TGF-ß Promotes Hepatocellular Carcinoma Metastasis Through Through m6A Modification of PCDHGA9.

Objective: Hepatocellular carcinoma (HCC) is a highly lethal cancer with significant mortality, primarily attributed to metastasis. Although Protocadherin Gamma Subfamily A, 9 (PCDHGA9) has been identified as a tumor suppressor gene in cancer metastasis, its role in HCC remains ambiguous. This study aims to clarify the role of PCDHGA9 in HCC by examining its expression, clinical significance, and molecular activities. Methods: Tissue microarray immunofluorescence analysis evaluated the expression of PCDHGA9 and its clinical relevance. In vitro experiments involved manipulating PCDHGA9 levels in SK-HEP-1 cells to assess migration through wound-healing and transwell assays. In vivo, shPCDHGA9 cell injections were utilized to observe effects on tumor growth and metastasis. Protein analysis and Western Blot validated epithelial-mesenchymal transition (EMT)-related proteins. Subsequent to TGF-ß treatment, cell proliferation and apoptosis were quantified using Cell counting kit-8 and flow cytometry, respectively, followed by investigation of TGF-ß effects on PCDHGA9 N6-methyladenosine (m6A) modification via Methylated RNA immunoprecipitation, RT-qPCR, and Western blot analysis. Results: Downregulation of PCDHGA9 expression in HCC tissues is correlated with poor prognosis. In vitro experiments demonstrated that modulating PCDHGA9 expression influenced HCC cell migration. In vivo, PCDHGA9 knockdown is correlated with increased metastasis. Furthermore, TGF-ß stimulation promoted cell proliferation and inhibited apoptosis. Mechanistically, TGF-ß-mediated m6A modification led to PCDHGA9 decay, promoting EMT in HCC cells. Conclusion: PCDHGA9 serves as a potential tumor suppressor in HCC by inhibiting EMT. During this process, TGF-ß is observed to exert regulatory control over m6A modifications of PCDHGA9.

Synergistic quorum sensing inhibition and mild-temperature photothermal therapy of integrated nanoplatform for implant-associated biofilm infections.

In current clinical practice, the presence of biofilms poses a significant challenge in the effective elimination of bacterial infections because of the physical and chemical barriers formed by biofilms, which offer persistent protection to bacteria. Here, we developed hollow mesoporous polydopamine (hMP) nanoparticles (NPs) loaded with luteolin (Lu) as a quorum sensing inhibitor, which were further coated with hyaluronic acid (HA) shells to create hMP-Lu@HA NPs. We observed that upon reaching the infection site, the HA shells underwent initial degradation by the hyaluronidase enzyme present in the bacterial infection's microenvironment to expose the hMP-Lu NPs. Subsequently, Lu was released in response to the acidic conditions characteristic of bacterial infections, which effectively hindered and dispersed the biofilm. Moreover, when subjected to near-infrared irradiation, the robust photothermal conversion effect of hMP NPs accelerated the release of Lu and disrupted the integrity of the biofilms by localized heating. This dual action enhanced the eradication of the biofilm infection. Importantly, hMP-Lu@HA NPs also promoted tissue regeneration and healing at the implantation site, concurrently addressing biofilm infection. Taken together, this nanosystem, combined with mild-temperature photothermal therapy and quorum sensing inhibition strategy, holds significant potential for applications in the treatment of implantation-associated infections.

Semaglutide alleviates gut microbiota dysbiosis induced by a high-fat diet.

