Surface hydrophobization of zeolite enables mass transfer matching in gas-liquid-solid three-phase hydrogenation under ambient pressure.

Attaining high hydrogenation performance under mild conditions, especially at ambient pressure, remains a considerable challenge due to the difficulty in achieving efficient mass transfer at the gas-liquid-solid three-phase interface. Here, we present a zeolite nanoreactor with joint gas-solid-liquid interfaces for boosting H2 gas and substrates to involve reactions. Specifically, the Pt active sites are encapsulated within zeolite crystals, followed by modifying the external zeolite surface with organosilanes. The silane sheath with aerophilic/hydrophobic properties can promote the diffusion of H2 and the mass transfer of reactant/product molecules. In aqueous solutions, the gaseous H2 molecules can rapidly diffuse into the zeolite channels, thereby augmenting H2 concentration surround Pt sites. Simultaneously, the silane sheath with lipophilicity nature promotes the enrichment of the aldehydes/ketones on the catalyst and facilitates the hydrophilia products of alcohol rediffusion back to the aqueous phase. By modifying the wettability of the catalyst, the hydrogenation of aldehydes/ketones can be operated in water at ambient H2 pressure, resulting in a noteworthy turnover frequency up to 92.3 h-1 and a 4.3-fold increase in reaction rate compared to the unmodified catalyst.

Cascaded p-d Orbital Hybridization Interaction in Ultrathin High-Entropy Alloy Nanowires Boosts Complete Non-CO Pathway of Methanol Oxidation Reaction.

Designing high efficiency platinum (Pt)-based catalysts for methanol oxidation reaction (MOR) with high "non-CO" pathway selectivity is strongly desired and remains a grand challenge. Herein, PtRuNiCoFeGaPbW HEA ultrathin nanowires (HEA-8 UNWs) are synthesized, featuring unique cascaded p-d orbital hybridization interaction by inducing dual p-block metals (Ga and Pb). In comparison with Pt/C, HEA-8 UNWs exhibit 15.0- and 4.2-times promotion of specific and mass activity for MOR. More importantly, electrochemical in situ FITR spectroscopy reveals that the production/adsorption of CO (CO*) intermediate is effectively avoided on HEA-8 UNWs, leading to the complete "non-CO" pathway for MOR. Theoretical calculations demonstrate the optimized electronic structure of HEA-8 UNWs can facilitates a lower energy barrier for the "non-CO" pathway in the MOR.

Tumor-infiltrating mast cells stimulate ICOS+ regulatory T cells through an IL-33 and IL-2 axis to promote gastric cancer progression.

INTRODUCTION: In solid tumors, regulatory T cell (Treg) and mast cell perform different roles depending on the microenvironment. Nevertheless, mast cell and Treg-mediated interactions in gastric cancer (GC) are unclear, as are their regulation, function, and clinical significance. OBJECTIVE: The present study demonstrated the mechanism of tumor-infiltrating mast cells stimulating ICOS+ regulatory T cells via the IL-33/IL-2 axis to promote the growth of gastric cancer. METHODS: Analyses of 98 patients with GC were conducted to examine mast cell counts, ICOS+ Tregs, and the levels of IL-33 or IL-2. Isolated ICOS+ Treg and CD8+ T cell were stimulated, cultured and tested for their functional abilities in vitro and in vivo. RESULTS: GC patients exhibited a significantly more production of IL-33 in tumors. Mast cell stimulated by tumor-derived IL-33 exhibited a prolonged lifespan through IL-33 mediated inhibition of apoptosis. Moreover, mast cells stimulated by tumor-derived IL-33 secreted IL-2, which induced Treg expansion. These inducible Tregs displayed an activated immunosuppressive phenotype with positive expression for the inducible T cell co-stimulator (ICOS). In vitro, IL-2 from IL to 33-stimulated mast cells induced increased numbers of ICOS+ Tregs with increased immunosuppressive activity against proliferation and effector function of CD8+ T cell. In vivo, ICOS+ Tregs were treated with anti-IL-2 neutralizing antibody followed by co-injection with CD8+ T cells in GC mouse model, which showed an increased CD8+ T cell infiltration and effector molecules production, meanwhile tumor growth and progression were inhibited. Besides, reduction in GC patient survival was associated with tumor-derived ICOS+ Tregs. CONCLUSION: Our results highlight a crosstalk between GC-infiltrating mast cells and ICOS+ Tregs and provide a novel mechanism describing ICOS+ Treg expansion and induction by an IL-33/mast cell/IL-2 signaling axis in GC, and also provide functional evidence that the modulation of this immunosuppressive pathway can attenuate GC-mediated immune tolerance.

