Activation of angiogenin expression in macrophages by lipopolysaccharide via the TLR4/NF-κB pathway in colitis.

Inflammatory bowel disease (IBD) is a debilitating condition that can lead to life-threatening complications. Macrophages are crucial in IBD management because they secrete various cytokines and regulate tissue repair. Macrophage-derived angiogenin (ANG) has been shown to be essential for limiting colonic inflammation, but its upstream regulatory pathway and role in macrophages remain unclear. Here we show that ANG expression is up-regulated in macrophages during colitis treatment or upon lipopolysaccharides (LPS) treatment. Mechanistically, LPS activates Toll-like receptor 4 (TLR4) to initiate NF-κB translocation from the cytoplasm to the nucleus, where it binds to the ANG promoter and enhances its transcriptional activity, leading to increased ANG expression. Interestingly, our data also reveal that the deletion of ANG in macrophages has no adverse effect on key macrophage functions, such as phagocytosis, chemotaxis, and cell survival. Our findings establish a "LPS-TLR4-NF-κB-ANG" regulatory axis in inflammatory disorders and confirm that ANG controls inflammation in a paracrine manner, highlighting the importance of ANG as a key mediator in the complex network of inflammatory processes.

Parenteral n-3 polyunsaturated fatty acids supplementation improves postoperative recovery for patients with Crohn's disease after bowel resection: a randomized, unblinded controlled clinical trial.

BACKGROUND: The postoperative inflammatory response is associated with postoperative recovery in surgery. n-3 (ω-3) polyunsaturated fatty acids have been reported to lower inflammation. The postoperative role of parenteral n-3 polyunsaturated fatty acids supplementation on outcomes in Crohn's disease after bowel resection is unclear. OBJECTIVES: We aimed to investigate the effects of postoperative parenteral n-3 polyunsaturated fatty acids supplementation in Crohn's disease. METHODS: A prospective randomized, unblinded controlled clinical trial was conducted for patients with Crohn's disease who underwent bowel resection between May 2019 and February 2022. Postoperative complications, complete blood count, serum biochemical values, and cytokine concentrations were compared in patients with and without parenteral n-3 polyunsaturated fatty acids supplementation for 5 d postoperatively. RESULTS: There were 268 patients randomly assigned in the analysis, with 134 in the control group (a mix of long-chain and medium-chain fats at 1.0 g/kg/d) and 134 in the treatment group (long-chain, medium-chain, and n-3 polyunsaturated fats at 1.2 g/kg/d). Twenty-six did not complete the allocated treatment, and 8 patients were lost to follow-up. The intention-to-treat analysis and the per-protocol analysis showed that there were a significant reduction in overall complication rates (22.4% compared with 49.3%; P < 0.001 and 21.8% compared with 38.2%; P = 0.006) and postoperative stay (8.8 ± 4.5 d compared with 11.2 ± 6.8 d; P = 0.001 and 8.7 ± 4.0 d compared with 11.5 ± 7.3 d; P < 0.001) in patients with parenteral n-3 polyunsaturated fatty acids supplementation compared with patients in the control group. In the secondary outcomes, the mean ± standard deviation of interleukin (IL)-6 (17.11 ± 2.14 pg/mL compared with 30.50 ± 5.14 pg/mL; P = 0.014), IL-1ß (2.01 ± 0.05 pg/mL compared with 2.24 ± 0.09 pg/mL; P = 0.019), tumor necrosis factor-α (2.09 ± 0.06 pg/mL compared with 2.29 ± 0.06 pg/mL; P = 0.029), and C-reactive protein concentrations (51.3 ± 4.2 mg/L compared with 64.4 ± 5.3 mg/L; P = 0.050) on postoperative day 5 in the treatment group were much lower than those in the control group. CONCLUSIONS: Parenteral n-3 polyunsaturated fatty acids supplementation promotes postoperative recovery in patients with Crohn's disease following bowel resection, with fewer complications and reduced inflammatory cytokines. This trial was registered at clinicaltrials.gov as NCT03901937 at https://classic. CLINICALTRIALS: gov/ct2/show/NCT03901937?term=NCT03901937&cond=Crohn+Disease&draw=2&rank=1.

Angiogenin promotes angiogenesis via the endonucleolytic decay of miR-141 in colorectal cancer.