This study investigated the effects of semaglutide (Sema) on the gut microbiota of obese mice induced with high-fat diet (HFD). Male C57BL/6 J mice aged 6 weeks were enrolled and randomly distributed to four groups, which were provided with a normal control diet (NCD,NCD + Sema) and a 60% proportion of a high-fat diet (HFD,HFD + Sema), respectively. HFD was given for 10 weeks to develop an obesity model and the intervention was lasted for 18 days. The results showed semaglutide significantly reduced body weight gain, areas under the curve (AUC) of glucose tolerance test and insulin resistance test, as well as adipose tissue weight in mice. Semaglutide effectively reduced lipid deposition and lipid droplet formation in the liver of obese mice, and regulated the expression of genes related to abnormal blood glucose regulation. Additionally, semaglutide influenced the composition of gut microbiota, mitigating the microbial dysbiosis induced by a high-fat diet by impacting the diversity of the gut microbiota. After the high-fat diet intervention, certain strains such as Akkermansia, Faecalibaculum, and Allobaculum were significantly decreased, while Lachnospiraceae and Bacteroides were significantly increased. However, the application of semaglutide restored the lost flora and suppressed excessive bacterial abundance. Moreover, semaglutide increased the content of tight junction proteins and repaired the damage to intestinal barrier function caused by the high-fat diet intervention. Furthermore, correlation analysis revealed inverse relationship among Akkermansia levels and weight gain, blood glucose levels, and various obesity indicators. Correlation analysis also showed that Akkermansia level was negatively correlated with weight gain, blood glucose levels and a range of obesity indicators. This phenomenon may explain the anti-obesity effect of semaglutide, which is linked to alterations in gut microbiota, specifically an increase in the abundance of Akkermansia. In summary, our findings indicate that semaglutide has the potential to alleviate gut microbiota dysbiosis, and the gut microbiota may contribute to the obesity-related effects of this drug.

Risk assessment and partitioning behavior of PFASs in environmental matrices from an e-waste recycling area.

OBJECTIVE: Perfluoroalkyl and polyfluoroalkyl substance (PFAS) contamination and their human exposure risks are a major concern. However, knowledge of PFAS contamination in environments near e-waste recycling sites and their health risk assessment are scarce. METHODS: We measured the concentrations of PFASs in soil (n = 12), water (n = 12) and atmospheric samples (n = 26) by LCP-MS/MS, analyzed the source apportionment of PFASs by PCA, and investigated the child health risk assessment from an e-waste recycling area (Guiyu) and a reference area (Haojiang). RESULTS: We found high concentrations of PFASs in the atmosphere and low concentrations of PFASs in soil. The average concentration of perfluoro-n-heptanoic acid (PFHpA) (9.43 ng/L) was highest among PFASs in water. The concentrations PFASs in the atmosphere and water were higher in the e-waste recycling area than in the reference area (p < 0.05). According to Multi-Linear regression model, we found that daily intake doses for PFASs in air of PFODA [ß (95 % CI): -0.217 (-0.332, -0.048), p < 0.05] and PFBS [ß (95 % CI): -0.064 (-0.106, -0.006), p < 0.05] were negatively associated with child BMI. PFBA [ß (95 % CI: -1.039 (-2.454, -0.010), p < 0.05] was negatively correlated with child head circumference. CONCLUSION: The concentrations of PFASs in the water and atmosphere are higher in the e-waste recycling site than in the reference area. We found that their intake affected growth and development in children. We need to reduce pollution from PFASs in the e-waste recycling area while maintaining a focus on their impact on child health.

Design, synthesis and anti-inflammatory activity study of lansiumamide analogues for treatment of acute lung injury.

Acute lung injury (ALI) is an inflammation-mediated respiratory disease with a high mortality rate. Medications with anti-inflammatory small molecules have been demonstrated in phase I and II clinical trials to considerably reduce the ALI mortality. In this study, two series of lansiumamide analogues were designed, synthesized, and evaluated for anti-inflammatory activity for ALI treatment. We found that compound 8n exhibited the best anti-inflammatory activity through inhibiting LPS-induced expression of the proinflammatory cytokines interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) in Raw264.7 cells and activating the Nrf2/HO-1 pathway. Furthermore, we discovered in a LPS-induced ALI mice model that compound 8n significantly reduced the infiltration of inflammatory cells into lung tissue to achieve the effect of protecting lung tissues and improving ALI. Additionally, our mice model study revealed that compound 8n had a good expectorant effect. These results consistently support that lansiumamide analogue 8n represents a new class of anti-inflammatory agents with potential as a lead compound for further development into a therapeutic drug for ALI treatment.

