Targeting EBV-encoded products: Implications for drug development in EBV-associated diseases.

Epstein-Barr virus, a human gamma-herpesvirus, has a close connection to the pathogenesis of cancers and other diseases, which are a burden for public health worldwide. So far, several drugs or biomolecules have been discovered that can target EBV-encoded products for treatment, such as Silvestrol, affinity toxin, roscovitine, H20, H31, curcumin, thymoquinone, and ribosomal protein L22. These drugs activate or inhibit the function of some biomolecules, affecting subsequent signalling pathways by acting on the products of EBV. These drugs usually target LMP1, LMP2; EBNA1, EBNA2, EBNA3; EBER1, EBER2; Bam-HI A rightward transcript and BHRF1. Additionally, some promising findings in the fields of vaccines, immunological, and cellular therapies have been established. In this review, we mainly summarise the function of drugs mentioned above and unique mechanisms, hoping that we can help giving insight to the design of drugs for the treatment of EBV-associated diseases.

Downregulation of KLF5 by EBER1 via the ERK signaling pathway in EBV-positive nasopharyngeal carcinoma cells: implications for latent EBV infection.

Nasopharyngeal carcinoma (NPC) carcinogenesis and malignant transformation are intimately associated with Epstein-Barr virus (EBV) infection. A zinc-fingered transcription factor known as Krüppel-like factor 5 (KLF5) has been shown to be aberrantly expressed in a number of cancer types. However, little is known about the regulatory pathways and roles of KLF5 in EBV-positive NPC. Our study found that KLF5 expression was significantly lower in EBV-positive NPC than in EBV-negative NPC. Further investigation revealed that EBER1, which is encoded by EBV, down-regulates KLF5 via the extracellular signal-regulated kinase (ERK) signalling pathway. This down-regulation of KLF5 by EBER1 contributes to maintaining latent EBV infection in NPC. Furthermore, we uncovered the biological roles of KLF5 in NPC cells. Specifically, KLF5 may influence the cell cycle, prevent apoptosis, and encourage cell migration and proliferation - all of which have a generally pro-cancer impact. In conclusion, these findings offer novel strategies for EBV-positive NPC patients' antitumour treatment.

Antagonizing roles of SHP1 in the pathogenesis of Helicobacter pylori infection.

BACKGROUND: SHP1 has been documented as a tumor suppressor and it was thought to play an antagonistic role in the pathogenesis of Helicobacter pylori infection. In this study, the exact mechanism of this antagonistic action was studied. MATERIALS AND METHODS: AGS, MGC803, and GES-1 cells were infected with H. pylori, intracellular distribution changes of SHP1 were first detected by immunofluorescence. SHP1 overexpression and knockdown were then constructed in these cells to investigate its antagonistic roles in H. pylori infection. Migration and invasion of infected cells were detected by transwell assay, secretion of IL-8 was examined via ELISA, the cells with hummingbird-like alteration were determined by microexamination, and activation of JAK2/STAT3, PI3K/Akt, and ERK pathways were detected by immunoblotting. Mice infection model was established and gastric pathological changes were evaluated. Finally, the SHP1 activator sorafenib was used to analyze the attenuating effect of SHP1 activation on H. pylori pathogenesis in vitro and in vivo. RESULTS: The sub-localization of SHP1 changed after H. pylori infection, specifically that the majority of the cytoplasmic SHP1 was transferred to the cell membrane. SHP1 inhibited H. pylori-induced activation of JAK2/STAT3 pathway, PI3K/Akt pathway, nuclear translocation of NF-κB, and then reduced EMT, migration, invasion, and IL-8 secretion. In addition, SHP1 inhibited the formation of CagA-SHP2 complex by dephosphorylating phosphorylated CagA, reduced ERK phosphorylation and the formation of CagA-dependent hummingbird-like cells. In the mice infection model, gastric pathological changes were observed and increased IL-8 secretion, indicators of cell proliferation and EMT progression were also detected. By activating SHP1 with sorafenib, a significant curative effect against H. pylori infection was obtained in vitro and in vivo. CONCLUSIONS: SHP1 plays an antagonistic role in H. pylori pathogenesis by inhibiting JAK2/STAT3 and PI3K/Akt pathways, NF-κB nuclear translocation, and CagA phosphorylation, thereby reducing cell EMT, migration, invasion, IL-8 secretion, and hummingbird-like changes.

