Anti-inflammatory discovery of sesquiterpenoids and a jasmonic acid derivative from Artemisia stolonifera.

Eleven previously undescribed sesquiterpenoids (8-18), one undescribed jasmonic acid derivative (35) and 28 known compounds were isolated from the leaves of Artemisia stolonifera. Undescribed compounds with their absolute configurations were determined by extensive spectroscopic analysis, single-crystal X-ray diffraction and ECD calculation. Compound 8 was identified as a rare sesquiterpenoid featuring a rearranged 5/8 bicyclic ring system, whereas compound 17 was found to be an unprecedented monocyclic sesquiterpenoid with methyl rearrangement. Evaluation of biological activity showed that compounds 1-5 and 7 displayed cytotoxicity against six tumor cells. In the meantime, compounds 11, 12, 18 and 35 exhibited inhibitory effects against LPS-stimulated NO production in RAW 264.7 macrophage cells and reduced the transcription of IL-6 and IL-1ß in a dose-dependent manner at 25, 50 and 100 µM. Moreover, the anti-inflammatory-based network pharmacology and molecular docking analyses revealed potential target proteins of 11, 12, 18 and 35.

Manual acupuncture ameliorates inflammatory pain by upregulating adenosine A3 receptor in complete Freund's adjuvant-induced arthritis rats.

BACKGROUND: Adenosine A3 receptor (A3R) exerts analgesic, anti-inflammatory, and anti-nociceptive effects. In this study, we determined the analgesic mechanism of manual acupuncture (MA) in rats with complete Freund's adjuvant (CFA)-induced arthritis and explored whether MA ameliorates inflammation in these rats by upregulating A3R. METHODS: Sixty Sprague Dawley (SD) rats were randomly divided into the following groups: Control, CFA, CFA + MA, CFA + sham MA, CFA + MA + DMSO, CFA + MA + IB-MECA, and CFA + MA + Reversine groups. The arthritis rat model was induced by injecting CFA into the left ankle joints. Thereafter, the rats were subjected to MA (ST36 acupoint) for 3 days. The clinical indicators paw withdrawal latency (PWL), paw withdrawal threshold (PWT), and open field test (OFT) were used to determine the analgesic effect of MA. In addition, to explore the effect of A3R on inflammation after subjecting arthritis rats to MA, IB-MECA (A3R agonist) and Reversine (A3R antagonist) were injected into ST36 before MA. RESULTS: MA ameliorated the pathological symptoms of CFA-induced arthritis, including the pain indicators PWL and PWT, number of rearing, total ambulatory distance, and activity trajectory. Furthermore, after MA, the mRNA and protein expression of A3R was upregulated in CFA-induced arthritis rats. In contrast, the protein levels of TNF-α, IL-1ß, Rap1, and p-p65 were downregulated after MA. Interestingly, the A3R agonist and antagonist further downregulated and upregulated inflammatory cytokine expression, respectively, after MA. Furthermore, the A3R antagonist increased the degree of ankle swelling after MA. CONCLUSION: MA can alleviate inflammatory pain by inhibiting the NF-κB signaling pathway via upregulating A3R expression of the superficial fascia of the ST36 acupoint site in CFA-induced arthritis rats.

Endoscopic-ultrasound-guided biliary drainage with placement of electrocautery-enhanced lumen-apposing metal stent for palliation of malignant biliary obstruction: Updated meta-analysis.

BACKGROUND: Endoscopic ultrasound-guided biliary drainage using electrocautery-enhanced (ECE) delivery of lumen-apposing metal stent (LAMS) is gradually being recognized as a viable palliative technique for malignant biliary obstruction after endoscopic retrograde cholangiopancreatography (ERCP) failure. However, most of the studies that have assessed its efficacy and safety were small and heterogeneous. Prior meta-analyses of six or fewer studies that were published 2 years ago were therefore underpowered to yield convincing evidence. AIM: To update the efficacy and safety of ECE-LAMS for treatment of biliary obstruction after ERCP failure. METHODS: We searched PubMed, EMBASE, and Scopus databases from the inception of the ECE technique to May 13, 2022. Primary outcome measure was pooled technical success rate, and secondary outcomes were pooled rates of clinical success, reintervention, and adverse events. Meta-analysis was performed using a random-effects model following Freeman-Tukey double-arcsine transformation in R software (version 4.1.3). RESULTS: Fourteen eligible studies involving 620 participants were ultimately included. The pooled rate of technical success was 96.7%, and clinical success was 91.0%. Adverse events were reported in 17.5% of patients. Overall reintervention rate was 7.3%. Subgroup analyses showed results were generally consistent. CONCLUSION: ECE-LAMS has favorable success with acceptable adverse events in relieving biliary obstruction when ERCP is impossible. The consistency of results across most subgroups suggested that this is a generalizable approach.

