Morin inhibits osteosarcoma migration and invasion by suppressing urokinase plasminogen activator through a signal transducer and an activator of transcription 3.

Osteosarcoma, the most common primary bone cancer that affects adolescents worldwide, has the early metastatic potential to be responsible for high mortality rates. Morin has a multipurpose role in numerous cancers, whereas little is known about its role in osteosarcoma migration and invasion. Therefore, we hypothesized that morin suppresses the invasive activities and the migratory potential of human osteosarcoma cells. Our results showed that morin reduced migration and invasion capabilities in human osteosarcoma U2OS and HOS cells. Moreover, morin inhibited the urokinase plasminogen activator (uPA) expression through a signal transducer and an activator of transcription-3 (STAT3) phosphorylation. After STAT3 overexpression, the decrease of the migratory potential and uPA expression caused by 100 µM of morin in U2OS cells was countered, indicating that STAT3 contributes to the antimetastatic property of morin in human osteosarcoma cells by reducing uPA. In conclusion, morin may be a potential candidate for the antimetastatic treatment of human osteosarcoma.

The probiotic Lactiplantibacillus plantarum attenuates ovariectomy-induced osteoporosis through osteoimmunological signaling.

Osteoporosis is characterized by low bone mass and bone tissue microarchitectural deterioration with increased fracture risk in numerous populations. Probiotics are reported to be a potential biotherapeutic for the prevention and treatment of osteoporosis. In this study, the IL-10 secretion properties of probiotics were simulated in vitro and the potential applications of the novel strain Lactiplantibacillus plantarum 622 were investigated in an in vivo osteoporosis model. Female Sprague-Dawley rats were ovariectomized (OVX) and orally administered Lp. plantarum GMNL-662 or alendronate for 14 weeks. The Lp. plantarum treatment group exhibited an increase in the level of fecal Lp. plantarum, Lactobacillus, and Lachnospiraceae. Bone marker analysis indicated improvements in the levels of osteocalcin and N-terminal telopeptides in the Lp. plantarum treatment group. Compared with the OVX control group, the Lp. plantarum treatment group exhibited marked improvements in femur bone mineral density, trabecular bone volume, trabecular number, and lumbar vertebrae. Moreover, biomechanical three-point bending testing indicated considerably higher improvements in femur maximum load, stiffness, and energy to maximum load in the Lp. plantarum treatment group than in the OVX control group. Quantitative polymerase chain reaction analysis indicated reduced expression levels of OVX-induced IL-1, IL-6, TNFα, and RANKL and increased expression levels of IL-10, TGF-ß, and osteoprotegerin in the Lp. Plantarum treatment group. In summary, Lp. plantarum GMNL-662 exhibits high probiotic potential and potentially influences osteoimmunity through the modulation of proinflammatory cytokines and bone metabolism-related markers.

Suppressive Effects of Lactobacillus on Depression through Regulating the Gut Microbiota and Metabolites in C57BL/6J Mice Induced by Ampicillin.

Depression is a medical and social problem. Multiple metabolites and neuroinflammation regulate it. Modifying the gut microbiota with probiotics to reduce depression through the gut-brain axis is a potential treatment strategy. In this study, three anti-depressive potentials of Lactobacillus spp. (LAB), including L. rhamnosus GMNL-74, L. acidophilus GMNL-185 and L. plantarum GMNL-141, which combined to produce low dosage LAB (1.6 × 108 CFU/mouse, LABL) and high dosage LAB (4.8 × 108 CFU/mouse, LABH), were administered to C57BL/6 mice induced depression by ampicillin (Amp). A behavioral test of depression, 16S ribosomal RNA gene amplicon sequencing, bioinformatic analysis, and short-chain fatty acid (SCFA) content measurement were executed to investigate the gut microbiota composition, activation of nutrient metabolism pathways, levels of inflammatory factors, gut-derived 5-HT biosynthesis genes, and SCFA levels in C57BL/6 mice. Results showed that after mice were induced by Amp, both LAB groups recovered from depressive behaviors, decreased the abundance of Firmicutes, and increased the abundance of Actinobacteria and Bacteroidetes in the mouse ileum. The prediction of metabolism pathways of microbes revealed the activation of arginine and proline metabolism, cyanoamino acid metabolism, and nicotinate and nicotinamide metabolism were increased, and fatty acid synthesis was decreased in both LAB groups. The LABH groups showed increased levels of acetic acid, propanoic acid, and iso-butyric acid and decreased butyric acid levels in the cecum. LABH treatment increased claudin-5 and reduced IL-6 mRNA expression. Both LAB groups also reduced monoamine oxidase, and the LABH group increased vascular endothelial growth factor mRNA expression. These results showed that the composite of three LAB exerts antidepressant effects by regulating the gut microbiota and modifying the levels of depression-related metabolites in C57BL/6J Amp-treated mice.