Short-Term PM2.5 Exposure and DNA Methylation Changes of Circadian Rhythm Genes: Evidence from Two Experimental Studies.

The circadian rhythm regulates many crucial physiological processes, impacting human aging and aging-related outcomes. Observational evidence links circadian rhythm disturbance to PM2.5 exposure, yet the underlying DNA methylation mechanisms remain unclear due to limited PM2.5-dominated experimental settings. Therefore, we investigated the associations between short-term PM2.5 exposure and DNA methylation changes of 1188 CpG candidates across circadian genes among 32 young adults in the FDU study, with the validation in 26 individuals from the PKU study. Further mediation analyses tested whether DNA methylation of circadian genes could mediate the influence of PM2.5 on aging measured by three epigenetic ages: DNAmGrimAge, DunedinPoAm, and the mortality risk score. We identified three CpG sites associated with personal PM2.5 exposure: cg01248361 (CSNK2A2), cg17728065 (RORA), and cg22513396 (PRKAG2). Acute effects of PM2.5 on the three loci could be mediated by several circulating biomarkers, including MDA and EGF, with up to ∼30% of mediated proportions. Three loci further showed varying potentials in mediating the aging acceleration effect of PM2.5. Locus cg17728065 is the key site exhibiting a robust mediating effect (7.54-12.52%) on PM2.5-induced aging acceleration. Our findings demonstrated that PM2.5, even short-term peaks, could leave imprints on human aging via inducing aberrant temporal fluctuation in circadian homeostasis captured by DNA methylation profiles.

A new lysosome-targeted fluorescent probe for hydrogen peroxide based on a benzothiazole derivative.

As an important member of reactive oxygen species, hydrogen peroxide (H2O2) plays a key role in oxidative stress and cell signaling. Abnormal levels of H2O2 in lysosomes can induce damage or even loss of lysosomal function, leading to certain diseases. Therefore, real-time monitoring of H2O2 in lysosomes is very important. In this work, we designed and synthesized a novel lysosome-targeted fluorescent probe for H2O2-specific detection based on a benzothiazole derivative. A morpholine group was used as a lysosome-targeted unit and a boric acid ester was chosen as the reaction site. In the absence of H2O2, the probe exhibited very weak fluorescence. In the presence of H2O2, the probe showed an increased fluorescence emission. The fluorescence intensity of the probe for H2O2 displayed a good linear relationship in the concentration range of H2O2 from 8.0 × 10-7 to 2.0 × 10-4 mol·L-1. The detection limit was estimated to be 4.6 × 10-7 mol·L-1 for H2O2. The probe possessed high selectivity, good sensitivity and short response time for the detection of H2O2. Moreover, the probe had almost no cytotoxicity and had been successfully applied to confocal imaging of H2O2 in lysosomes of A549 cells. These results illustrated that the developed fluorescent probe in this study could provide a good tool for the determination of H2O2 in lysosomes.

Enhancing immune responses of ESC-based TAA cancer vaccines with a novel OMV delivery system.

