Enhanced LRP8 expression induced by Helicobacter pylori drives gastric cancer progression by facilitating ß-Catenin nuclear translocation.

INTRODUCTION: Helicobacter pylori (H. pylori) infection has been associated with gastric carcinogenesis. However, the precise involvement of LRP8, the low-density lipoprotein receptor-related protein 8, in H. pylori pathogenesis and gastric cancer (GC) remains poorly understood. OBJECTIVES: To investigate the potential role of LRP8 in H. pylori infection and gastric carcinogenesis. METHODS: Three-dimensional human-derived gastric organoids (hGO) and gastric cancer organoids (hGCO) were synthesized from the tissues obtained from human donors. In this work, multi-omics combined with in vivo and in vitro studies were conducted to investigate the potential involvement of LRP8 in H. pylori-induced GC. RESULTS: We found that H. pylori infection significantly upregulated the expression of LRP8 in human GC tissues, cells, organoids, and mouse gastric mucous. In particular, LRP8 exhibited a distinct enrichment in cancer stem cells (CSC). Functionally, silencing of LRP8 affected the formation and proliferation of tumor spheroids, while increased expression of LRP8 was associated with increased proliferation and stemness of GC cells and organoids. Mechanistically, LRP8 promotes the binding of E-cadherin to ß-catenin, thereby promoting nuclear translocation and transcriptional activity of ß-catenin. Furthermore, LRP8 interacts with the cytotoxin-associated gene A (CagA) to form the CagA/LRP8/ß-catenin complex. This complex further amplifies H. pylori-induced ß-catenin nuclear translocation, leading to increased transcription of inflammatory factors and CSC markers. Clinical analysis demonstrated that abnormal overexpression of LRP8 is correlated with a poor prognosis and resistance to 5-Fluorouracil in patients with GC. CONCLUSION: Our findings provide valuable information on the molecular intricacies of H. pylori-induced gastric carcinogenesis, offering potential therapeutic targets and prognostic markers for GC.

The role of lncRNAKCNQ1OT1/miR-301b/Tcf7 axis in cardiac hypertrophy.

OBJECTIVE: Cardiac hypertrophy, acting as a pathologic process of chronic hypertension and coronary disease, and its underlying mechanisms still need to be explored. Long non-coding RNA (LncRNA) potassium voltage-gated channel subfamily Q member 1 Transcript 1 (KCNQ1OT1) has been implicated in myocardial infarction. However, its role in cardiac hypertrophy remains reported. METHOD: To explore the regulated effect of lncRNAKCNQ1OT1 and miR-301b in cardiac hypertrophy, gain-and-lose function assays were tested. The expression of lncRNAKCNQ1OT1 and miR-301b were tested by quantitative real time polymerase chain reaction (qRT-PCR). The levels of transcription factor 7 (Tcf7), Proto-oncogene c-myc (c-myc), Brainnatriureticpeptide (BNP) and ß-myosin heavy chain (ß-MHC) were detected by Western blot. Additionally, luciferase analysis revealed interaction between lncRNAKCNQ1OT1, BNPß-MHCmiR-301b, and Tcf7. RESULT: LncRNAKCNQ1OT1 overexpression significantly induced cardiac hypertrophy. Furthermore, lncRNAKCNQ1OT1 acts as a sponge for microRNA-301b, which exhibited lower expression in cardiac hypertrophy model, indicating an anti-hypertrophic role. Furthermore, the BNP and ß-MHC expression increased, as well as cardiomyocyte surface area, with Ang II treatment, while the effect was repealed by miR-301b. Moreover, the protein expression of Tcf7 was inversely regulated by miR-301b and Antisense miRNA oligonucleotides (AMO)-301b. CONCLUSION: Our study has shown that overexpression of lncRNAKCNQ1OT1 could promote the development of cardiac hypertrophy by regulating miR-301b and Tcf7. Therefore, inhibition of lncRNAKCNQ1OT1 might be a potential therapeutic strategy for cardiac hypertrophy.

