Apigenin Induces Autophagy and Cell Death by Targeting EZH2 under Hypoxia Conditions in Gastric Cancer Cells.

Hypoxia is a major obstacle to gastric cancer (GC) therapy and leads to chemoresistance as GC cells are frequently exposed to the hypoxia environment. Apigenin, a flavonoid found in traditional medicine, fruits, and vegetables and an HDAC inhibitor, is a powerful anti-cancer agent against various cancer cell lines. However, detailed mechanisms involved in the treatment of GC using APG are not fully understood. In this study, we investigated the biological activity of and molecular mechanisms involved in APG-mediated treatment of GC under hypoxia. APG promoted autophagic cell death by increasing ATG5, LC3-II, and phosphorylation of AMPK and ULK1 and down-regulating p-mTOR and p62 in GC. Furthermore, our results show that APG induces autophagic cell death via the activation of the PERK signaling, indicating an endoplasmic reticulum (ER) stress response. The inhibition of ER stress suppressed APG-induced autophagy and conferred prolonged cell survival, indicating autophagic cell death. We further show that APG induces ER stress- and autophagy-related cell death through the inhibition of HIF-1α and Ezh2 under normoxia and hypoxia. Taken together, our findings indicate that APG activates autophagic cell death by inhibiting HIF-1α and Ezh2 under hypoxia conditions in GC cells.

Procyanidin B2 induces apoptosis and autophagy in gastric cancer cells by inhibiting Akt/mTOR signaling pathway.

BACKGROUND: Procyanidin B2 (PB2), a unique component of the grape seed and other medicinal plants. PB2 has shown wide anticancer activity in various human cancer cells. However, it remains unclear about the biological effects and associated mechanisms of PB2 on gastric cancer cells. METHODS: Cell proliferation was measured by CCK8 assay, and cellular lactate dehydrogenase (LDH) release was measured in the culture medium. Cellular apoptosis was observed via TUNEL staining assay and measured by caspase-3 and -9 activities. Autophagy was observed by LC3 staining. Western blot analysis was performed to verify autophagy-associated proteins (Beclin1 and Atg5) and Akt-mTOR pathway. RESULTS: PB2 reduced the viability of BGC-823 and SGC-7901 cells in a concentration-dependent manner. Furthermore, PB2 induced increased apoptosis rate of gastric cancer cells and enhanced caspase-3 and -9 activities. Simultaneously, PB2 triggered autophagy in gastric cancer cells, with enhanced LC3 staining and increased expression of Beclin1 and Atg5, while the inhibition of autophagy by 3-MA reversed the PB2-induced suppression on cell viability. In addition, PB2 significantly decreased p-Akt and p-mTOR protein expression of gastric cancer cells. CONCLUSION: PB2 exerts anti-proliferative and apoptotic effects and induces autophagy by modulating Akt/mTOR signaling pathway. PB2 may be developed as a potential therapeutic drug for gastric cancer.

Post-discharge oral nutritional supplements with dietary advice in patients at nutritional risk after surgery for gastric cancer: A randomized clinical trial.

BACKGROUND & AIMS: Malnutrition frequently occurs and deteriorates in patients after surgery for gastric cancer, especially after hospital discharge, which has been consistently associated with negative outcomes. However, information regarding the impact of post-discharge nutritional interventions is poorly described. The aim of this study was thus to evaluate the impact of post-discharge oral nutritional supplements (ONS) with dietary advice compared with dietary advice alone on nutritional outcomes, including body mass index (BMI) and skeletal muscle index (SMI), sarcopenia prevalence, chemotherapy tolerance, the 90-day readmission rate, and quality of life in patients at nutritional risk after surgery for gastric cancer. METHODS: Three hundred and fifty-three patients who underwent surgery for gastric cancer and were at nutritional risk (Nutritional Risk Screening 2002 [NRS 2002] score ≥3 points) in our institution were randomly assigned to receive either ONS with dietary advice or dietary advice alone (control) for 3 months after discharge. The primary endpoints were nutritional outcomes and sarcopenia prevalence; the secondary endpoints included chemotherapy tolerance, the 90-day readmission rate, and quality of life. RESULTS: Three hundred and thirty-seven patients completed the study and were included in the analyses, consisting of 171 in the ONS group and 166 in the control group. The average daily intake of ONS in the intervention group was 370 mL. After 3 months of the intervention, the patients who received ONS and dietary advice had significantly less weight loss and higher BMI and SMI than those given dietary advice alone (P < 0.05). The incidence of sarcopenia was significantly lower in the ONS group than in the control group (P < 0.05). Similar number of patients in the two groups underwent postoperative chemotherapy, but the patients who received ONS and dietary advice had significantly less chemotherapy modifications, including delay, dose reduction, or termination (P < 0.05). The two groups had no significant differences in the 90-day readmission rate (P > 0.05). Regarding the quality of life, the patients who received ONS and dietary advice reported significantly less fatigue and appetite loss than those given dietary advice alone (P < 0.05), but the two groups showed no significant differences in the other outcomes (P > 0.05). CONCLUSIONS: Post-discharge ONS with dietary advice in patients at nutritional risk after surgery for gastric cancer improved nutritional outcomes, skeletal muscle maintenance, chemotherapy tolerance and some quality of life variables. These findings strongly support the concept of the introduction of post-discharge ONS with dietary advice to this patient cohort.