Carboxymethyl Chitosan/Sodium Alginate/Chitosan Quaternary Ammonium Salt Composite Hydrogel Supported 3J for the Treatment of Oral Ulcer.

Oral ulcer is a common inflammatory disease of oral mucosa, causing severe burning pain and great inconvenience to daily life. In this study, compound 3J with anti-inflammatory activity was synthesized beforehand. Following that, an intelligent composite hydrogel supported 3J was designed with sodium alginate, carboxymethyl chitosan, and chitosan quaternary ammonium salt as the skeleton, and its therapeutic effect on the rat oral ulcer model was investigated. The results show that the composite hydrogel has a dense honeycomb structure, which is conducive to drug loading and wound ventilation, and has biodegradability. It has certain antibacterial effects and good anti-inflammatory activity. When loaded with 3J, it reduced levels of TNF-α and IL-6 in inflammatory cells by up to 50.0%. It has excellent swelling and water retention properties, with a swelling rate of up to 765.0% in a pH 8.5 environment. The existence of a large number of quaternary ammonium groups, carboxyl groups, and hydroxyl groups makes it show obvious differences in swelling in different pH environments, which proves that it has double pH sensitivity. It is beneficial to adapt to the highly dynamic changes of the oral environment. Compared with single hydrogel or drug treatment, the drug-loaded hydrogel has a better effect on the treatment of oral ulcers.

Plastic or plastic-free life: From formation to removal.

Microplastics (MPs) and nanoplastics (NPs) have caused global environmental concerns due to their ubiquitous existence in our surrounding environment and the potential threats posed to the ecosystem and human health. This review aims to extend current knowledge on the formation and degradation of MPs and NPs. The paper presents the potential sources of MPs and NPs including plastic containers, textiles, cosmetics, personal care products, COVID-19 wastes, and other plastic products. Once in the natural environment, the fragmentation and degradation of plastic wastes are thought to be initiated by physical, chemical, and biological factors. The corresponding degradation mechanism will be presented in the present review. Given the plastic life and environment, humans are inevitably exposed to MPs and NPs through ingestion, inhalation, and dermal contact. The potential risks MPs/NPs pose to humans will be also discussed in our study. Currently, the relevance of MP/NP exposure to human health outcomes is still controversial and not yet fully understood. Deciphering the translocation and degradation of plastics in the human body will be helpful to reveal their potential organotoxicity. In this case, available approaches to alleviate MP/NP pollution and advanced strategies to reduce MP/NP toxicity in humans are recommended to build a plastic-free life.

Blood lead levels of children exposed to e-waste: a systematic review and meta-analysis.

Blood lead levels (BLLs) have been decreasing worldwide for decades. However, systematic reviews and quantitative syntheses of BLLs in electronic waste (e-waste)-exposed children are lacking. To summarize temporal trend of BLLs among children in e-waste-recycling areas. Fifty-one studies met the inclusion criteria and included participants from six countries. Meta-analysis was performed using the random-effects model. Results showed that among e-waste-exposed children, the total geometric mean (GM) BLL was 7.54 µg/dL (95% CI: 6.77, 8.31). Children's BLLs displayed a decreasing temporal trend, from 11.77 µg/dL in phase I (2004-2006) to 4.63 µg/dL in phase V (2016-2018). Almost 95% of eligible studies found that children exposed to e-waste had significantly higher BLLs than reference groups. The difference of children's BLLs between the exposure group and the reference group was from 6.60 µg/dL (95% CI: 6.14, 7.05) in 2004 to 1.99 µg/dL (95% CI: 1.61, 2.36) in 2018. For subgroup analyses, except for Dhaka and Montevideo, the BLLs of children from Guiyu in the same survey year were higher than those of children from other regions. Our findings indicate that the gap between BLLs of children exposed to e-waste and those of reference group children is closing, and we appeal that the critical value for blood lead poisoning in children should be lowered in key e-waste-dismantling areas of developing countries, such as Guiyu.