Embryonic stem cell (ESC)-derived epitopes can act as therapeutic tumor vaccines against different types of tumors Jin (Adv Healthc Mater 2023). However, these epitopes have poor immunogenicity and stimulate insufficient CD8+ T cell responses, which motivated us to develop a new method to deliver and enhance their effectiveness. Bacterial outer membrane vesicles (OMVs) can serve as immunoadjuvants and act as a delivery vector for tumor antigens. In the current study, we engineered a new OMV platform for the co-delivery of ESC-derived tumor antigens and immune checkpoint inhibitors (PD-L1 antibody). An engineered Staphylococcal Protein A (SpA) was created to non-specifically bind to anti-PD-L1 antibody. SpyCatcher (SpC) and SpA were fused into the cell outer membrane protein OmpA to capture SpyTag-attached peptides and PD-L1 antibody, respectively. The modified OMV was able to efficiently conjugate with ESC-derived TAAs and PD-L1 antibody (SpC-OMVs + SpT-peptides + anti-PD-L1), increasing the residence time of TAAs in the body. The results showed that the combination therapy of ESC-based TAAs and PD-L1 antibody delivered by OMV had significant inhibitory effects in mouse tumor model. Specifically, it was effective in reducing tumor growth by enhancing IFN-γ-CD8+ T cell responses and increasing the number of CD8+ memory cells and antigen-specific T cells. Overall, the new OMV delivery system is a versatile platform that can enhance the immune responses of ESC-based TAA cancer vaccines.

When AHR signaling pathways meet viral infections.

Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcriptional factor widely expressed among immune, epithelial, endothelial and stromal cells in barrier tissues. It can be activated by small molecules provided by pollutants, microorganisms, food, and metabolism. It has been demonstrated that AHR plays an important role in modulating the response to many microbial pathogens, and the abnormal expression of AHR signaling pathways may disrupt endocrine, cause immunotoxicity, and even lead to the occurrence of cancer. Most humans are infected with at least one known human cancer virus. While the initial infection with these viruses does not cause major disease, the metabolic activity of infected cells changes, thus affecting the activation of oncogenic signaling pathways. In the past few years, lots of studies have shown that viral infections can affect disease progression by regulating the transmission of multiple signaling pathways. This review aims to discuss the potential effects of virus infections on AHR signaling pathways so that we may find a new strategy to minimize the adverse effects of the AHR pathway on diseases. Video Abstract.

CK1α, CK1δ, and CK1ε are necrosome components which phosphorylate serine 227 of human RIPK3 to activate necroptosis.

Necroptosis is a regulated necrotic cell death pathway, mediated by a supermolecular complex called the necrosome, which contains receptor-interacting protein kinase 1 and 3 (RIPK1, RIPK3) and mixed-lineage kinase domain-like protein (MLKL). Phosphorylation of human RIPK3 at serine 227 (S227) has been shown to be required for downstream MLKL binding and necroptosis progression. Tandem immunoprecipitation of RIPK3 reveals that casein kinase 1 (CK1) family proteins associate with the necrosome upon necroptosis induction, and this interaction depends on the kinase activity of RIPK3. In addition, CK1 proteins colocalize with RIPK3 puncta during necroptosis. Importantly, CK1 proteins directly phosphorylate RIPK3 at S227 in vitro and in vivo. Loss of CK1 proteins abolishes S227 phosphorylation and blocks necroptosis. Furthermore, a RIPK3 mutant with mutations in the CK1 recognition motif fails to be phosphorylated at S227, does not bind or phosphorylate MLKL, and is unable to activate necroptosis. These results strongly suggest that CK1 proteins are necrosome components which are responsible for RIPK3-S227 phosphorylation.

Necroptosis-blocking compound NBC1 targets heat shock protein 70 to inhibit MLKL polymerization and necroptosis.

Necroptosis is a regulated necrotic cell death pathway involved in development and disease. Its signaling cascade results in the formation of disulfide bond-dependent amyloid-like polymers of mixed lineage kinase domain-like protein (MLKL), which mediate proinflammatory cell membrane disruption. We screened compound libraries provided by the National Cancer Institute and identified a small-molecule inhibitor of necroptosis named necroptosis-blocking compound 1 (NBC1). Biotin-labeled NBC1 specifically conjugates to heat shock protein Hsp70. NBC1 and PES-Cl, a known Hsp70 substrate-binding inhibitor, block the formation of MLKL polymers, but not MLKL tetramers in necroptosis-induced cells. In vitro, recombinant Hsp70 interacts with the N-terminal domain (NTD) of MLKL and promotes NTD polymerization, which has been shown to mediate the cell killing activity. Furthermore, the substrate-binding domain (SBD) of Hsp70 is sufficient to promote MLKL polymerization. NBC1 covalently conjugates cysteine 574 and cysteine 603 of the SBD to block its function. In addition, an SBD mutant with both cysteines mutated to serines loses its ability to promote MLKL polymerization. Interestingly, knockdown of Hsp70 in cells leads to MLKL destabilization, suggesting that MLKL might also be a client protein of Hsp70. In summary, using NBC1, an inhibitor of necroptosis, we identified Hsp70 as a molecular chaperone performing dual functions in necroptosis. It stabilizes MLKL protein under normal condition and promotes MLKL polymerization through its substrate-binding domain during necroptosis.

