Rare flavanone-diarylheptanoid hybrids from Typha angustifolia shows anti breast cancer activity via activating TGF-ß1/Smad signaling pathway.

Four new flavanone-diarylheptanoid hetero dimers, typhatifolins A-D (1-4), were separated from the pollen of a widely distributed medicinal plant Typha angustifolia. Structures of these rare hybrids were elucidated by detailed interpretation of spectroscopic data, and their absolute configurations were determined on the basis of Mosher's method and ECD analyses. All the four compounds showed moderate to significant cytotoxicities against a panel of tumor cell lines with IC50 values ranging from 0.67 to 12.48 µM. Further in vitro antitumor evaluation for typhatifolin B (TTB, 2) on two breast cancer cells (4T1 and MDA-MB231) revealed that it could remarkably induce cell apoptosis and G0/G1 cycle arrest, as well as block cell migration and invasion. Mechanistically, TTB could exert its antitumor effect via activating the TGF-ß1 (transforming growth factor beta 1) signaling pathway as evidenced by RNA-seq analysis and immunoblotting experiments, which was further corroborated by treating cancer cells with a TGF-ß signaling inhibitor. Lastly, the in vivo anti breast cancer activity was demonstrated by applying the mixture of typhatifolins A-D to a preclinical animal model.

Predictors of pain response after endoscopic ultrasound-guided celiac plexus neurolysis for abdominal pain caused by pancreatic malignancy.

BACKGROUND: Endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) has gained popularity as a minimally invasive approach and is currently widely used to treat pancreatic cancer-associated pain. However, response to treatment is variable. AIM: To identify the efficacy of EUS-CPN and explore determinants of pain response in EUS-CPN for pancreatic cancer-associated pain. METHODS: A retrospective study of 58 patients with abdominal pain due to inoperable pancreatic cancer who underwent EUS-CPN were included. The efficacy for palliation of pain was evaluated based on the visual analog scale pain score at 1 wk and 4 wk after EUS-CPN. Univariable and multivariable logistic regression analyses were performed to explore predictors of pain response. RESULTS: A good pain response was obtained in 74.1% and 67.2% of patients at 1 wk and 4 wk, respectively. Tumors located in the body/tail of the pancreas and patients receiving bilateral treatment were weakly associated with a good outcome. Multivariate analysis revealed patients with invisible ganglia and metastatic disease were significant factors for a negative response to EUS-CPN at 1 wk and 4 wk, respectively, particularly for invasion of the celiac plexus (odds ratio (OR) = 13.20, P = 0.003 for 1 wk and OR = 15.11, P = 0.001 for 4 wk). No severe adverse events were reported. CONCLUSION: EUS-CPN is a safe and effective form of treatment for intractable pancreatic cancer-associated pain. Invisible ganglia, distant metastasis, and invasion of the celiac plexus were predictors of less effective response in EUS-CPN for pancreatic cancer-related pain. For these patients, efficacy warrants attention.

Bioinformatics analysis of immune infiltration in glioblastoma multiforme based on data using a methylation chip in the GEO database.

BACKGROUND: Glioblastoma multiforme (GBM) is the most aggressive and malignant tumor of the central nervous system. The study was to obtain the data of immune cell infiltration based on the data of a methylation chip in the GEO, and to clarify its prognostic significance for GBM. METHODS: The methylation data of glioblastoma was obtained by using the Illumina human methylation 450k BeadChip. The corrected expression was obtained by using edge R. Limma was used to correct the expression amount of the samples, and EpiDISH was used to translate the methylation expression data, so that the expression amount was transformed into the expression matrix of immune cells. The immune cells were then co-expressed, and the proportion and correlation of related immune cells was determined. The results of the cells in each of two groups were analyzed by enrichment and PCA mapping to establish the relevant differences. RESULTS: The data of GBM patients were obtained from the methylation chip of the GEO database. Patients were divided into a long-term (SNU-LTS) (21 cases), and short-term survival group (SNU-STS) (12 cases). There were 73 genes with significant individual differences between the two groups (P<0.05). EpiDISH was used to translate the methylation expression data into the expression matrix of immune cells, which showed that the highest proportion of cells in groups were mono cells, while Gran cells and CD8T appeared in a very small number of samples. The positive correlation between mono and B cells was the strongest, while the negative correlation between mono and Gran cells was the strongest. A violin chart shows that there was no significant difference in the infiltration degree of six kinds of immune cells between the two groups. Principal component analysis (PCA) showed that there was individual difference between the two groups, but the overall consistency was high. CONCLUSIONS: Data on tumor immune cell infiltration can be obtained by using a methylation chip in the GEO database. This not only extends the application abilities of methylation chips but provides obvious individual differences. The study of tumor immune infiltrating cells may pave the way for targeted therapy in the treatment of GBM.

