Viperin inhibits interferon-γ production to promote Mycobacterium tuberculosis survival by disrupting TBK1-IKKε-IRF3-axis and JAK-STAT signaling.

OBJECTIVES AND DESIGN: As an interferon-inducible protein, Viperin has broad-spectrum antiviral effects and regulation of host immune responses. We aim to investigate how Viperin regulates interferon-γ (IFN-γ) production in macrophages to control Mycobacterium tuberculosis (Mtb) infection. METHODS: We use Viperin deficient bone-marrow-derived macrophage (BMDM) to investigate the effects and machines of Viperin on Mtb infection. RESULTS: Viperin inhibited IFN-γ production in macrophages and in the lung of mice to promote Mtb survival. Further insight into the mechanisms of Viperin-mediated regulation of IFN-γ production revealed the role of TANK-binding kinase 1 (TBK1), the TAK1-dependent inhibition of NF-kappa B kinase-epsilon (IKKε), and interferon regulatory factor 3 (IRF3). Inhibition of the TBK1-IKKε-IRF3 axis restored IFN-γ production reduced by Viperin knockout in BMDM and suppressed intracellular Mtb survival. Moreover, Viperin deficiency activated the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, which promoted IFN-γ production and inhibited Mtb infection in BMDM. Additionally, a combination of the anti-TB drug INH treatment in the absence of Viperin resulted in further IFN-γ production and anti-TB effect. CONCLUSIONS: This study highlights the involvement of TBK1-IKKε-IRF3 axis and JAK-STAT signaling pathways in Viperin-suppressed IFN-γ production in Mtb infected macrophages, and identifies a novel mechanism of Viperin on negatively regulating host immune response to Mtb infection.

Viperin deficiency promotes dendritic cell activation and function via NF-kappaB activation during Mycobacterium tuberculosis infection.

OBJECTIVES AND DESIGN: Dendritic cells (DCs) are one of the key immune cells in bridging innate and adaptive immune response against Mycobacterium tuberculosis (Mtb) infection. Interferons (IFNs) play important roles in regulating DC activation and function. Virus-inhibitory protein, endoplasmic reticulum-associated, interferon-inducible (Viperin) is one of the important IFN-stimulated genes (ISGs), and elicits host defense against infection. METHODS: We investigated the effects and mechanisms of Viperin on DC activation and function using Viperin deficient bone marrow-derived dendritic cells (BMDCs) during Mtb infection. RESULTS: Viperin deficiency enhanced phagocytic activity and increased clearance of Mtb in DCs, produced higher abundance of NO, cytokine including interleukin-12 (IL-12), Tumor necrosis factor-α (TNF-α), IL-1ß, IL-6 and chemokine including CXCL1, CXCL2 and CXCL10, elevated MHC I, MHC II and co-stimulatory molecules expression, and enhanced CD4+ and CD8+ T cell responses. Mechanistically, Viperin deficiency promoted DC activation and function through NF-κB p65 activation. NF-κB p65 inhibitor prevented cytokine and chemokine production, and co-stimulatory molecules expression promoted by Viperin deficiency. CONCLUSIONS: These results suggest that Mtb induced Viperin expression could impair the activation of host defense function of DCs and DC-T cell cross talk during Mtb infection. This research may provide a potential target for future HDT in TB therapy.

Manipulation of polarization conversion and dual foci in a twisted caustic vector optical field in free space.

Manipulation of polarization states in a complex structured optical field during propagation has become an important topic due to its fundamental interest and potential applications. This work demonstrates the effect of the caustic and twisting phases on the polarization states of a vector beam experimentally and theoretically. The novel properties of polarization evolution, especially the conversions of different states of polarization (SoPs) in a twisted caustic vector beam, occur during propagation in free space because of the modulation of twisting and caustic phases. The orthogonal polarization components tend to appear on the beam centers of two foci, and the two focal distances are closely related to the caustic and twisting phases. The twisting and caustic phases can manipulate the conversions between linear and circular polarization components that occur during propagation. These results provide a new approach to more complex manipulations of a structured optical field, especially in tailoring the evolution of polarization states and two foci. They may find potential applications in the corresponding field.

Sorafenib suppresses the activation of type I interferon pathway induced by RLR-MAVS and cGAS-STING signaling.

