 and White Matter Integrity Before and After the Treatment of Drug-Naïve Patients With Major Depressive Disorder.

Background: Previous studies have noticed that systemic inflammation may alter the integrity of white matter. However, how the levels of serum cytokine affect the integrity of white matter in major depressive disorder (MDD) patients are unclear. Our study aimed to investigate the association between the inflammatory cytokine levels and white matter microstructure in drug-naïve patients with MDD pre- and post-treatment. Method: In total, 29 MDD patients and 25 healthy controls (HC) were included in this study. Diffusion tensor imaging (DTI) was conducted in all subjects at baseline, and the MDD patients were reassessed after venlafaxine treatment, using a tract-based spatial statistics (TBSS) analysis. Morning serum interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and high-sensitivity C-reactive protein (hs-CRP) concentrations in MDD patients were also measured pre- and post-treatment. Results: Significantly reduced fractional anisotropy (FA) values were found in the bilateral superior fronto-occipital fasciculus (SFO), posterior limb of the internal capsule (IC-PL), and fornix compared with the HC, and FA values in these regions in MDD patients have risen to normal levels except the bilateral SFO after treatment. The FA value of the left IC-PL was inversely correlated with the peripheral hs-CRP levels in both pre- and post-treatment MDD patients. Conclusion: Our results suggested that the white matter integrity in the left IC-PL was significantly inversely correlated with the peripheral hs-CRP levels in both pre- and post-treatment MDD patients.

Comprehensively Improved Performance of ß-Ga2O3 Solar-Blind Photodetector Enabled by a Homojunction with Unique Passivation Mechanisms.

Ga2O3-based solar-blind photodetectors have been extensively investigated for a wide range of applications. However, to date, a lot of research has focused on optimizing the epitaxial technique or constructing a heterojunction, and studies concerning surface passivation, a key technique in electronic and optoelectronic devices, are severely lacking. Here, we report an ultrasensitive metal-semiconductor-metal photodetector employing a ß-Ga2O3 homojunction structure realized by low-energy surface fluorine plasma treatment, in which an ultrathin fluorine-doped layer served for surface passivation. Without inserting/capping a foreign layer, this strategy utilized fluorine dopants to both passivate local oxygen vacancies and suppress surface chemisorption. The dual effects have opposite impacts on device current magnitude (by suppressing metal/semiconductor junction leakage and inhibiting surface-chemisorption-induced carrier consumption) but dominate in dark and under illumination, respectively. By means of such unique mechanisms, the simultaneous improvement on dark and photo current characteristics was achieved, leading to the sensitivity enhanced by nearly 1 order of magnitude. Accordingly, the 15 min treated sample exhibited striking competitiveness in terms of comprehensive properties, including a dark current as low as 6 pA, a responsivity of 18.43 A/W, an external quantum efficiency approaching 1 × 104%, a specific detectivity of 2.48 × 1014 Jones, and a solar-blind/UV rejection ratio close to 1 × 105. Furthermore, the response speed was effectively accelerated because of the reduction on metal/semiconductor interface trap states. Our findings provide a facile, economical, and contamination-free surface passivation technique, which unlocks the potential for comprehensively improving the performance of ß-Ga2O3 solar-blind metal-semiconductor-metal photodetectors.

The SUMOylation of TAB2 mediated by TRIM60 inhibits MAPK/NF-κB activation and the innate immune response.

Activation of the TAK1 signalosome is crucial for mediating the innate immune response to pathogen invasion and is regulated by multiple layers of posttranslational modifications, including ubiquitination, SUMOylation, and phosphorylation; however, the underlying molecular mechanism is not fully understood. In this study, TRIM60 negatively regulated the formation and activation of the TAK1 signalosome. Deficiency of TRIM60 in macrophages led to enhanced MAPK and NF-κB activation, accompanied by elevated levels of proinflammatory cytokines but not IFN-I. Immunoprecipitation-mass spectrometry assays identified TAB2 as the target of TRIM60 for SUMOylation rather than ubiquitination, resulting in impaired formation of the TRAF6/TAB2/TAK1 complex and downstream MAPK and NF-κB pathways. The SUMOylation sites of TAB2 mediated by TRIM60 were identified as K329 and K562; substitution of these lysines with arginines abolished the SUMOylation of TAB2. In vivo experiments showed that TRIM60-deficient mice showed an elevated immune response to LPS-induced septic shock and L. monocytogenes infection. Our data reveal that SUMOylation of TAB2 mediated by TRIM60 is a novel mechanism for regulating the innate immune response, potentially paving the way for a new strategy to control antibacterial immune responses.

To TRIM the Immunity: From Innate to Adaptive Immunity.

