In this study, we evaluated accumulation and adverse effects of ingestion of microplastics in the monogonont rotifer (Brachionus koreanus). The dependence of microplastic toxicity on particle size ...was investigated by measuring several in vivo end points and studying the ingestion and egestion using 0.05-, 0.5-, and 6-μm nonfunctionalized polystyrene microbeads. To identify the defense mechanisms activated in response to microplastic exposure, the activities of several antioxidant-related enzymes and the phosphorylation status of mitogen-activated protein kinases (MAPKs) were determined. Exposure to polystyrene microbeads of all sizes led to significant size-dependent effects, including reduced growth rate, reduced fecundity, decreased lifespan and longer reproduction time. Rotifers exposed to 6-μm fluorescently labeled microbeads exhibited almost no fluorescence after 24 h, while rotifers exposed to 0.05- and 0.5-μm fluorescently labeled microbeads displayed fluorescence until 48 h, suggesting that 6-μm microbeads are more effectively egested from B. koreanus than 0.05- or 0.5-μm microbeads. This observation provides a potential explanation for our findings that microbead toxicity was size-dependent and smaller microbeads were more toxic. In vitro tests revealed that antioxidant-related enzymes and MAPK signaling pathways were significantly activated in response to microplastic exposure in a size-dependent manner.
Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of ...diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5‐fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X‐linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor β receptor 2‐mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling.
Metformin and phenformin decreased the expression of pro‐apoptotic proteins by inhibiting STAT3 phosphorylation at Ser‐727 and suppressed invasion and migration by inhibiting TGFBR2‐mediated signaling
•Self-esteem and disabled member status were important for social capital and health.•Well-designed and equipped home environments were important for social trust and health.•Safe environments and ...external facilities for the disabled were important for health.•Perceived access to amenities for daily needs was significant for social capital and health.•Perceived access to amenities for recreational needs showed insignificant results.
The increase in the supply of public rental housing since 1989 has mitigated the low-income housing shortage and contributed to stabilizing the housing market in South Korea. However, despite this policy-driven achievement, the living environment quality of public rental housing and its relationship to residents’ social capital and health have not been thoroughly examined. Using survey data from 3009 householders located across public rental housing complexes within administrative districts in Seoul, Korea, this study performed a multi-level analysis to examine the associations of multiple domains of perceived and objective residential environments with dependent variables of social capital (trust, interaction, and norm of reciprocity) and health (self-rated health, chronic health conditions, and stress level). While better-perceived residential environments for daily needs (e.g., home environments with better utilities/equipment and barrier-free space, safe environments and external facilities for the disabled, and accessible public transit stations and groceries) were significant for social capital or health, perceived access to amenities for recreational needs (e.g., green and recreational space, cultural facilities) were not significant. Some significance from the objective measures of such recreational needs was found, but most objective measures showed inconsistent, mixed results. Among individual characteristics, self-esteem and having a disabled member appeared important. Our findings suggest the need for inclusive policy strategies that make good use of existing resources and respond to the actual and accessible needs of residents, especially those of low socioeconomic status, from the psychological, physical, and environmental perspectives. More attention needs to be directed to improving the environmental quality of public rental housing.
Non-thermal atmospheric pressure plasma has been proposed as a new tool for various biological and medical applications. Plasma in close proximity to cell culture media or water creates reactive ...oxygen and nitrogen species containing solutions known as plasma-activated media (PAM) or plasma-activated water (PAW) – the latter even displays acidification. These plasma-treated solutions remain stable for several days with respect to the storage temperature. Recently, PAM and PAW have been widely studied for many biomedical applications. Here, we reviewed promising reports demonstrating plasma-liquid interaction chemistry and the application of PAM or PAW as an anti-cancer, anti-metastatic, antimicrobial, regenerative medicine for blood coagulation and even as a dental treatment agent. We also discuss the role of PAM on cancer initiation cells (spheroids or cancer stem cells), on the epithelial mesenchymal transition (EMT), and when used for metastasis inhibition considering its anticancer effects. The roles of PAW in controlling plant disease, seed decontamination, seed germination and plant growth are also considered in this review. Finally, we emphasize the future prospects of PAM, PAW or plasma-activated solutions in biomedical applications with a discussion of the mechanisms and the stability and safety issues in relation to humans.
Microplastic pollution causes a major concern in the marine environment due to their worldwide distribution, persistence, and adverse effects of these pollutants in the marine ecosystem. Despite its ...global presence, there is still a lack of information on the effect of microplastics on marine organisms at the molecular level. Herein we demonstrated ingestion and egestion of nano- (0.05 μm) and micro-sized (0.5 and 6 μm) polystyrene microbeads in the marine copepod Paracyclopina nana, and examined molecular responses to exposure to microbeads with in vivo endpoints such as growth rate and fecundity. Also, we proposed an adverse outcome pathway for microplastic exposure that covers molecular and individual levels. This study provides the first insight into the mode of action in terms of microplastic-induced oxidative stress and related signaling pathways in P. nana.
Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting ...lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis. SPON2-α4β1 integrin signaling activated RhoA and Rac1, increased F-actin reorganization, and promoted M1-like macrophage recruitment. F-Actin accumulation also activated the Hippo pathway by suppressing LATS1 phosphorylation, promoting YAP nuclear translocation, and initiating downstream gene expression. However, SPON2-α5β1 integrin signaling inactivated RhoA and prevented F-actin assembly, thereby inhibiting HCC cell migration; the Hippo pathway was not noticeably involved in SPON2-mediated HCC cell migration. In HCC patients, SPON2 levels correlated positively with prognosis. Overall, our findings provide evidence that SPON2 is a critical factor in mediating the immune response against tumor cell growth and migration in HCC.
Matricellular protein SPON2 acts as an HCC suppressor and utilizes distinct signaling events to perform dual functions in HCC microenvironment.
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Background & Aims Desmoplasia and poor vascularity cause severe metabolic stress in pancreatic ductal adenocarcinomas (PDACs). Serotonin (5-HT) is a neuromodulator with neurotransmitter and ...neuroendocrine functions that contributes to tumorigenesis. We investigated the role of 5-HT signaling in the growth of pancreatic tumors. Methods We measured the levels of proteins that regulate 5-HT synthesis, packaging, and degradation in pancreata from KrasG12D/+ /Trp53R172H/+ /Pdx1-Cre (KPC) mice, which develop pancreatic tumors, as well as in PDAC cell lines and a tissue microarray containing 81 human PDAC samples. We also analyzed expression levels of proteins involved in 5-HT synthesis and degradation by immunohistochemical analysis of a tissue microarray containing 311 PDAC specimens, and associated expression levels with patient survival times. 5-HT level in 14 matched PDAC tumor and non-tumor tissues were analyzed by ELISA. PDAC cell lines were incubated with 5-HT and cell survival and apoptosis were measured. We analyzed expression of the 5-HT receptor HTR2B in PDAC cells and effects of receptor agonists and antagonists, as well as HTR2B knockdown with small hairpin RNAs. We determined the effects of 5-HT stimulation on gene expression profiles of BxPC-3 cells. Regulation of glycolysis by 5-HT signaling via HTR2B was assessed by immunofluorescence and immunoprecipitation analyses, as well as by determination of the extracellular acid ratio, glucose consumption, and lactate production. Primary PDACs, with or without exposure to SB204741 (a selective antagonist of HTR2B), were grown as xenograft tumors in mice, and SB204741 was administered to tumor-bearing KPC mice; tumor growth and metabolism were measured by imaging analyses. Results In immunohistochemical analysis of a tissue microarray of PDAC specimens, increased levels of TPH1 and decreased level of MAOA, which regulate 5-HT synthesis and degradation, correlated with stage and size of PDACs and shorter patient survival time. We found levels of 5-HT to be increased in human PDAC tissues compared with non-tumor pancreatic tissues, and PDAC cell lines compared with non-transformed pancreatic cells. Incubation of PDAC cell lines with 5-HT increased proliferation and prevented apoptosis. Agonists of HTR2B, but not other 5-HT receptors, promoted proliferation and prevented apoptosis of PDAC cells. Knockdown of HTR2B in PDAC cells, or incubation of cells with HTR2B inhibitors, reduced their growth as xenograft tumors in mice. We observed a correlation between 5-HT and glycolytic flux in PDAC cells; levels of metabolic enzymes involved in glycolysis, the phosphate pentose pathway, and hexosamine biosynthesis pathway increased significantly in PDAC cells following 5-HT stimulation. 5-HT stimulation led to formation of the HTR2B–LYN–p85 complex, which increased PI3K–Akt–mTOR signaling and the Warburg effect by increasing protein levels of MYC and HIF1A. Administration of SB204741 to KPC mice slowed growth and metabolism of established pancreatic tumors and prolonged survival of the mice. Conclusions Human PDACs have increased levels of 5-HT, and PDAC cells increase expression of its receptor, HTR2B. These increases allow for tumor glycolysis under metabolic stress and promote growth of pancreatic tumors and PDAC xenograft tumors in mice.