Extensive identification of serum metabolites related to microbes in different gut locations and evaluating their associations with porcine fatness.

Gut microbiota plays important roles in host metabolism. Whether and how much the gut microbiota in different gut locations contributes to the variations of host serum metabolites are largely unknown, because it is difficult to obtain microbial samples from different gut locations on a large population scale. Here, we quantified the gut microbial compositions using 16S rRNA gene sequencing for 1070 samples collected from the ileum, cecum and faeces of 544 F6 pigs from a mosaic pig population. Untargeted metabolome measurements determined serum metabolome profiles. We found 1671, 12,985 and 103,250 significant correlations between circulating serum metabolites and bacterial ASVs in the ileum, cecum, and faeces samples. We detected nine serum metabolites showing significant correlations with gut bacteria in more than one gut location. However, most metabolite-microbiota pairwise associations were gut location-specific. Targeted metabolome analysis revealed that CDCA, taurine, L-leucine and N-acetyl-L-alanine can be used as biomarkers to predict porcine fatness. Enriched taxa in fat pigs, for example Prevotella and Lawsonia intracellularis were positively associated with L-leucine, while enriched taxa in lean pigs, such as Clostridium butyricum, were negatively associated with L-leucine and CDCA, but positively associated with taurine and N-acetyl-L-alanine. These results suggested that the contributions of gut microbiota in each gut location to the variations of serum metabolites showed spatial heterogeneity.

Design, synthesis, and biological evaluation of diaryl heterocyclic derivatives targeting tubulin polymerization with potent anticancer activities.

A series of diaryl heterocyclic analogues were designed and synthesized as tubulin polymerization inhibitors. Among them, compound 6y showed the highest antiproliferative activity against HCT-116 colon cancer cell line with an IC50 values of 2.65 µM. Compound 6y also effectively inhibited tubulin polymerization in vitro (IC50 of 10.9 µM), and induced HCT-116 cell cycle arrest in G2/M phase. In addition, compound 6y exhibited high metabolic stability on human liver microsomes (T1/2 = 106.2 min). Finally, 6y was also effective in suppressing tumor growth in a HCT-116 mouse colon model without apparent toxicity. Collectively, these results suggest that 6y represents a new class of tubulin inhibitors deserving further investigation.

Epidemiological evidence for the effect of environmental heavy metal exposure on the immune system in children.

Heavy metals exist widely in daily life, and exposure to heavy metals caused by environmental pollution has become a serious public health problem worldwide. Due to children's age-specific behavioral characteristics and imperfect physical function, the adverse health effects of heavy metals on children are much higher than in adults. Studies have found that heavy metal exposure is associated with low immune function in children. Although there are reviews describing the evidence for the adverse effects of heavy metal exposure on the immune system in children, the summary of evidence from epidemiological studies involving the level of immune molecules is not comprehensive. Therefore, this review summarizes the current epidemiological study on the effect of heavy metal exposure on childhood immune function from multiple perspectives, emphasizing its risks to the health of children's immune systems. It focuses on the effects of six heavy metals (lead (Pb), cadmium (Cd), arsenic (As), mercury (Hg), nickel (Ni), and manganese (Mn)) on children's innate immune cells, lymphocytes and their subpopulations, cytokines, total and specific immunoglobulins, and explores the immunotoxicological effects of heavy metals. The review finds that exposure to heavy metals, particularly Pb, Cd, As, and Hg, not only reduced lymphocyte numbers and suppressed adaptive immune responses in children, but also altered the innate immune response to impair the body's ability to fight pathogens. Epidemiological evidence suggests that heavy metal exposure alters cytokine levels and is associated with the development of inflammatory responses in children. Pb, As, and Hg exposure was associated with vaccination failure and decreased antibody titers, and increased risk of immune-related diseases in children by altering specific immunoglobulin levels. Cd, Ni and Mn showed activation effects on the immune response to childhood vaccination. Exposure age, sex, nutritional status, and co-exposure may influence the effects of heavy metals on immune function in children.

Current status of indoor dust PBDE pollution and its physical burden and health effects on children.