Type I interferon pathway is a crucial component of innate immune signaling upon pathogen infection or endogenous instability. An imbalance of type I interferon can lead to many diseases, such as autoimmune diseases and inflammatory diseases. Meanwhile, the side effects of clinical drugs on type I interferon signaling may result in impaired outcomes in clinical treatment, especially in cancer immunotherapy which is associated with type I interferon signaling. Here, we found that sorafenib, an FDA-approved drug for HCC chemotherapy, suppresses both DNA- and RNA-sensing mediated type I interferon pathway. Mechanistically, sorafenib treatment induces the autophagic degradation of MAVS, cGAS, TBK1, and IRF3, and attenuates the signaling transduction. In addition, sorafenib also inhibits the recruiting of STING or MAVS with TBK1 and IRF3. This work reveals the negative role of sorafenib in the regulation of type I interferon pathway. Sorafenib treatment is not only a potential drug for autoimmune disease and inflammation diseases, but also needs to be noticed in HCC chemotherapy.

TRIM25 Promotes TNF-α-Induced NF-κB Activation through Potentiating the K63-Linked Ubiquitination of TRAF2.

As an important effector in response to various intracellular or extracellular stimuli, the NF-κB family extensively participates in a wide spectrum of biological events, and its dysregulation may result in many pathological conditions, such as microbial infection, tumor progression, and neurodegenerative disorders. Previous investigations showed that multiple types of ubiquitination play critical roles in the modulation of the NF-κB signaling pathway, yet the molecular mechanisms are still poorly understood. In the current study, we identified TRIM25, an E3 ubiquitin ligase, as a novel positive regulator in mediating NF-κB activation in human embryonic kidney 293T (HEK293T), HeLa cells, THP-1 cells, and PBMCs. The expression of TRIM25 promoted TNF-α-induced NF-κB signaling, whereas the knockdown had the opposite effect. Furthermore, TRIM25 interacted with TRAF2 and enhanced the K63-linked polyubiquitin chains attached to TRAF2. Moreover, TRIM25 bridged the interaction of TRAF2 and TAK1 or IKKß. To our knowledge, our study has identified a previously unrecognized role for TRIM25 in the regulation of NF-κB activation by enhancing the K63-linked ubiquitination of TRAF2.

EsigGOBP1: The Key Protein Binding Alpha-Phellandrene in Endoclita signifer Larvae.

Endoclita signifer larvae show olfactory recognition towards volatiles of eucalyptus trunks and humus soils. Further, EsigGOBP1 was identified through larval head transcriptome and speculated as the main odorant-binding proteins in E. signifer larvae. In this study, the highest expression of EsigGOBP1 was only expressed in the heads of 3rd instar larvae of E. signifer, compared with the thorax and abdomen; this was consistent with the phenomenon of habitat transfer of 3rd instar larvae, indicating that EsigGOBP1 was a key OBP gene in E. signifer larvae. Results of fluorescence competition binding assays (FCBA) showed that EsigGOBP1 had high binding affinities to eight GC-EAD active ligands. Furthermore, screening of key active odorants for EsigGOBP1 and molecular docking analysis, indicated that EsigGOBP1 showed high binding activity to alpha-phellandrene in 3rd instar larvae of E. signifer. Conformational analysis of the EsigGOBP1-alpha-phellandrene complex, showed that MET49 and GLU38 were the key sites involved in binding. These results demonstrated that EsigGOBP1 is a key odorant-binding protein in E. signifer larvae, which recognizes and transports eight key volatiles from eucalyptus trunk, especially the main eucalyptus trunks volatile, alpha-phellandrene. Taken together, our results showed that EsigGOBP1 is involved in host selection of E. signifer larvae, which would aid in developing EsigGOBP1 as molecular targets for controlling pests at the larval stage.

Clinical Relevance of Splenic Hilar Lymph Node Dissection for Proximal Gastric Cancer: A Propensity Score-Matching Case-Control Study.