Unprecedented Spatial Manipulation and Transformation of Dynamic Thermal Radiation Based on Vanadium Dioxide.

Reconfigurable infrared (IR) materials have widespread applications in thermal management and smart IR concealment. Although various reconfigurable IR materials can be customized by positive or negative differential VO2-based resonators, their insightful mechanism remains unknown. Here, we comprehensively investigate the fundamental design rule of reconfigurable thermal radiation between positive and negative differential thermal radiation properties for the first time. Importantly, the skin depth of VO2 film in the metal state is investigated to clarify the transformation from positive to negative differential thermal radiation properties, and the critical thickness is further derived, providing important guidance in designing the reconfigurable thermal radiation regulator. Furthermore, the reconfigurable multistate thermal images had been presented into one plate. The resulting emittance variation (△ε8-14 µm) of the VO2-based resonator can change from 0.61 to -0.53, which consummates the ability for diverse demands such as infrared concealment, thermal illusion, and thermal management. This work constitutes a promising and universal route toward designing whole smart devices and may create new scientific and technological opportunities for platforms that can benefit from reconfigurable electromagnetic manipulation.

ZNF131 facilitates the growth of hepatocellular carcinoma by acting as a transcriptional activator of SMC4 expression.

ZNF131 is a Zinc finger protein that acts as a transcription factor with oncogenic effects in multiple cancers. In this study, we aimed to explore the alternative splicing profile of ZNF131 in hepatocellular carcinoma (HCC), its regulatory effects on cell-cycle progression, and the downstream effectors. ZNF131 transcriptional profile and HCC survival analysis were conducted using data from the Cancer Genome Atlas (TCGA)-Liver Hepatocellular Cancer (LIHC) dataset. Chromatin immunoprecipitation (ChIP)-qPCR and dual-luciferase reporter assays were utilized to explore transcriptional regulation. CCK-8, colony formation and xenograft tumor models were used to study HCC tumor growth. Results showed that ZNF131 isoform 2 is upregulated in HCC tissues and its upregulation was associated with unfavorable overall survival (OS) and progression-free interval (PFI). Knockdown of endogenous ZNF131 inhibits HCC cell growth and induces G2/M cell-cycle arrest. ZNF131 binds to the SMC4 promoter by interacting with ZBTB33 and the ZBTB33 recognizing motif. ZNF131 transcriptionally activates SMC4 expression in HCC cells. The tumor-suppressive effects of ZNF131 shRNA could be partially reversed by enforced SMC4 overexpression. In summary, this study highlights the ZNF131/ZBTB33/SMC4 axis as a driver of pathological cell cycling and proliferation in HCC.

Ginsenoside Rb1 protects hippocampal neurons in depressed rats based on mitophagy-regulated astrocytic pyroptosis.

BACKGROUND: Astrocytes play a vital role in offering functional support for neurons, which are related to the pathogenic mechanism of depression. Ginsenoside Rb1 (GRb1) is demonstrated with antidepressant-like activities. PURPOSE: We aimed to investigate whether GRb1 can inhibit mitophagy-mediated astrocytic pyroptosis to protect neurons in depression. STUDY DESIGN: Model rats were subjected to chronic unpredictable mild stress (CUMS) for determining the in vivo antidepressant activity of GRb1. METHODS: The mitophagy-mediated antipyroptosis role of GRb1 was assessed in lipopolysaccharide (LPS) + ATP-stimulated astrocytes. The mechanism by which GRb1 protects synaptic plasticity was investigated using hippocampal neurons incubated in an astrocyte medium. The rat depressive-like behaviors were determined through sucrose preference, forced swimming, and the open-field tests. Escitalopram was used in the anti-depression control of GRb1. Cyclosporin A (CsA), a mitophagy inhibitor, and interleukin (IL)-1ß were used to reverse the role of GRb1 in mitophagy and pyroptosis, respectively. RESULTS: GRb1 inhibited LPS-induced inflammation and activation in the astrocytes and repressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Also, GRb1 repressed LPS + ATP-promoted astrocytic pyroptosis. During GRb1 treatment, the activation of mitophagy with a decrease in ROS was observed in LPS + ATPs-stimulated astrocytes. CsA enhanced GRb1-decreased ROS and promoted astrocytic pyroptosis. The GRb1-treated astrocyte medium suppressed neuron death and increased neuron viability and synaptic density. Escitalopram and GRb1 improved the depressive-like behaviors of the rats. GRb1 activated mitophagy and inhibited astrocytic activation and pyroptosis in rats with depression. It also reduced impairments in synaptic structures and increased synaptic density in depressive-like rats. IL-1ß increased astrocytic pyroptosis and reversed GRb1-enhanced synaptic plasticity in the rats exposed to CUMS. There were no statistical changes in depressive-like behaviors between GRb1 and Escitalopram groups. CONCLUSION: GRb1 modulates mitophagy and the NF-κB pathway to inhibit astrocytic pyroptosis, thereby maintaining neurological homeostasis by repressing inflammation and enhancing synaptic plasticity.

