The spectrum of Ih ice using terahertz time-domain spectroscopy.

Here, we report the frequency-dependent spectrum of ice Ih in the range of 0.2-2 THz. We confirm the presence of a feature that blue-shifts from around 1.55-1.65 THz with a decreasing temperature from 260 to 160 K. There is also a change in the trend of the refractive index of ice corresponding to a dispersion, which is also around 1.6 THz. The features are reproduced in data acquired with three commercial terahertz time-domain spectrometers. Computer-simulated spectra assign the feature to lattice translations perpendicular to the 110 and 1̄10 planes of the ice Ih crystal. The feature's existence should be recognized in the terahertz measurements of frozen aqueous solution samples to avoid false interpretations.

Identification of SNPs and Candidate Genes Associated with Monocyte/Lymphocyte Ratio and Neutrophil/Lymphocyte Ratio in Duroc × Erhualian F2 Population.

Understanding the pig immune function is crucial for disease-resistant breeding and potentially for human health research due to shared immune system features. Immune cell ratios, like monocyte/lymphocyte ratio (MLR) and neutrophil/lymphocyte ratio (NLR), offer a more comprehensive view of immune status compared to individual cell counts. However, research on pig immune cell ratios remains limited. This study investigated MLR and NLR in a Duroc × Erhualian F2 resource population. Heritability analysis revealed high values (0.649 and 0.688 for MLR and NLR, respectively), suggesting a strong genetic component. Furthermore, we employed an ensemble-like GWAS (E-GWAS) strategy and functional annotation analysis to identify 11 MLR-associated and 6 NLR-associated candidate genes. These genes were significantly enriched in immune-related biological processes. These findings provide novel genetic markers and candidate genes associated with porcine immunity, thereby providing valuable insights for addressing biosecurity and animal welfare concerns in the pig industry.

miR-21-regulated M2 polarization of macrophage is involved in arsenicosis-induced hepatic fibrosis through the activation of hepatic stellate cells.

Arsenicosis induced by chronic exposure to arsenic is recognized as one of the main damaging effects on public health. Exposure to arsenic can cause hepatic fibrosis, but the molecular mechanisms by which this occurs are complex and elusive. It is not known if miRNAs are involved in arsenic-induced liver fibrosis. We found that in the livers of mice exposed to arsenite, there were elevated levels of microRNA-21 (miR-21), phosphorylated mammalian target of rapamycin (p-mTOR), and arginase 1 (Arg1); low levels of phosphatase and tensin homolog (PTEN); and more extensive liver fibrosis. For cultured cells, arsenite-induced miR-21, p-mTOR, and Arg1; decreased PTEN; and promoted M2 polarization of macrophages derived from THP-1 monocytes (THP-M), which caused secretion of fibrogenic cytokines, including transforming growth factor-ß1. Coculture of arsenite-treated, THP-M with LX-2 cells induced α-SMA and collagen I in the LX-2 cells and resulted in the activation of these cells. Downregulation of miR-21 in THP-M inhibited arsenite-induced M2 polarization and activation of LX-2 cells, but cotransfection with PTEN siRNA or a miR-21 inhibitor reversed this inhibition. Moreover, knockout of miR-21 in mice attenuated liver fibrosis and M2 polarization compared with WT mice exposed to arsenite. Additionally, LN, PCIII, and HA levels were higher in patients with higher hair arsenic levels, and levels of miR-21 were higher than controls and positively correlated with PCIII, LN, and HA levels. Thus, arsenite induces the M2 polarization of macrophages via miR-21 regulation of PTEN, which is involved in the activation of hepatic stellate cells and hepatic fibrosis. The results establish a previously unknown mechanism for arsenicosis-induced fibrosis.

Wnt/ß-Catenin Pathway Is Involved in Cadmium-Induced Inhibition of Osteoblast Differentiation of Bone Marrow Mesenchymal Stem Cells.

Cadmium is a common environmental pollutant that causes bone damage. However, the effects of cadmium on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs) and its mechanism of action in this process are unclear. Here, we determined the effects of cadmium chloride (CdCl2) on the osteogenic differentiation of BMMSCs and the potential mechanism involved in this process. As determined in the present investigation, CdCl2, in a concentration-dependent manner, affected the viability of BMMSCs and their cytoskeletons. Exposure to 0.1 or 0.2 µM CdCl2 inhibited osteogenic differentiation of BMMSCs, which was reflected in the down-regulation of osteoblast-related genes (ALP, OCN, Runx2, OSX, and OPN); in suppression of the protein expression of alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2); and in decreased ALP activity and capacity for mineralization. Moreover, mRNA microarray was performed to determine the roles of these factors in BMMSCs treated with CdCl2 in comparison to control BMMSCs. As determined with the microarrays, the Wingless-type (Wnt), mothers against decapentaplegic and the C. elegans gene Sam (SMAD), and Janus kinase-Signal Transducers and Activators of Transcription (JAK-STAT) signaling pathways were involved in the effects caused by CdCl2. Moreover, during differentiation, the protein levels of Wnt3a, ß-catenin, lymphoid enhancer factor 1 (LEF1), and T-cell factor 1 (TCF1) were reduced by CdCl2. The current research shows that CdCl2 suppresses the osteogenesis of BMMSCs via inhibiting the Wnt/ß-catenin pathway. The results establish a previously unknown mechanism for bone injury induced by CdCl2.