Surface Preparation for Single-Molecule Fluorescence Imaging in Organic Solvents.

The development of single-molecule techniques provides opportunities to investigate the properties and heterogeneities of individual molecules, which are almost impossible to be obtained in ensemble measurements. Recently, single-molecule fluorescence microscopy is being applied more and more to study chemical reactions in organic solvents. However, little has been done to optimize the surface preparation procedures for single-molecule fluorescence imaging in organic solvents. In this work, we developed a method to prepare the surface for single-molecule fluorescence imaging in organic solvents with a well-controlled surface density of chemically immobilized dye molecules and a low density of nonspecifically adsorbed impurities. We also compared the surfaces prepared by two different procedures and studied the impacts of the polarities of the solvent and the surface functionality on the quality of prepared surface. We found that higher polarities of both the solvent and the surface functionality provided better control of the surface density of chemically immobilized dyes and helped reduce the nonspecific adsorption of both dyes and fluorescent impurities in organic solvents. We further performed single-molecule fluorescence imaging in DMF and investigated the photophysical properties of dyes and fluorescent impurities, which could be used to filter out false counts in single-molecule fluorescence measurements.

Adherence to dietary guide for elderly adults and health risks of older adults in ethnic minority areas in China: a cross-sectional study.

BACKGROUND: The impact of dietary guidelines on health in ethnic minority regions needs to be further explored because of multiple sociocultural factors. Therefore, this study was conducted to analyze the association between adherence to dietary guidelines and health risks in an elderly population in an ethnic minority region. METHODS: A cross-sectional survey was conducted among 836 older adults in ethnic minority areas. They were asked to describe their daily dietary intake levels through a semi-quantitative food frequency questionnaire. The closeness coefficient for each study subject was calculated by using the technique for order preference by similarity to an ideal solution (TOPSIS), which measures the adherence to Dietary Guide for Elderly Adults (DGEA). Regression models were used to analyze the association between adherence and health risks. RESULTS: The daily food of the elderly in this area comprised cereals and vegetables. They had low intake of milk, dairy products, and water and high intake of salt. The closeness coefficient for the total population was 0.51, and the adherence of this population to dietary guidelines for the elderly was low. In both the crude model and the models adjusted for covariates, the closeness coefficient was not significantly associated with clinical indicators and health outcomes (p > 0.05). CONCLUSIONS: No association was found between adherence to large sample-based dietary guidelines and clinical indicators or health outcomes in ethnic minority populations. The applicability of dietary guidelines to ethnic minority areas and whether they yield the expected health benefits require further study.

Geographical distinctions of longevity indicators and their correlation with climatic factors in the area where most Chinese Yao are distributed.