Mature microRNA (miRNA) decay is a key step in miRNA turnover and gene expression regulation. Angiogenin (ANG), the first human tumor-derived angiogenic protein and also a member of the RNase A superfamily, can promote tumor growth and metastasis by regulating rRNA biogenesis and tiRNA production. However, its effect on miRNA has not been explored. In this study, we find that ANG exclusively downregulates mature miR-141 in human umbilical endothelial cells (HUVECs) via its ribonuclease activity and preferably cleaves single-stranded miR-141 at the A5/C6, U7/G8, and U14/A15 sites via endonucleolytic digestion. By downregulating miR-141, ANG promotes HUVECs proliferation, migration, tube formation, and angiogenesis both in vitro and in vivo. Conversely, downregulated ANG inhibits ANG-mediated miR-141 decay, thus decreasing the angiogenesis process of HUVECs. We also find an inverse correlation between ANG and miR-141 expression in colorectal cancer (CRC) tissues. Our study indicates that ANG regulates CRC progression by disrupting miR-141 and its regulation on angiogenesis-related target genes, not only revealing a new mechanism of ANG action but also newly identifying miR-141 as a substrate of ANG. This study suggests that targeting ANG nuclease activity might be valuable in treating angiogenesis-related diseases through coordinately regulating the metabolism of rRNA, tiRNA, and miRNA.

Sarcopenia assessed by computed tomography is associated with colectomy in patients with acute severe ulcerative colitis.

BACKGROUND: Altered body composition is an important characteristic of malnutrition that may better reflect the clinical course. This study aimed to evaluate the prognostic role of sarcopenia by computed tomography (CT) on colectomy in acute severe ulcerative colitis (ASUC) during index hospitalization and follow-up. METHODS: 254 ASUC patients undergoing CT scans at admission were retrospectively included. Sarcopenia was assessed by the skeletal muscle index (SMI) with CT scans at L3, and patients with an SMI below the lowest sex-specific quartile were diagnosed with sarcopenia. Body mass index (BMI) < 18.5 kg/m2 was defined as clinical malnutrition. Univariate and multivariate analyses were performed to determine the association between sarcopenia and colectomy. RESULTS: The prevalence of sarcopenia in ASUC was 50.0%, and malnutrition was 25.2%. Among sarcopenic patients, 36.2% was malnutrition, 51.2% had normal BMI, 11.8% was overweight, and 0.8% was obese. During index hospitalization, 66.9% patients needed rescue therapy with 52.4% received medical rescue therapy and 14.6% received colectomy. During follow-up, 33.2% patients needed colectomy. Significantly more sarcopenic patients required colectomy (22.0% vs 7.1%, p = 0.001) and rescue therapy (81.9% vs 52.0%, p < 0.001) during index hospitalization and colectomy during follow-up (44.4% vs 23.7%, p = 0.001) than non-sarcopenic patients. However, BMI < 18.5 kg/m2 was not related to the clinical course. In multivariate analyses, sarcopenia remained an independent risk factor for rescue therapy and colectomy during index hospitalization and colectomy during follow-up. CONCLUSION: Sarcopenia rather than BMI was associated with clinical outcomes in ASUC and played an important role in predicting the need for colectomy.

The importance of sarcopenia as a prognostic predictor of the clinical course in acute severe ulcerative colitis patients.

BACKGROUND AND AIM: Acute severe ulcerative colitis (ASUC) is a life-threatening condition that requires timely referral for therapy. Sarcopenia has been associated with clinical outcomes of inflammatory bowel disease (IBD). This study investigated the role of sarcopenia in predicting the clinical course of ASUC. METHODS: This retrospective cohort study included ASUC patients with abdominal CT scans. Univariate and multivariable regression analyses were performed to identify a practical predictive index for the clinical course of ASUC. RESULTS: Of 233 included patients, 151 had intravenous corticosteroid (IVS) failure, among whom 32 received surgery without medical rescue therapy. Fifty patients underwent colectomy after medical rescue therapy failure. Of these 82 surgical patients, 42 suffered postoperative complications. Multivariable regression analysis showed that sarcopenia remained an independent risk factor for IVS failure (OR=2.969; 95% CI, 1.547-5.701; p = 0.001), colectomy after medical rescue therapy failure (OR=3.411; 95% CI, 1.147-10.141; p = 0.027), and postoperative complications after colectomy (OR=4.157; 95% CI, 1.364-12.667; p = 0.012). During follow-up, patients with colectomy after first-line treatment had a lower comprehensive complication index and better health-related quality of life. CONCLUSION: Sarcopenia is useful in predicting the clinical course and postoperative outcomes of ASUC.