Apoptotic effect and cell arrest of deoxyshikonin in human osteosarcoma cells through the p38 pathway.

Osteosarcoma is the most common primary bone cancer that affects adolescents with early metastatic potential and drastically reduces their long-term survival rate if pulmonary metastases are detected at diagnosis. The natural naphthoquinol compound deoxyshikonin exhibits anticancer properties, so we hypothesized that it has an apoptotic effect on osteosarcoma U2OS and HOS cells and studied its mechanisms. After deoxyshikonin treatment, dose-dependent decreases in cell viability, induction of cell apoptosis and arrest in the sub-G1 phase of U2OS and HOS cells were observed. The increases in cleaved caspase 3 expression and the decreases in X-chromosome-linked IAP (XIAP) and cellular inhibitors of apoptosis 1 (cIAP-1) expressions after deoxyshikonin treatment in the human apoptosis array were identified in HOS cells, and dose-dependent expression changes of IAPs and cleaved caspase 3, 8 and 9 were verified by Western blotting in U2OS and HOS cells. Phosphorylation of extracellular signal-regulated protein kinases (ERK)1/2, c-Jun N-terminal kinases (JNK)1/2 and p38 expressions in U2OS and HOS cells was also increased by deoxyshikonin in a dose-dependent manner. Subsequently, cotreatment with inhibitors of ERK (U0126), JNK (JNK-IN-8) and p38 (SB203580) was performed to show that p38 signalling is responsible for deoxyshikonin-induced apoptosis in U2OS and HOS cells, but not via the ERK and JNK pathways. These discoveries demonstrate that deoxyshikonin may be a possible chemotherapeutic candidate to induce cell arrest and apoptosis by activating extrinsic and intrinsic pathways through p38 for human osteosarcoma.

Lacticaseibacillus paracasei GM-080 Ameliorates Allergic Airway Inflammation in Children with Allergic Rhinitis: From an Animal Model to a Double-Blind, Randomized, Placebo-Controlled Trial.

Background: Probiotics may facilitate the clinical management of allergic diseases. However, their effects on allergic rhinitis (AR) remain unclear. We examined the efficacy and safety of Lacticaseibacillus paracasei GM-080 in a mouse model of airway hyper-responsiveness (AHR) and in children with perennial AR (PAR) by using a double-blind, prospective, randomized, placebo-controlled design. Methods: The production of interferon (IFN)-γ and interleukin (IL)-12 was measured by using an enzyme-linked immunosorbent assay. GM-080 safety was evaluated via the whole-genome sequencing (WGS) of virulence genes. An ovalbumin (OVA)-induced AHR mouse model was constructed, and lung inflammation was evaluated by measuring the infiltrating leukocyte content of bronchoalveolar lavage fluid. A clinical trial was conducted with 122 children with PAR who were randomized to receive different doses of GM-080 or the placebo for 3 months, and their AHR symptom severity scores, total nasal symptom scores (TNSSs), and Investigator Global Assessment Scale scores were examined. Results: Among the tested L. paracasei strains, GM-080 induced the highest IFN-γ and IL-12 levels in mouse splenocytes. WGS analysis revealed the absence of virulence factors or antibiotic-resistance genes in GM-080. The oral administration of GM-080 at 1 × 107 colony forming units (CFU)/mouse/day for 8 weeks alleviated OVA-induced AHR and reduced airway inflammation in mice. In children with PAR, the oral consumption of GM-080 at 2 × 109 CFU/day for 3 months ameliorated sneezing and improved Investigator Global Assessment Scale scores significantly. GM-080 consumption led to a nonsignificant decrease in TNSS and also nonsignificantly reduced IgE but increased INF-γ levels. Conclusion: GM-080 may be used as a nutrient supplement to alleviate airway allergic inflammation.