Longevity research is a hot topic in the health field. Considerable research focuses on longevity phenomenon in Bama Yao Autonomous County, which has a typical karst landform and is located in Southwest China. This study aims to illustrate the spatial feature of longevity indicators in other Yao areas, to analyze the correlation between climatic factors and longevity indicators, and to provide new clues and targets for further longevity studies. We collect and integrate population, climate, and terrain data into a spatial database. The main analysis methods include spatial autocorrelation, high/low clustering, and multiscale geographically weighted regression (MGWR). Two longevity clusters are identified in Guijiang River Basin (longevity index (LI%): 2.49 ± 0.63) and Liujiang River Basin (LI%: 2.13 ± 0.60). The spatial distribution of longevity indicators is autocorrelative (Moran's I = 0.652, p < 0.001) and clustered significantly (Z score = 4.268, p < 0.001). MGWR shows that the atmospheric pressure significantly affects the spatial distribution of LI% (estimate value (EV) = - 0.566, p = 0.012), centenarity index (CI%) (EV = - 0.425, p = 0.007), UC (EV = - 0.502, p = 0.006), and CH (EV = - 0.497, p = 0.007). Rainfall significantly affects the spatial distribution of LI% (EV = 0.300, p = 0.003) and CI% (EV = - 0.191, p = 0.016). The spatial distribution of the main longevity indicators shows significant heterogeneity and autocorrelation, and they cluster in the Guijiang River and Liujiang River basins. Atmospheric pressure and rainfall may contribute to the longevity phenomenon through complex mechanisms. The longevity phenomenon in the Yao nationality in Guijiang River Basin requires further study to improve our understanding of the health effect of meteorological, environmental, and social conditions on longevity.

Spectrochemical determination of effects on rat liver of binary exposure to benzo[a]pyrene and 2,2',4,4'-tetrabromodiphenyl ether.

Benzo[a]pyrene (B[a]P) and polybrominated diphenyl ethers (PBDEs) are persistent environmental contaminants. The effects in organisms of exposures to binary mixtures of such contaminants remain obscure. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy is a label-free, non-destructive analytical technique allowing spectrochemical analysis of macromolecular components, and alterations thereof, within tissue samples. Herein, we employed ATR-FTIR spectroscopy to identify biomolecular changes in rat liver post-exposure to B[a]P and BDE-47 (2,2',4,4'-tetrabromodiphenyl ether) congener mixtures. Our results demonstrate that significant separation occurs between spectra of tissue samples derived from control versus exposure categories (accuracy = 87%; sensitivity = 95%; specificity = 79%). Additionally, there is significant spectral separation between exposed categories (accuracy = 91%; sensitivity = 98%; specificity = 90%). Segregation between control and all exposure categories were primarily associated with wavenumbers ranging from 1600 to 1700 cm-1 . B[a]P and BDE-47 alone, or in combination, induces liver damage in female rats. However, it is suggested that binary exposure apparently attenuates the toxic effects in rat liver of the individual contaminants. This is supported by morphological observations of liver tissue architecture on hematoxylin and eosin (H&E)-stained liver sections. Such observations highlight the difficulties in predicting the endpoint effects in target tissues of exposures to mixtures of environmental contaminants.

Intrauterine exposure to 2,3',4,4',5-pentachlorobiphenyl alters spermatogenesis and testicular DNA methylation levels in F1 male mice.

Polychlorinated biphenyls (PCBs) are synthetic biphenyl compounds with high toxicity. There are a total of 209 homologs, among which 2,3',4,4',5-pentachlorobiphenyl (PCB118) is one of the dioxin-like PCBs. PCB118 can accumulate in pregnant mice, leading to fetus directly exposure during development. The stage of migration of mouse primordial germ cells ranges from 8.5 to 13.5 days of pregnancy, which is the stage undergoing a genome-wide DNA demethylation process. In this study, the mice were exposed to 20 µg/kg/day and 100 µg/kg/day PCB118 from 8.5 to 13.5 days of pregnancy. During the embryo stage at 18.5 days (E18.5 days), the expression level of DNA methyltransferase 1 (Dnmt1) was reduced in the testes, and the DNA methylation level in mouse testes were also decreased. We found that the seminiferous tubules showed vacuolization and that the sperm deformity rate increased in the treated groups compared with the control group in 7-week-old mice. Because exposure to PCB118 during pregnancy causes damage to the reproductive system of male offspring mice, attention should be devoted to the toxicity transmission of persistent environmental pollutants such as PCBs.

Correlation between urinary contents of some metals and fasting plasma glucose levels: A cross-sectional study in China.

