Enhanced glucose homeostasis via Clostridium symbiosum-mediated glucagon-like peptide 1 inhibition of hepatic gluconeogenesis in mid-intestinal bypass surgery.

BACKGROUND: The small intestine is known to play a crucial role in the development and remission of diabetes mellitus (DM). However, the exact mechanism by which mid-small intestinal bypass improves glucose metabolism in diabetic rats is not fully understood. AIM: To elucidate the mechanisms by which mid-small intestinal bypass improves glucose metabolism. METHODS: Streptozotocin (STZ) was used to induce DM in Sprague-Dawley (SD) rats at a dose of 60 mg/kg. The rats were then randomly divided into two groups: The mid-small intestine bypass (MSIB) group and the sham group (underwent switch laparotomy). Following a 6-wk recovery period post-surgery, the rats underwent various assessments, including metabolic parameter testing, analysis of liver glycogen levels, measurement of key gluconeogenic enzyme activity, characterization of the gut microbiota composition, evaluation of hormone levels, determination of bile acid concentrations, and assessment of the expression of the intestinal receptors Takeda G protein-coupled receptor 5 and farnesoid X receptor. RESULTS: The MSIB group of rats demonstrated improved glucose metabolism and lipid metabolism, along with increased hepatic glycogen content. Furthermore, there was a decrease in the expression of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 and glucose-6-phosphatase. Importantly, the MSIB group exhibited a substantial increase in the abundances of intestinal Lactobacillus, Clostridium symbiosum, Ruminococcus gnavus, and Bilophila. Moreover, higher levels of secondary bile acids, such as intestinal lithocholic acid, were observed in this group. Remarkably, the changes in the gut microbiota showed a significant correlation with the expression of key gluconeogenic enzymes and glucagon-like peptide 1 (GLP-1) at 6 wk postoperatively, highlighting their potential role in glucose regulation. These findings highlight the beneficial effects of mid-small intestine bypass on glucose metabolism and the associated modulation of the gut microbiota. CONCLUSION: The findings of this study demonstrate that the introduction of postoperative intestinal Clostridium symbiosum in the mid-small intestine contributes to the enhancement of glucose metabolism in nonobese diabetic rats. This improvement is attributed to the increased inhibition of hepatic gluconeogenesis mediated by GLP-1, resulting in a favorable modulation of glucose homeostasis.

Differences in metabolic improvement after metabolic surgery are linked to the gut microbiota in non-obese diabetic rats.

BACKGROUND: Different metabolic/bariatric surgery approaches vary in their effect on weight loss and glucose levels, although the underlying mechanism is unclear. Studies have demonstrated that the gut microbiota might be an important mechanism of improved metabolism after metabolic/bariatric surgery. AIM: To investigate the relationship between the improvement in metabolic disturbances and the changes in gut microbiota after gastric or intestinal bypass. METHODS: We performed sleeve gastrectomy (SG), distal small intestine bypass (DSIB) or sham surgery in nonobese rats with diabetes induced by 60 mg/kg streptozotocin (STZ-DM). RESULTS: The group comparisons revealed that both SG and DSIB induced a reduction in body weight and significant improvements in glucose and lipid metabolism in the STZ-DM rats. Furthermore, DSIB exhibited a stronger glucose-lowering and lipid-reducing effect on STZ-DM rats than SG. 16S ribosomal RNA gene sequencing revealed the gut abundance of some Lactobacillus spp. increased in both the SG and DSIB groups after surgery. However, the DSIB group exhibited a more pronounced increase in the gut abundance of Lactobacillus spp. compared to the SG group, with more Lactobacillus spp. types increased in the gut. CONCLUSION: The gut abundance of Lactobacillus was significantly correlated with the improvement in glycolipid metabolism and the change in serum fibroblast growth factor 21 levels.

Monoterpenoid indole alkaloids from the fruits of Gelsemium elegans and their anti-inflammatory activities.