Hyaluronic acid synthase 2 (HAS2) is suggested to play a critical role in malignancy and is abnormally expressed in many carcinomas. However, its role in colorectal cancer (CRC) malignancy and ...specific signaling mechanisms remain obscure. Here, we report that HAS2 was markedly increased in both CRC tissue and malignant CRC cell lines. Depletion of HAS2 in HCT116 and DLD1 cells, which express high levels of HAS2, critically increased sensitivity of radiation/oxaliplatin‐mediated apoptotic cell death. Moreover, downregulation of HAS2 suppressed migration, invasion and metastasis in nude mice. Conversely, ectopic overexpression of HAS2 in SW480 cells, which express low levels of HAS2, showed the opposite effect. Notably, HAS2 loss‐ and gain‐of‐function experiments revealed that it regulates CRC malignancy through TGF‐β expression and SMAD2/Snail downstream components. Collectively, our findings suggest that HAS2 contributes to malignant phenotypes of CRC, at least partly, through activation of the TGF‐β signaling pathway, and shed light on the novel mechanisms behind the constitutive activation of HAS2 signaling in CRC, thereby highlighting its potential as a therapeutic target.
HAS2 is preferentially overexpressed in malignant‐type CRC cancer cells compared with that in mildtype CRC. By studying cells with loss‐ and gain‐of‐function of HAS2, we demonstrated that HAS2 is a critical regulator for the malignant behavior of CRC such as therapeutic resistance or metastatic ability. Importantly, HAS2 promoted CRC malignancy through HA ligand‐independent TGF‐β regulation.
Recent studies claimed the important role of cold atmospheric plasma (CAP) with nanotechnology in cancer treatments. In this study, silymarin nanoemulsion (SN) was used along with air CAP as ...therapeutic agent to counter human melanoma.
In this study, we examined the combined treatment of CAP and SN on G-361 human melanoma cells by evaluating cellular toxicity levels, reactive oxygen and nitrogen species (RONS) levels, DNA damage, melanoma-specific markers, apoptosis, caspases and poly ADP-ribose polymerase-1 (PARP-1) levels using flow cytometer. Dual-treatment effects on the epithelial-mesenchymal transition (EMT), Hepatocyte growth factor (HGF/c-MET) pathway, sphere formation and the reversal of EMT were also assessed using western blotting and microscopy respectively. SN and plasma-activated medium (PAM) were applied on tumor growth and body weight and melanoma-specific markers and the mesenchymal markers in the tumor xenograft nude mice model were checked.
Co-treatment of SN and air CAP increased the cellular toxicity in a time-dependent manner and shows maximum toxicity at 200 nM in 24 h. Intracellular RONS showed significant generation of ROS (< 3 times) and RNS (< 2.5 times) in dual-treated samples compared to control. DNA damage studies were assessed by estimating the level of γ-H2AX (1.8 times), PD-1 (> 2 times) and DNMT and showed damage in G-361 cells. Increase in Caspase 8,9,3/7 (> 1.5 times), PARP level (2.5 times) and apoptotic genes level were also observed in dual treated group and hence blocking HGF/c-MET pathway. Decrease in EMT markers (E-cadherin, YKL-40, N-cadherin, SNAI1) were seen with simultaneously decline in melanoma cells (BRAF, NAMPT) and stem cells (CD133, ABCB5) markers. In vivo results showed significant reduction in SN with PAM with reduction in tumor weight and size.
The use of air CAP using μ-DBD and the SN can minimize the malignancy effects of melanoma cells by describing HGF/c-MET molecular mechanism of acting on G-361 human melanoma cells and in mice xenografts, possibly leading to suitable targets for innovative anti-melanoma approaches in the future.
Non-thermal atmospheric pressure plasma sources operated in ambient environments are known to generate a variety of reactive oxygen and nitrogen species which could be applied for various biomedical ...applications. Herein, we fabricate a micro-dielectric barrier discharge plasma device by using screen-printing technology and apply it for studying immuno-stimulatory effects. We demonstrate a tumor-suppressive role for plasma-stimulated macrophages in metastatic solid cancers that directly elicit proliferation and are responsible for tumor relapse mediated by mesenchymal shift. Using microarray analysis, we observed that cold plasma stimulates and differentiates monocyte cells into macrophages as demonstrated by expression of several cytokine/chemokine markers. Moreover, plasma treatment stimulates the differentiation of pro-inflammatory (M1) macrophages to a greater extent. These stimulated macrophages favor anti-tumorigenic immune responses against metastasis acquisition and cancer stem cell maintenance in solid cancers in vitro. Differentiation of monocytes into anticancer macrophages could improve the efficacy of plasma treatment, especially in modifying pro-tumor inflammatory microenvironment through effecting highly resistant immunosuppressive tumor cells associated with tumor relapse.
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