BACKGROUND: The application of splenic hilar lymph node (no. 10 LN) dissection (no. 10 LND) for proximal gastric cancer (PGC) remains controversial. This study aimed to investigate the clinical relevance of no. 10 LND from the perspective of long-term survival. METHODS: The main study population included 995 previously untreated patients who underwent laparoscopic radical total gastrectomy between January 2008 and December 2014. Of these 995 patients, 564 underwent no. 10 LND (no. 10D+ group) and the remaining 431 patients did not (no. 10D- group). Propensity score-matching was applied to reduce the effects of confounding factors. The study end points were overall survival (OS) and disease-free survival (DFS). Additionally, 39 patients who received neoadjuvant chemotherapy during the same period also were included as a separate population for analysis. RESULTS: The metastasis rate for no. 10 LN was 10.5 % (59/564). No significant differences were observed in intra- and postoperative complications nor in mortality between the no. 10D+ and no. 10D- groups (all P > 0.05). After 1:1 matching, the two groups were comparable in clinicopathologic characteristics. The no. 10D+ group had significantly better survival than the no. 10D- group (5-year OS: 63.3 % vs 52.2 %, P = 0.003; 5-year DFS: 60.4 % vs 48.1 %, P = 0.013). For the patients who received neoadjuvant chemotherapy, the 5-year OS rates in the no. 10D+ and no. 10D- groups were respectively 50.6 % and 31.3 % (P = 0.150) and the 5-year DFS rates were respectively 51.5 % and 31.3 % (P = 0.123). CONCLUSIONS: Patients with untreated PGC may achieve the benefit of long-term survival from no. 10 LND. For patients with PGC who undergo neoadjuvant chemotherapy, no. 10 LND may not bring survival benefits. However, further validation with a large-sample study is needed.

Direct and pleiotropic effects of the Masou Salmon Delta-5 Desaturase transgene in F1 channel catfish (Ictalurus punctatus).

Channel catfish (Ictalurus punctatus) is the primary culture species in the US along with its hybrid made with male blue catfish, I. furcatus. In an effort to improve the nutritional value of channel catfish, the masou salmon Δ5-desaturase like gene (D5D) driven by the common carp beta-actin promoter (ßactin) was inserted into channel catfish. The objectives of this study were to determine the effectiveness of ßactin-D5D for improving n-3 fatty acid production in F1 transgenic channel catfish, as well as examine pleiotropic effects on growth, proximate analysis, disease resistance, and other performance traits. Transgenic F1 channel catfish showed a 33% increase in the relative proportion of n-3 fatty acids coupled with a 15% decrease in n-6 fatty acids and a 17% decrease in n-9 fatty acids when compared to non-transgenic full-siblings (P < 0.01, P < 0.01, P < 0.01). However, while the relative proportion of n-3 fatty acids was achieved, the total amount of fatty acids in the transgenic fish decreased resulting in a reduction of all fatty acids. Insertion of the ßactin-D5D transgene into channel catfish also had large effects on the body composition, and growth of channel catfish. Transgenic channel catfish grew faster, were more disease resistant, had higher protein and moisture percentage, but lower fat percentage than full-sib controls. There were sex effects as performance changes were more dramatic and significant in males. The ßactin-D5D transgenic channel catfish were also more uniform in their fatty acid composition, growth and other traits.

Prognostic importance of dynamic changes in systemic inflammatory markers for patients with gastric cancer.

PURPOSE: To investigate the effect of dynamic changes in systemic inflammatory markers (SIM) on long-term prognosis of patients with gastric cancer (GC). METHODS: A retrospective analysis was performed on the data of 2180 patients with GC who underwent radical gastrectomy in the Fujian medical university Union Hospital from January 2009 to December 2014. Changes in SIM between preoperatively and 1-6 months and 12 months postoperatively were reported. RESULTS: In multivariate analysis, higher preoperative systemic inflammation score (pre-SIS) was independent predictor of poor prognosis (p < 0.05). The optimal time of remeasurement was 12 months postoperatively, based on a longitudinal profile of SIS and accuracy in predicting 5-year overall survival (OS) (area under the curve: 0.712 [95% confidence interval: 0.630-0.785]). According to the association between the conversion of SIS and OS, we classified patients into three risk groups. Kaplan-Meier curves showed significant differences in OS among risk groups. Further Cox multivariate regression analysis showed that only risk groups of SIS and pTNM stage were independent prognostic factors for OS. CONCLUSION: The efficacy of SIS in predicting prognosis 12 months after surgery is superior, and the elevation of SIS 12 months after surgery predicts poor prognosis.

Age-adjusted Charlson Comorbidity Index (ACCI) is a significant factor for predicting survival after radical gastrectomy in patients with gastric cancer.