Parthenolide increases the sensitivity of gastric cancer cells to chemotherapy.

OBJECTIVE: To investigate the effect of parthenolide (PTL), a sesquiterpene lactone medicinal compound, on the sensitivity of the gastric cancer cell line SGC7901 and the DPP- and ADR-resistant sublines SGC7901/DDP and SGC7901/ADR to cisplatin [diamminedichloroplatinum (Ⅱ), DDP] and adriamycin (ADR) in vitro. METHODS: SGC7901, SGC7901/DDP, and SGC7901/ADR were treated with various concentrations of PTL alone or in combination with DDP or ADR. The effects on cell proliferation, apoptosis, and expression/activity of several proliferation/apoptosis-related proteins [B-cell lymphoma-2 (Bcl-2), cyclin D1, nuclear factor-kappa B (NF-κB), and Caspase-8] and drug transporters (P-glycoprotein and multidrug resistance protein-1) were measured using flow cytometry, Western blotting, and in vitro activity assays. RESULTS: Treatment of SGC7901 cells with PTL inhibited cell growth, increased apoptosis, and sensitized the cells to DPP. Mechanistically, PTL treatment resulted in downregulation of NF-κB activity and Bcl-2 expression, and upregulation of Caspase-8 activity. Similarly, PTL co-treatment of SGC7901/DDP and SGC7901/ADR overcame their resistance to DDP and ADR, respectively, with concomitant inhibition of NF-κB, Bcl-2, Cyclin D1, P-glycoprotein, and multidrug resistance protein-1 expression and/or activity. CONCLUSION: PTL treatment decreases drug resistance in SGC7901, SGC7901/DDP, and SGC7901/ADR cells, as reflected by induction of apoptosis, inhibition of proliferation, downregulation of pro-survival and drug resistance pathways, and upregulation of pro-apoptotic pathways. Our results suggest that co-treatment with PTL may thus complement existing therapies for gastric cancer.

Emphysematous gastritis after metastatic malignant melanoma: a radiological surprise.

Malignant melanoma is cancer of the skin which commonly metastasises to the stomach. There have been no reported cases of emphysematous gastritis secondary to metastasis of malignant melanomas, to date. However, a 61-year-old woman with metastatic malignant melanoma of the left great toe presented to us with symptoms of severe left hypochondrium pain associated with high-grade fever, gross abdominal distension and recurrent vomiting. Two months earlier, metastasis was observed to have spread to the stomach and inguinal lymph nodes. At this stage, the patient opted for traditional medication instead of definitive surgery and chemotherapy. Radiological imaging revealed an emphysematous change to the stomach which was radiologically consistent with gastric malignant melanoma. Unfortunately, the patient succumbed to this rare condition.

Efficacy and safety of Kanglaite injection for gastric cancer: A protocol for systematic review and meta-analysis.