Graphynes and Graphdiynes for Energy Storage and Catalytic Utilization: Theoretical Insights into Recent Advances.

Carbon allotropes have contributed to all aspects of people's lives throughout human history. As emerging carbon-based low-dimensional materials, graphyne family members (GYF), represented by graphdiyne, have a wide range potential applications due to their superior physical and chemical properties. In particular, graphdiyne (GDY), as the leader of the graphyne family, has been practically applied to various research fields since it was first successfully synthesized. GYF have a large surface area, both sp and sp2 hybridization, and a certain band gap, which was considered to originate from the overlap of carbon 2pz orbitals and the inhomogeneous π-bonds of carbon atoms in different hybridization forms. These properties mean GYF-based materials still have many potential applications to be developed, especially in energy storage and catalytic utilization. Since most of the GYF have yet to be synthesized and applications of successfully synthesized GYF have not been developed for a long time, theoretical results in various application fields should be shared to experimentalists to attract more intentions. In this Review, we summarized and discussed the synthesis, structural properties, and applications of GYF-based materials from the theoretical insights, hoping to provide different viewpoints and comments.

A pH/H2 O2 /MMP9 Time-Response Gel System with Sparchigh Tregs Derived Extracellular Vesicles Promote Recovery After Acute Myocardial Infarction.

Regulatory T cells overexpressing SPARC (secreted protein acidic and cysteine rich) (Sparchigh Tregs) can help repair infarct tissues after acute myocardial infarction (AMI). This research demonstrates that Sparchigh Treg-derived extracellular vesicles (EVs) effectively improved cardiac function through proinflammatory factors IL-1ß, IL-6, and TNF-α inhibition and collagen synthesis related gene Col3a1 promotion in AMI; moreover, a composite hydrogel-EVs system (DHPM(4APPC)_EVs) is designed based on Sparchigh Treg-derived EVs with CXCR2 overexpressing and pH/H2 O2 /MMP9 temporally responsive gel microspheres. In AMI, due to the levels of chemokine, pH, H2 O2 , and MMP9 enzymes in the infarct area, DHPM(4APPC)_EVs can effectively target the infarct area, release the loaded EVs, form the gel to capture the released EVs, and slowly release the captured EVs, contribute to promote EVs to stay in the infarct area for a long time to play the repair function, so as to reduce myocardial injury and promote the improvement of cardiac function. The proposed system in this research provides a potential approach for the treatment of AMI in the future.

Targeted Intervention of NF2-YAP Signaling Axis in CD24-Overexpressing Cells Contributes to Encouraging Therapeutic Effects in TNBC.

Triple-negative breast cancer (TNBC) cells have not been usefully classified, and no targeted therapeutic plans are currently available, resulting in a high recurrence rate and metastasis potential. In this research, CD24high cells accounted for the vast majority of TNBC cells, and they were insensitive to Taxol but sensitive to ferroptosis agonists and effectively escaped phagocytosis by tumor-associated macrophages. Furthermore, the NF2-YAP signaling axis modulated the expression of ferroptosis suppressor protein 1 (FSP1) and CD24 in CD24high cells, with subsequent ferroptotic regulation and macrophage phagocytosis. In addition, a precision targeted therapy system was designed based on the pH level and glutathione response, and it can be effectively used to target CD24high cells to induce lysosomal escape and drug burst release through CO2 production, resulting in enhanced ferroptosis and macrophage phagocytosis through FSP1 and CD24 inhibition mediated by the NF2-YAP signaling axis. This system achieved dual antitumor effects, ultimately promoting cell death and thus inhibiting TNBC tumor growth, with some tumors even disappearing. The composite nanoprecision treatment system reported in this paper is a potential strategic tool for future use in the treatment of TNBC.