Lactobacillus acidophilus NCFM and Lactiplantibacillus plantarum Lp-115 inhibit Helicobacter pylori colonization and gastric inflammation in a murine model.

Purpose: To determine the role of Lactobacillus strains and their combinations in inhibiting the colonization of H. pylori and gastric mucosa inflammation. Methods: Human gastric adenocarcinoma AGS cells were incubated with H. pylori and six probiotic strains (Lactobacillus acidophilus NCFM, L. acidophilus La-14, Lactiplantibacillus plantarum Lp-115, Lacticaseibacillus paracasei Lpc-37, Lacticaseibacillus rhamnosus Lr-32, and L. rhamnosus GG) and the adhesion ability of H. pylori in different combinations was evaluated by fluorescence microscopy and urease activity assay. Male C57BL/6 mice were randomly divided into five groups (uninfected, H. pylori, H. pylori+NCFM, H. pylori+Lp-115, and H. pylori+NCFM+Lp-115) and treated with two lactobacilli strains (NCFM and Lp-115) for six weeks. H. pylori colonization and tissue inflammation statuses were determined by rapid urease test, Hematoxylin-Eosin (HE) staining, immunohistochemistry, and qRT-PCR and ELISA. Results: L. acidophilus NCFM, L. acidophilus La-14, L. plantarum Lp-115, L. paracasei Lpc-37, L. rhamnosus Lr-32, and L. rhamnosus GG reduced H. pylori adhesion and inflammation caused by H. pylori infection in AGS cells and mice. Among all probiotics L. acidophilus NCFM and L. plantarum, Lp-115 showed significant effects on the H. pylori eradication and reduction of inflammation in-vitro and in-vivo. Compared with the H. pylori infection group, the mRNA and protein expression levels of IL-8 and TNF-α in the six Lactobacillus intervention groups were significantly reduced. The changes in the urease activity (ureA and ureB) for 1-7h in each group showed that L. acidophilus NCFM, L. acidophilus La-14, L. plantarum Lp-115, and L. rhamnosus GG effectively reduced the colonization of H. pylori. We observed a higher ratio of lymphocyte and plasma cell infiltration into the lamina propria of the gastric mucosa and neutrophil infiltration in H. pylori+NCFM+Lp-115 mice. The infiltration of inflammatory cells in lamina propria of the gastric mucosa was reduced in the H. pylori+NCFM+Lp-115 group. Additionally, the expression of IFN-γ was decreased significantly in the NCFM and Lp-115 treated C57BL/6 mice. Conclusions: L. acidophilus NCFM and L. plantarum Lp-115 can reduce the adhesion of H. pylori and inhibit the gastric inflammatory response caused by H. pylori infection.

NAD+ associated genes as potential biomarkers for predicting the prognosis of gastric cancer.