BACKGROUND: Kanglaite injection is a broad-spectrum anti-tumor drug, which is extracted from the seeds of the Chinese medicinal herb Coix lacryma-jobi, and has been widely used for the treatment of gastric cancer (GC). This study aimed to systematically investigate the efficacy and safety of Kanglaite injection for the treatment of GC. METHODS: We will perform the comprehensive literature search in English and Chinese electronic database from its inception to June 2020. Two trained researchers will independently select the qualified studies for data extraction and assess the quality and risk of bias. Cochrane Risk of Bias tool will be used to assess the risk of bias of included studies. The outcomes included overall response rate, complete response rate, 3-year progression-free survival rate, 3-year overall survival rate, and different types of treatment-related adverse events. Funnel plot analysis and Egger test will be used to assess the publication bias. Finally, the quality of evidence will be assessed by the grading of recommendations assessment, development, and evaluate system . We will calculate the risk ratio as well as their 95% confidence intervals of these outcomes and pool the results using RevMan 5.4 software and STATA 16.0 software. RESULTS: The results of our research will be published in a peer-reviewed journal. CONCLUSION: The conclusion of our systematic review will provide evidence to judge whether Kanglaite injection is an effective intervention for patient with GC. OSF REGISTRATION NUMBER: 10.17605/OSF.IO/HF679.

Heated fennel therapy promotes the recovery of gastrointestinal function in patients after complex abdominal surgery: A single-center prospective randomized controlled trial in China.

BACKGROUND: Postoperative gastrointestinal dysfunction remains a major determinant of the duration of stay after complex abdominal surgery. This study was performed to evaluate the effectiveness of heated fennel therapy in accelerating the recovery of gastrointestinal function. METHODS: This surgeon-blinded, prospective randomized controlled study included 381 patients with hepatobiliary, pancreatic, and gastric tumors who were divided into 2 groups. The patients in the experimental groups received heated fennel therapy, and those in the control groups received heated rice husk therapy. We compared the baseline characteristics, time to first postoperative flatus and defecation, fasting time, duration of postoperative hospital stay, grading of abdominal pain, classification of abdominal distension, inflammatory markers, and nutritional status indicators. RESULTS: The time to first flatus and first defecation and the fasting time were statistically significantly less in the heated fennel therapy group than those in the control groups (P < .05 each); and abdominal distension was also relieved in the experimental groups (P < .001). Heated fennel therapy had no obvious beneficial effect on inflammatory markers but improved the serum albumin (ALB) level of the patients at postop day 9 (P < .001). Among the patients with alimentary tract reconstruction, those in the heated fennel therapy group had a clinically important, lesser hospital stay than those in the control group (9.2 5 ± 5.1 versus 11.1 ± 6.4; P < .023). CONCLUSION: Heated fennel therapy facilitated the gastrointestinal motility function of patients early postoperatively.

Wound healing after excision of subcutaneous tumors treated with near-infrared photoimmunotherapy.

Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer therapy that employs a combination of infrared light and tumor-targeted monoclonal antibody-photoabsorber conjugates to cause both direct tumor necrosis and immunogenic cell death. NIR-PIT may have potential in the perioperative setting before surgery, and therefore it is important to know the effect of NIR-PIT on wound healing. Fifty mice were implanted with subcutaneous xenografts of N87 human gastric cancer cells, and tumors were excised after reaching a predetermined size. After excision, 30 mice were split into three groups: Controls, NIR-PIT 1 day prior to surgery and NIR-PIT 3 days prior to surgery. The quantity of reactive oxygen species (ROS) in each wound was measured on Postoperative Days 2 and 4, and mice were monitored weekly for 4 weeks for evidence of local tumor recurrence as well as clinical evidence of wound healing complications (eg, dehiscence, infection). The remaining 20 mice (10 controls, 10 treated with NIR-PIT 1 day prior to surgery) were sacrificed on either Postoperative Day 7 or 14, the skin around wounds were excised, and tensile strength was measured with a digital force gauge. There were no significant differences between treatment and control groups with respect to wound ROS levels, wound tensile strength, local tumor recurrence, or postoperative complication rates (P > .05). In conclusion, neoadjuvant (pre-operative) NIR-PIT shows no evidence of adverse wound healing effects, and it is likely a safe adjunctive treatment to surgery. Postoperative use of NIR-PIT merits investigation.

Dual-Targeted Gold Nanoprism for Recognition of Early Apoptosis, Dual-Model Imaging and Precise Cancer Photothermal Therapy.