HO-3867 Induces Apoptosis via the JNK Signaling Pathway in Human Osteosarcoma Cells.

Metastatic osteosarcoma often results in poor prognosis despite the application of surgical en bloc excision along with chemotherapy. HO-3867 is a curcumin analog that induces cell apoptosis in several cancers, but the apoptotic effect and its mechanisms on osteosarcoma cells are still unknown. After observing the decrease in cellular viability of three human osteosarcoma U2OS, HOS, and MG-63 cell lines, and the induction of cellular apoptosis and arrest in sub-G1 phase in U2OS and HOS cells by HO-3867, the human apoptosis array showed that heme oxygenase (HO)-1 and cleaved caspase-3 expressions had significant increases after HO-3867 treatment in U2OS cells and vice versa for cellular inhibitors of apoptosis (cIAP)1 and X-chromosome-linked IAP (XIAP). Western blot analysis verified the results and showed that HO-3867 activated the initiators of both extrinsic caspase 8 and intrinsic caspase 9, and significantly increased cleaved PARP expression in U2OS and HOS cells. Moreover, with the addition of HO-3867, ERK1/2, and JNK1/2 phosphorylation were increased in U2OS and HOS cells. Using the inhibitor of JNK (JNK in 8), HO-3867's increases in cleaved caspases 3, 8, and 9 could be expectedly suppressed, indicating that JNK signaling is responsible for both apoptotic pathways, including extrinsic and intrinsic, in U2OS and HOS cells caused by HO-3867. Through JNK signaling, HO-3867 has proven to be effective in causing both extrinsic and intrinsic apoptotic pathways of human osteosarcoma cells.

Heat-Killed Lacticaseibacillus paracasei GMNL-653 Exerts Antiosteoporotic Effects by Restoring the Gut Microbiota Dysbiosis in Ovariectomized Mice.

Osteoporosis is a metabolic inflammatory disease, an imbalance occurs between bone resorption and formation, leading to bone loss. Anti-inflammatory diet is considered having the potential to ameliorate osteoporosis. Heat-killed probiotics exhibit health benefits in relation to their immunomodulatory effects, but the detail mechanism involved in gut microbiota balance, host metabolism, immunity, and bone homeostasis remains unclear. In this study, we evaluated the antiosteoporotic effects of heat-killed Lacticaseibacillus paracasei GMNL-653 in vitro and in ovariectomized (OVX) mice. Furthermore, whole-genome sequencing and comparative genomics analysis demonstrated potentially genes involved in antiosteoporotic activity. The GMNL-653 exerts anti-inflammatory activity which restored gut microbiota dysbiosis and maintained intestinal barrier integrity in the OVX mice. The levels of IL-17 and LPS in the sera decreased following GMNL-653 treatment compared with those of the vehicle control; mRNA levels of RANKL were reduced and TGF-ß and IL-10 enhanced in OVX-tibia tissue after treatment. The levels of IL-17 were significantly associated with gut microbiota dysbiosis. Gut microbial metagenomes were further analyzed by PICRUSt functional prediction, which reveal that GMNL-653 intervention influence in several host metabolic pathways. The analysis of whole-genome sequencing accompanied by comparative genomics on three L. paracasei strains revealed a set of GMNL-653 genes that are potentially involved in antiosteoporotic activity. Our findings validated antiosteoporotic activity of heat-killed GMNL-653 using in vitro and in vivo models, to whole-genome sequencing and identifying genes potentially involved in this gut microbiota-bone axis.

Heat-Killed Lactobacilli Preparations Promote Healing in the Experimental Cutaneous Wounds.