Nicotinamide adenine dinucleotide (NAD+) plays an essential role in cellular metabolism, mitochondrial homeostasis, inflammation, and senescence. However, the role of NAD+-regulated genes, including coding and long non-coding genes in cancer development is poorly understood. We constructed a prediction model based on the expression level of NAD+ metabolism-related genes (NMRGs). Furthermore, we validated the expression of NMRGs in gastric cancer (GC) tissues and cell lines; additionally, ß-nicotinamide mononucleotide (NMN), a precursor of NAD+, was used to treat the GC cell lines to analyze its effects on the expression level of NMRGs lncRNAs and cellular proliferation, cell cycle, apoptosis, and senescence-associated secretory phenotype (SASP). A total of 13 NMRGs-related lncRNAs were selected to construct prognostic risk signatures, and patients with high-risk scores had a poor prognosis. Some immune checkpoint genes were upregulated in the high-risk group. In addition, cell cycle, epigenetics, and senescence were significantly downregulated in the high-risk group. Notably, we found that the levels of immune cell infiltration, including CD8 T cells, CD4 naïve T cells, CD4 memory-activated T cells, B memory cells, and naïve B cells, were significantly associated with risk scores. Furthermore, the treatment of NMN showed increased proliferation of AGS and MKN45 cells. In addition, the expression of SASP factors (IL6, IL8, IL10, TGF-ß, and TNF-α) was significantly decreased after NMN treatment. We conclude that the lncRNAs associated with NAD+ metabolism can potentially be used as biomarkers for predicting clinical outcomes of GC patients.

Relationship Between CNVs and Immune Cells Infiltration in Gastric Tumor Microenvironment.

Gastric cancer (GC) is a highly fatal and common malignancy of the digestive system. Recent therapeutic advancements have significantly improved the clinical outcomes in GC, but due to the unavailability of suitable molecular targets, a large number of patients do not respond to the immune checkpoint inhibitors (ICI) therapy. To identify and validate potential therapeutic and prognostic targets of gastric cancer, we used the "inferCNV" R package for analyzing single-cell sequencing data (GSE112302) of GC and normal epithelial cells. First, by using LASSO, we screened genes that were highly correlated with copy number variations (CNVs). Therefrom, five gene signature (CPVL, DDC, GRTP1, ONECUT2, and PRSS21) was selected by cross-validating the prognosis and risk management with the GC RNA-seq data obtained from GEO and TCGA. Moreover, the correlation analyses between CNVs of these genes and immune cell infiltration in gastric cancer identified CPVL as a potential prognostic marker. Finally, CPVL showed high expression in gastric cancer samples and cell lines, then siRNA-mediated silencing of CPVL expression in gastric cancer cells showed significant proliferation arrest in MGC803 cells. Here, we conclude that CNVs are key regulators of the immune cells infiltration in gastric TME as well as cancer development, and CPVL could potentially be used as a prognostic and therapeutic marker in gastric cancer.

High Mobility Group Protein B1 Decreases Surface Localization of PD-1 to Augment T-cell Activation.

High-mobility group protein B1 (HMGB1) is a danger signaling molecule that has been found to trigger an effective antitumor immune response. However, the mechanisms underlying its antitumor effects are not fully understood. Here, we found that HMGB1 release induced by chemotherapy in patients with non-small cell lung cancer was negatively correlated with PD-1 expression on CD8+ T cells. In vitro analysis indicated that treatment with HMGB1 led to a significant decrease in the level of expression of PD-1 on CD8+ T cells. Further analysis demonstrated that HMGB1 reduced PD-1 expression by inducing dynamin-mediated internalization of the protein, leading to early endocytosis in the cytoplasm, and subsequently degradation in the lysosomes. In a xenograft model, HER2-targeted chimeric antigen receptor (CAR) T cells had enhanced function in the presence of HMGB1. These data identify a role for HMGB1 as a negative regulator of PD-1 signaling in lung cancer and the observed antitumor effect of HMGB1 on CAR T cells may provide a theoretical foundation for a new immunotherapy combination.

Ginsenoside Rg1 Reduced Microglial Activation and Mitochondrial Dysfunction to Alleviate Depression-Like Behaviour Via the GAS5/EZH2/SOCS3/NRF2 Axis.