Photothermal therapy as novel strategy to convert near-infrared (NIR) light into heat for treatment cancers has attracted great attention and been widely studied. However, side effects and low efficiency remain the main challenge of precise cancer photothermal therapy. Methods: In this study, we have successfully fabricated and characterized the dual-targeted gold nanoprisms, whereby bare gold nanoprisms (Au NPR) were conjugated to a phenanthroline derivatives-functionalized tetraphenylethene (TPE) and further stabilized with target peptide aptamers via Au-S bonds (Au-Apt-TPE). Then, the remaining nitrogen atoms of the Au-Apt-TPE could effectively chelate with Zn2+ ions (Au-Apt-TPE@Zn) for monitoring early stage apoptotic cells. Results: The as-synthesized Au-Apt-TPE@Zn exhibited good monodispersity, size stability and consistent spectral characteristics. TPE synthesized here showed aggregation-induced emission (AIE) characteristics, and zinc conjunction (TPE@Zn) endowed Au-Apt-TPE@Zn with the cell membrane-targeted ability to selectively recognize the membranes of early stage apoptotic cells but not respond to healthy cells, which provided valuable diagnosis information on therapeutic efficacy. Au-Apt-TPE@Zn achieved specifically nuclear-targeted ability by surface decoration of AS1411 DNA aptamer. Au-Apt-TPE@Zn under NIR irradiation showed effective photothermal therapy against SGC-7901 human gastric carcinoma cells growth in vitro by inducing apoptosis through triggering reactive oxygen species (ROS) overproduction and regulating multiple signal crosstalk. In vivo studies revealed that Au-Apt-TPE@Zn under NIR irradiation showed deep penetration and dual-model imaging application (cancer-targeted fluorescence imaging and light-up photoacoustic imaging). Au-Apt-TPE@Zn under NIR irradiation also displayed strong photothermal therapy against gastric carcinoma xenograft growth in vivo by induction of apoptosis. Importantly, analysis of histopathology, hematotoxicity and immunocytotoxicity indicated that Au-Apt-TPE@Zn had less side effect and high biocompatibility. Conclusions: Our findings validated the design of using Au nanoprism with AIE materials and dual-targeted decoration could be an effective strategy in recognition of early apoptosis, dual-model imaging and precise cancer photothermal therapy.

Costunolide induces mitochondria-mediated apoptosis in human gastric adenocarcinoma BGC-823 cells.

BACKGROUND: Costunolide, a sesquiterpene lactone extracted from Radix Aucklandiae, has the activity against multiple cancers. However, the effect of costunolide on gastric cancer (GC) have remained to be ambiguous. In this study, we investigated the underlying mechanisms of apoptosis induced by costunolide in human gastric adenocarcinoma BGC-823 cells in vitro and in vivo. METHODS: The viability of BGC-823 cells was detected by MTT assay. The apoptosis and mitochondrial membrane potential (ΔΨm) of BGC-823 cells induced by costunolide were analyzed by flow cytometry. The inhibiton of costunolide on human gastric adenocarcinoma was estimated in xenografts in nude mice. Apoptosis related proteins and genes were detected by Western blot and Q-PCR. RESULTS: Costunolide inhibited the viability of BGC-823 cells in a time and concentration dependent manner. Costunolide induced the apoptosis and lowered the ΔΨm of BGC-823 cells significantly. Costunolide increased the expression of Bax, cleaved caspase 9, cleaved caspase 7, cleaved caspase 3 and cleaved poly ADP ribose polymerase (PARP) proteins and decreased the expression of Bcl-2, pro-caspase 9, pro-caspase 7, pro-caspase 3 and PARP proteins. Costunolide upregulated the expression of puma, Bak1 and Bax mRNA and downregulated the expression of Bcl-2 mRNA. In addition, we demonstrated that costunolide inhibited the growth and induced apoptosis of BGC-823 cells xenografted in athymic nude mice. Costunolide increased the expression of cleaved caspase 9, cleaved caspase 3 and Bax proteins and decreased the expression of Bcl-2 protein in xenografted tumor. Costunolide upregulated the expression of puma and Bax mRNA and decreased the expression of Bcl-2 mRNA in xenografted tumor. CONCLUSIONS: Collectively, our results suggested that costunolide induced mitochondria-mediated apoptosis in human gastric adenocarcinoma BGC-823 cells and could be the candidate drug against GC in clinical practice.