A Prospective Investigation of Patient Satisfaction and Psychosocial Status Following Facial Bone Contouring Surgery using the Face-Q.

OBJECTIVE: The objective of this study was to assess satisfaction and psychosocial status before and after facial bone contouring surgery using the Face-Q. METHODS: The Face-Q, a multimodular patient-reported outcome (PRO) instrument, comprises independently functioning scales and checklists designed to assess outcomes in facial aesthetic patients. A prospective cohort study was conducted from November 2020 to May 2022. Participants undergoing facial bone contouring surgery (reduction mandibuloplasty and/or malarplasty) were asked to complete the Face-Q preoperatively and 12 months postoperatively. Comparative analyses were conducted using normative Face-Q data from 534 matched normal individuals. Face-Q scores were evaluated for each domain on a scale of 0 to 100, with higher scores indicating greater satisfaction with appearance or a superior quality of life. RESULTS: A total of 284 patients (274 female and 10 male) completed the Face-Q preoperatively and 12 months postoperatively. Of these, 146 underwent reduction mandibuloplasty, 18 underwent malarplasty, and 120 underwent both procedures. Post-surgery, patients experienced significant improvements in overall appearance, features altered by surgery, and quality of life, excluding the patient-perceived age. Preoperatively, patients demonstrated significantly lower scores compared to normative data, with scores significantly increasing postoperatively to levels representative of the general population. Satisfaction with outcome was significantly correlated with postoperative Face-Q measurements but not preoperatively. CONCLUSION: Facial bone contouring surgery significantly improves the satisfaction and quality of life in patients with square faces, reaching a level at least equivalent to the normative population. The use of Face-Q should be highlighted in the clinic practice. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors   www.springer.com/00266.

Characterization of lysosomal acid lipase in Ly6G+ and CD11c+ myeloid-derived suppressor cells.

Lysosomal acid lipase (LAL) is a key enzyme in the metabolic pathway of neutral lipids, whose deficiency (LAL-D) induces the differentiation of myeloid lineage cells into myeloid-derived suppressor cells (MDSCs), which promotes tumor growth and metastasis. This protocol provides detailed procedures for assessment of various LAL biochemical and physiological activities in Ly6G+ and CD11c+ MDSCs, including isolation of Ly6G+ and CD11c+ cells from the bone marrow and blood of mice, assays of LAL-D-induced cellular metabolic and mitochondrial activities, assessment of LAL-D-induced pathogenic immunosuppressive activity and tumor stimulatory activity. Pharmacological inhibition of the LAL activity was also described in both murine myeloid cells and human white blood cells.

[Characterization of Metal Elements in Atmospheric PM2.5 and Health Risk Assessment in Heze in Winter from 2017 to 2018].

Atmospheric PM2.5 samples were collected in Heze, Shandong Province, from a total of three sampling sites at Heze College, Huarun Pharmacy, and a wastewater treatment plant between October 15, 2017 and January 31, 2018, to determine the concentrations of 21 metal elements in PM2.5 using inductively coupled plasma mass spectrometry (ICP-MS). The degree of elemental enrichment was also discussed, the health risks and potential heavy metal ecological risks were assessed. The results showed that ρ (PM2.5) ranged from 26.7 to 284.1 µg·m-3 at the three sampling sites during the sampling period, and the concentration values did not differ significantly, all of which were at high pollution levels. The highest concentrations of K were found in the three sampling sites, accounting for 31.03%, 39.47%, and 38.43% of the total, respectively, mainly due to the high contribution of biomass burning in autumn and winter in Heze, a large agricultural city. The highest concentrations of Zn, 89.70, 84.21, and 67.68 ng·m-3, were found in the trace elements at the three sampling sites, respectively. The enrichment factor results showed that the enrichment factor values of Zn, Pb, Sn, Sb, Cd, and Se were higher than 100, among which the enrichment factors of Cd and Se were higher than 2 000 and 4 000, respectively, which were significantly influenced by anthropogenic activities and might have been related to industrial production, metal smelting, road sources, and coal combustion emissions. The health risk results showed that there was some potential non-carcinogenic risk (HQ>0.1 for children and adults) for As and a combined potential non-carcinogenic risk (HI>0.1) and some potential carcinogenic risk (CRT>1×10-6) for both children and adults at the three sampling sites. There was a more significant carcinogenic risk (CRT>1×10-4) for adults at the wastewater treatment plant, and the slightly higher carcinogenic risk for adults than that for children may have been related to the longer outdoor activity and higher PM2.5 exposure for adults. The elements with the highest potential ecological risk values were Cd, As, and Pb, with Cd exhibiting a very high potential ecological risk that should be taken seriously. All three sampling sites showed a very high combined potential ecological risk, with the intensity spatially expressed as Heze College>Huarun Pharmacy>wastewater treatment plant.