INTRODUCTION: To assess the ability of the Age-Adjusted Charlson Comorbidity Index (ACCI) to predict survival after radical gastrectomy in patients with gastric cancer (GC). METHOD: Data from patients with GC who underwent radical gastrectomy from January 2008 to December 2012 in Fujian Medical University Union Hospital were retrospectively analyzed. Patients were categorized into either high ACCI group or low ACCI group based on the effect of ACCI on long-term GC prognosis. 1:1 propensity score matching (PSM) was used to reduce confounding bias. To further analyze the impact of ACCI on the long-term prognosis of patients after radical gastrectomy, a nomogram was built based on the Cox proportional hazards regression model. RESULTS: A total of 1476 patients were included in the analysis. After PSM, there was no statistically significant differences in tumor location, tumor size and tumor stage between low ACCI group (429 cases) and high ACCI group (429 cases) (all P > 0.05). Before and after PSM, the incidence of postoperative complications in high ACCI group was significantly higher than that in low ACCI group (P < 0.05). The 5-year overall survival rate (OS) in low ACCI group was significantly higher than that in high ACCI group. Multivariate analysis showed that ACCI was an independent risk factor for OS (P < 0.05). The Harrell's C-statistics (C-index) of TNMA, a prognostic evaluation system combining ACCI and TNM staging system, was significantly higher than that of TNM staging system in both the modeling and validation groups (all P < 0.05). CONCLUSIONS: ACCI was an independent risk factor for the long-term prognosis of GC patients after radical gastrectomy that could effectively improve the predictive efficacy of the TNM staging system for GC.

Influence of Heat Treatment Condition on the Microstructure, Microhardness and Corrosion Resistance of Ag-Sn-In-Ni-Te Alloy Wire.

Ag-Sn-In-Ni-Te alloy ingots were produced through a heating-cooling combined mold continuous casting technique; they were then drawn into wires. However, during the drawing process, the alloy wires tended to harden, making further diameter reduction challenging. To overcome this, heat treatment was necessary to soften the previously drawn wires. The study investigated how variations in heat treatment temperature and holding time affected the microstructure, microhardness and corrosion resistance of the alloy wires. The results indicate that the alloy wires subjected to heat treatment at 700 °C for 2 h not only exhibited a uniform microstructure distribution, but also demonstrated low microhardness and excellent corrosion resistance.

Effect of Chemical Composition on the Thermoplastic Formability and Nanoindentation of Ti-Based Bulk Metallic Glasses.

A series of Ti41Zr25Be34-xNix (x = 4, 6, 8, 10 at.%) and Ti41Zr25Be34-xCux (x = 4, 6, 8 at.%) bulk metallic glasses were investigated to examine the influence of Ni and Cu content on the viscosity, thermoplastic formability, and nanoindentation of Ti-based bulk metallic glasses. The results demonstrate that Ti41Zr25Be30Ni4 and Ti41Zr25Be26Cu8 amorphous alloys have superior thermoplastic formability among the Ti41Zr25Be34-xNix and Ti41Zr25Be34-xCux amorphous alloys due to their low viscosity in the supercooled liquid region and wider supercooled liquid region. The hardness and modulus exhibit obvious variations with increasing Ni and Cu content in Ti-based bulk metallic glasses, which can be attributed to alterations in atomic density. Optimal amounts of Ni and Cu in Ti-based bulk metallic glasses enhance thermoplastic formability and mechanical properties. The influence of Ni and Cu content on the hardness of Ti-based bulk metallic glasses is discussed from the perspective of the mean atomic distance.

Gamma-Aminobutyric Acid Enhances Cadmium Phytoextraction by Coreopsis grandiflora by Remodeling the Rhizospheric Environment.