Ginsenoside Rg1 is the principal active ingredient in ginseng. The antidepressant effects of Rg1 have been validated; however, the specific underlying mechanism of this effect needs further research. Rats were subjected to the chronic restraint stress (CRS) depression model. Rg1, or a positive control drug, was administered to the rats. Depression-like behaviours were evaluated through behavioural experiments. Cytokine, mRNA, protein, ATP, and mitochondria DNA levels were detected using the indicated methods. Lentivirus-packaged plasmids were injected into the rat brain for GAS5 overexpression or knockdown. In vitro mitochondrial dysfunction was evaluated by detecting mitochondrial reactive oxygen species and mitochondrial membrane potential. Direct interaction between GAS5 and EZH2 was validated by RNA immunoprecipitation and RNA pull-down assay. The enrichment of EZH2 and H3K27me3 was evaluated through chromatin immunoprecipitation quantitative real-time PCR. Rg1 treatment alleviated depression-like behaviours, microglial activation, and mitochondrial dysfunction in CRS rats. Similarly, GAS5 knockdown revealed a similar protective effect of Rg1 treatment. GAS5 overexpression in the rat brain compromised the protective effect of Rg1 treatment. Moreover, Rg1 treatment or GAS5 knockdown attenuated microglial activation and mitochondrial dysfunction in vitro. Mechanically, GAS5 was suppressed SOCS3 and NRF2 expression by facilitating EZH2-mediated transcriptional repression. Rg1 attenuated microglial activation and improved mitochondrial dysfunction in depression by downregulating GAS5 expression. Mechanically, GAS5 might regulate microglial activation and mitochondrial dysfunction via the epigenetic suppression of NRF2 and SOCS3.

VO2-Based Infrared Radiation Regulator with Excellent Dynamic Thermal Management Performance.

Dynamic thermal management materials attract fast-increasing interest due to their adaptability to changing environments and greater energy savings as compared to static materials. However, the high transition temperature and the low emittance tunability of the vanadium dioxide (VO2)-based infrared radiation regulators limit their practical applications. This study addresses these issues by proposing a smart infrared radiation regulator based on a Fabry-Pérot cavity structure (VO2/HfO2/Al), which is prepared by high-power impulse magnetron sputtering (HiPIMS) and has the potential for large-scale production. Remarkably, the outstanding emittance tunability reaches 0.51, and the phase transition temperature is lowered to near a room temperature of 27.5 °C by tungsten (W) doping. In addition, a numerical thermal management power of 196.3 W/m2 (at 8-14 µm band) can be obtained from 0 to 60 °C. As a proof-of-concept, the demonstrated capabilities of the VO2 infrared radiation regulator show great potentials in a wide range of applications for the thermal management of buildings and vehicles.

Immune infiltration profiling in gastric cancer and their clinical implications.

The abundance and type of immune cells in the tumor microenvironment (TME) significantly influence immunotherapy and tumor progression. However, the role of immune cells in the TME of gastric cancer (GC) is poorly understood. We studied the correlations, proportion, and infiltration of immune and stromal cells in GC tumors. Data analyses showed a significant association of infiltration levels of specific immune cells with the pathological characteristics and clinical outcomes of GC. Furthermore, based on the difference in infiltration levels of immune and stromal cells, GC patients were divided into two categories, those with "immunologically hot" (hot) tumors and those with "immunologically cold" (cold) tumors. The assay for transposase-accessible chromatin using sequencing and RNA sequencing analyses revealed that the hot and cold tumors had altered epigenomic and transcriptional profiles. Claudin-3 (CLDN3) was found to have high expression in the cold tumors and negatively correlated with CD8+ T cells in GC. Overexpression of CLDN3 in GC cells inhibited the expression of MHC-I and CXCL9. Finally, the differentially expressed genes between hot and cold tumors were utilized to generate a prognostic model, which predicted the overall survival of GC as well as patients with immunotherapy. Overall, we undertook a comprehensive analysis of the immune cell infiltration pattern in GC and provided an accurate model for predicting the prognosis of GC patients.

Cancer-associated fibroblasts induce monocytic myeloid-derived suppressor cell generation via IL-6/exosomal miR-21-activated STAT3 signaling to promote cisplatin resistance in esophageal squamous cell carcinoma.