Angiogenin maintains gut microbe homeostasis by balancing α-Proteobacteria and Lachnospiraceae.

OBJECTIVE: Antimicrobial peptides (AMPs) play essential roles in maintaining gut health and are associated with IBD. This study is to elucidate the effect of angiogenin (ANG), an intestine-secreted AMP, on gut microbiota and its relevance with IBD. DESIGN: The effect of ANG on microbiota and its contribution to colitis were evaluated in different colitis models with co-housing and faecal microbiota transplantation. ANG-regulated bacteria were determined by 16S rDNA sequencing and their functions in colitis were analysed by bacterial colonisation. The species-specific antimicrobial activity of ANG and its underlying mechanism were further investigated with microbiological and biochemical methods. ANG level and the key bacteria were characterised in IBD faecal samples. RESULTS: ANG regulated microbiota composition and inhibited intestinal inflammation. Specifically, Ang1 deficiency in mice led to a decrease in the protective gut commensal strains of Lachnospiraceae but an increase in the colitogenic strains of α-Proteobacteria. Direct binding of ANG to α-Proteobacteria resulted in lethal disruption of bacterial membrane integrity, and consequently promoted the growth of Lachnospiraceae, which otherwise was antagonised by α-Proteobacteria. Oral administration of ANG1 reversed the dysbiosis and attenuated the severity of colitis in Ang1-deficient mice. The correlation among ANG, the identified bacteria and IBD status was established in patients. CONCLUSION: These findings demonstrate a novel role of ANG in shaping gut microbe composition and thus maintaining gut health, suggesting that the ANG-microbiota axis could be developed as a potential preventive and/or therapeutic approach for dysbiosis-related gut diseases.

Myeloid cells protect intestinal epithelial barrier integrity through the angiogenin/plexin-B2 axis.

Communication between myeloid cells and epithelium plays critical role in maintaining intestinal epithelial barrier integrity. Myeloid cells interact with intestinal epithelial cells (IECs) by producing various mediators; however, the molecules mediating their crosstalk remain incompletely understood. Here, we report that deficiency of angiogenin (Ang) in mouse myeloid cells caused impairment of epithelial barrier integrity, leading to high susceptibility to DSS-induced colitis. Mechanistically, myeloid cell-derived angiogenin promoted IEC survival and proliferation through plexin-B2-mediated production of tRNA-derived stress-induced small RNA (tiRNA) and transcription of ribosomal RNA (rRNA), respectively. Moreover, treatment with recombinant angiogenin significantly attenuated the severity of experimental colitis. In human samples, the expression of angiogenin was significantly down-regulated in patients with inflammatory bowel disease (IBD). Collectively, we identified, for the first time to our knowledge, a novel mediator of myeloid cell-IEC crosstalk in maintaining epithelial barrier integrity, suggesting that angiogenin may serve as a new preventive agent and therapeutic target for IBD.

YTHDF1-mediated translation amplifies Wnt-driven intestinal stemness.

N6-methyladenosine (m6 A) mRNA methylation has emerged as an important player in many biological processes by regulating gene expression. However, its roles in intestinal stem cell (ISC) homeostasis remain largely unknown. Here, we report that YTHDF1, an m6 A reader, is highly expressed in ISCs and its expression is upregulated by Wnt signaling at the translational level. Whereas YTHDF1 is dispensable for normal intestinal development in mice, genetic ablation of Ythdf1 dramatically blocks Wnt-driven regeneration and tumorigenesis with reduced ISC stemness. Mechanistically, YTHDF1 facilitates the translation of Wnt signaling effectors including TCF7L2/TCF4, while this process is enhanced during Wnt activation to augment ß-catenin activity. Targeting YTHDF1 in ISCs of established tumors leads to tumor shrinkage and prolonged survival. Collectively, our studies unveil YTHDF1 as an amplifier of Wnt/ß-catenin signaling at the translational level, which is required for the maintenance of ISCs during regeneration and tumorigenesis.

Associations of fluoride exposure with sex steroid hormones among U.S. children and adolescents, NHANES 2013-2016.