Two novel monoterpenoid indole alkaloids (MIAs), gelsechizines A-B (1-2), along with four known ones (3-6) were isolated from the fruits of Gelsemium elegans. Compound 1 features a new carbon skeleton with two additional carbon atoms forming a 4-methylpyridine unit. Their structures with absolute configurations were elucidated by NMR, MS, X-ray diffraction and electronic circular dichroism (ECD) calculations. Compounds 1-3 showed significant anti-inflammatory effects in vivo and in vitro, which may be related to the inhibition of the trecruitment of neutrophils and macrophages as well as the secretion of TNF-α and IL-6. Preliminary structure-activity relationship analysis revealed that the ß-N-acrylate moiety plays an important role in the anti-inflammatory effect.

Methionine represses the autophagy of gastric cancer stem cells via promoting the methylation and phosphorylation of RAB37.

This study focused on the role of methionine (MET) in the autophagy of gastric cancer stem cells (GCSCs) and aims to elaborate its regulatory mechanism. In the present study, the GCSCs were isolated from human gastric cancer cell lines using an anti-CD44 antibody, and then cultured in MET+ homocysteine (HCY)- or MET-HCY+ medium. In MET+HCY-treated GCSCs, autophagy was suppressed, the methylation and phosphorylation of RAB37 were elevated, and miR-200b expression was down-regulated. Lentiviral vector (LV-) carrying methionine-γ lyase (an enzyme that could specifically lyse MET; Metase) promoted autophagy, reduced the methylation and phosphorylation of RAB37, and up-regulated miR-200b expression in MET+HCY--treated GCSCs. Then, we found that miR-200b suppressed the expression of protein kinase C α (PKCα), a protein that could inactivate RAB37 through promoting its phosphorylation. LV-Metase down-regulated RAB37 phosphorylation via miR-200b/PKCα, thus promoting the RAB37-mediated autophagy and suppressing cell viability in MET+HCY-treated GCSCs. Finally, the in vivo study proved that LV-Metase treatment inhibited tumor growth through up-regulating RAB37 expression. In conclusion, MET suppressed RAB37 expression via enhancing its methylation and suppressed RAB37 activity via miR-200b/PKCα axis, thus repressing RAB37-mediated autophagy in GCSCs. The supplementation of Metase lysed MET, thus inducing the autophagy of GCSCs and inhibiting tumor growth.

Intraoperative Correction of Femoral Rotational Deformity Using a Conventional Navigation System and a Smartphone: A Novel Technique.

The intraoperatively rotational control of femoral shaft fractures treated with a closed intramedullary interlocking nailing is a challenging problem. A novel surgical technique that includes respective insertions of guidewires into the proximal and distal femur under the guidance of a 2-dimensional fluoroscopy-based navigation system and the measurements of the intersection angle subtended by the proximal and distal guidewires with the smartphone positional software has been designed to provide intraoperatively quantitative parameters of femoral rotation deformation. The comparison of these parameters with preoperative measurement values of the contralateral intact femur on computed tomography images was used to align the proximal and distal femur fragments based on periaxial rotation. The purpose of this study was to evaluate its clinical suitability. Ten adult patients with femoral shaft fractures were attempted to correct intraoperatively femoral rotational deformity using this novel technique. The additional operation time was 20.04 ± 3.27 minutes. The angle of femoral anteversion was 20.85° ± 4.22°, 38.14° ± 19.07°, and 22.77° ± 3.38° in the contralateral intact and preoperatively and postoperatively injured femur, respectively. The mean absolute difference between both limbs was preoperatively 21.55° ± 10.14° with a statistically significant difference ( P = .005) and postoperatively 3.24° ± 1.69° with no statistically significant difference ( P = .092). Our results showed this novel technique could become an effective tool to correct intraoperatively rotational malalignment of femoral fractures.

Synergistic effects of dimethyloxallyl glycine and recombinant human bone morphogenetic protein-2 on repair of critical-sized bone defects in rats.