Helicobacter pylori-induced REDD1 modulates Th17 cell responses that contribute to gastritis.

OBJECTIVE: Regulated in development and DNA damage responses-1 (REDD1) is a conserved and ubiquitous protein, which is induced in response to multiple stimuli. However, the regulation, function and clinical relevance of REDD1 in Helicobacter pylori-associated gastritis are presently unknown. APPROACH: Immunohistochemistry, real-time PCR and Western blot analyses were performed to examine the levels of REDD1 in gastric samples from H. pylori-infected patients and mice. Gastric tissues from Redd1-/- and wildtype (WT, control) mice were examined for inflammation. Gastric epithelial cells (GECs), monocytes and T cells were isolated, stimulated and/or cultured for REDD1 regulation and functional assays. RESULTS: REDD1 was increased in gastric mucosa of H. pylori-infected patients and mice. H. pylori induced GECs to express REDD1 via the phosphorylated cytotoxin associated gene A (cagA) that activated MAPKp38 pathway to mediate NF-κB directly binding to REDD1 promoter. Human gastric REDD1 increased with the severity of gastritis, and mouse REDD1 from non-marrow chimera-derived cells promoted gastric inflammation that was characterized by the influx of MHCII+ monocytes. Importantly, gastric inflammation, MHCII+ monocyte infiltration, IL-23 and IL-17A were attenuated in Redd1-/- mice. Mechanistically, REDD1 in GECs regulated CXCL1 production, which attracted MHCII+ monocytes migration by CXCL1-CXCR2 axis. Then H. pylori induced MHCII+ monocytes to secrete IL-23, which favored IL-17A-producing CD4+ cell (Th17 cell) polarization, thereby contributing to the development of H. pylori-associated gastritis. CONCLUSIONS: The present study identifies a novel regulatory network involving REDD1, which collectively exert a pro-inflammatory effect within gastric microenvironment. Efforts to inhibit this REDD1-dependent pathway may prove valuable strategies in treating of H. pylori-associated gastritis.

L-Plastin Promotes Gastric Cancer Growth and Metastasis in a Helicobacter pylori cagA-ERK-SP1-Dependent Manner.

Actin cytoskeleton dynamic rearrangement is required for tumor cell metastasis and is a key characteristic of Helicobacter pylori (H. pylori)-infected host cells. Actin cytoskeleton modulation is coordinated by multiple actin-binding proteins (ABP). Through Kyoto encyclopedia of gene and genomes database, GEPIA website, and real-time PCR data, we found that H. pylori infection significantly induced L-plastin, a key ABP, in gastric cancer cells. We further explored the regulation and function of L-plastin in H. pylori-associated gastric cancer and found that, mechanistically, H. pylori infection induced gastric cancer cells to express L-plastin via cagA-activated ERK signaling pathway to mediate SP1 binding to L-plastin promoter. Moreover, this increased L-plastin promoted gastric cancer cell proliferation and migration in vitro and facilitated the growth and metastasis of gastric cancer in vivo. Finally, we detected the expression pattern of L-plastin in gastric cancer tissues, and found that L-plastin was increased in gastric cancer tissues and that this increase of L-plastin positively correlated with cagA + H. pylori infection status. Overall, our results elucidate a novel mechanism of L-plastin expression induced by H. pylori, and a new function of L-plastin-facilitated growth and metastasis of gastric cancer, and thereby implicating L-plastin as a potential therapeutic target against gastric cancer. IMPLICATIONS: Our results elucidate a novel mechanism of L-plastin expression induced by H. pylori in gastric cancer, and a new function of L-plastin-facilitated gastric cancer growth and metastasis, implicating L-plastin as a potential therapeutic target against gastric cancer.