Fluoride mediated disruption of sex steroid hormones has been demonstrated in animals. However, evidence from humans was limited and contradictory, especially for children and adolescents. Based on data of the National Health and Nutrition Survey (NHANES) 2013-2016, a total of 3392 subjects aged 6-19 years were analyzed in this cross-sectional study. Both plasma and water fluoride levels were quantified electrometrically using the ion-specific electrode. Sex steroid hormones of total testosterone, estradiol and sex hormone-binding globulin (SHBG) were tested in serum. Percent changes and 95% confidence intervals (CIs) in sex steroid hormones associated with tertiles of fluoride levels (setting the first as reference) were estimated using adjusted linear regression models by stratification of gender and age. Compared with subjects at the first tertile of plasma fluoride, percent changes (95% CIs) in testosterone were -8.08% (-17.36%, 2.25%) and -21.65% (-30.44%, -11.75%) for the second and third tertiles, respectively (P trend <0.001). Male adolescents at the third tertile of plasma fluoride had decreased levels of testosterone (percent change = -21.09%, 95% CIs = -36.61% to -1.77%). Similar inverse associations were also found when investigating the relationships between plasma fluoride and estradiol. Besides, the data indicated decreased levels of SHBG associated with water and plasma fluoride among the male adolescents (percent change of the third tertile = -9.39%, 95% CIs = -17.25% to -0.78%) and female children (percent change of the second tertile = -10.78%, 95% CIs = -17.55% to -3.45%), respectively. The data indicated gender- and age-specific inverse associations of fluoride in plasma and water with sex steroid hormones of total testosterone, estradiol and SHBG in U.S. children and adolescents. Prospective cohort studies are warranted to confirm the causality.

Association of blood metal exposure with testosterone and hemoglobin: A cross-sectional study in Hangzhou Birth Cohort Study.

BACKGROUND: Few epidemiological studies have investigated associations of exposure to multiple metals with testosterone homeostasis and erythropoiesis, especially for the pregnant women. METHODS: Among all the 1644 participants enrolled in Hangzhou Birth Cohort Study (HBCS) at baseline, a total of 918 pregnant women with complete data of interest were analyzed. The whole blood metals levels were examined by inductively coupled plasma mass spectrometry (ICP-MS), and serum testosterone level was evaluated by chemiluminescent microparticle immunoassay (CMIA), and erythropoietic parameters values were extracted from medical record. Multivariable linear regression models were applied to estimate the relationships between metals levels and testosterone level, and between metals levels and erythropoietic parameters, and potential confounders were adjusted. RESULTS: Single metal model analysis revealed a significant association of blood As, Mn and Pb level with serum testosterone level. After controlling for multiple testing, the dose-response trend with statistical significance (FDR-adjusted p trend <0.05) was observed across tertiles of Pb with testosterone. This association, when by stratified by gender, remained in pregnant women with a male fetus but did not reach significant in those with a female fetus. Furthermore, blood Pb level was positively associated with red blood cell counts, hemoglobin level and hematocrit. Serum testosterone level was positively associated with red blood cell counts, hemoglobin level and hematocrit. Mediation analyses indicated that testosterone might act as a mediator in the association between Pb exposure and erythropoietic parameters. CONCLUSIONS: Serum testosterone level and hemoglobin level was positively related to blood Pb level among Chinese pregnant women, and testosterone might mediate the effect of Pb exposure on hemoglobin. Additional prospective studies are warranted to confirm the causality.

Associated of rs895819 with risk of stomach neoplasms.

A recent study published in GENE performed a meta-analysis on the relationship between genetic variant rs895819 in microRNA-27a and risk of stomach neoplasms, and the results indicated an association of rs895819 with increased risk of stomach neoplasms in heterogenous model among Chinese. However, the meta-analysis did not include one large sample size of study that met inclusion criteria. When including all related studies, our meta-analysis showed no significant association of rs895819 with stomach neoplasms risk in each different model in all population, Chinese and Europeans. Thus, pooling all related studies did not provide evidence on the association of rs895819 with increased risk of stomach neoplasms.

Inhibition of RNA polymerase III transcription by Triptolide attenuates colorectal tumorigenesis.