In bone remodeling, osteogenesis is closely coupled to angiogenesis. Bone tissue engineering using multifunctional bioactive materials is a promising technique which has the ability to simultaneously stimulate osteogenesis and angiogenesis for repair of bone defects. We developed mesoporous bioactive glass (MBG)-doped poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) composite scaffolds as delivery vehicle. Two bioactive molecules, dimethyloxalylglycine (DMOG), a small-molecule angiogenic drug, and recombinant human bone morphogenetic protein-2 (rhBMP-2), an osteoinductive growth factor, were co-incorporated into the scaffold. The synergistic effects of DMOG and rhBMP-2 released in the composite scaffolds on osteogenic and angiogenic differentiation of hBMSCs were investigated using real-time quantitative polymerase chain reaction and western blotting. Moreover, in vivo studies were conducted to observe bone regeneration and vascular formation of critical-sized bone defects in rats using micro-computed tomography, histological analyses, Microfil® perfusion, fluorescence labeling, and immunohistochemical analysis. The results showed that DMOG and rhBMP-2 released in the MBG-PHBHHx scaffolds did exert synergistic effects on the osteogenic and angiogenic differentiation of hBMSCs. Moreover, DMOG and rhBMP-2 produced significant increases in newly-formed bone and neovascularization of calvarial bone defects in rats. It is concluded that the co-delivery strategy of both rhBMP-2 and DMOG can significantly improve the critical-sized bone regeneration.

Sulfamic and succinic acid derivatives of 25-OH-PPD and their activities to MCF-7, A-549, HCT-116, and BGC-823 cell lines.

In the search for new anti-tumor agents with higher potency than our previously identified compound 1 (25-OH-PPD, 25-hydroxyprotopanaxadiol), 12 novel sulfamic and succinic acid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 1, compounds 2, 3, and 7 exhibited higher cytotoxic activity on A-549 and BGC-823 cell lines, together with lower toxicity in the normal cell. In particular, compound 2 exhibited the best anti-tumor activity in the in vitro assays, which may provide valuable data for the research and development of new anti-tumor agents.

Using a Novel CD133+ Immune Magnetic Particle to Separate Gastric Adenocarcinoma Stem Cells from Peripheral Blood and the Pluripotency Study About the Separated Cells.

Background: Stem cells isolated from peripheral blood of gastric adenocarcinoma patients have noninvasive advantages. However, at present, there is no simple and effective separation technique. Purpose: In this study, CD133+ cells were isolated from peripheral blood of patients with gastric adenocarcinoma by using specific immunomagnetic particles, and the immunology of subcultured cells was identified to evaluate whether the immune magnetic particle separation had any effect on the cells themselves. Methods: Immune magnetic particles, made by a specific technique, are used to sort out the cells whose membrane could express CD133 from peripheral blood of gastric adenocarcinoma patients. By observing the sorted cells within serum-free culturing, we compare the differences in morphology and proliferation ability between the collected cells and cells from a standard tumor cell line. At the same time, an immunofluorescence method is used to detect the expression of the CD133 antibody. Moreover, this study explores the inhibition effect on gastric adenocarcinoma stem cell growth when combining 5-fluorouracil and methionine enzymes. Results and Conclusions: The specific immunomagnetic particles have a small diameter and strong sorting characteristics. In the experiment, there were 20 patients with gastric adenocarcinoma. CD133+ cells were separated successfully from peripheral blood of 13 patients (65%), among which subcultured cells of 9 cases (69.2%) were found to express CD44+ antigens. The sorted cells grew vigorously with a variety of morphologies in non-inducing culture, while the cells induced by ß transforming growth factor presented slow growth and uniform morphology. There was a significant difference (P < 0.05) in cell proliferation between these two groups and the standard tumor cell line. In addition, 5-fluorouracil combined with methionine enzyme inhibited the growth of gastric adenocarcinoma stem cells significantly (P < 0.05). Accordingly, the CD133+/CD44+ cells from peripheral blood of gastric adenocarcinoma patients, sorted by specific immune magnetic particles, had clear stem cell properties as determined by cell function and structure. This lays a foundation for gastric adenocarcinoma stem cell extraction, culture and further research on stem cell characteristics.

One-pot synthesis, anti-tumor evaluation and structure-activity relationships of novel 25-OCH3-PPD derivatives.