Polybrominated diphenyl ethers (PBDEs) are widely detected in indoor dust, which has been identified as a more important route of PBDE exposure for children than food intake. The physical burden and health hazards to children of PBDE exposure in house dust have not been adequately summarized; therefore, this article reviews the current status of PBDE pollution in indoor dust associated with children, highlighting the epidemiological evidence for physical burden and health risks in children. We find that PBDEs remain at high levels in indoor dust, including in homes, schools, and cars, especially in cars showing a significant upward trend. There is a trend towards an increase in the proportion of BDE-209 in household dust, which is indicative of recent PBDE contamination. Conversely, PBDE congeners in car and school indoor dust tended to shift from highly brominated to low brominated, suggesting a shift in current pollution patterns. Indoor dust exposure causes significantly higher PBDE burdens in children, especially infants in early life, than in adults. Exposure to dust also affects breast milk, putting infants at high risk of exposure. Although evidence is limited, available epidemiological studies suggest that exposure to indoor dust PBDEs promotes neurobehavioral problems and cancer development in children.

A pre-column derivatization high-performance liquid chromatography method for simultaneous determination of short-chain and medium-chain fatty acids in a fecal sample.

Short-chain and medium-chain fatty acids have plentiful biological functions, which play a crucial role in the diagnosis and therapy of many diseases. Herein, a new method for simultaneous quantifying 17 short-chain and medium-chain fatty acids with high-performance liquid chromatography coupled with an ultraviolet detector was developed and the pre-column derivatization by indole-3-acetic acid hydrazide was performed to improve the separation and detection. The conditions of the derivatization reaction were systematically investigated. Subsequently, the method was validated and the results showed a satisfactory linearity (linear regression coefficients > 0.9969), the limit of detection (4.0×10-3 -1.9×10-2 µmol/L), precision (0.9%-7.3% for intra-day and 2.0%-9.8% for inter-day), recovery (90.0%-109.1% with relative standard deviation <7.7%) and stability (0.1%-3.3% for standard solution and 0.2%-3.9% for fecal sample). Finally, the established method was successfully applied to quantify short-chain and medium-chain fatty acids in the feces of healthy control and diabetic rats. Eleven kinds of short-chain and medium-chain fatty acids were detected and six of them showed a significant difference between the control group and the model group.

A novel biocompatible Eu-based coordination polymers of cytarabine anticancer drug: Preparation, luminescence properties and in vitro anticancer activity studies.

In this study, we use cytarabine anticancer drug to synthesize a new rare earth complex with Europium ion. The study work is an attempt to investigate luminescence and biological properties of the Eu-based coordination polymers of cytarabine (Eu-CP-Ara) anticancer drug which have been prepared by us. Eu-CP-Ara has luminescence properties with emission centering at about 619 nm excited with 394 nm. We study cytarabine and Eu-CP-Ara in vitro cytotoxicity. Cytotoxicity of Eu-CP-Ara against lung cancer cells (A549) could even be comparable to the inhibitory effect of cytarabine ligands, showing the advantage of antitumor activity. In addition, Eu-CP-Ara showed lower cytotoxicity to normal liver cells (L02). At the same, from the CLSM images, Eu-CP-Ara has successfully entered the A549 cell. Hence, Eu-CP-Ara can be used as a potential anticancer drug. Eu-CP-Ara may be an effective strategy for the tracking cytarabine against tumours and might impart better accurate treatment effect and therapeutic efficiency.

HIV-1 pretreatment drug resistance and genetic transmission network in the southwest border region of China.