TMEM16A Inhibition Preserves Blood-Brain Barrier Integrity After Ischemic Stroke.

The inflammatory response plays a pivotal role in Blood-Brain Barrier (BBB) destruction following ischemic brain injury. Enhanced leukocyte adhesion to vascular endothelial cells is an essential event in the inflammatory process. TMEM16A, a newly discovered protein regulating calcium-activated chloride channels, is widely expressed in eukaryotes. Recent studies have suggested that upregulated expression of TMEM16A is associated with the occurrence and development of many diseases. However, the role of TMEM16A in regulating BBB integrity after ischemic stroke has not been fully investigated. In this study, we found that TMEM16A is mainly expressed in brain endothelial cells and upregulated after ischemic stroke in the mouse brain. Caccinh-A01, an TMEM16A inhibitor that reduced its upregulation, attenuated brain infarct size and neurological deficits after ischemic stroke. ICAM-1 and MPO expression and BBB permeability were decreased after TMEM16A inhibitor administration. In addition, TMEM16A silencing rescued oxygen-glucose deprivation/reoxygenation (OGD/R)-induced transendothelial permeability in vitro accompanied by decreased ICAM-1 expression and leukocyte adhesion. Furthermore, our mechanistic study showed that TMEM16A knockdown alleviated NF-κB activation and nuclear translocation, indicating that TMEM16A knockdown downregulated OGD/R-induced ICAM-1 expression in an NF-κB-dependent manner. Finally, NF-κB inhibitor treatment also alleviated OGD/ R-induced BBB permeability, confirming that activated NF-κB and increased ICAM-1 are essential factors involved in ischemia-induced BBB damage. Thus, our research provides a promising treatment strategy against BBB destruction after ischemic stroke, and TMEM16A may become a potential target for the treatment of ischemic stroke.

Identification of Long Noncoding RNA MIR22HG as a Novel Biomarker in Thyroid Cancer.

Thyroid cancer (TC) is the one of the most common endocrine malignancy. However, currently there are no specific and sensitive biomarkers for predicting the prognosis for TC. In this study, we for the first time showed MIR22HG was down-regulated in thyroid cancer by analyzing public datasets, including TCGA, GSE29265, GSE33630, and GSE55091. Furthermore, we observed the lower expression levels of MIR22HG were significantly related to higher age, lymph node metastasis status, residual tumor status, N stage, Grade, and T stage in TC. We also observed higher MIR22HG expression was associated with longer overall and disease-free survival time in TC. In order to explore the potential mechanisms of MIR22HG regulating TC progression, 4 hub gene networks regulated by MIR22HG were constructed in the present study. Bioinformatics analysis showed MIR22HG was associated with apoptotic process, regulation of transcription, mRNA splicing, regulation of cell cycle, and Hippo signaling pathway in TC. These results suggested MIR22HG could serve as a novel biomarker for thyroid cancer.

ERCP-related complication is not the only cause of GI bleeding in post-liver transplantation patients: A case report.

RATIONALE: Endoscopic retrograde cholangiopancreatography (ERCP) is the treatment of choice for biliary complications in liver transplantation (LT) recipients as it is both diagnostic and therapeutic. The specific risks following ERCP among LT recipients have not been well studied. PATIENT CONCERNS: A 56-year-old man with a history of orthotopic LT underwent endoscopic retrograde cholangiopancreatography (ERCP) as a treatment of biliary strictures, whereby a plastic stent was implanted. Thirteen days after ERCP the patient developed multiple episodes of hematemesis. DIAGNOSIS: Digital subtraction angiography (DSA) of the hepatic artery and superior mesenteric artery showed a hepatic pseudoaneurysm (PA) in the left hepatic artery. The final diagnosis was bleeding from the PA. INTERVENTION: Interventional embolization of the branch with PA was performed to stop the bleeding. OUTCOME: The patient remained free of GI bleeding for 25 days after interventional embolization, but he developed another bout of bleeding and unfortunately passed away. LESSONS: ERCP-related complication is not the only cause of post-ERCP bleeding, and that other primary causes should also be ruled out.