Based on the fact that 25-OCH3-PPD, a natural ginsengenin isolated from the leaves of Panax ginseng, is a promising lead compound, novel 25-OCH3-PPD derivatives were synthesized to find more potent anti-tumor agents by a simple and facile synthetic method. These derivatives were classified into three types and screened for their cytotoxic activities against seven human cancer cell lines. Compared with 25-OCH3-PPD, compounds a5, a7, b5 and b7 exhibited higher anti-tumor activities on all tested cell lines with almost 5-fold to 15-fold increases. In particular, compound a7 showed the greatest cytotoxic activity against α-2 cells (IC50 = 2.4 ± 0.4 µM). The preliminary study on the mechanisms indicated that compound a7 could induce α-2 cell apoptosis. Structure-activity relationships demonstrated that the carbon-carbon double bond at the C-20 position could enhance the antiproliferative activity. In conclusion, the novel derivatives a5, a7, b5 and b7 could be further studied as potential candidates for the treatment of cancer. This research provides a theoretical reference for the exploration of new antiproliferative agents.

Comparison of transanal endoscopic microsurgery with or without neoadjuvant therapy and standard total mesorectal excision in the treatment of clinical T2 low rectal cancer: a meta-analysis.

Some clinical trials demonstrated local resection for clinical T1 rectal cancer was safe and effective. But for clinical T2 rectal cancer, the results were controversial. Neoadjuvant therapy (NT) is proven to reduce the opportunity of advanced rectal cancer recurrence in various researches. The objective of this Meta-Analysis was to evaluate the oncological outcomes of transanal endoscopic microsurgery (TEM) with or without NT comparing with conventional total mesorectal excision (TME) for the treatment of clinical T2 rectal cancer.To search for the relevant studies, an electronic search was done from the databases of Pubmed, Embase, and the Cochrane Library in this meta-analysis. We compared the effectiveness of transanal endoscopic microsurgery with or without NT and standard total mesorectal excision in the treatment of T2 Rectal Cancer. 1RCT and 3nRCTs including 121 TEM patients (TEM + NT: 59, TEM: 62) and 174 TME patients with T2 rectal cancer were retrieved. Compared with TME, there were no significant differences in the outcomes of local recurrence, overall recurrence, overall survival between TEM + NT group. However in compassion with TME, TEM without NT was associated with an increased local recurrence, overall recurrence, and a shorter overall survival, with individual ORs being 3.04 (95% Cl: 1.17-7.90; I2 = 0%), 5.67 (95% Cl: 1.58-20.38; I2 = 0%) and 0.12 (95% Cl: 0.02-0.65; I2 = 0%), respectively. Compared with TME, TEM after NT may be a feasible and safe organ preservative approach for patients with clinical T2 low rectal cancer. But for those without NT, TEM always seem be associated with worse oncological outcomes.

Prognostic Significance of Dickkopf-1 in Gastric Cancer Survival: A Meta-Analysis.

AIMS: The prognostic role of dickkopf-1 (DKK1) in gastric cancer (GC) remains poorly characterized. We performed a meta-analysis to evaluate correlations between DKK1 overexpression and the prognosis of patients with GC. MATERIALS AND METHODS: We included five published studies to assess the relationship between DKK1 and the clinicopathological characteristics and overall survival of GC patients. Literature searches, article selection, data collection, and statistical analysis were performed using RevMan 5.3 software. RESULTS: Our analyses revealed that DKK1 overexpression was significantly associated with vascular invasion (odds ratio [OR] = 2.43, 95% confidence interval [CI] = [1.21, 4.89], p = 0.01, random effect), lymphatic invasion (OR = 2.61, 95% CI = [1.30, 5.24], p = 0.007, random effect), and distant metastasis (OR = 2.99, 95% CI = [1.95, 4.59], p < 0.00001, fixed effect). Moreover, we also found that DKK1 overexpression was significantly associated with poor overall survival in GC patients (risk ratio = 2.67, 95% CI = [2.24, 3.48], p < 0.00001, fixed effect). CONCLUSION: This meta-analysis demonstrated that DKK1 may be a useful prognostic marker for GC.

Two new isoaurones derivatives from Callistephus chinensis flower.