Helicobacter pylori-Induced Rev-erbα Fosters Gastric Bacteria Colonization by Impairing Host Innate and Adaptive Defense.

BACKGROUND & AIMS: Rev-erbα represents a powerful transcriptional repressor involved in immunity. However, the regulation, function, and clinical relevance of Rev-erbα in Helicobacter pylori infection are presently unknown. METHODS: Rev-erbα was examined in gastric samples from H pylori-infected patients and mice. Gastric epithelial cells (GECs) were isolated and infected with H pylori for Rev-erbα regulation assays. Gastric tissues from Rev-erbα-/- and wild-type (littermate control) mice or these mice adoptively transferred with CD4+ T cells from IFN-γ-/- and wild-type mice, bone marrow chimera mice and mice with in vivo pharmacological activation or inhibition of Rev-erbα were examined for bacteria colonization. GECs, CD45+CD11c-Ly6G-CD11b+CD68- myeloid cells and CD4+ T cells were isolated, stimulated and/or cultured for Rev-erbα function assays. RESULTS: Rev-erbα was increased in gastric mucosa of H pylori-infected patients and mice. H pylori induced GECs to express Rev-erbα via the phosphorylated cagA that activated ERK signaling pathway to mediate NF-κB directly binding to Rev-erbα promoter, which resulted in increased bacteria colonization within gastric mucosa. Mechanistically, Rev-erbα in GECs not only directly suppressed Reg3b and ß-defensin-1 expression, which resulted in impaired bactericidal effects against H pylori of these antibacterial proteins in vitro and in vivo; but also directly inhibited chemokine CCL21 expression, which led to decreased gastric influx of CD45+CD11c-Ly6G-CD11b+CD68- myeloid cells by CCL21-CCR7-dependent migration and, as a direct consequence, reduced bacterial clearing capacity of H pylori-specific Th1 cell response. CONCLUSIONS: Overall, this study identifies a model involving Rev-erbα, which collectively ensures gastric bacterial persistence by suppressing host gene expression required for local innate and adaptive defense against H pylori.

Implanting Atomic Dispersed Ru in PtNi Colloidal Nanocrystal Clusters for Efficient Catalytic Performance in Electro-oxidation of Liquid Fuels.

Although PtRu alloy nanocatalysts have been certified to possess excellent electrocatalytic performance and CO-poisoning tolerance toward formic acid and methanol electro-oxidation, the unaffordable usages of ruthenium (Ru) and platinum (Pt) have greatly limited their widespread adoption. Here, a facile one-pot method is reported for implanting atomic dispersed Ru in PtNi colloidal nanocrystal clusters with different Ru/Pt/Ni molar ratios, greatly reducing the dosages of Pt and Ru, and further improving the catalytic performances for the electro-oxidation of formic acid and methanol. Through simple control of the amount of Ni(acac)2 precursor, trimetallic Ru0.3 Pt70.5 Ni29.2 , Ru0.6 Pt55.9 Ni43.5 , Ru0.2 Pt77.3 Ni22.5 , and Ru0.9 Pt27.3 Ni71.8 colloidal nanocrystal clusters (CNCs) are obtained. In particular, the Ru0.3 Pt70.5 Ni29.2 CNCs exhibit excellent specific activities for formic acid and methanol electro-oxidation, that is, 14.2 and 15.3 times higher, respectively, than those of the Pt/C catalyst. Moreover, the Ru0.3 Pt70.5 Ni29.2 CNCs also possess better anti-CO-poisoning properties and diffusion ability than the other RuPtNi CNCs. The excellent formic acid and methanol electro-oxidation activities of RuPtNi CNCs are ascribed to the optimal ligand effects derived from the Pt, Ni, and atomic dispersed Ru atoms, which can improve the OH adsorption ability and further the anti-CO-poisoning capability. This research opens a new door for increasing the electro-oxidation properties of liquid fuels by using lower dosages of noble metals in Pt-based catalysts.

Noni (Morinda citrifolia L.) wine prevents the oxidative stress and obesity in mice induced by high-fat diet.