[Decreases of progressive motility, total motility, and acrosin activity of sperm from oligoasthenoteratospermia males at different time points after sperm activation].

OBJECTIVE: To investigate the progressive motility, (PR), total motility (progressive + non-progressive motility, PR + NP), and acrosin activity of sperm from normal and infertile men at different time points after sperm activation. METHODS: Based on the 5th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen and the results of modified Papanicolaou staining, we divided the semen samples into groups A (normal, n = 28), B (oligoasthenoteratospermia, n = 30), and C (asthenoteratospermia, n = 32). At 1, 24, and 48 hours after sperm activation, we detected sperm PR and PR + NP by CASA and chemical colorimetry, and determined sperm acrosin activity using the modified Kennedy method. RESULTS: Sperm PR and PR + NP were significantly decreased in all the three groups at 1-24 hours and even more significantly at 24-48 hours after sperm activation as compared with the baseline (P < 0.05). Sperm acrosin activity showed remarkable reduction in group A (P = 0. 013) , even more significant at 1-24 hours than at 24-48 hours after sperm activation, but not in groups B and C (P = 0.519 and 0.979). CONCLUSION: Sperm PR, PR + NP, and acrosin activity are all decreased with the extension of time after sperm activation, each in a specific manner. Examination of sperm acrosin activity should be applied as a routine tool in the assessment of male fertility.

Effects of vitamin E on expressions of eight microRNAs in the liver of Nile tilapia (Oreochromis niloticus).

Currently, microRNAs (miRNAs) are known to regulate cellular processes such as apoptosis, differentiation, cell cycle, and immune functions, and their expression can be altered by distinct stress conditions, such as oxidative stress. In immune systems of fish, vitamin E (VE) has a defined role as an antioxidant. In order to understand the molecular mechanism of vitamin E defending from oxidative stress, three groups of juvenile Nile tilapia (Oreochromis niloticus) (initial weight 3.25 ± 0.02 g) were fed to satiation with 3 semi-purified diets containing VE (DL-α-tocopherol acetate) of 0, 50, and 2500 mg/kg supplementation, respectively, with the expressions of eight miRNAs (miR-21, miR-223, miR-146a, miR-125b, miR-181a, miR-16, miR-155 and miR-122) in the liver of tilapia subsequently detected after 8-week growth experiment. Results showed that VE-deficient (0 mg/kg supplementation) decreased the activity of superoxide dismutase (SOD), and decreased the expressions of miR-223, miR-146a, miR-16 and miR-122, while excessive supplementation of VE (2500 mg/kg) decreased SOD activity and increased the expressions of all the eight miRNAs. The targets of the eight miRNAs were further predicated with bioinformatic approach and the possible regulating mechanisms of VE via miRNAs were analyzed. The present study confirmed that the differences in dietary VE affected expression of hepatic miRNAs which may partly demonstrate the molecular mechanism of VE, and the new idea of introducing miRNAs into research will provide the basic data for researches of molecular nutrition.

Protective effects of the ethanolic extract of Melia toosendan fruit against colon cancer.

Colorectal cancer is one of the leading causes of death in the world. Plant-derived products have proven to be valuable sources for discovery and development of unique anticancer drugs. In this study, the inhibitory effects of ethanolic extract of Melia toosendan fruit (EMTF), a traditional medicine in the Chinese Pharmacopeia were evaluated in vitro and in vivo against colon cancer. Human colon cancer cells SW480 and murine colorectal adenocarcinoma cells CT26 were used to investigate cell proliferation. The results showed that EMTF inhibited cell proliferation of SW480 and CT26 by promoting apoptosis as indicated by nuclear chromatin condensation and DNA fragmentation. Through increasing mitochondrial membrane permeability and cytochrome c release from mitochondria, EMTF induced caspase-9 activity which further activated caspase-3 and poly(ADP-ribose) polymerase cleavage, leading the tumor cells to apoptosis. The in vivo results confirmed reduction of tumor volume and apoptotic effects and the side effects were not induced by EMTF. Therefore, EMTF may be an effective chemotherapeutic agent for colon cancer treatment.