BACKGROUND: HIV drug resistance increased with the widespread use of antiretroviral drugs, and posed great threat to antiretroviral therapy (ART). Pu'er Prefecture, lying in the southwest of Yunnan Province, China, borders Myanmar, Laos and Vietnam, is also the area where AIDS was discovered earlier, however, in which there has been no information on HIV drug resistance. METHODS: A cross-sectional survey of pretreatment drug resistance (PDR) was conducted in Pu'er Prefecture in 2021. Partial pol gene sequences were obtained to analyze drug resistance and construct genetic transmission network. HIV drug resistance was analyzed using the Stanford University HIVdb algorithm. RESULTS: A total of 295 sequences were obtained, among which 11 HIV-1 strain types were detected and CRF08_BC (62.0%, 183/295) was the predominant one. Drug resistance mutations (DRMs) were detected in 42.4% (125/295) of the sequences. The prevalence of PDR to any antiretroviral drugs, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 10.8% (32/295), 9.5% (28/295), 1.0% (3/295) and 0.3% (1/295), respectively. The risk of PDR occurrence was higher among individuals with CRF01_AE strain types. HIV-1 molecular network was constructed, in which 56.0% (42/75) of links were transregional, and 54.7% (41/75) of links were associated with Lancang County. Among the sequences in the network, 36.8% (35/95) harbored DRMs, and 9.5% (9/95) were drug resistance strains. Furthermore, 8 clusters had shared DRM. CONCLUSION: The overall prevalence of PDR in this study was in a moderate level, but NNRTIs resistance was very approaching to the threshold of public response initiation. PDR was identified in the transmission network, and DRMs transmission was observed. These findings suggested that the consecutive PDR surveillance should be conducted in this region.

Kindergarten indoor dust metal(loid) exposure associates with elevated risk of anemia in children.

Exposure to metals and metalloids in indoor dust is associated with adverse health effects in young children, but there is limited evidence for an association with anemia, which is at high risk in children. The aim of this study was to investigate the association between exposure to multiple metal(loid)s in indoor dust in kindergartens and the risk of anemia in children. In 2021, 2165 children from 25 kindergartens in eastern China were included in the study and had their hemoglobin (Hb) measured. Indoor dust samples were collected from the children's kindergartens, and the concentrations of 11 metals and metalloids in the samples were measured using inductively coupled plasma mass spectrometry (ICP-MS). The daily exposure dose (DED) of dust was used to assess the risk of metal(loid) exposure in the children. The results showed that of the 2165 children with available data, 351 (16.2 %) met the WHO definition of anemia. In multiple linear regression and logistic regression analyses, we found that for each quartile of DED increase in Cd inhalation, child Hb levels decreased by 2.703 g/L (95 % CI: -4.055, -1.351), and the risk of anemia increased 1.602-fold (95 % CI: 1.087, 2.360). Mn ingestion was associated with increased odds of anemia [odds ratio (OR) = 1.760 (95 % CI: 1.217, 2.544)]. Interaction analysis indicated that metal(loid)s exposure effects were modified by child sex, age, and body mass index (BMI). Cluster analysis found that children at high risk of metal(loid) exposure in the school environment tended to have lower Hb levels and higher prevalence of anemia compared with those at low risk, although this was not statistically significant. These findings suggest that child school exposure to metal(loid)s in indoor dust is associated with an increased risk of developing anemia in children, modified by child sex, age, and BMI.

[Effect of Gegen Qinlian Decoction on methylation and expression of Scd1gene in adipose tissue of insulin resistant rats and correlations between methylation and physiological and biochemical parameters].