Effects of Celastrus orbiculatus on Epithelial Mesenchymal Transition in Gastric Mucosal Epithelial Cells by Inhibiting Lgr5 Expression from Rats with Gastric Precancerous Lesions.

The extract of Celastrus orbiculatus (COE) has been shown to possess anti-Helicobacter pylori (H. pylori) activity and anticancer effects in vitro and in vivo. However, the molecular mechanism by which COE on precancerous lesions of gastric cancer (PLGC) has not been fully elucidated so far. The purpose of this study is to evaluate the effect and mechanism of COE in the rat model of PLGC, after the rat model of PLGC was successfully constructed. The effects of COE in gastric mucosa of rats with PLGC were tested using routine pathology and a transmission electron microscope (TEM) analysis. The protein and mRNA expression levels of epithelial mesenchymal transition (EMT) markers (E-cadherin, N-cadherin and Vimentin) and leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) were detected adopting techniques of immunohistochemistry (IHC), real-time PCR (RT-PCR) and western blot assays. The body weight of PLGC rats was significantly higher in the COE group than that in the untreated group. The process of PLGC was significantly reversed after COE treatment, shown by observing the changes of histopathological morphology and ultrastructure. Gastric mucosal epithelial cells in COE high dose (COE-H) group showed significantly higher expression levels of E-cadherin, and lower expression levels of N-cadherin, Vimentin and Lgr5 than those of the untreated group. COE could suppress the spatial distribution of Lgr5[Formula: see text] cell changes in PLGC rats. These findings suggested that the therapeutic mechanisms of COE in treating PLGC might be related with its effects on reversing the EMT process and inhibiting Lgr5 expression.

Further insights on tomato plant: Cytotoxic and antioxidant activity of leaf extracts in human gastric cells.

This study focused the toxicity against human gastric adenocarcinoma cells (AGS) and the antioxidant activity of hydromethanol (HME), acetone (AcE) and alkaloid (AE) extracts prepared from the leaves of tomato plant cultivars (Caramba, Valentine, Negro, Abuela, and Anairis). AE, HME and AcE extracts of all cultivars reduced cell viability, IC50 values ranging from 9 ± 2 to 55 ± 11, from 103 ± 25 to 171 ± 29 and from 291 ± 26 to 459 ± 14 µg mL-1, respectively. Moreover, both HME and AcE extracts scavenged •NO (IC50 values ranged from 0.87 ± 0.12 to 1.54 ± 0.23 and from 0.90 ± 0.01 to 2.23 ± 0.14 mg mL-1, respectively), but only HMEs was able to scavenge O2•- showing IC50 values from 0.12 ± ≤0.01 to 0.43 ± 0.08 mg mL-1. Our results demonstrate that tomato leaves, a by-product of tomato processing industry, are a valuable source of bioactive compounds, providing beneficial properties for human health.

The Nutritive Value of Organic and Conventional White Cabbage (Brassica Oleracea L. Var. Capitata) and Anti-Apoptotic Activity in Gastric Adenocarcinoma Cells of Sauerkraut Juice Produced Therof.

White cabbage is one of the most important vegetables grown both in Poland and worldwide. Cabbage contains considerable amounts of bioactive compounds such as glucosinolates, vitamin C, carotenoids, and polyphenols. Some experiments indicate that vegetables from organic production contain more bioactive compounds than those from conventional production, however, only a few studies have been conducted on cruciferous plants. The presented study has proved that organic fresh cabbage, compared to the conventional one, contained significantly less total flavonoids in both years of experiments (3.95 ± 0.21 mg/100 g FW and 3.71 ± 0.33 mg/100 g FW), several flavonoid compounds, total chlorophylls (1.51 ± 0.17 mg/100 g FW and 1.30 ± 0.22 mg/100 g FW) carotenoids, nitrites (0.55 ± 0.04 mg/kg FW and 0.45 ± 0.02 mg/kg FW), and nitrates (0.50 ± 0.13 g/kg FW and 0.47 ± 0.11 g/kg FW). The organic sauerkraut juice, compared to the conventional one, contained significantly more total polyphenols (5.39 ± 0.22 mg/100 g FW and 9.05 ± 1.10 mg/100 g FW) as well as several flavonoids. Only CONV sauerkraut juice produced with the highest N level of fertilization induced a statistical significant increase of the level of necrosis of human stomach gastric adenocarcinoma cell line AGS.