The tripartite motif (TRIM) proteins have been intensively studied as essential modulators in various biological processes, especially in regulating a wide range of signaling pathways involved in immune responses. Most TRIM proteins have E3 ubiquitin ligase activity, mediating polyubiquitination of target proteins. Emerging evidence demonstrates that TRIM proteins play important roles in innate immunity by regulating pattern recognition receptors, vital adaptor proteins, kinases, and transcription factors in innate immune signaling pathways. Additionally, the critical roles of TRIM proteins in adaptive immunity, especially in T cell development and activation, are increasingly appreciated. In this review, we aim to summarize the studies on TRIMs in both innate and adaptive immunity, focusing on their E3 ubiquitin ligase functions in pattern recognition receptor signaling pathways and T cell functions, shedding light on the developing new strategies for modulating innate and adaptive immune responses against invading pathogens and avoiding autoimmunity.

MiR-124 suppression in the prefrontal cortex reduces depression-like behavior in mice.

Depression is a potentially life-threatening mental disorder with unknown etiology. Several microRNAs (miRNAs) have been shown to play critical roles in the etiology of depression. Here, we aim to elucidate the anti-depressive behavior of miR-124 suppression in prefrontal cortex (PFC). Quantitative real-time PCR (RT-PCR) was used to evaluate the expression of miR-124 and SIRT1 in the PFC of a chronic unpredictable mild stress (CUMS) model. The PFC of C57BL/6J mice was bilaterally injected with lentiviral vectors (LV) for ectopic expression of SIRT1, miR-124, or miR-124 inhibitor (si-miR-124). The anti-depressive behavior was observed after injection of LV-SIRT1 or LV-si-miR-124 into the PFC, using behavior tests including latency to feed, food and water intake, sucrose preference test, and forced swimming test. MiR-124 overexpression and inhibition resulted in upregulation and down-regulation of SIRT1 and cyclic AMP responsive element binding protein 1 (CREB1), respectively. MiR-124 overexpression exacerbated depression-like behaviors and decreased SIRT1. Further, dual-luciferase assay confirmed that SIRT1 was a target of miR-124. Taken together, a potential molecular regulation of miR-124 on SIRT1 is revealed by our study and miR-124 suppression in PFC is a potential strategy to reduce depression-like behavior.

USP19 suppresses cellular type I interferon signaling by targeting TRAF3 for deubiquitination.

AIM: To investigate host factors that mediate the immune escape of enterovirus 71 (EV71) in the context of deubiquitinating enzymes. MATERIALS & METHODS: Utilize PCR array to screen candidate genes that may be involved in EV71-induced cellular antiviral immune responses, and utilize protein mass spectrometry analysis to identify the functional targets of the candidate regulator. RESULTS: EV71 infection induces the upregulation of ubiquitin-specific protease 19 (USP19) gene expression, which negatively regulates cellular antiviral type I interferon signaling. Additionally, we identify that USP19 suppresses cellular type I interferon signaling by targeting tumor necrosis factor receptor-associated factor 3 (TRAF3) molecule and decreasing TRAF3 ubiquitination of K63-linkage. CONCLUSION: This work suggests that USP19 is a previously unrecognized regulator employed by EV71 to evade host antiviral defenses.

Manipulation of viral infection by deubiquitinating enzymes: new players in host-virus interactions.

Ubiquitination regulates gene expression post-translationally through the well-characterized ubiquitin system, which has been clearly established to have important functions in the regulation of many intracellular biological activities. Being obligate intracellular microbes, viruses inevitably co-opt this conserved host cytosolic machinery to accomplish their own life cycle, from entry into host cells to the release of progeny viral particles. Deubiquitinating enzymes (DUBs) remove ubiquitins from target proteins to reverse the modification of ubiquitination, and thusly affect a great number of signaling pathways, as well as viral infections. This review presents what is known about how viruses bypass or employ DUBs to evade host immune defenses and discusses new therapeutic strategies targeting DUBs for diseases treatment.

Resveratrol inhibits enterovirus 71 replication and pro-inflammatory cytokine secretion in rhabdosarcoma cells through blocking IKKs/NF-κB signaling pathway.

Polydatin and resveratrol, as major active components in Polygonum cuspidatum, have anti-inflammatory, antioxidant and antitumor functions. However, the effect and mechanism of polydatin and resveratrol on enterovirus 71 (EV71) have not been reported. In this study, resveratrol revealed strong antiviral activity on EV71, while polydatin had weak effect. Neither polydatin nor resveratrol exhibited influence on viral attachment. Resveratrol could effectively inhibit the synthesis of EV71/VP1 and the phosphorylation of IKKα, IKKß, IKKγ, IKBα, NF-κB p50 and NF-κB p65, respectively. Meanwhile, the remarkably increased secretion of IL-6 and TNF-α in EV71-infected rhabdosarcoma (RD) cells could be blocked by resveratrol. These results demonstrated that resveratrol inhibited EV71 replication and cytokine secretion in EV71-infected RD cells through blocking IKKs/NF-κB signaling pathway. Thus, resveratrol may have potent antiviral effect on EV71 infection.