This study aimed to explore the effect of Gegen Qinlian Decoction(GQD) on the methylation and mRNA expression level of stearoyl CoA desaturase(SCD) gene in the adipose tissue of rats with insulin resistance(IR) induced by high-fat diet as well as the correlations between methylation and physiological and biochemical indicators. The animals were divided into seven groups, namely, blank control(C) group, IR model group, low-(1.65 g·kg~(-1)), medium-(4.95 g·kg~(-1)), and high(14.85 g·kg~(-1))-dose GQD(GQDL, GQDM, and GQDH) groups, rosiglitazone(RGN, 5 mg·kg~(-1)) group, and simvastatin(SVT, 10 mg·kg~(-1)) group. The rat epididymal adipose tissue was collected for detecting all the cytosine methylation levels in two fragments of Scd1 gene by bisulfite sequencing PCR(BSP). Scd1-1 was located in CG shores and Scd1-2 in CG islands, including the transcriptional start site(TSS). The Scd1 mRNA level was determined by quantitative real-time PCR(q-PCR). Spearman correlation coefficient was used to analyze the correlations between amplified fragment C methylation and physiological and biochemical indicators. The results showed that GQDM remarkably reversed the elevated CG7 methylation in the TSS upstream region of Scd1-2 triggered by high-fat diet. GQDL significantly reversed the lowered total CG methylation in the downstream region of Scd1-2 induced by the high-fat diet. GQD did not significantly improve the decreased Scd1 mRNA expression caused by high-fat diet. Changes in methylation of the total CG, CG5 and CT11 of Scd1-1 in CG shores exhibited significant negative correlations with the serum triglyceride(TG) but positive correlation with the Scd1 mRNA level. The methylation of several C sites in the TSS upstream region of Scd1-2 was positively correlated with physiological and biochemical parameters. The methylation of several CG sites in the TSS downstream region of Scd1-2 was negatively associated with physiological and biochemical parameters. Besides, the methylation of several CH sites in the downstream fragment was positively correlated with physiological and biochemical parameters. All these have demonstrated that GQD may exert the therapeutic effect by regulating the methylation of CG7 in the TSS upstream region and total CG site in the TSS downstream region of Scd1 gene. The methylation of total CG, CG5 and CT11 sites in CG shores of Scd1 gene may be important targets for regulating Scd1 mRNA level and affecting serum TG.

Identification of significant prognostic risk markers for pancreatic ductal adenocarcinoma: a bioinformatic analysis.

OBJECTIVE: This study aimed to identify novel prognostic biomarkers of pancreatic ductal adenocarcinoma (PDAC) using bioinformatics analyzes. METHODS: Clinical information, microRNAs (miRNAs), and genes expression profile data from PDAC cases were downloaded from the Cancer Genome Atlas (TCGA) database. The potential prognostic risk miRNAs and genes were screened using the Elastic Net Cox proportional risk regression hazards (EN-COX) model. The receiver operating characteristic (ROC) curve and the Kaplan-Meier (KM) curve were used to identify miRNAs and genes of significant prognostic risk. Furthermore, significant prognostic risk miRNAs were functional enrichment analyses based on their target genes. Furthermore, the survival analyzes of the hub genes were validated through OncoLnc. RESULTS: Complete clinical records and expression data of 797 miRNAs and 19969 genes from 137 PDAC cases were obtained, of which 59 potential prognostic risk factors, including 54 genes and 5 miRNAs, were selected by EN-COX analyzes. A total of 17 significant prognostic risk markers were identified (all P<0.05), including 16 genes and 1 miRNA (miRNA-125a). The miRNA-125a target genes were found in the MiRWalk database and the function enrichment analyzes were performed in the the DAVID website. Furthermore, according to data from the Oncomine and Human Protein Atlas (HPA) databases, the mRNA and protein level of frizzled class receptor 8 (FZD8) were overexpressed in pancreatic cancer tissues compared to the corresponding noncancer normal tissues (P<0.001). However, both glutathione S-transferase mu 4 (GSTM4) and inducible T cell costimulator ligand (ICOSLG) were negatively regulated in tissues of pancreatic cancer tissues (P<0.001). Finally, survival analysis was used to validate these factors by the OncoLnc database, and the results revealed that overexpression of ICOSLG was associated with a better prognosis (P=0.025). CONCLUSIONS: This study showed that the expression levels of FZD8, GSTM4 and ICOSLG were significantly different between PDAC and non-tumor tissues, especially ICOSLG, which could be a prognostic indicator and therapeutic target for PDAC.

Maternal exposure to atmospheric PM2.5 and fetal brain development: Associations with BAI1 methylation and thyroid hormones.