Anti-tumor bioactivities of curcumin on mice loaded with gastric carcinoma.

Curcumin, a derivative from the dried rhizome of curcuma longa, has been proven to possess anti-tumor effects. However, the detailed molecular mechanisms have not been fully elucidated. In this study, we aimed to explore the anti-tumor mechanisms of curcumin in treating gastric cancer. BALB/C mice grafted with a mouse gastric adenocarcinoma cell line (MFC) were used as the experimental model. Mice received different doses of curcumin after grafting. Tumor size was measured and tumor weight was determined after tumor inoculation. TUNEL assay and flow cytometric analysis were applied to evaluate the apoptosis of the cancer cells. Serum cytokines IFN-γ, TNF-α, granzyme B and perforin were detected by ELISA assay. The anti-tumor effect was determined using cytotoxic T-lymphocyte (CTL) assays and in vivo tumor prevention tests. The expression of DEC1, HIF-1α, STAT3 and VEGF in tumor tissues was examined by immunostaining and analyzed using an Image J analysis system. Compared with controls, tumor growth (size and weight) was significantly inhibited by curcumin treatment (P < 0.05). The apoptotic index in gastric cancer cells was significantly increased in the curcumin treatment group. Splenocyte cells from mice treated with curcumin exhibited higher cytolytic effects on MFC cancer cells than those from mice treated with saline (P < 0.01). The expression of DEC1, HIF-1α, STAT3 and VEGF in tumor tissues was down-regulated after curcumin treatment. Our results indicate that curcumin inhibits the proliferation of gastric carcinoma by inducing the apoptosis of tumor cells, activating immune cells to secrete a large amount of cytokines, and down-regulating the DEC1, HIF-1α, VEGF and STAT3 signal transduction pathways.

CRA(Crosolic Acid) isolated from Actinidia valvata Dunn.Radix induces apoptosis of human gastric cancer cell line BGC823 in vitro via down-regulation of the NF-κB pathway.

A natural ursolic compound, 2α,3ß-dihydroxy-urs-12-en-28-oic acid (corosolic acid, CRA) was isolated from the root of Actinidia valvata Dunn. (A. valvata Radix). Since a large number of triterpenoid compound has marked anticancer effects toward various types of cancer cell lines in vitro, this study was carried out to investigate the anticancer effect of CRA in human gastric cancer cell line BGC823 cells and the underlying apoptotic mechanism of CRA was examined in BGC823 cell lines. The results showed that CRA significantly suppressed the viability of BGC823 cells in a concentration- and time-dependent manner. CRA also significantly increased the sub G1 population by cell cycle analysis in a concentration dependent manner. Exposure to CRA decreased p65, bcl-2, Fas, smac mRNA and protein expression, and increased IκBα, bax, survivin mRNA and protein expression. Results of immunofluorescence staining and EMSA further indicated CRA induced apoptosis by inhibiting nuclear translocation of nuclear factor NF-κB subunit p65. Consistently overall, our findings suggest that CRA induces apoptosis via inhibition of NF-κB (p65) expression level and activation of IκBα in BGC cells as a potent anticancer candidate for gastric cancer treatment.

[Effect of polyunsaturated fatty acids ω-3 and ω-6 on angiogenesis formation in human gastric cancer].