Drug resistance remains the major obstacle limiting the effectiveness of chemotherapy for esophageal squamous cell carcinoma (ESCC)[1]. However, how stromal cells cooperate with immune cells to contribute to drug resistance is not yet fully understood. In this study, we observed that monocytic myeloid-derived suppressor cells (M-MDSCs) were correlated with cisplatin resistance in patients with ESCC. Furthermore, CAFs promoted differentiation of monocytes into M-MDSCs phenotypically and functionally in vitro. Mechanically, both interleukin (IL)-6 and exosome-packed microRNA-21 (miR-21) secreted by CAFs synergistically promoted the generation of M-MDSCs via activating the signal transducing activator of transcription 3 (STAT3) by IL-6 in an autocrine manner. Combined blocking of IL-6 receptor and inhibition of miR-21 significantly reversed CAF-mediated M-MDSC generation. Notably, the effects of CAFs on M-MDSC induction were abolished by inhibiting STAT3 signaling. Functionally, CAF-induced M-MDSCs promoted drug resistance of tumor cells upon cisplatin treatment. Clinically, ESCC patients with high infiltration of CAFs and CD11b+ myeloid cells had unfavorable predicted overall survival both in our cohort and in TCGA data. Taken together, our study reveals a paracrine and autocrine of IL-6 caused by CAFs co-activate STAT3 signaling, promoting the generation of M-MDSCs, and highlights the important role of CAFs in cooperation with M-MDSCs in promoting drug resistance, thus providing potential opportunities for reversing drug resistance through inhibition of STAT3 signaling.

Smart Materials for Dynamic Thermal Radiation Regulation.

Thermal radiation in the mid-infrared region profoundly affects human lives in various fields, including thermal management, imaging, sensing, camouflage, and thermography. Due to their fixed emissivities, radiance features of conventional materials are usually proportional to the quadruplicate of surface temperature, which set the limit, that one type of material can only present a single thermal function. Therefore, it is necessary and urgent to design materials for dynamic thermal radiation regulations to fulfill the demands of the age of intelligent machines. Recently, the ability of some smart materials to dynamically regulate thermal radiation has been evaluated. These materials are found to be competent enough for various commands, thereby, providing better alternatives and tremendously promoting the commercial potentials. In this review, the dynamic regulatory mechanisms and recent progress in the evaluation of these smart materials are summarized, including thermochromic materials, electrochromic materials, mechanically and humidity responsive materials, with the potential applications, insufficient problems, and possible strategies highlighted.

cGAS regulates the DNA damage response to maintain proliferative signaling in gastric cancer cells.

The activation of some oncogenes promote cancer cell proliferation and growth, facilitate cancer progression and metastasis by induce DNA replication stress, even genome instability. Activation of the cyclic GMP-AMP synthase (cGAS) mediates classical DNA sensing, is involved in genome instability, and is linked to various tumor development or therapy. However, the function of cGAS in gastric cancer remains elusive. In this study, the TCGA database and retrospective immunohistochemical analyses revealed substantially high cGAS expression in gastric cancer tissues and cell lines. By employing cGAS high-expression gastric cancer cell lines, including AGS and MKN45, ectopic silencing of cGAS caused a significant reduction in the proliferation of the cells, tumor growth, and mass in xenograft mice. Mechanistically, database analysis predicted a possible involvement of cGAS in the DNA damage response (DDR), further data through cells revealed protein interactions of the cGAS and MRE11-RAD50-NBN (MRN) complex, which activated cell cycle checkpoints, even increased genome instability in gastric cancer cells, thereby contributing to gastric cancer progression and sensitivity to treatment with DNA damaging agents. Furthermore, the upregulation of cGAS significantly exacerbated the prognosis of gastric cancer patients while improving radiotherapeutic outcomes. Therefore, we concluded that cGAS is involved in gastric cancer progression by fueling genome instability, implying that intervening in the cGAS pathway could be a practicable therapeutic approach for gastric cancer.