Maternal exposure to atmospheric fine particulate matter (PM2.5) during pregnancy is associated with adverse fetal development, including abnormal brain development. However, the underlying mechanisms and influencing factors remain uncertain. This study investigated the roles of DNA methylation in genes involving neurodevelopment and thyroid hormones (THs) in fetal brain development after maternal exposure to PM2.5 from e-waste. Among 939 healthy pregnant women recruited from June 2011 to September 2012, 101 e-waste-exposed and 103 reference mother-infant pairs (204 pairs totally) were included. Annual ground-level PM2.5 concentrations over e-waste-exposed area (116.38°E, 23.29°N) and reference area (116.67°E, 23.34°N) in 2011, 2012 were obtained by estimates and maternal exposure was evaluated by calculating individual chronic daily intakes (CDIs) of PM2.5. Methylation and THs including thyroid-stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) level were measured in umbilical cord blood collected shortly after delivery. We found higher ground-level PM2.5 concentrations led to greater individual CDI of PM2.5 in e-waste-exposed pregnant women. After adjustment for gender and birth BMI, significant mediation effects on the adverse associations of maternal PM2.5 exposure with birth head circumference were observed for methylations at positions +13 and + 32 (respectively mediated proportion of 9.8% and 5.3%, P < 0.05 and P < 0.01) in the brain-specific angiogenesis inhibitor 1 (BAI1) gene, but not for methylations in the catenin cadherin-associated protein, alpha 2 (CTNNA2) gene. BAI1 (position +13) methylation was also significantly correlated with FT3 levels (rs = -0.156, P = 0.032), although maternal CDI of PM2.5 was positively associated with higher odds of abnormal TSH levels (OR = 5.03, 95% CI: 1.00, 25.20, P = 0.05) rather than FT3 levels. Our findings suggest that methylation (likely linked to THs) in neonates may play mediation roles associated with abnormal brain development risk due to maternal exposure to atmospheric PM2.5 from e-waste.

Anoectochilus roxburghii flavonoids extract ameliorated the memory decline and reduced neuron apoptosis via modulating SIRT1 signaling pathway in senescent mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Anoectochilus roxburghii (A. roxburghii) is a precious herb and folk medicine in many Asian countries. It has been used traditionally to treat diabetes, etc., and also used as a dietary therapy to delay senescence. AIM OF THE STUDY: This study was to evaluate the neuroprotective effects of A. roxburghii flavonoids extract (ARF) and whether its effects were due to the regulation of SIRT1 signaling pathway in senescent mice and in D-galactose (D-gal) induced aging in SH-SY5Y cells. MATERIALS AND METHODS: 18-month-old mice were randomly divided into senescent model, low-dose ARF, high-dose ARF and vitamin E group. 2-Month-old mice were as a control group. After 8 weeks treatment, Morris water maze (MWM) was performed. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), monoamine oxidase (MAO) and acetylcholinesterase (ACh-E) in the cortex were determined. Hippocampus morphologic changes were observed with haematoxylin and eosin (H&E), Nissl, senescence-associated-galactosidase (SA-ß-gal) and terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) staining. Apoptosis-related molecular expressions in the hippocampus were performed by western blotting. Furthermore, after stimulated by EX527 (a SIRT1 inhibitor), the SIRT1-dependent neuroprotective effects of ARF were determined by measuring SRIT1 and p53 expression in SH-SY5Y aging cells induced by D-gal. RESULTS: ARF could significantly ameliorate memory decline in senescent mice and reduce the generations of ROS, MDA and the activities of MAO and ACh-E, while increasing SOD activities in the cortex of aging mice. ARF obviously improved hippocampus pathological alterations, increased the number of Nissl bodies, while reducing senescent and apoptotic cells in senescent mice hippocampus. Further, ARF positively regulated SIRT1 expression, and reduced apoptosis-related molecules p53, p21 and Caspase-3 expression, while increasing the ratio of Bcl-2/Bax. In D-gal-induced SH-SY5Y cells, the effects of ARF on SIRT1 and p53, and the ability of scavenging ROS were mostly abolished after incubation with the EX527. CONCLUSIONS: ARF, in a SIRT1-dependent manner, exerted neuroprotection via modulating SIRT1/p53 signaling pathway against memory decline and apoptosis due to age-induced oxidative stress damage in senescent mice.