Many metals are involved in the pathogenesis of diabetes, but most of existing studies focused on single metals. The study of mixtures represents real-life exposure scenarios and deserves attention. This study aimed to explore the potential relationship of urinary copper (Cu), zinc (Zn), arsenic (As), selenium (Se), and strontium (Sr) contents with fasting plasma glucose (FPG) levels in 2766 participants. The levels of metals in urine were determined by inductively coupled plasma-mass spectrometry. We used linear regression models and the Bayesian kernel machine regression (BKMR) to evaluate the association between metals and FPG levels. In the multiple metals linear regression, Zn (ß = 0.434), Se (ß = 0.172), and Sr (ß = -0.143) showed significant association with FPG levels (all P < 0.05). The BKMR model analysis showed that the results of single metal association were consistent with the multiple metals linear regression. The mixture of five metals had a positive over-all effect on FPG levels, and Zn (PIP = 1.000) contributed the most to the FPG levels. Cu and As were negatively correlated with FPG levels in women. The potential interaction effect between Cu and Sr was observed in participants aged ≥ 60 years old (Pinteraction = 0.035). In summary, our results suggested that multiple metals in urine are associated with FPG levels. Further studies are needed to confirm these findings and clarify the underlying mechanisms.

Association between oil tea intake and the risk of type 2 diabetes in adults: A cross-sectional study in Gongcheng, Guangxi, China.

BACKGROUND AND OBJECTIVES: The associations between oil tea and type 2 diabetes (T2D) have been little studied in the population. This study aimed to evaluate whether oil tea intake is related to the reduced risk of T2D in adults. METHODS AND STUDY DESIGN: A rural-based cross-sectional study was conducted in Gongcheng Yao Autonomous County, Guangxi, southern China (2018-2019), with a total of 3178 population included in the final analysis. A multivariable logistic regression model was used to analyze the associations between the intake frequency, daily intake of oil tea and the risk of T2D. We further compared the association differences between the daily intake of oil tea and the risk of diabetes under different dietary patterns, which were generated from food frequency intake data using principal factor analysis. RESULTS: The differences in the frequency and daily intake of oil tea in both groups (diabetes group and the non-diabetes group) were statistically significant (p<0.05). After adjusting for age, sex, smoking status, physical activity, body mass index (BMI), compared with non-oil tea drinkers, intake ≥3 times /d had an inverse association with T2D (OR=0.417; 95% CI: 0.205-0.848, p<0.05); while daily intake of more than 600 mL/d but less than 900 mL/d was significantly associated with reduced T2D risk (OR=0.492; 95% CI: 0.284-0.852, p=0.011). In the Chinese traditional dietary and the plant-based dietary model, compared with the non-oil tea drinkers, the fourth intake group had a lower risk of diabetes, with an OR (95%CI) value of 0.500 (0.291-0.854) and 0.505 (0.298-0.855), respectively, but no statistical significance (All p>0.05). CONCLUSIONS: Our study suggests that oil tea was associated with a reduced risk of T2D aged 30 years or older.

The miR-106b/NR2F2-AS1/PLEKHO2 Axis Regulates Migration and Invasion of Colorectal Cancer through the MAPK Pathway.

Increasing numbers of miRNAs have been observed as oncogenes or tumor suppressors in colorectal cancer (CRC). It was recently reported that hsa-miR-106b-5p (miR-106b) promoted CRC cell migration and invasion. However, there were also studies showing contradictory results. Therefore, in the present study, we further explore the role of miR-106b and its downstream networks in the carcinogenesis of CRC. We observed that the expression of miR-106b is significantly increased in Pan-Cancer and CRC tissues compared with normal tissues from The Cancer Genome Atlas (TCGA) database. Furthermore, we used Transwell, Cell Counting Kit-8, and colony formation assays to clarify that miR-106b promotes the migratory, invasive, and proliferative abilities of CRC cells. For the first time, we systematically screened the target mRNAs and lncRNAs of miR-106b using TCGA database and the bioinformatics algorithms. Dual-luciferase reporter assay confirmed that NR2F2-AS1 and PLEKHO2 are the direct targets of miR-106b. Furthermore, NR2F2-AS1 acts as a competing endogenous RNA (ceRNA) to regulate PLEKHO2 expression by sponging miR-106b. The results of Gene set enrichment analysis (GSEA) and Western blot indicated that they play important roles in CRC progression by regulating MAPK pathway. Thus, miR-106b/NR2F2-AS1/PLEKHO2/MAPK signaling axis may suggest the potential usage in CRC treatment.