BACKGROUND: Upregulation of RNA polymerase (Pol) III products, including tRNAs and 5S rRNA, in tumor cells leads to enhanced protein synthesis and tumor formation, making it a potential target for cancer treatment. In this study, we evaluated the inhibition of Pol III transcription by triptolide and the anti-cancer effect of this drug in colorectal tumorigenesis. METHODS: The effect of triptolide on colorectal cancer development was assessed in colorectal cancer mouse models, 3D organoids, and cultured cells. Colorectal cancer cells were treated with triptolide. Pol III transcription was measured by real-time quantitative polymerase chain reaction (PCR). The formation of TFIIIB, a multi-subunit transcription factor for Pol III, was determined by chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and fluorescence resonance energy transfer (FRET). RESULTS: Triptolide reduced both tumor number and tumor size in adenomatous polyposis coli (Apc) mutated (ApcMin/+) mice as well as AOM/DSS-induced mice. Moreover, triptolide effectively inhibited colorectal cancer cell proliferation, colony formation, and organoid growth in vitro, which was associated with decreased Pol III target genes. Mechanistically, triptolide treatment blocked TBP/Brf1interaction, leading to the reduced formation of TFIIIB at the promoters of tRNAs and 5S rRNA. CONCLUSIONS: Together, our data suggest that inhibition of Pol III transcription with existing drugs such as triptolide provides a new avenue for developing novel therapies for colorectal cancer.

Angiogenin promotes colorectal cancer metastasis via tiRNA production.

Metastasis of colorectal cancer (CRC) is the leading cause of CRC-associated mortality. Angiogenin (ANG), a member of the ribonuclease A superfamily, not only activates endothelial cells to induce tumor angiogenesis, but also targets tumor cells to promote cell survival, proliferation and/or migration. However, its clinical significance and underlying mechanism in CRC metastasis are still largely unknown. Here, we reported that ANG was upregulated in CRC tissues and associated with metastasis in CRC patients. We then revealed that ANG enhanced CRC growth and metastasis in both in vitro and in vivo systems. Intriguingly, we characterized a bunch of tRNA-derived stress-induced small RNAs (tiRNAs), produced through ANG cleavage, that was enriched in both CRC tumor tissues and highly metastatic cells, and functioned in ANG-promoted CRC metastasis. Moreover, higher level of a 5'-tiRNA from mature tRNA-Val (5'-tiRNA-Val) was observed in CRC patients and was correlated with tumor metastasis. Taken together, we propose that a novel ANG-tiRNAs-cell migration and invasion regulatory axis promotes CRC metastasis, which might be of potential target for CRC diagnosis and treatment.

Autophagic flux blockage in alveolar epithelial cells is essential in silica nanoparticle-induced pulmonary fibrosis.

Silica nanoparticles (SiNPs) have been reported to induce pulmonary fibrosis (PF) with an unknown mechanism. Recently, the activation of autophagy, a lysosome-dependent cell degradation pathway, by SiNPs has been identified in alveolar epithelial cells (AECs). However, the underlying mechanism and the relevance of SiNPs-induced autophagy to the development of PF remain elusive. Here, we report that autophagy dysfunction and subsequent apoptosis in AECs are involved in SiNPs-induced PF. SiNPs engulfed by AECs enhance autophagosome accumulation and apoptosis both in vivo and in vitro. Mechanically, SiNPs block autophagy flux through impairing lysosomal degradation via acidification inhibition. Lysosomal reacidification by cyclic-3',5'-adenosine monophosphate (cAMP) significantly enhances autophagic degradation and attenuate apoptosis. Importantly, enhancement of autophagic degradation by rapamycin protects AECs from apoptosis and attenuates SiNPs-induced PF in the mouse model. Altogether, our data demonstrate a repressive effect of SiNPs on lysosomal acidification, contributing to the decreased autophagic degradation in AECs, thus leading to apoptosis and subsequent PF. These findings may provide an improved understanding of SiNPs-induced PF and molecular targets to antagonize it.

The regulatory network of miR-141 in the inhibition of angiogenesis.