Noni (Morinda citrifolia L.) is rich in polyphenols, flavonoids, terpenoids, and iridoids. However, its bad taste and smell make noni fruit unsuitable for consumption. After fermentation, noni wine becomes free from the undesirable smell. Nevertheless, it is still unclear whether processed noni could retain its original nutrients and effects. Therefore, we conducted a series of evaluations on the nutritional composition and efficacy of noni wine. Our results showed that the polyphenol, flavonoid, and vitamin C contents in noni wine were 558.80, 234.42, and 0.30 mg/L, respectively. Our animal experiments showed that 40 ml kg-1  day-1 noni wine could reduce bodyweight, as well as the levels of body fat, serum triglycerides, total cholesterol, and low-density lipoprotein, while it simultaneously increased the amount of energy expenditure and activity, and improved the systemic antioxidant capacity in mice following a high-fat diet. The results of the gene expression and western blot analyses showed that 40 ml kg-1  day-1 noni wine could regulate the Nrf2 pathway and improve the antioxidant enzyme gene expression in mice maintained on a high-fat diet, thereby improving body lipid metabolism, reducing fatty acid synthesis, and promoting fatty acid ß-oxidation. Our study indicated that drinking 40 ml kg-1  day-1 noni wine could effectively prevent high-fat diet-induced oxidative stress and obesity in mice. PRACTICAL APPLICATIONS: Noni fruit is rich in nutrients but its bad smell and hardship of processing make its commercialization difficult. Previous studies mainly focused on fresh noni juice and its primary processed products, while few noni products, of poor taste and low quality, are available in the market. Therefore, the fruit wine with both the nutritive values and the special flavor of noni has broad market prospects. Our work provides a valuable reference for the commercialization of noni wine.

Gardner syndrome with a giant mass in the thoracic cavity: a case report and analysis of the related complications.

Gardner syndrome (GS) is a form of familial adenomatous polyposis (FAP) and is characterized by colonic polyposis, osteomas, and soft-tissue tumors. Desmoid tumors (DT) are lesions of mesenchymal origin and are an extra-colonic manifestation of GS. Gardner-associated fibroma (GAF) is considered to be a benign soft-tissue lesion related to DT and FAP. Here we present a case of an 18-year-old female patient with a huge lump in her right thoracic cavity and another lump located in her left lumbar muscles who was diagnosed with GS through a colonoscopy and through adenomatous polyposis coli (APC) gene mutation detection. The patient underwent a surgical resection of the right thoracic tumor. Three months later, the left waist lump underwent medical treatment with tamoxifen and celecoxib and was monitored using computed tomography (CT). Subsequently, colonoscopy screening was performed annually to prevent colorectal cancer. GAF is frequent in GS, and such a huge GAP in the thorax is very rare, with few cases reported in the literature. Patients with GS must be closely monitored, and clinical and imaging examinations must be performed to detect any signs of tumors.

PD-1 does not mark tumor-infiltrating CD8+ T cell dysfunction in human gastric cancer.

BACKGROUND: Overexpression of programmed cell death protein 1 (PD-1) is linked to CD8+ T cell dysfunction and contributes to tumor immune escape. However, the prevalence and functional regulations of PD-1 expression on CD8+ T cells in human gastric cancer (GC) remain largely unknown. METHODS: Flow cytometry was performed to analyze the level, phenotype, functional and clinical relevance of PD-1+CD8+ T cells in GC patients. Peripheral blood CD8+ T cells were purified and subsequently exposed to culture supernatants from digested primary GC tumor tissues (TSN) in vitro for PD-1 expression and functional assays. Tumor responses to adoptively transferred TSN-stimulated CD8+ T cells or to the TSN-stimulated CD8+ T cell transfer combined with an anti-PD-1 antibody injection were measured in an in vivo xenograft mouse model. RESULTS: GC patients' tumors showed a significantly increased PD-1+CD8+ T cell infiltration. However, these GC-infiltrating PD-1+CD8+ T cells showed equivalent function to their PD-1-CD8+ counterparts and they did not predict tumor progression. High level of transforming growth factor-ß1 (TGF-ß1) in tumors was positively correlated with PD-1+CD8+ T cell infiltration, and in vitro GC-derived TGF-ß1 induced PD-1 expression on CD8+ T cells via Smad3 signaling, whereas Smad2 signaling was involved in GC-derived TGF-ß1-mediated CD8+ T cell dysfunction. Furthermore, GC-derived TGF-ß1-mediated CD8+ T cell dysfunction contributed to tumor growth in vivo that could not be attenuated by PD-1 blockade. CONCLUSIONS: Our data highlight that GC-derived TGF-ß1 promotes PD-1 independent CD8+ T cell dysfunction. Therefore, restoring CD8+ T cell function by a combinational PD-1 and TGF-ß1 blockade might benefit future GC immunotherapy.