Gamma-aminobutyric acid (GABA) significantly affects plant responses to heavy metals in hydroponics or culture media, but its corresponding effects in plant-soil systems remain unknown. In this study, different GABA dosages (0-8 g kg-1) were added to the rhizosphere of Coreopsis grandiflora grown in Cd-contaminated soils. Cd accumulation in the shoots of C. grandiflora was enhanced by 38.9-159.5% by GABA in a dose-dependent approach because of accelerated Cd absorption and transport. The increase in exchangeable Cd transformed from Fe-Mn oxide and carbonate-bound Cd, which may be mainly driven by decreased soil pH rather than GABA itself, could be a determining factor responsible for this phenomenon. The N, P, and K availability was affected by multiple factors under GABA treatment, which may regulate Cd accommodation and accumulation in C. grandiflora. The rhizospheric environment dynamics remodeled the bacterial community composition, resulting in a decline in overall bacterial diversity and richness. However, several important plant growth-promoting rhizobacteria, especially Pseudomonas and Sphingomonas, were recruited under GABA treatment to assist Cd phytoextraction in C. grandiflora. This study reveals that GABA as a soil amendment remodels the rhizospheric environment (e.g., soil pH and rhizobacteria) to enhance Cd phytoextraction in plant-soil systems.

Verticillium dahliae Effector VdCE11 Contributes to Virulence by Promoting Accumulation and Activity of the Aspartic Protease GhAP1 from Cotton.

Verticillium dahliae is a soilborne plant fungal pathogen that causes Verticillium wilt, a disease that reduces the yields of many economically important crops. Despite its worldwide distribution and harmful impacts, much remains unknown regarding how the numerous effectors of V. dahliae modulate plant immunity. Here, we identified the intracellular effector VdCE11 that induces cell death and defense responses in Nicotiana benthamiana to counter leaf pathogens such as Sclerotinia sclerotiorum and Botrytis cinerea. VdCE11 also contributes to the virulence of V. dahliae in cotton and Arabidopsis. Yeast two-hybrid library screening and immunoprecipitation revealed that VdCE11 interacts physically with the cotton aspartic protease GhAP1. GhAP1 and its Arabidopsis homolog AtAP1 are negative regulators of plant immunity, since disruption of either increased the resistance of cotton or Arabidopsis to V. dahliae. Further, VdCE11 plays a role in promoting the accumulation of the AP1 proteins and increasing its hydrolase activity. Taken together, these results indicate a novel mechanism regulating virulence whereby the secreted effector VdCE11 increases cotton susceptibility to V. dahliae by promoting the accumulation and activity of GhAP1. IMPORTANCE Verticclium dahliae is a plant fungal pathogen that causes a destructive vascular disease on a large number of plant hosts, resulting in great threat to agricultural production. In this study, we identified a V. dahliae effector VdCE11 that induces cell death and defense responses in Nicotiana benthamiana. Meanwhile, VdCE11 contributes to the virulence of V. dahliae in cotton and Arabidopsis. Yeast two-hybrid library screening and immunoprecipitation revealed that VdCE11 interacts physically with the cotton aspartic protease GhAP1. GhAP1 and its Arabidopsis homolog AtAP1 are negative regulators of plant immunity since disruption of either increased the resistance of cotton or Arabidopsis to V. dahliae. Further research showed that VdCE11 plays a role in promoting the accumulation of the AP1 proteins and increasing its hydrolase activity. These results suggested that a novel mechanism regulating virulence whereby VdCE11 increases susceptibility to V. dahliae by promoting the accumulation and activity of GhAP1 in the host.

Comparison of Cold-Sprayed Coatings of Copper-Based Composite Deposited on AZ31B Magnesium Alloy and 6061 T6 Aluminum Alloy Substrates.

Copper-coated graphite and copper mixture powders were deposited on AZ31B magnesium alloy and 6061 T6 aluminum alloy substrates under different process parameters by a solid-state cold spray technique. The microstructure of the copper-coated graphite and copper composite coatings was visually examined using photographs taken with an optical microscope and a scanning electron microscope. The surface roughness of the coatings was investigated with a 3D profilometer. The thickness of the coatings was determined through the analysis of the microstructure images, while the adhesion of the coatings was characterized using the scratch test method. The results indicate that the surface roughness of the coatings sprayed on the two different substrates gradually decreases as gas temperature and gas pressure increase. Additionally, the thickness and adhesion of the coatings deposited on the two different substrates both increase with an increase in gas temperature and gas pressure. Comparing the surface roughness, thickness, and adhesion of the coatings deposited on the two different substrates, the surface roughness and adhesion of the coatings on the soft substrate are greater than those of the coatings on the hard substrate, while the thickness of the coatings is not obviously affected by the hardness of the substrate. Furthermore, it is noteworthy that the surface roughness, thickness, and adhesion of the copper-coated graphite and copper composite coatings sprayed on the two different substrates exhibit a distinct linear relationship with particle velocity.