Metabolic Alterations Related to Glioma Grading Based on Metabolomics and Lipidomics Analyses.

Gliomas are the most aggressive phenotypes of brain tumors and are classified into four grades according to the malignancy degree by the World Health Organization. Metabolic profiling can provide an overview of metabolic reprogramming at a specific stage of tumor initiation and development. Studies about metabolic alterations related to different grades of gliomas are helpful to understand the molecular mechanism for progression of glioma. In the current study, metabolomics and lipidomics analyses based on chromatography-mass spectrometry were performed on different grades of glioma tissues. Differential metabolites between glioma and para-tumor tissues were studied and used as the basis to explore metabolic alterations related to glioma grading. It was found that short-chain acylcarnitines were elevated, whereas lysophosphatidylethanolamines (LPEs) were decreased in high-grade gliomas. Furthermore, the gene expression of short/branched-chain acyl-coenzyme dehydrogenase (ACADSB), which is involved in fatty acid oxidation, was found down-regulated with glioma progression by analyzing related genes and pathways. In addition, LPE metabolism showed a significant difference among different grades of gliomas. These important metabolic pathways related to glioma progression may provide potential clues for further study on the mechanisms and treatment of glioma.

A ceRNA network and a potential regulatory axis in gastric cancer with different degrees of immune cell infiltration.

Immune cell infiltration is an important indicator of whether tumor patients will benefit from immunotherapy. Gastric cancer is one of the most common tumors in the world, and new indicators of immunotherapy are urgently needed. The aim of this study was to construct ceRNA networks in gastric cancer with different degrees of immune cell infiltration. We analyzed the expression profiles of different gastric cancer with different degrees of immune cell infiltration retrieved from The Cancer Genome Atlas (TCGA) database and found differentially expressed lncRNAs, mRNAs, and miRNAs. A ceRNA regulatory network of gastric cancer with different degrees of immune cell infiltration was constructed using functional annotation, RNA-RNA interaction prediction, correlation analysis, survival analysis, and other comprehensive bioinformatics methods. The interaction and correlation between ceRNAs were verified using experiments on tumor tissues and cell lines. Cell line experiments showed a potential RP11-1094M14.8/miR-1269a/CXCL9 axis that was consistent with the ceRNA theory. qRT-PCR results showed that RP11-1094M14.8 knockdown significantly reduced the expression of CXCL9, and RP11-1094M14.8 overexpression had the opposite effect. The results of clinical analysis of gastric cancer samples showed that RP11-1094M14.8 and CXCL9 were highly expressed in hot tumors, and CXCL9 was positively correlated with a better prognosis for patients. The constructed novel ceRNA network and the potential regulatory axis may provide a comprehensive understanding of the potential mechanisms of development in gastric cancer with different degrees of immune cell infiltration. The RP11-1094M14.8/miR-1269a/CXCL9 axis may serve as a potential immune-therapeutic target for gastric cancer with different degrees of immune cell infiltration.

Apigenin induces apoptosis and counteracts cisplatin-induced chemoresistance via Mcl-1 in ovarian cancer cells.

Ovarian cancer (OC) is one of the prominent causes of mortality in female patients diagnosed with gynecologic malignancies. While it has previously been demonstrated that apigenin inhibits cell growth in colon and breast cancer cells, the effect of apigenin in OC cells is not fully understood. Therefore, the aim of the present study was to investigate the impact of apigenin on cell death and resistance to cisplatin in OC cells. It was found that apigenin inhibited proliferation, hindered cell cycle progression and promoted SKOV3 cell apoptosis. Moreover, these effects were also observed in cisplatin-resistant SKOV3/DDP cells. Furthermore, apigenin reduced the mitochondrial transmembrane potential, and elevated the ratios of cleaved caspase-3/caspase-3 and Bax/Bcl-2 in the two cell types. Reverse transcription-quantitative PCR and western blotting results demonstrated that apigenin significantly downregulated Mcl-1 at the transcriptional and translational levels in SKOV3 and SKOV3/DDP cells, which was responsible for its cytotoxic functions and chemosensitizing effects. Collectively, the present results identified the impact of apigenin on OC cell death and resistance to cisplatin, and the potential molecular mechanisms. However, additional studies are required to further elucidate the underlying mechanisms.