Arrestin domain containing 3 promotes Helicobacter pylori-associated gastritis by regulating protease-activated receptor 1.

Arrestin domain containing 3 (ARRDC3) represents a newly discovered α-arrestin involved in obesity, inflammation, and cancer. Here, we demonstrate a proinflammation role of ARRDC3 in Helicobacter pylori-associated gastritis. Increased ARRDC3 was detected in gastric mucosa of patients and mice infected with H. pylori. ARRDC3 in gastric epithelial cells (GECs) was induced by H. pylori, regulated by ERK and PI3K-AKT pathways in a cagA-dependent manner. Human gastric ARRDC3 correlated with the severity of gastritis, and mouse ARRDC3 from non-BM-derived cells promoted gastric inflammation. This inflammation was characterized by the CXCR2-dependent influx of CD45+CD11b+Ly6C-Ly6G+ neutrophils, whose migration was induced via the ARRDC3-dependent production of CXCL2 by GECs. Importantly, gastric inflammation was attenuated in Arrdc3-/- mice but increased in protease-activated receptor 1-/- (Par1-/-) mice. Mechanistically, ARRDC3 in GECs directly interacted with PAR1 and negatively regulated PAR1 via ARRDC3-mediated lysosomal degradation, which abrogated the suppression of CXCL2 production and following neutrophil chemotaxis by PAR1, thereby contributing to the development of H. pylori-associated gastritis. This study identifies a regulatory network involving H. pylori, GECs, ARRDC3, PAR1, and neutrophils, which collectively exert a proinflammatory effect within the gastric microenvironment. Efforts to inhibit this ARRDC3-dependent pathway may provide valuable strategies in treating of H. pylori-associated gastritis.

Helicobacter pylori-induced adrenomedullin modulates IFN-γ-producing T-cell responses and contributes to gastritis.

Adrenomedullin (ADM) is a multifunctional peptide that is expressed by many surface epithelial cells, but its relevance to Helicobacter pylori (H. pylori)-induced gastritis is unknown. Here, we found that gastric ADM expression was elevated in gastric mucosa of H. pylori-infected patients and mice. In H. pylori-infected human gastric mucosa, ADM expression was positively correlated with the degree of gastritis; accordingly, blockade of ADM resulted in decreased inflammation within the gastric mucosa of H. pylori-infected mice. During H. pylori infection, ADM production was promoted via PI3K-AKT signaling pathway activation by gastric epithelial cells in a cagA-dependent manner, and resulted in increased inflammation within the gastric mucosa. This inflammation was characterized by the increased IFN-γ-producing T cells, whose differentiation was induced via the phosphorylation of AKT and STAT3 by ADM derived from gastric epithelial cells. ADM also induced macrophages to produce IL-12, which promoted the IFN-γ-producing T-cell responses, thereby contributing to the development of H. pylori-associated gastritis. Accordingly, blockade of IFN-γ or knockout of IFN-γ decreased inflammation within the gastric mucosa of H. pylori-infected mice. This study identifies a novel regulatory network involving H. pylori, gastric epithelial cells, ADM, macrophages, T cells, and IFN-γ, which collectively exert a pro-inflammatory effect within the gastric microenvironment.