Effect of right internal mammary artery versus radial artery as a second graft vessel in coronary artery bypass grafting on postoperative wound infection in patients: A meta-analysis.

Few studies have shown that radial artery (RA), which is used as a secondary arterial graft, offers superior results compared with right internal thoracic artery (RIMA) in coronary artery bypass grafting (CABG). In a meta-analysis of observational studies starting in 2023, we looked at the effect of re-operation on postoperative infection and haemorrhage in CABG with RA vs. RIMA. The electronic database up to October 2023 was examined in the course of the research. Analysis was carried out on the clinical trials of postoperative wound infections and haemorrhage re-surgery. Among 912 trials associated with CABG, we selected 8 trials to be included in the final data analysis. The main results were secondary wound infection and re-operation after surgery. The odds ratios (OR) and confidence intervals (CIs) were computed on the basis of a randomized or fixed-effect model of wound infection and re-operation. Seven trials showed a significant reduction in the risk of wound infection in RA treated as a secondary artery transplant compared with RIMA (OR, 1.60; 95% CI, 1.03, 2.47 p = 0.04); Four trials showed that RIMA was not significantly different from RA in the rate of re-operation for postoperative bleeding (OR, 1.31; 95% CI, 0.60, 2.88 p = 0.50). In CABG, RA is used as a secondary arterial conduit graft to lower the risk of wound infection in CABG patients.

No Genetic Causality between Tobacco Smoking and Venous Thromboembolism: A Two-Sample Mendelian Randomization Study.

BACKGROUND: Given the current debate in clinical research about the relationship between tobacco smoking and the risk of venous thromboembolism (VTE), a Mendelian randomization (MR) study was conducted aimed at elucidating the causal associations of current and past tobacco smoking with the risk of VTE, from the perspective of genetics. METHODS: Two-sample univariate and multivariable MR analyses were designed, using summary-level data from large genome-wide association studies involving European individuals. Causality was primarily assessed using multiplicative fixed-effects or random-effects model and inverse variance weighting, supplemented by MR-Egger regression, MR-PRESSO, Cochran's Q test, and leave-one-out for sensitivity analysis to test the reliability of the results. RESULTS: In the univariate MR analysis, no significant causal effects were found between current tobacco smoking and the risk of VTE, deep vein thrombosis (DVT), and pulmonary embolism (PE). Similarly, no significant causal effects were found between past smoking and VTE, DVT, and PE. As for the multivariable MR analysis, results were consistent with univariate MR analysis, with no significant causal effect of either current or past tobacco smoking on the risk of VTE, DVT, and PE. CONCLUSION: Evidence from both univariate and multivariable MR analyses demonstrated no significant causal relationships between current and past tobacco smoking and VTE, DVT, and PE. This contradicts positive correlations reported in some previous observational studies, which may be explained by other confounding factors. This provided genetic evidence for the conclusion reported in other observational studies that smoking did not affect VTE risk.

Tumor-derived Prevotella intermedia aggravates gastric cancer by enhancing Perilipin 3 expression.