The association of Helicobacter pylori CagA EPIYA motifs and vacA genotypes with homologous recombination repair markers during the gastric precancerous cascade.

BACKGROUND: Helicobacter pylori-induced DNA damage and impaired homologous recombination repair are vital molecular mechanisms for gastric cancer, which mainly count on its virulence factors cytotoxic-associated gene A (CagA) and vacuolating cytotoxin A (VacA). However, the relationship between H. pylori CagA EPIYA motifs and vacA genotypes with DNA damage and homologous recombination repair markers is still not clear. METHODS: H. pylori positive and negative gastric biopsies were taken from 165 subjects with different gastric precancerous pathologic stages, and DNA damage marker γH2AX and key homologous recombination repair proteins (CtIP and Rad51) were investigated for their association with H. pylori CagA EPIYA motifs and vacAs-, m-, i-, and d-region genotypes and histology (Sydney classification). RESULTS: Out of 165 patients, 78 were identified as H. pylori-positive. CagA EPIYA motifs were identified as AB, ABC, and ABD in 2 (3.3%), 21 (35%), and 37 (61.7%) patients, respectively, while vacA alleles were identified as: s1, s2, m1, m2, i1, i2, d1, and d2 in 50 (89.3%), 6 (10.7%), 24 (42.9%), 32 (57.1%), 45 (80.4%), 11 (19.6%), 40 (71.4%), and 16 (28.6%) patients, respectively. vacAs1m1i1d1, s1m2i1d1, and s1m2i2d2 were the most prevailing genotypes. γH2AX was highly localized in H. pylori-positive tissues with corresponding CagA EPIYA motifs and vacA genotypes, while Rad51 and CtIP signals were weak. CONCLUSION: H. pylori were positively correlated with the DNA damage marker in precancerous lesions, but were negatively correlated with the key homologous recombination repair proteins, which may be due to the specific CagA EPIYA motifs and vacA genotypes.

Gut Microbiota Regulates Depression-Like Behavior in Rats Through the Neuroendocrine-Immune-Mitochondrial Pathway.

PURPOSE: Gut microbiota affects various physiological functions in the host and has crucial effects on the nervous system. There is increasing evidence of a correlation between gut microbiota and depression; however, the mechanisms underlying the regulation of depression-like behavior by gut microbiota remain unclear. In this study, we assessed the regulatory mechanism of gut microbiota on depression-like behavior in rats. METHODS: We transplanted fecal microbiota obtained from patients with depression and healthy individuals into germ-free (GF) rats (n=18) through fecal microbiota transplantation technology. Next, we assessed the affective behavior in the rats using the forced swimming test and a sucrose preference test. We used enzyme-linked immunosorbent assay (ELISA) to determine the hippocampal levels of 5-hydroxytryptamine (5-HT), dopamine (DA), and noradrenaline (NE) and the serum levels of corticosterone (CORT), adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-6 (IL-6), interleukin-1 (IL-1), interleukin-1 (IL-4), and interleukin-1 (IL-10). The mitochondrial morphology of small intestinal epithelial cells was observed through transmission electron microscopy. RESULTS: Rats that received fecal microbiota from patients with depression (depression microbiota) exhibited depression-like behavior. They presented decreased levels of hippocampal neurotransmitters, serum CORT levels, and anti-inflammatory cytokine levels, as well as increased ACTH, CRH, and serum levels of multiple pro-inflammatory cytokines. Observation of the mitochondria ultrastructure showed damaged mitochondria in the intestinal epithelial cells, significant endoplasmic reticulum expansion, and border aggregation of nuclear chromatin. CONCLUSION: Our findings suggested that the depression-like behaviors induced by the depression microbiota through the neuroendocrine-immune-mitochondrial pathway, which were associated with neuroendocrine disorders, inflammatory responses, and mitochondrial damage.