Probiotics are defined as microorganisms with beneficial health effects when consumed by humans, being applied mainly to improve allergic or intestinal diseases. Due to the increasing resistance of pathogens to antibiotics, the abuse of antibiotics becomes inefficient in the skin and in systemic infections, and probiotics may also provide the protective effect for repairing the healing of infected cutaneous wounds. Here we selected two Lactobacillus strains, L. plantarum GMNL-6 and L. paracasei GMNL-653, in heat-killed format to examine the beneficial effect in skin wound repair through the selection by promoting collagen synthesis in Hs68 fibroblast cells. The coverage of gels containing heat-killed GMNL-6 or GMNL-653 on the mouse tail with experimental wounds displayed healing promoting effects with promoting of metalloproteinase-1 expression at the early phase and reduced excessive fibrosis accumulation and deposition in the later tail-skin recovery stage. More importantly, lipoteichoic acid, the major component of Lactobacillus cell wall, from GMNL-6/GMNL-653 could achieve the anti-fibrogenic benefit similar to the heat-killed bacteria cells in the TGF-ß stimulated Hs68 fibroblast cell model. Our study offers a new therapeutic potential of the heat-killed format of Lactobacillus as an alternative approach to treating skin healing disorders.

Dihydromyricetin suppresses cell metastasis in human osteosarcoma through SP-1- and NF-κB-modulated urokinase plasminogen activator inhibition.

BACKGROUND: Metastasis caused a decline in the 5-years survival rate of osteosarcoma. Therefore, developing new targeted therapeutics for osteosarcoma treatment is imperative. Dihydromyricetin (DHM) has several physiological functions: it counteracts inflammation, oxidation, and antitumor properties. However, the effects of DHM on osteosarcoma and its underlying mechanisms are still not well understood. PURPOSE: In this study, we investigated the antimetastatic properties of DHM in human osteosarcoma U-2 OS and HOS cells. METHODS: The effects of DHM (0, 25, 50, 75, and 100 µM) on cell viability, migration, and invasion were examined. Western blotting, RT-PCR, and quantitative real-time PCR (QPCR) were determined urokinase plasminogen activator (uPA) expression. The expression of transcriptional factor SP-1 and NF-κB was determined by using immunofluorescence assay, chromatin immunoprecipitation assay, and site-directed mutagenesis luciferase reporter. RESULTS: We observed that DHM suppresses cell migration and invasion in osteosarcoma cell lines. In addition, DHM inhibits metastasis by downregulating urokinase plasminogen activator (uPA) expression. Moreover, real-time polymerase chain reaction and promoter activity assays revealed that DHM decreased uPA expression at transcription levels. Furthermore, the inhibition of uPA expression was associated with the suppression of SP-1 and NF-κB, which bind to the uPA promoter. Regardless of blocking or inducing the extracellular signal-regulated kinase (ERK) pathway, we verified that the DHM-related suppression of uPA and cell metastasis occurred through the p-ERK pathway. CONCLUSION: We are the first study to propose that DHM suppresses osteosarcoma metastasis through the ERK pathway and through the suppression of SP-1 and NF-κB to inhibit downstream uPA expression. DHM is a potential therapeutic agent for antimetastatic therapy against osteosarcoma.

TRIM21 Polymorphisms are associated with Susceptibility and Clinical Status of Oral Squamous Cell Carcinoma patients.

Squamous cell cancer of head and neck (HNSCC) is the sixth most common malignancy worldwide. One of the most common HNSCC types is oral squamous cell carcinoma (OSCC), which is the fifth leading cause of cancer death in Taiwan. Tripartite motif 21 (TRIM21) has been reported to play an important role in different cancer types. We found a correlation between TRIM21 and survival of HNSCC patients, but little information exists about how altered TRIM21 expression contributes to tumorigenesis. Thus, we investigated the combined effect of TRIM21 polymorphisms and exposure to environmental carcinogens on the susceptibility and clinicopathological characteristics of OSCC. Two single-nucleotide polymorphisms (SNPs) of TRIM21 (rs4144331, rs915956) from 1194 healthy controls and 1192 OSCC patients were analyzed by real-time PCR. Among 1632 smokers, TRIM21 polymorphism carriers with the betel-nut chewing habit had a ~4.8-fold greater risk of OSCC than TRIM21 wild-type carriers without the betel-nut chewing habit. After adjusting for other covariants, OSCC patients with G/T at TRIM21 rs4144331 had a high risk for distant metastasis compared with G/G homozygotes. This study is the first to examine the risk factors associated with TRIM21 SNPs in OSCC progression and development. Thus, our findings suggest that this study is the first to examine the risk factors associated with TRIM21 SNPs in OSCC progression and development and suggest that interactions between mutant genes may alter the susceptibility to OSCC.