Upexpression of BHLHE40 in gastric epithelial cells increases CXCL12 production through interaction with p-STAT3 in Helicobacter pylori-associated gastritis.

BHLHE40, a member of the basic helix-loop-helix transcription factor family, has been reported to play an important role in inflammatory diseases. However, the regulation and function of BHLHE40 in Helicobacter pylori (H pylori)-associated gastritis is unknown. We observed that gastric BHLHE40 was significantly elevated in patients and mice with H pylori infection. Then, we demonstrate that H pylori-infected GECs express BHLHE40 via cagA-ERK pathway. BHLHE40 translocates to cell nucleus, and then binds to cagA protein-activated p-STAT3 (Tyr705). The complex increases chemotactic factor CXCL12 expression (production). Release of CXCL12 from GECs fosters CD4+ T cell infiltration in the gastric mucosa. Our results identify the cagA-BHLHE40-CXCL12 axis that contributes to inflammatory response in gastric mucosa during H pylori infection.

Helicobacter pylori-induced matrix metallopeptidase-10 promotes gastric bacterial colonization and gastritis.

The interaction between gastric epithelium and immune response plays key roles in H. pylori-associated pathology. We demonstrated a procolonization and proinflammation role of MMP-10 in H. pylori infection. MMP-10 is elevated in gastric mucosa and is produced by gastric epithelial cells synergistically induced by H. pylori and IL-22 via the ERK pathway. Human gastric MMP-10 was correlated with H. pylori colonization and the severity of gastritis, and mouse MMP-10 from non-BM-derived cells promoted bacteria colonization and inflammation. H. pylori colonization and inflammation were attenuated in IL-22-/-, MMP-10-/-, and IL-22-/-MMP-10-/- mice. MMP-10-associated inflammation is characterized by the influx of CD8+ T cells, whose migration is induced via MMP-10-CXCL16 axis by gastric epithelial cells. Under the influence of MMP-10, Reg3a, E-cadherin, and zonula occludens-1 proteins decrease, resulting in impaired host defense and increased H. pylori colonization. Our results suggest that MMP-10 facilitates H. pylori persistence and promotes gastritis.

Increased intratumoral mast cells foster immune suppression and gastric cancer progression through TNF-α-PD-L1 pathway.

BACKGROUND: Mast cells are prominent components of solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, the nature, regulation, function, and clinical relevance of mast cells in human gastric cancer (GC) are presently unknown. METHODS: Flow cytometry analyses were performed to examine level and phenotype of mast cells in samples from 114 patients with GC. Multivariate analysis of prognostic factors for overall survival was performed using the Cox proportional hazards model. Kaplan-Meier plots for patient survival were performed using the log-rank test. Mast cells, T cells and tumor cells were isolated or generated, stimulated and/or cultured for in vitro and in vivo function assays. RESULTS: Patients with GC showed a significantly higher mast cell infiltration in tumors. Mast cell levels increased with tumor progression and independently predicted reduced overall survival. These tumor-infiltrating mast cells accumulated in tumors by CXCL12-CXCR4 chemotaxis. Intratumoral mast cells expressed higher immunosuppressive molecule programmed death-ligand 1 (PD-L1), and mast cells induced by tumors strongly express PD-L1 proteins in both time-dependent and dose-dependent manners. Significant correlations were found between the levels of PD-L1+ mast cells and pro-inflammatory cytokine TNF-α in GC tumors, and tumor-derived TNF-α activated NF-κB signaling pathway to induce mast cell expression of PD-L1. The tumor-infiltrating and tumor-conditioned mast cells effectively suppressed normal T-cell immunity through PD-L1 in vitro, and tumor-conditioned mast cells contributed to the suppression of T-cell immunity and the growth of human GC tumors in vivo; the effect could be reversed by blocking PD-L1 on these mast cells. CONCLUSION: Thus, our results illuminate novel immunosuppressive and protumorigenic roles of mast cells in GC, and also present a novel mechanism in which PD-L1 expressing mast cells link the proinflammatory response to immune tolerance in the GC tumor milieu.