The miR-200 family, consisting of miR-200a/b/c, miR-141, and miR-429, is well known to inhibit epithelial-to-mesenchymal transition (EMT) in cancer invasion and metastasis. Among the miR-200 family members, miR-200a/b/c and miR-429 have been reported to inhibit angiogenesis. However, the role of miR-141 in angiogenesis remains elusive, as contradicting results have been found in different cancer types and tumor models. Particularly, the effect of miR-141 in vascular endothelial cells has not been defined. In this study, we used several in vitro and in vivo models to demonstrate that miR-141 in endothelial cells inhibits angiogenesis. Additional mechanistic studies showed that miR-141 suppresses angiogenesis through multiple targets, including NRP1, GAB1, CXCL12ß, TGFß2, and GATA6, and bioinformatics analysis indicated that miR-141 and its targets comprise a powerful and precise regulatory network to modulate angiogenesis. Taken together, these data not only demonstrate an anti-angiogenic effect of miR-141, further strengthening the critical role of miR-200 family in the process of angiogenesis, but also provides a valuable cancer therapeutic target to control both angiogenesis and EMT, two essential steps in tumor growth and metastasis.

Associations of urinary polycyclic aromatic hydrocarbons with age at natural menopause in U.S. women aged 35-65, NHANES 2003-2012.

Polycyclic aromatic hydrocarbons (PAHs) mediated ovarian toxicity has been demonstrated in animal experiments. However, this issue has not been assessed in humans. Based on the National Health and Nutrition Examination Survey (NHANES) 2003-2012, data analysis was restricted to 1221 general U.S. women aged 35-65 years with complete data of interest. Levels of nine PAH metabolites in spot urine specimens were measured by isotope dilution gas chromatography/tandem mass spectrometry (GC-MS/MS). Self-reported information on the menopause status and age at menopause were obtained during interview. Cox proportional hazards regression was employed to assess the associations between PAH levels and natural menopause. Compared with women in the first quartile, subjects in the highest quartile of 1-Hydroxynapthalene [hazard ratio (HR) = 1.46, 95% confidence interval (CI) = 1.06 to 2.01], 2-Hydroxynapthalene (HR = 1.51, 95% CI = 1.12 to 2.05) and 3-Hydroxyfluorene (HR = 1.51, 95% CI = 1.06 to 2.16), or in the second quartile of 9-Hydroxyfluorene (HR = 1.53, 95% CI = 1.05 to 2.22), had elevated risks of earlier onset of natural menopause. Our findings suggested positive associations between urinary PAH levels and earlier age at natural menopause in the general U.S. women. Prospective studies are warranted to confirm the causality in the future.

Relationships between acrylamide and glycidamide hemoglobin adduct levels and allergy-related outcomes in general US population, NHANES 2005-2006.

BACKGROUND: Acrylamide-induced immunotoxicity and allergic dermatitis have been reported in animal experiments and clinical reports, respectively. However, epidemiological evidence from the general population is limited. OBJECTIVES: The purpose of the present study was to estimate the associations between acrylamide exposure and allergy-related outcomes in the general US population. METHODS: A total of 6982 subjects were selected from the National Health and Nutrition Examination Survey 2005-2006 (NHANES). Internal exposure was measured by the hemoglobin adducts of acrylamide (HbAA) and its metabolite glycidamide (HbGA). Allergy-related outcomes including asthma, hay fever, allergy, itchy rash, sneeze, wheeze and eczema were obtained by self-administered questionnaires. Allergic sensitization was assessed by the total immunoglobulin E (IgE) levels. The associations of HbAA and HbGA quartiles with allergy-related outcomes were calculated using logistic regression models with multivariable adjustments. Analyses were additionally stratified according to age, gender and serum cotinine levels. RESULTS: When setting quartile 1 of HbAA as reference, the odds ratios (ORs) [95% confidence intervals (CIs)] of quartile 2 to 4 for eczema were 1.18 (0.79-1.76), 1.14 (0.73-1.78) and 1.58 (1.14-2.18), respectively (ptrend = 0.002). Individuals at the highest quartile of HbGA had significantly elevated likelihoods of itchy rash (OR = 1.37, 95% CI = 1.02-1.83, ptrend = 0.032) and eczema (OR = 1.45, 95% CI = 1.06-1.97, ptrend = 0.044). The stratification analyses indicated various results in different subgroups. CONCLUSIONS: This study indicated significant associations between HbAA and HbGA levels and the likelihoods of allergy-related outcomes in the general US population, depending on age, gender and smoke exposure status. These findings suggested potential public health concerns for the widespread exposure to acrylamide.

Red emissive AIE nanodots with high two-photon absorption efficiency at 1040 nm for deep-tissue in vivo imaging.