Long-term prognostic benefit of adjuvant chemotherapy for patients with hepatoid adenocarcinoma of the stomach after radical resection: A national multicenter study.

BACKGROUND: There is no consensus on whether adjuvant chemotherapy (AC) is effective for hepatoid adenocarcinoma of the stomach (HAS). The aim of this study was to investigate the relationship between AC and the long-term prognosis of patients with HAS. METHODS: The clinicopathological data of 239 patients with primary HAS who underwent radical surgery from April 1, 2004 to December 31, 2019 in 14 centers in China were retrospectively analyzed. Patients were divided into the AC group (127 patients) and the nonadjuvant chemotherapy (NAC) group (112 patients). RESULTS: Kaplan‒Meier (KM) analysis showed that there were no significant differences in the 1-year3-year overall survival rate (OS) and 1-year, 3-year recurrence-free survival rate (RFS) between the AC group and the NAC group (1-year OS: 85.6% vs. 79.8%, 3-year OS: 59.8% vs. 62.4%, 1-year RFS: 69.8% vs. 74.4%, 3-year RFS: 57.2% vs. 55.9%, all P > 0.05). The subpopulation treatment effect pattern plots (STEPP) did not show treatment heterogeneity of AC in patients with HAS. The proportions of local recurrence and metastasis sites in the two groups were similar. Although the smoothed hazard curves of the NAC and AC groups crossed, the peak hazard time was later in the AC group (5.9 and 4.7 months), and the peak hazard rate was lower (0.032 and 0.038, P = 0.987). CONCLUSION: The current AC regimen may not significantly improve the survival of patients with HAS after radical surgery.

Phytoremediation potential evaluation of three rhubarb species and comparative analysis of their rhizosphere characteristics in a Cd- and Pb-contaminated soil.

Screening or breeding exceptional plant species for heavy metal phytoremediation is as important as adopting feasible measures to enhance phytoremediation efficiency, which are largely based on clarifying the mechanisms of heavy metal tolerance and accumulation by plants. In this study, cadmium (Cd) and lead (Pb) tolerance and accumulation characteristics of Rheum officinale, R. palmatum, and R. tanguticum were analysed to assess their phytoremediation potential. The seed germination test indicated that these three rhubarb species could tolerate 10 mg L-1 Cd and 100 mg L-1 Pb. However, when sown in Cd- and Pb-contaminated soil, all three rhubarb species exhibited a relatively high Cd accumulation capacity but a considerably low Pb accumulation capacity according to the bioconcentration factors of Cd (0.42-0.47 in shoots and 0.11-0.15 in roots) and Pb (0.004-0.008 in shoots and 0.007-0.013 in roots). The high Cd translocation factors (3.04-4.24) indicated that these three rhubarb species were suitable for Cd phytoextraction. The changes in rhizospheric physicochemical indices were generally similar among the three rhubarb plants in comparison with those of the unplanted soil. However, differential indicator rhizobacteria were identified for the three rhubarb plants, which may be primarily attributed to their different root system characteristics. These enriched rhizobacteria included many plant growth-promoting bacteria, and several of them were also involved in regulating heavy metal uptake by plants, indicating that three rhubarb species likely recruit differentially beneficial rhizobacteria to maintain plant growth and vitality and to regulate heavy metal uptake in the Cd- and Pb-polluted soil. This study identifies new candidate plant resources for the phytoremediation of Cd-polluted soils and provides novel insights into understanding the interactions among heavy metals, rhizobacteria, and plants.

Hyperbaric oxygen facilitates teniposide-induced cGAS-STING activation to enhance the antitumor efficacy of PD-1 antibody in HCC.