OBJECTIVE: To investigate the effects of polyunsaturated fatty acids (PUFA) ω-3 and ω-6, and their middle metabolites PGE2 and PGE3 on angiogenesis formation of gastric cancer, and to explore associated mechanism. METHODS: The effects of ω-3, ω-6, PGE2, PGE3 on the proliferation and migration of human umbilical vein endothelial cell (HUVEC) were measured by proliferation and migration assay respectively. The angiogenesis assay in vivo was used to measure the effects of ω-3, ω-6, PGE2 and PGE3 on neovascularization. In all the assays, groups without ω-3, ω-6, PGE2 and PGE3 were designed as the control. RESULTS: With the increased concentration of ω-6 from 1 µmol/L to 10 µmol/L, the proliferation ability of HUVECs enhanced, and the number of migration cells also increased from 28.2±3.0 to 32.8±2.1, which was higher than control group (21.2±3.2) respectively (both P<0.05). With the increased concentration of ω-3 from 1 µmol/L to 10 µmol/L, the proliferation ability of HUVECs was inhibited, and the number of migration cells decreased from 15.8±2.0 to 11.0±2.1, which was lower than control group (22.1±3.0) respectively (both P<0.05). In the angiogenesis assay, compared with control group (standard number: 43 721±4 654), the angiogenesis ability of HUVECs was significantly enhanced by ω-6 in concentration-dependent manner (1 µmol/L group: 63 238±4 795, 10 µmol/L group: 78 166±6 123, all P<0.01). Meanwhile, with the increased concentration of ω-3 from 1 µmol/L to 10 µmol/L, the angiogenesis ability was significantly decreased from 30 129±3 102 to 20 012±1 541(all P<0.01). The proliferation and migration ability of HUVECs were significantly promoted by ω-6 metabolites PGE2 (P<0.05) in a concentration-dependent manner. In contrast, ω-3 metabolites PGE3 significantly inhibited the proliferation and migration ability of HUVECs in a concentration-dependent manner (all P<0.05). After rofecoxib (a COX-2 specific inhibitor) inhibited the expression of COX-2, the expression level of PGE2 was significantly decreased in a dose-dependent manner. In co-culture system, whose gastric cancer cells expressed positive COX-2, ω-6 could increase angiogenesis of gastric cancer cells(P<0.01), but ω-3 could inhibit such angiogenesis(P<0.01). In co-culture system, whose gastric cancer cells did not express COX-2, ω-3 could inhibit the angiogenesis of gastric cancer cells (P<0.05), but ω-6 had no effect on angiogenesis. CONCLUSIONS: The PUFA ω-6 can enhance the angiogenesis via the promotion of proliferation and migration of HUVECs, and COX-2 and PGE2 may play an important role in this process, whereas, the ω-3 can inhibit the angiogenesis through its middle metabolites PGE3 to inhibit the proliferation and migration of HUVECs. Results of this experiment may provide a new approach to inhibit and prevent the spread of gastric cancer.

Baicalin extracted from Huangqin (Radix Scutellariae Baicalensis) induces apoptosis in gastric cancer cells by regulating B cell lymphoma (Bcl-2)/Bcl-2-associated X protein and activating caspase-3 and caspase-9.

OBJECTIVE: To evaluate the effects of baicalin in human gastric cancer cells, including apoptosis-inducing effects, and to investigate its underlying mechanisms of action. METHODS: Cell proliferation and apoptosis assays were performed to investigate the anti-proliferation effects of baicalin in human gastric cancer BGC-823 and MGC-803 cells. Real time-quantitative polymerase chain reaction and Western blotting analysis were performed to elucidate the molecular mechanisms underlying the anti-tumor properties of baicalin. RESULTS: In BGC-823 and MGC-803 gastric cancer cells treated with 80, 120, and 160 µmol/L baicalin for 48 h, a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay showed that baicalin significantly inhibited cell proliferation in a dose-dependent manner, while flow cytometric analysis demonstrated that baicalin could induce apoptosis, also in a dose-dependent manner. Moreover, baicalin up-regulated the expression of caspase-3, caspase-9, and B cell lymphoma (Bcl-2)-associated X protein and down-regulated the expression of Bcl-2 at both the mRNA and protein level. CONCLUSION: Baicalin has potential as a therapeutic agent for gastric cancer by inducing apoptosis in cancer cells.

Effect of prehabilitation in gastro-oesophageal adenocarcinoma: study protocol of a multicentric, randomised, control trial-the PREHAB study.