Lipocalin-2 Inhibits Osteosarcoma Cell Metastasis by Suppressing MET Expression via the MEK-ERK Pathway.

Higher neutrophil-derived cytokine lipocalin-2 (LCN2) expression possesses a versatile role in a myriad of cancers, but little is known about the role of LCN2 on osteosarcoma metastasis. In this study, we demonstrated that higher LCN2 inhibited cellular motility, migration, and invasion of osteosarcoma cells. Moreover, using RNA sequencing technology, we found that LCN2 repressed MET gene expression in U2OS cells. Manipulation of LCN2 levels influenced the migratory potential of osteosarcoma cells as cellular migration was enhanced by transfecting with vectors containing a constitutively active LCN2 cDNA and recombinant human LCN2. Moreover, the phosphorylation of mitogen-activated protein kinases/extracellular signal-regulated kinase (ERK) kinase (MEK) 1/2 and ERK 1/2 was decreased by LCN2 knockdown. Furthermore, the use of ERK inhibitor (U0126) and activator (tBHQ) confirmed that the pharmaceutic inhibition of MEK-ERK augmented the LCN2-mediated MET suppression and migration of U2OS and HOS cells. Conclusively, LCN2 inhibits osteosarcoma cell metastasis by suppressing MET via the MEK-ERK pathway.

Regulatory effects of Lactobacillus plantarum-GMNL6 on human skin health by improving skin microbiome.

Bacteria response to their environment by producing some compounds which are used in cosmetic and pharmaceutical applications. Some probiotics can regulate immune response and modulate the symptoms of several diseases. Bacteria affect skin response to skin care products. Bacteria are thought to play an important role in acne incidence, skin moisture, and nutrient metabolism, but only a few studies have focused on the extracts of Lactobacillus plantarum in skin care. In this study, we identified that L. plantarum-GMNL6 enhanced collagen synthesis and the gene expression of serine palmitoyltransferase small subunit A. Meanwhile, L. plantarum-GMNL6 reduced the melanin synthesis, the biofilm of Staphylococcus aureus, and the proliferation of Cutibacterium acnes. Information from clinical observation during the ointment for external face use in people displayed that the syndromes of skin moisture, skin color, spots, wrinkles, UV spots, and porphyrins were improved. The diversification of human skin microbiomes was affected by smearing the face of volunteers with L. plantarum-GMNL6. Understanding the potential mechanisms of the action of L. plantarum-GMNL6 in dermatologic conditions promotes the development of care products.

The effect of high-pressure processing on reducing the glycaemic index of atemoya puree.

BACKGROUND: This study investigated the effects of high-pressure processing (HPP) on the glycaemic index (GI) of atemoya puree (AP) in rats. Sprague-Dawley rats were fed with unprocessed and high-pressure processed atemoya puree (HPP-AP), and the GIs for the unprocessed AP and HPP-AP were calculated from changes in blood glucose concentrations within 2 h after meals. The physicochemical properties of AP were analysed to understand the mechanism affecting its GI. RESULTS: The results showed that HPP (600 MPa for 15 min) could delay increase in postprandial blood glucose levels, decrease the peak value of postprandial blood glucose by 76.1%, and significantly decrease the GI of AP to 49.8 in the experimental group compared to 65.4 in the control group. HPP did not exert a significant effect on the glucose and pectin contents of AP, but it increased the viscosity of the puree and its dietary fibre content and delayed the time of peak glucose response. In the analysis of enzymes of the puree, we found that HPP significantly decreased the activities of sucrose invertase, pectin methylesterase and polygalacturonase, thereby decreasing the rate of glucose generation in the puree and stabilizing the pectin structure, which decreased the absorption of glucose by the small intestine, thus decreasing the GI value. CONCLUSION: Our findings suggest that HPP technology could effectively delay increase in postprandial blood glucose levels and decrease the GI value of AP, thus having a potential application in developing atemoya puree products with low GI. © 2020 Society of Chemical Industry.

IGF2BP2 Polymorphisms Are Associated with Clinical Characteristics and Development of Oral Cancer.

Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is associated with insulin resistance, lipid metabolism, and tumorigenesis. However, the association between the IGF2BP2 polymorphism and oral cancer risk remains unclear. We recruited 1349 male patients with oral cancer and 1198 cancer-free controls. Three single nucleotide polymorphisms IGF2BP2 rs11705701, rs4402960, and rs1470579 were assessed using real-time polymerase chain reaction. The results indicate that the male patients with oral cancer and with the rs11705701 GA+AA, rs4402960 GT+TT, and rs1470579 AC+CC genotypes had increased risk of advanced clinical stage, larger tumor, and progression of lymph node metastasis compared with those with wild-type IGF2BP2. Moreover, according to The Cancer Genome Atlas dataset, high expression of the IGF2BP2 gene is associated with poor survival in patients with head and neck squamous cell carcinoma. In conclusion, our results suggest that IGF2BP2 polymorphisms are associated with less favorable oral cancer clinical characteristics.

Impact of SRY-Box Transcription Factor 11 Gene Polymorphisms on Oral Cancer Risk and Clinicopathologic Characteristics.

Oral cancer is among the most common cancers worldwide and has become a major global health problem because of its relatively high morbidity and mortality rates. The sex-determining region on the Y-chromosome-related high-mobility-group box (SOX) transcription factor 11 (SOX11) plays a key role in human development and differentiation and is frequently increased in various human cancers. However, the clinical significance of SOX11 polymorphisms in oral cancer and their association with oral cancer risk are unclear. In this study, we included 1196 patients with oral cancer and 1200 controls. Real-time polymerase chain reaction was applied to analyze three SOX11 single-nucleotide polymorphisms (rs77996007, rs66465560, and rs68114586). Our results shown that SOX11 polymorphisms carriers with betel quid chewing were found to have an 8.38- to 9.23-fold risk to have oral cancer compared to SOX11 wild-type carriers without betel quid chewing. Furthermore, oral cancer patients who carried SOX11 rs77996007 "TC + CC" variants were significantly associated with large tumor size (AOR, 1.324; 95% CI, 1.047-1.674; p= 0.019). Moreover, a database analysis using the Cancer Genome Atlas suggested that SOX11 mRNA expression was high during the tumor development process. In conclusion, our results suggest that SOX11 rs77996007 is involved in oral cancer progression and clinical characteristics.

Progenitor Cells Derived from Drain Waste Product of Open-Heart Surgery in Children.

Human cardiac progenitor cells isolated from the same host may have advantages over other sources of stem cells. The aim of this study is to establish a new source of human progenitor cells collected from a waste product, pericardiac effusion fluid, after open-heart surgery in children with congenital heart diseases. The fluid was collected every 24 h for 2 days after surgery in 37 children. Mononuclear cells were isolated and expanded in vitro. These pericardial effusion-derived progenitor cells (PEPCs) exhibiting cardiogenic lineage markers, were highly proliferative and enhanced angiogenesis in vitro. Three weeks after stem cell transplantation into the ischemic heart in mice, cardiac ejection fraction was improved significantly without detectable progenitor cells. Gene expression profiles of the repaired hearts revealed activation of several known repair mechanisms including paracrine effects, cell migration, and angiogenesis. These progenitor cells may have the potential for heart regeneration.

Functional Genetic Variant of Long Pentraxin 3 Gene Is Associated With Clinical Aspects of Oral Cancer in Male Patients.

Long pentraxin 3 (PTX3) is produced by various cell types and is correlated with tumor progression in various tumor types. However, the clinical significance of PTX3 polymorphisms in oral cancer and their correlation with the risk of cancer are still unclear. In this study, we assessed the influence of PTX3 gene polymorphisms and environmental factors on susceptibility to oral tumorigenesis. We recruited 865 cases with oral cancer and 1,189 controls. Four single-nucleotide variations of the PTX3 gene (rs1840680, rs2305619, rs3816527, and rs2120243) were verified using a real-time polymerase chain reaction in control participants and cases with oral cancer. We found that rs3816527 in smokers was correlated with the development of late-stage cancer (odds ratio [OR], 2.328; 95% confidence interval [CI], 1.078-5.027) and increased lymph node metastasis (OR, 2.152; 95% CI, 1.047-4.422). Moreover, additional bioinformatics analysis results showed that the rs3816527 C allele variant to the A allele exhibited the strongest exonic splicing enhancer activity. In conclusion, our results suggested that PTX3 rs3816527 plays a role in oral cancer development.