The clinical significance and function of miR-146 in the promotion of epidural fibrosis.

Epidural fibrosis is the main cause of failed back surgery syndrome. To investigate the role of miR-146 in the diagnosis and development of epidural fibrosis. Lumbar disc tissues were collected from 72 lumbar disc herniation patients (45 developed epidural fibrosis and 27 did not). The expression of miR-146 in collected tissues and isolated epidural fibroblasts was detected by RT-qPCR. The relative levels of pro-inflammatory cytokines were analyzed by ELISA. The effect of miR-146 on the proliferation of fibroblasts was evaluated by MTT assay. miR-146 was significantly upregulated in epidural fibrosis patients compared with control patients. The expression of miR-146 was closely associated with the location, lower limb symptom and duration of disease of epidural fibrosis patients, and was positively correlated with the relative levels of pro-inflammatory cytokines. Moreover, miR-146 could discriminate epidural fibrosis patients from control patients. In isolated epidural fibroblasts, the overexpression of miR-146 dramatically enhanced its proliferation and the inflammatory response. miR-146 serves as a diagnostic biomarker for the early detection of epidural fibrosis. The upregulation of miR-146 enhanced the fibroblasts proliferation and inflammatory response in epidural fibrosis. This study provides a novel potential therapeutic target for epidural fibrosis.

Effects of Polychlorinated Biphenyls on Animal Reproductive Systems and Epigenetic Modifications.

Polychlorinated biphenyls (PCBs) are a group of highly toxic endocrine-disrupting chemicals comprising 209 homologs. PCBs are extensively found in the environment and can induce typical estrogenic and profound, long-lasting effects on animals. In this article, the introduction of PCB residues into the environment and the pathways of PCB enrichment in animals are described. PCBs are widely deposited and eventually accumulate in human tissues and body fluids through biomagnification. PCBs can significantly decrease animal fertility and interfere with endocrine processes, leading to the development of various diseases and even cancer. The effects of PCBs on the reproductive systems of animals can also be passed to their offspring, indicating that PCBs may affect the epigenetic modification process. There is currently no treatment to effectively inhibit the toxicity of PCBs in organisms; therefore, the severity of PCB toxicity needs to be widely recognized.

MiR-496 promotes migration and epithelial-mesenchymal transition by targeting RASSF6 in colorectal cancer.

Aberrant loss of tumor-suppressor genes plays a crucial role in tumorigenesis and development of colorectal cancer (CRC). Extensive studies have reported tha hypermethylation of Ras association domain family member 6 (RASSF6) is common in various solid tumors. Another important mode of epigenetic regulation, microRNA (miRNA) regulation of RASSF6, is far from clear. The aim of the present work was to screen out novel miRNA regulating RASSF6, and to explore its underlying mechanism in CRC. With the use of bioinformatics, clinical sample data, and luciferase binding assay, we determined that microRNA-496 (miR-496) could be a novel oncomiR that directly binds to RASSF6. Next, a series of miR-496 mimics or inhibitor, or RASSF6 small interfering RNA (siRNA) introduced into CRC cells were applied to examine the effect of miR-496 on CRC cell viability, migration, and epithelial-mesenchymal transition (EMT). The results demonstrated that miR-496/RASSF6 could promote cell migration and EMT via Wnt signaling activation, but had no effect on cell viability. Our results confirmed that the miR-496/RASSF6 axis is involved in Wnt pathway-mediated tumor metastasis, highlighting its potential as a therapeutic target for CRC.