Two new isoaurones derivatives were obtained from Callistephus chinensis flower. Their structures were elucidated on the basis of extensive spectroscopic analyses. Both of the new compounds were evaluated cytotoxic activity. Phytochemical investigation of Callistephus chinensis flower led to the isolation of two new isoaurones derivatives (Z)-4',4,10-trihydroxy-siamaurone (1) and (E)-4',4,10-trihydroxy-siamaurone (2). The structures of these new compounds were identified by the interpretation of spectroscopic data (mainly 1D and 2D NMR) and by comparison with data reported in the literature. Both of the new compounds were evaluated for their cytotoxicity.

Novel dammarane-type triterpenes isolated from hydrolyzate of total Gynostemma pentaphyllum saponins.

In this study, five novel triterpenes were isolated from hydrolyzate of total saponins from Gynostemma pentaphyllum and identified as gypensapogenin H (1), gypensapogenin I (2), gypensapogenin L (3), gypensapogenin J (4) and gypensapogenin K (5), three of which (1-3) possess unprecedented ring A. All the isolated compounds were evaluated for cytotoxic activities in five cell lines and all the tested compounds showed significant anti-cancer activities against a series of human cancer cell lines, while having much weaker effect on the growth of normal cell. Among them, compound 1 showed strong inhibition toward MCF-7 human breast cancer cells (IC50 values 6.85 µM). Further mechanistic study demonstrated that compound 1 significantly induced MCF-7 cell apoptosis. Our results indicated that compound 1 may be a promising lead agent for further study.

Novel 25-hydroxyprotopanaxadiol derivatives incorporating chloroacetyl chloride and their anti-tumor evaluation.

In the current work, 12 novel 25-hydroxyprotopanaxadiol (25-OH-PPD) derivatives were synthesized by reacting with chloroacetyl chloride. And their in vitro antitumor activities were evaluated on six human tumor cell lines by MTT assay. The results demonstrated that, as compared with 25-OH-PPD, compounds 4, 6 and 7 exhibited higher cytotoxic activity on all tested cell lines. Of them, compound 4 showed strongly inhibition against MCF-7, HCT-116 and Lovo cells with IC50 values of 1.7, 1.6 and 2.1 µM, respectively. The IC50 values of compound 6 against HCT-116 and 7 against MCF-7 were the lowest (1.2 and 1.6 µM, respectively). It was also noted that compound 4 showed a 20- to 100-fold greater growth inhibition than ginsenoside-Rg3 (an anti-cancer regular drug in China). In conclusion, the data revealed that compounds 4, 6 and 7 were potential candidates for anti-tumor treatment and may be useful for the development of novel antiproliferative agents.

MDM2 oncogene, E3 ubiquitin protein ligase T309G polymorphism and risk of oesophageal or gastric cancer: meta-analysis of 15 studies.

OBJECTIVE: To investigate the association between potentially functional MDM2 oncogene, E3 ubiquitin protein ligase (MDM2) T309G polymorphism and susceptibility to oesophageal or gastric cancer. METHODS: Two investigators independently searched the PubMed and Chinese National Knowledge Infrastructure databases for studies published before September 2013. RESULTS: Pooled results showed that the variant homozygous 309 GG genotype (versus TT) was significantly associated with increased risk of both oesophageal (odds ratio [OR] 0.77; 95% confidence interval [CI] 0.65, 0.90) and gastric cancer (OR 0.52; 95% CI 0.38, 0.72). Subgroup analysis revealed a 309 GG-associated increased risk for both cancer types in Asian populations, particularly among Chinese and Japanese ethnicity. When stratified for Helicobacter pylori infection and histological type of gastric cancer, the 309 GG-related risk was higher in H. pylori-positive patients (T versus G: OR 0.37; 95% CI 0.22, 0.63) and the association was stronger with intestinal (TT + TG versus GG: OR 0.68; 95% CI 0.54, 0.87) rather than diffuse gastric-cancer type. CONCLUSIONS: The MDM2 T309G polymorphism may be significantly associated with increased susceptibility to oesophageal or gastric cancer, particularly among Eastern Asian populations.

[Safety and feasibility of early oral feeding after gastrectomy: a meta-analysis].