INTRODUCTION: Perioperative chemotherapy is the gold standard treatment of the resectable gastro-oesophageal adenocarcinoma. However, 70% of patients cannot receive the complete sequence because of a postoperative complication or a decrease in functional and nutritional reserves. Recently, a new concept appeared in digestive surgery: prehabilitation. This interventional process consists of patient preparation, between surgical consultation and surgery, and is based on 3 components: (1) physical management, (2) nutritional care and (3) psychological care. Prehabilitation should decrease postoperative complications and improve nutritional and physical status during the preoperative and postoperative periods. Therefore, it is becoming essential to evaluate the effect of prehabilitation, compared to conventional care, on the percentage of patients reaching the complete oncological treatment. METHODS AND ANALYSIS: The PREHAB trial aimed to evaluate the efficacy of prehabilitation compared to conventional care, in patients with gastro-oesophageal cancer with perioperative chemotherapy. This trial is a prospective, randomised, controlled, open-blind and interventional study in 4 centres. Patients (n=60 per group) will be randomly assigned for management with either prehabilitation or conventional care. The primary outcome is the percentage of patients reaching the complete oncological treatment decided in a multidisciplinary tumour board. The secondary outcomes are the postoperative morbidity, disease-free survival, overall survival, feasibility of the protocol, length of stay, variation of the functional reserve after the preoperative chemotherapy (defined by the VO2peak, ventilatory threshold and 6-min walk test), preoperative and postoperative nutritional status, preoperative anxiety, quality of life, 30-day and 90-day mortality and cumulative dose of cytotoxic treatment received. ETHICS AND DISSEMINATION: The study was approved by an independent medical ethics committee (IRB00008526, CPP Sud-Est VI, Clermont-Ferrand, France) and by the competent French authority (ANSM, Saint Denis, France) and registered on Clinicaltrial.gov. The results will be disseminated in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02780921.

Anti-proliferative and apoptotic effects of S1, a tetrandrine derivative, in human gastric cancer BGC-823 cells.

The aim of the study was to investigate the anti-proliferation and apoptosis-inducing effects of S1, a novel tetrandrine derivative, in human gastric cancer BGC-823 cells and explore the possible mechanism of action. The anti-proliferative activity was determined by MTT assay; the induction of cell cycle arrest and apoptosis were detected by flow cytometry. Quantitative real time RT-PCR and Western blotting were used to evaluate the mRNA and protein expression levels in mitochondrial pathway. S1 significantly reduced cell viability and induced a G2/M phase arrest and apoptosis in dose- and time-dependent manner. Further studies showed that S1 increased mRNA and protein expression of Bax and the Bax/Bcl-2 ratio. Moreover, S1 decreased the protein expression of procaspase-9 and procaspase-3, suggesting that the induction of apoptosis may be related to the alteration of the ratio of Bax/Bcl-2 and the activation of caspases. These findings suggested that S1 merits further investigation as a novel therapeutic agent for the treatment of human gastric cancer.

Black Currant (Ribes nigrum L.) Extract Induces Apoptosis of MKN-45 and TE-1 Cells Through MAPK- and PI3K/Akt-Mediated Mitochondrial Pathways.

Black currant extract (BCE) is rich in polyphenols and can induce apoptosis in various cancer cells, but the molecular mechanism by which BCE induces cancer cell apoptosis has not been reported. The aim of this work was to elucidate the antitumor effect of BCE and the signal transduction pathways involved. MTT test results revealed that the viability of MKN-45 and TE-1 cells treated with BCE gradually decreased in a concentration-dependent manner, with significant effects achieved after 12 h of treatment. MKN-45 and TE-1 cells clearly showed characteristics of apoptosis: shrinkage, cytoplasmic condensation, and formation of cytoplasmic filaments, even partial detachment. In addition, these results showed MKN-45 cells showed a higher level of apoptosis than TE-1 cells when treated with BCE. Western blot assays showed that the Bcl-2/Bax ratio decreased in both MKN-45 and TE-1 cells, indicating that BCE induced apoptosis through the mitochondrial pathway. In addition, BCE-induced apoptosis was mediated by mitochondrial dysfunction involving the PI3K/Akt pathway in both MKN-45 and TE-1 cells. However, BCE-induced cell apoptosis was mediated by the Fas receptor pathway in MKN-45 cells but not in TE-1 cells. BCE-induced apoptosis in MKN-45 cells was associated with the MAP-kinase signaling pathway through the activation of p38 and JNK and the inactivation of Erk1/2. However, it was associated with the MAP-kinase signaling pathway only by means of activation of p38 and JNK in TE-1 cells. These results showed that BCE induces apoptosis of MKN-45 and TE-1 cells through MAPK- and PI3K/Akt-mediated mitochondrial pathways. Thus, BCE may be a promising anticancer candidate.