Asiatic acid induces colon cancer cell growth inhibition and apoptosis through mitochondrial death cascade.

Cancer is one of the leading causes of death in the world. The triterpenoid compound asiatic acid derived from the tropical medicinal plant Centella asiatica displays cytotoxic activity on fibroblast cells and several other kinds of cells. The present work studies asiatic acid-mediated growth inhibition of cancer cells and the underlying mechanism. Asiatic acid markedly inhibited cancer cell proliferation. Apoptosis of SW480 human colon cancer cells was induced by asiatic acid as shown by flow cytometry, DNA fragmentation and nuclear chromatin condensation experiments. Through increasing mitochondrial membrane permeability and cytochrome c release from mitochondria into cytosol, asiatic acid induced caspase-9 activity, which further activated caspase-3 and poly(ADP-ribose) polymerase cleavage resulting in irreversible apoptotic death in the tumor cells. Taken together, these results suggest that mitochondrial death apoptosis cascade plays very important roles in asiatic acid-induced cancer apoptosis.

Semi-vioxanthin isolated from marine-derived fungus regulates tumor necrosis factor-alpha, cluster of differentiation (CD) 80, CD86, and major histocompatibility complex class II expression in RAW264.7 cells via nuclear factor-kappaB and mitogen-activated protein kinase signaling pathways.

Semi-vioxanthin isolated from marine-derived fungus was assessed for immunoregulatory activity in mouse RAW264.7 macrophages. In the present study, the facilitative effects of semi-vioxanthin on tumor necrosis factor-alpha (TNF-alpha) and its mRNA expression and on expression of the co-stimulatory molecules, cluster of differentiation (CD) 80, CD86 and major histocompatibility complex class II (MHC II), as well as the molecular mechanism underlying the immunologic enhancement properties of semi-vioxanthin were studied. Our results clearly indicated that semi-vioxanthin treatment resulted in the degradation of IkappaB alpha, which led to the activation and nuclear translocation of the p65 subunit of nuclear factor-kappaB (NF-kappaB), as determined by immunoblotting, immunofluorescence and electrophoretic mobility shift assays (EMSA). Moreover, TNF-alpha production was prevented by NF-kappaB and mitogen-activated protein kinase (MAPK) inhibitors. Inhibition of NF-kappaB and extracellular signal regulated kinases (ERK1/2) activity by specific inhibitors blunted the effect of semi-vioxanthin on the up-regulation of CD80, CD86 and MHCII expression, but neither p38 MAPK nor c-Jun N-terminal kinase (JNK) inhibitor had this effect. Thus, we demonstrate that semi-vioxanthin regulates TNF-alpha production through NF-kappaB and MAPK signaling pathways. Activation of NF-kappaB and ERK1/2 were necessary for CD80, CD86 and MHCII expression induced by semi-vioxanthin. These data suggest that semi-vioxanthin has immunoregulatory effects.

[Polymorphism of catechol-O-methyltransferase gene in relation to the risk of endometrial cancer].

OBJECTIVE: The 4- and 16-hydroxylated metabolites of estrogens have been implicated in carcinogenesis, whereas its 2-hydroxylated metabolites have been shown to have antiangiogenic effects. We aimed to examine whether the polymorphisms of catechol-O-methyltransferase (COMT) involved in the estrogen metabolism are associated with endometrial cancer risk. METHODS: Polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) analysis was used to study the variant allele frequency distributions of COMT Val158Met genetic polymorphism in a population based case-control study with 132 endometrial cancer cases and 110 controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by unconditional logistic regression after adjustment for known or suspected risk factors for endometrial cancer. RESULTS: The most frequent genotype was COMT(Val/Val) (47.2%, 52/110) in control group and COMT(Val/Met) (58.3%, 77/132) in endometrial cancer group. The difference between the two groups was of statistical significance (P < 0.05). Compared with COMT(Met/Met) genotype, the COMT(Val/Val) genotype was inversely correlated with endometrial cancer risk, and the adjusted OR value was 0.262 (95% CI: 0.080 - 0.862, P = 0.027). CONCLUSIONS: Among the genotypes in women in South China, genotype COMT(Val/Val) is mostly seen, followed by COMT(Val/Met), and COMT(Met/Met) is the least in control group. The endometrial cancer susceptivity of genotype COMT(Val/Val) carriers may be lower than COMT(Met/Met) carriers.