OBJECTIVE: To systematically evaluate the safety and feasibility of early oral feeding after gastric cancer surgery. METHODS: Available literatures of Embase, PubMed, Journals@Ovid, Web of Science, Springerlink, Google Scholar, Wanfang, and CNKI published before October 2012 were searched. Inclusion criteria and quality assessment were performed. RESULTS: Nine studies including 778 patients undergoing gastrectomy were enrolled. Among them, 381 started oral intake before the recovery of bowel function(early oral feeding group), and 397 received traditional feeding. Differences in overall complication(RR=0.88, 95%CI:0.68-1.16) and tolerance (RR=1.01, 95%CI:0.96-1.06) between the two groups were not statistically significant. Patients the in early oral feeding group had faster bowel function recovery (MD=-0.86, 95%CI:-1.20--0.51) and shorter hospital stay(MD=-2.40, 95%CI:-3.33--1.47). CONCLUSION: Early oral feeding after gastrectomy is safe and feasible, and associated with faster recovery of bowel function and earlier discharge from hospital.

25-Methoxylprotopanaxadiol derivatives and their anti-proliferative activities.

(20R)-25-Methoxyl-dammarane-3ß,12ß,20-triol (25-OCH3-PPD) is a dammarane-type sapogenin showing anti-proliferative potential. In our study, two series of analogs substituted at the C-3 or C-3 and C-12 positions with fatty acids were prepared conveniently. The cytotoxic activity of these compounds was evaluated using four different human tumor cell lines (A549, Hela, HT-29 and MCF-7) and a normal cell line (IOSE144). As compared with 25-OCH3-PPD, compounds 1a, 1b, 2a and 2b showed better anti-proliferative activities against all tumor cell lines and all the derivatives, with low toxicities in the normal cell line. Compound 1a (C-3 monoformiate) exhibited the strongest activity with the IC50 value of 5.2 µM towards HT29 cells. The results indicated that the difference in the substituents may affect the anti-proliferative activity of the compounds. The longer the side chain of 25-OCH3-PPD is, the lower the anti-proliferative activity would be. This information may be useful for evaluating the structure-activity relationship of other dammarane-type sapogenins and for development of novel antineoplastic agents.

Semi-synthesis and anti-tumor evaluation of novel 25-hydroxyprotopanaxadiol derivatives.

30 novel compounds have been synthesized from 25-hydroxyprotopanaxadiol (25-OH-PPD) and their in vitro anti-tumor activities were tested on three cancer cell lines and one normal cell line (IOSE144) by standard MTT assay. The results showed that compound 27 exhibited the best anti-tumor activity in the in vitro assays. Compounds 1, 2, 16, 17, 18, 27, 28 and 29 have better anti-tumor activities against MCF-7 and A549 cancer cell lines than 25-OH-PPD, together with low toxicity in the normal cell. The results may provide useful data for researching and developing new antitumor agents.

New antitumor compounds from Carya cathayensis.

A new lignan (7R,8S,8'R)-4,4',9-trihydroxy-7,9'-epoxy-8,8'-lignan, and three new phenolics, carayensin-A, carayensin-B, and carayensin-C, together with 13 known compounds were isolated from the shells of Carya cathayensis. Their chemical structures were established mainly by 1D and 2D NMR techniques and mass spectrometry. All the compounds were evaluated for cytotoxicity against several human tumor types including human colorectal cancer cell lines (HCT-116, HT-29), human lung cancer cell line (A549), and human breast cancer cell line (MCF-7). The compounds 1, 5, 6, and 16 are considered to be potential as antitumor agents, which could significantly inhibit the cancer cell growth in a dose-dependent manner.

A new triterpenoid saponin from Gynostemma pentaphyllum.

A new dammarane-type triterpene saponin was isolated from the aerial parts of Gynostemma pentaphyllum (Thunb.) Makino. Its structural elucidation was accomplished mainly on the basis of the interpretation of spectroscopic data, such as IR, HR-TOF-MS and NMR. Its cytotoxic activity was evaluated against one human cancer cell line HL-60 using MTT assay.