Interleukin-3 Polymorphism is Associated with Miscarriage of Fresh in Vitro Fertilization Cycles.

The aim of this study was to examine the association between interleukin (IL) genes polymorphisms and in vitro fertilization (IVF) outcome. A prospective cohort analysis was performed at a Women's Hospital IVF centre of 1015 female patients undergoing fresh non-donor IVF cycles. The effects of the following six single nucleotide polymorphisms (SNPs) in five IL genes on IVF outcomes were explored: IL-1α (rs1800587 C/T), IL-3 (rs40401 C/T), IL-6 (rs1800795 C/G), IL-15 (rs3806798 A/T), IL-18 (rs187238 C/G) and IL-18 (rs1946518 G/T). The main outcome measures included clinical pregnancy, embryo implantation, abortion and live birth rates. There were no statistically significant differences in clinical pregnancy, embryo implantation and live birth rates in the analysis of 1015 patients attempting their first cycle of IVF. Infertile women with IL-3 homozygous major genotype had a higher abortion rate than those with heterozygous and homozygous minor genotype (16.5% vs. 7.9%, P = 0.025). In conclusion, our results indicated that the IL-3 rs40401 polymorphism is associated with increased risk of abortion of IVF patients. Future studies with inclusion of other ethnic populations must be conducted to confirm the findings of this study.

Associations of genetic variations of the endothelial nitric oxide synthase gene and environmental carcinogens with oral cancer susceptibility and development.

Oral cancer is a major head and neck cancer that is reported to be causally associated with genetic factors and environmental carcinogens. Endothelial nitric oxide synthase (eNOS) was reported to modulate carcinogenesis and progression through nitric oxide (NO) production. Genetic polymorphisms in the eNOS gene can regulate its transcription and further mediate NO production. The purpose of this study was to explore the influences of eNOS gene polymorphisms combined with environmental carcinogens on the predisposition for oral cancer. Two single-nucleotide polymorphisms (SNPs) of the eNOS gene, -786 T > C (rs2070744) and 894G > T (rs1799983), were genotyped in 1200 controls and 1044 patients with oral cancer using a TaqMan-based real-time polymerase chain reaction (PCR). We found that patients who carried the -786 T > C TC genotype were at higher risk for developing an advanced clinical stage (stage III/IV) compared to those with the -786 T > C TT genotype; however, there was no significant association of the two individual SNPs with oral cancer between patients and the control group. According to behavioral exposure to environmental carcinogens, the presence of these two eNOS SNPs combined with tobacco use and/or betel quid chewing profoundly enhanced the risk of oral cancer. Moreover, carriers with the betel quid-chewing habit who had haplotypes of the two eNOS SNPs more easily developed oral cancer. These results indicated an involvement of -786 T > C polymorphisms in the progression of oral cancer and support the interaction between eNOS gene polymorphisms and environmental carcinogens as a predisposing factor of oral carcinogenesis.

Impacts of WNT1-inducible signaling pathway protein 1 polymorphism on hepatocellular carcinoma development.

BACKGROUND: WNT1-inducible signaling pathway protein 1 (WISP1) is a member of CCN protein family and a downstream target of ß-catenin. Aberrant WISP1 expression is associated with carcinogenesis. In the current study, we focused on examining WISP1 single nucleotide polymorphisms (SNPs) to elucidate hepatocellular carcinoma (HCC) clinicopathologic characteristics. METHODOLOGY/PRINCIPAL FINDINGS: The WISP1 SNPs rs2977530, rs2977537, rs2929973, rs2929970, rs62514004, and rs16893344 were analyzed by real-time polymerase chain reaction in 332 patients with HCC and 664 cancer-free controls. RESULTS: The patients with higher frequencies of WISP1 rs62514004 (AG + GG) and rs16893344 (CT + TT) variants revealed a lower risk to reach a later clinical stage compared with their wild-type carriers. Furthermore, individuals who carried WISP1 rs62514004 and rs16893344 haplotype G-T showed a greater synergistic effect combined with alcohol drinking on HCC development (AOR = 26.590, 95% CI = 9.780-72.295). CONCLUSIONS: Our results demonstrated that the HCC patients with WISP1 SNPs are associated with HCC development, and WISP1 SNPs may serve as markers or therapeutic targets for HCC.