Deep-tissue penetration is highly required in in vivo optical bioimaging. We synthesized a type of red emissive fluorophore BT with aggregation-induced emission (AIE) property. BT molecules were then encapsulated with amphiphilic polymers to form nanodots, and a large two-photon absorption (2PA) cross-section of 2.9 × 10(6) GM at 1040 nm was observed from each BT nanodot, which was much larger than those at the wavelengths of 770 to 860 nm. In addition, 1040 nm light was found to have better penetration and focusing capability than 800 nm light in biological tissue, according to the Monte Carlo simulation. The toxicity and tissue distribution of BT nanodots were studied, and they were found to have good biocompatibility. BT nanodots were then utilized for in vivo imaging of mouse ear and brain, and an imaging depth of 700 µm was obtained with the femtosecond (fs) excitation of 1040 nm. The red emissive AIE nanodots with high 2PA efficiency at 1040 nm would be useful for deep-tissue functional bioimaging in the future.

MicroRNA-409-3p suppresses colorectal cancer invasion and metastasis partly by targeting GAB1 expression.

Colorectal cancer (CRC) is one of the most common cancers worldwide and its metastasis accounts for the majority of deaths. However, the molecular mechanisms underlying CRC progression are not well characterized. In this study, we identified miR-409-3p as a tumor suppressor of CRC. MiR-409-3p expression was significantly downregulated in CRC tissue compared to adjacent non-tumor tissue, and reduced miR-409-3p expression was correlated with CRC metastasis. In vitro and in vivo studies revealed that miR-409-3p negatively regulated CRC metastatic capacities, including suppressing cancer cell migration, invasion and metastasis. To explore the mechanism of action of miR-409-3p, we adopted a pathway and pathophysiological event-based target screening and validation approach, and found nine known metastasis-related genes as potential targets. The 3'-UTR binding assays between the candidates and miR-409-3p suggested that only GAB1, NR4A2 and LMO4 were directly regulated by the miRNA. However, endogenous expression analysis revealed that only GAB1 was modulated by miR-409-3p in CRC cells at both the mRNA and protein levels. Furthermore, we provided evidence to conclude that GAB1 was partially responsible for miR-409-3p-mediated metastasis. Taken together, our data demonstrate that miR-409-3p is a metastatic suppressor, and post-transcriptional inhibition of the oncoprotein GAB1 is one of the mechanisms of action of this miRNA. Our finding suggests miR-409-3p might be a novel target for CRC metastasis treatment.

Association of a pre-miR-27a polymorphism with cancer risk: an updated meta-analysis.

MicroRNA-27a is highly expressed in cancers and has been identified as an oncogenic microRNA. A genetic variant in pre-miR-27a (rs895819) with a transition of A to G has been demonstrated to be associated with cancer risk; however, the results of these studies remain conflicting rather than conclusive. Therefore, we performed a meta-analysis to derive a more precise estimation. Through searching PubMed or other databases up to March 2014 using the following MeSH terms and keywords, "miR-27a", "polymorphism" and "cancer", seventeen case-control studies were identified in this meta-analysis, including 7,813 cases and 9,602. Crude odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to investigate the association strength between rs895819 and the susceptibility of cancer. The results of the overall meta-analysis did not suggest any association between rs895819 polymorphism and cancer susceptibility, and this remained in Asians as a sub- group. In Caucasians, however, the rs895819 was associated with a reduced cancer risk in heterozygous (OR, 0.83; 95%CI, 0.75-0.93) and dominant models (OR, 0.84; 95%CI, 0.76-0.93), and the [G] allele of rs895819 showed a protective effect (OR, 0.90, 95%CI, 0.84-0.97). Further studies showed a significant association between the [G] allele of rs895819 and decreased risk of breast cancer (0.91; 95%CI, 0.85-0.98), and stratified analyses indicated a protective effect of the [G] allele in Caucasians (OR, 0.89; 95%CI, 0.82-0.98), younger breast cancer cases (OR, 0.87; 95%CI, 0.79-0.96), and in the group of unilateral breast cancer patients (OR, 0.90; 95%CI, 0.83-0.97). These findings suggest an association between pre-miR-27a polymorphism rs895819 and cancer risk in Caucasians. The protective effect of rs895819 [G] allele in younger breast cancer and in the group of unilateral breast cancer patients await further confirmation since the included studies in this meta-analysis were limited.