The indigenous microbial milieu within tumorous tissues exerts a pivotal influence on the genesis and advancement of gastric cancer (GC). This investigation scrutinizes the functions and molecular mechanisms attributed to Prevotella intermedia in the malignant evolution of GC. Isolation of P. intermedia from paired GC tissues was undertaken. Quantification of P. intermedia abundance in 102 tissues was accomplished using quantitative real-time PCR (qRT-PCR). Assessment of the biological effects of P. intermedia on GC cells was observed using culture medium supernatant. Furthermore, the protein profile of GC cells treated with tumor-derived P. intermedia was examined through label-free protein analysis. The functionality of perilipin 3 (PLIN3) was subsequently confirmed using shRNA. Our investigation revealed that the relative abundance of P. intermedia in tumor tissues significantly surpassed that of corresponding healthy tissues. The abundance of P. intermedia exhibited correlations with tumor differentiation (p = 0.006), perineural invasion (p = 0.004), omentum majus invasion (p = 0.040), and the survival duration of GC patients (p = 0.042). The supernatant derived from tumor-associated P. intermedia bolstered the proliferation, clone formation, migration, and invasion of GC cells. After indirect co-cultivation with tumor-derived P. intermedia, dysregulation of 34 proteins, including PLIN3, was discerned in GC cells. Knockdown of PLIN3 mitigated the malignancy instigated by P. intermedia in GC cells. Our findings posit that P. intermedia from the tumor microenvironment plays a substantial role in the malignant progression of GC via the modulation of PLIN3 expression. Moreover, the relative abundance of P. intermedia might serve as a potential biomarker for the diagnosis and prognosis of GC.

Bacoside a inhibits the growth of glioma by promoting apoptosis and autophagy in U251 and U87 cells.

Bacoside A (gypenoside, Gyp) is a potent bioactive compound derived from Gynostemma pentaphyllum, known to exert inhibitory effects on various malignant tumors. However, the effects of Gyp on glioma as well as the underlying mechanisms remain unclear. In the present study, we first conducted a comprehensive investigation into the anti-glioma potential of gypenosides using network pharmacology to identify potential glioma-related targets. Protein-protein interaction networks were assembled, and GO and KEGG enrichment analyses were performed for shared targets. Experimental validation involved assessing the viability of U251 and U87 cell lines using the MTS method. Furthermore, trans-well and scratch migration assays evaluated the cell migration, while flow cytometry and Hoechst 33342 staining were utilized for apoptosis assessment. The study also monitored changes in autophagy flow through fluorescence microscopy. The expression levels of proteins pertinent to migration, apoptosis, and autophagy were tested using Western blotting. Findings revealed that Gyp upregulated apoptosis-related proteins (Bax and cleaved caspase-9), downregulated anti-apoptotic protein Bcl-2, and migration-associated matrix metalloproteinases (MMP-2 and MMP-9). Furthermore, autophagy-related proteins (Beclin1 and LC3 II) were upregulated, and p62 protein expression was downregulated. Gyp displayed considerable potential in suppressing glioma progression by inhibiting cell proliferation, invasion, and migration and promoting apoptosis and autophagy. Gyp may offer potential clinical therapeutic choices in glioma management.