BACKGROUND: Emerging evidence indicates that the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis plays a pivotal role in intrinsic antitumor immunity. Previous studies demonstrate that the conventional chemotherapy agent, teniposide, effectively promotes the therapeutic efficacy of programmed cell death protein-1 antibody (PD-1 Ab) through robust cGAS-STING activation. Unfortunately, the cGAS expression of tumor cells is reported to be severely suppressed by the hypoxic status in solid tumor. Clinically, enhancing chemotherapy-induced, DNA-activated tumor STING signaling by alleviating tumor hypoxia might be one possible direction for improving the currently poor response rates of patients with hepatocellular carcinoma (HCC) to PD-1 Ab. METHODS: Teniposide was first screened out from several chemotherapy drugs according to their potency in inducing cGAS-STING signaling in human HCC cells. Teniposide-treated HCC cells were then cultured under hypoxia, normoxia or reoxygenation condition to detect change in cGAS-STING signaling. Next, oxaliplatin/teniposide chemotherapy alone or combined with hyperbaric oxygen (HBO) therapy was administered on liver orthotopic mouse tumor models, after which the tumor microenvironment (TME) was surveyed. Lastly, teniposide alone or combined with HBO was performed on multiple mouse tumor models and the subsequent anti-PD-1 therapeutic responses were observed. RESULTS: Compared with the first-line oxaliplatin chemotherapy, teniposide chemotherapy induced stronger cGAS-STING signaling in human HCC cells. Teniposide-induced cGAS-STING activation was significantly inhibited by hypoxia inducible factor 1α in an oxygen-deficient environment in vitro and the inhibition was rapidly removed via effective reoxygenation. HBO remarkably enhanced the cGAS-STING-dependent tumor type Ⅰ interferon and nuclear factor kappa-B signaling induced by teniposide in vivo, both of which contributed to the activation of dendritic cells and subsequent cytotoxic T cells. Combined HBO with teniposide chemotherapy improved the therapeutic effect of PD-1 Ab in multiple tumor models. CONCLUSIONS: By combination of two therapies approved by the Food and Drug Administration, we safely stimulated an immunogenic, T cell-inflamed HCC TME, leading to further sensitization of tumors to anti-PD-1 immunotherapy. These findings might enrich therapeutic strategies for advanced HCC andwe can attempt to improve the response rates of patients with HCC to PD-1 Ab by enhancing DNA-activated STING signaling through effective tumor reoxygenation.

UCHL1 Promoted Polarization of M1 Macrophages by Regulating the PI3K/AKT Signaling Pathway.

BACKGROUND: As deubiquitinases (DUBs), ubiquitin C-terminal hydrolase (UCH)-L1 has been shown to play a crucial role in regulating diverse biological processes. However, its function in macrophage polarization remains unclear. METHODS: We performed in vivo and in vitro experiments to investigate the role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), a kind of DUBs, in macrophage differentiation by using UCHL1-deficiency mice. RESULTS: We demonstrated that LPS stimulation induced UCHL1 expression in macrophages. The deficiency of UCHL1 expression decreased the expression of CD80 and CD86 but increased the expression of CD206. The expression of TNF-α, IL-6, iNOS, and IL-10 was downregulated, while that of Arg1, Ym1, and Fizz1 was upregulated in UCHL1 deficient macrophages. Moreover, we observed that UCHL1 promoted the degradation of p110α through autophagy, but paradoxically increased the activity of AKT, thereby promoting polarization of macrophages into pro-inflammatory states. CONCLUSION: In this study, we identified UCHL1 as a positive regulator of M1 macrophage polarization. Our findings may help in developing therapeutic interventions for the treatment of inflammatory diseases and pathogenic infections.

Viperin impairs the innate immune response through the IRAK1-TRAF6-TAK1 axis to promote Mtb infection.

Mycobacterium tuberculosis (Mtb) infection is a long-standing public health threat, and the development of host-directed therapy for eradicating Mtb infection requires better insights into Mtb-host interactions. Viperin [virus-inhibitory protein, endoplasmic reticulum-associated, interferon (IFN) inducible] is an IFN-inducible protein with broad antiviral activities. Here, we demonstrated that Viperin was increased in abundance in patients with lymphatic and pulmonary tuberculosis (TB). Viperin-deficient mice had decreased Mtb bacterial loads and enhanced macrophage responses compared with their wild-type counterparts. Viperin suppressed the formation of a complex containing interleukin-1 receptor-associated kinase 1, TNF receptor-associated factor 6, and transforming growth factor ß-activated kinase 1 (TAK1) and inhibited the TAK1-dependent activation of IκB kinase α/ß, thereby impairing the production of nitric oxide and proinflammatory cytokines. These results suggest that Viperin promotes Mtb infection by inhibiting host innate immune responses in macrophages, suggesting that Viperin may be a candidate target for adjunct host-directed therapy in patients with TB.