Mulberry leaf multi-components exert hypoglycemic effects through regulation of the PI-3K/Akt insulin signaling pathway in type 2 diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Phytochemicals have unique advantages in the treatment of diabetes due to their multi-target activity and low toxicity. Mulberry leaves, a traditional Chinese herbal medicine, have been used in the prevention and treatment of diabetes for centuries. The main active ingredients in mulberry leaves with regards to the hypoglycemic effect are 1-deoxynojirimycin, flavonoids, and polysaccharides. However, the combined hypoglycemic effects and mechanisms of mulberry leaf multi-components remain unclear. AIM OF THE STUDY: This study explored the anti-diabetic effects of mulberry leaf multi-components (MMC) and the role of the PI-3K/Akt insulin signalling pathway in improving insulin resistance. MATERIALS AND METHODS: The main chemical components of MMC were analyzed using the phenol-sulfuric acid method, aluminum nitrate-sodium nitrite method, and HPLC-ultraviolet/fluorescence detection method. The T2DM rat model was created via feeding a high-fat diet and peritoneal injection of streptozotocin. T2DM rats were divided into four groups: model, model plus metformin, model plus low-dose, and model plus high-dose MMC groups (100 and 200 mg/kg body weight/day, respectively), and plus normal group for a total of five groups. MMC was administered by oral gavage for six weeks. Fasting blood glucose and serum lipid profiles were measured using a glucometer and an automatic biochemistry analyzer, respectively. Serum insulin and adipocytokine levels were analyzed by ELISA. Hepatic glucose metabolizing enzyme activity was evaluated by ELISA and the double antibody sandwich method. Expression of PI-3K/Akt signalling pathway proteins was analyzed by RT-PCR and Western blotting. RESULTS: Extracted 1-deoxynojirimycin, flavonoid, and polysaccharide purity was 70.40%, 52.34%, and 32.60%, respectively. These components were then mixed at a ratio of 1:6:8 to form MMC. MMC significantly reduced serum glucose, insulin, and lipid levels. In diabetic rats, MMC enhanced insulin sensitivity and alleviated inflammatory and oxidative damage by lowing adipocytokine levels and increasing anti-oxidative enzyme activity. Insulin resistance was also mitigated. MMC regulated the activity of key downstream enzymes of hepatic glucose metabolism via activating the expression of PI-3K, Akt, PDX-1, and GLUT4 at the mRNA and protein levels, thereby correcting hepatic glucolipid metabolism disorders and exerting a hypoglycemic effect. CONCLUSION: MMC ameliorated hepatic glucolipid metabolism disorders and improved insulin resistance in T2DM rats by activating the PI-3K/Akt signaling pathway. These results highlight the multi-component, multi-target, and combined effects of MMC, and suggest it may be further developed as a hypoglycemic drug.

Cefiderocol: Clinical application and emergence of resistance.

Antibacterial drug resistance of gram-negative bacteria (GNB) results in high morbidity and mortality of GNB infection, seriously threaten human health globally. Developing new antibiotics has become the critical need for dealing with drug-resistant bacterial infections. Cefiderocol is an iron carrier cephalosporin that achieves drug accumulation through a unique "Trojan horse" strategy into the bacterial periplasm. It shows high antibacterial activity against multidrug-resistant (MDR) Enterobacteriaceae and MDR non-fermentative bacteria. The application of cefiderocol offers new hope for treating clinical drug-resistant bacterial infections. However, limited clinical data and uncertainties about its resistance mechanisms constrain the choice of its therapeutic use. This review aimed to summarize the clinical applications, drug resistance mechanisms, and co-administration of cefiderocol.

Regulatory Effects of the Kiss1 Gene in the Testis on Puberty and Reproduction in Hezuo and Landrance Boars.

Kisspeptin, a neuropeptide encoded by the Kiss1 gene, combines with its receptor Kiss1R to regulate the onset of puberty and male fertility by the hypothalamic-pituitary-gonadal axis. However, little is known regarding the expression signatures and molecular functions of Kiss1 in the testis. H&E staining revealed that well-arranged spermatogonia, spermatocytes, round and elongated spermatids, and spermatozoa, were observed in 4-, 6-, and 8-month-old testes compared to 1- and 3-month-old testes of Hezuo pigs; however, these were not observed in Landrance until 6 months. The diameter, perimeter, and cross-sectional area of seminiferous tubules and the perimeter and area of the tubular lumen increased gradually with age in both pigs. Still, Hezuo pigs grew faster than Landrance. The cloning results suggested that the Hezuo pigs' Kiss1 CDS region is 417 bp in length, encodes 138 amino acids, and is highly conserved in the kisspeptin-10 region. qRT-PCR and Western blot indicated that the expression trends of Kiss1 mRNA and protein were essentially identical, with higher expression levels at post-pubertal stages. Immunohistochemistry demonstrated that the Kiss1 protein was mainly located in Leydig cells and post-pubertal spermatogenic cells, ranging from round spermatids to spermatozoa. These studies suggest that Kiss1 is an essential regulator in the onset of puberty and spermatogenesis of boars.

Super-enhancer-associated EEPD1 facilitates EMT-mediated metastasis by regulating the PI3K/AKT/mTOR pathway in gastric cancer.

This study focused on exploring the mechanism of the EMT mediated by endonuclease/exonuclease/phosphatase family domain-containing 1 (EEPD1) in gastric cancer metastasis. Through bioinformatics analysis, EEPD1 was found to be a target gene of super enhancers (SEs) in gastric cancer tissues. EEPD1 exhibited higher expression levels in tumor tissues and was associated with poor prognosis. In vitro and in vivo studies have demonstrated that silencing EEPD1 significantly suppressed the proliferation, metastasis, and invasion of gastric cancer cells. Furthermore, EEPD1 knockdown was involved in the regulation of the EMT and suppressed expression of AKT, a downstream component of the PI3K pathway, leading to a reduction in the phosphorylation levels of AKT and its downstream molecule, mTOR. These results showed the potential of EEPD1 as a prognostic indicator and therapeutic target in gastric cancer.

Exploring the Immunomodulatory Properties of Red Onion (Allium cepa L.) Skin: Isolation, Structural Elucidation, and Bioactivity Study of Novel Onion Chalcones Targeting the A2A Adenosine Receptor.

Onions are versatile and nutritious food widely used in various cuisines around the world. In our ongoing pursuit of bioactive substances with health benefits from red onion (Allium cepa L.) skin, a comprehensive chemical investigation was undertaken. Consequently, a total of 44 compounds, including three previously unidentified chalcones (1-3) were extracted from red onion skin. Of these isolates, chalcones 1-4 showed high affinity to A2A adenosine receptor (A2AAR), and chalcone 2 displayed the best binding affinity to A2AAR, with the IC50 value of 33.5 nM, good A2AAR selectivity against A1AR, A2BAR, and A3AR, and high potency in the cAMP functional assay (IC50 of 913.9 nM). Importantly, the IL-2 bioassay and the cell-mediated cytotoxicity assay demonstrated that chalcone 2 could boost T-cell activation. Furthermore, the binding mechanism of chalcone 2 with hA2AAR was elucidated by molecular docking. This work highlighted that the active chalcones in red onion might have the potential to be developed as A2AAR antagonists used in cancer immunotherapy.

CircUSP10 promotes liver cancer progression by regulating miR-211-5p/TCF12/EMT signaling pathway.

There is no precise diagnosis or prognosis for liver cancer (LC) using a single biomarker. Circular RNAs (circRNAs) contribute to the pathogenesis of different cancers, but their role in LC is not entirely understood. In this study, circUSP10, an aberrantly expressed circRNA in LC, was screened using the Gene Expression Omnibus database, and its tissue-specific expression was verified using qRT-PCR. In vitro, functional assays and nude mouse tumorigenesis models were used to investigate circUSP10 role in LC. RNA immunoprecipitation and dual-luciferase reporter assays were performed to study the mechanistic relationship between circUSP10, miR-211-5p, and transcription factor 12 (TCF12). We found that circUSP10 expression was upregulated in LC tissues and cells. CircUSP10 expression was linked to tumor size and tumor node metastasis stage and negatively correlated with LC prognosis. In vitro assays confirmed circUSP10-mediated proliferation, migration, and invasion of LC cells and their association with the epithelial-mesenchymal transition (EMT) pathway. Mechanistically, circUSP10 adsorbed miR-211-5p, which regulated TCF12 and promoted tumorigenesis via the EMT signaling pathway. Therefore, our results suggest that circUSP10 may promote LC progression by modulating the miR-211-5p/TCF12/EMT signaling cascade and may serve as a potential biomarker for LC diagnosis and prognosis.

Death receptor 5 promotes tumor progression in gastric cancer.

Death receptor 5 (DR5) can inhibit malignant proliferation via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in many cancers. Here we examined the expression and sublocalization of DR5 in gastric cancer, as well as its effects on clinical prognosis and cellular processes. Our analysis included a cohort of 240 gastric cancer patients. Bioinformatic analysis showed a significant correlation between DR5 and DNA replication, tumor mutation burden (TMB), and tumor stemness. Unlike death receptor 4 (DR4TRAIL-R1), DR5 was expressed in the cytoplasm and nucleus, and was found to be positively correlated with lymphovascular invasion, lymph node metastasis, and TNM stage. Patients with positive DR5 had worse overall survival (OS) (P = 0.006). The multivariate Cox model showed that DR5 is an independent poor prognostic factor (hazard ratio = 1.693). Furthermore, knockdown of DR5 inhibited aggressive behaviors, including proliferation and metastasis in gastric cancer cells, and inhibited lung metastasis in vivo. In summary, nuclear localization of DR5 expression is a poor prognosis factor in gastric cancer and promotes growth, invasion, and metastasis of tumor cells in vitro and in vivo.