NF-κB-regulated miR-155, via repression of QKI, contributes to the acquisition of CSC-like phenotype during the neoplastic transformation of hepatic cells induced by arsenite.

Chronic exposure to arsenite can cause various human tumors. For the initiation and recurrence of human liver cancer, the acquisition of CSC-like properties is essential. In various cancers, microRNAs (miRNAs) act as regulators in induction of CSC-like properties. Liver cancers over-express miR-155, but the mechanism relating miR-155 and arsenite-induced liver cancer is unknown. Here, we show that long-term exposure of L-02 cells to arsenite increases miR-155 levels by activation of NF-κB and leads to the acquisition of CSC-like properties. In spheroids formed from arsenite-transformed L-02 cells, the levels of miR-155 positively relate to the levels of CD90, EpCAM, and OCT4. Inhibition of miR-155, by reduction of SOX2 and OCT4, results in suppression of spheroid formation. Luciferase reporter assays indicate that QKI is a target of miR-155. Inhibition of QKI expression by miR-155 promotes arsenite-induced acquisition of CSC-like properties, whereas QKI over-expression has the opposite effect. Collectively, the findings demonstrate that miR-155, driven by NF-κB, reduces QKI expression and is involved in acquisition of the CSC-like phenotype during neoplastic transformation of hepatic cells induced by arsenite.

Mechanical Robustness Enhanced Flexible Antennas Using Ti3C2 MXene and Nanocellulose Composites for Noninvasive Glucose Sensing.

Electromagnetic sensors with flexible antennas as sensing elements have attracted increasing attention in noninvasive continuous glucose monitoring for diabetic patients. The significant radiation performance loss of flexible antennas during mechanical deformation impairs the reliability of glucose monitoring. Here, we present flexible ultrawideband monopole antennas composed of Ti3C2 MXene and cellulose nanofibril (CNF) composite films for continuous glucose monitoring. The flexible MXene/CNF antenna with 20% CNF content can obtain a gain of up to 3.33 dBi and a radiation efficiency of up to 65.40% at a frequency range from 2.3 to 6.0 GHz. Compared with the pure MXene antenna, this antenna offers a comparable radiation performance and a lower performance loss in mechanical bending deformation. Moreover, the MXene/CNF antenna shows a stable response to fetal bovine serum/glucose, with a correlation of >0.9 at the reference glucose levels, and responds sensitively to the variations in blood glucose levels during human trials. The proposed strategy enhancing the mechanical robustness of MXene-based flexible antennas makes metallic two-dimensional nanomaterials more promising in wearable electromagnetic sensors.

Reciprocal interactions between lncRNAs and MYC in colorectal cancer: partners in crime.

Proto-oncogenic MYC is frequently dysregulated in colorectal cancer (CRC). In the past decades, long noncoding RNAs (lncRNAs) have emerged as important regulators in cancers, acting as scaffolds, molecular decoys, post-transcriptional regulators, and others. Interestingly, lncRNAs are able to control MYC expression both at transcriptional and post-transcriptional levels. It is suggested that the reciprocal interaction of MYC and lncRNAs often occurs in CRC. MYC can affect the cell fate by promoting or inhibiting the transcription of some lncRNAs. At the same time, some lncRNAs can also affect MYC expression or transcriptional activity, and in turn decide the cell fate. In this review we summarized the current knowledge about the MYC and lncRNA axis, focusing on its mutual regulation, roles in CRC, and proposed potential therapeutic prospects for CRC treatment.

Additive and Dominance Genome-Wide Association Studies Reveal the Genetic Basis of Heterosis Related to Growth Traits of Duhua Hybrid Pigs.

Heterosis has been extensively used for pig genetic breeding and production, but the genetic basis of heterosis remains largely elusive. Crossbreeding between commercial and native breeds provides a good model to parse the genetic basis of heterosis. This study uses Duhua hybrid pigs, a crossbreed of Duroc and Liangguang small spotted pigs, as materials to explore the genetic basis underlying heterosis related to growth traits at the genomic level. The mid-parent heterosis (MPH) analysis showed heterosis of this Duhua offspring on growth traits. In this study, we examined the impact of additive and dominance effects on 100 AGE (age adjusted to 100 kg) and 100 BF (backfat thickness adjusted to 100 kg) of Duhua hybrid pigs. Meanwhile, we successfully identified SNPs associated with growth traits through both additive and dominance GWASs (genome-wide association studies). These findings will facilitate the subsequent in-depth studies of heterosis in the growth traits of Duhua pigs.

Reciprocal regulation of lncRNA MEF and c-Myc drives colorectal cancer tumorigenesis.

More than half of all cancers demonstrate aberrant c-Myc expression, making this arguably the most important human oncogene. Deregulated long non-coding RNAs (lncRNAs) are also commonly implicated in tumorigenesis, and some limited examples have been established where lncRNAs act as biological tuners of c-Myc expression and activity. Here, we demonstrate that the lncRNA denoted c-Myc Enhancing Factor (MEF) enjoys a cooperative relationship with c-Myc, both as a transcriptional target and driver of c-Myc expression. Mechanistically, MEF functions by binding to and stabilizing the expression of hnRNPK in colorectal cancer cells. The MEF-hnRNPK interaction serves to disrupt binding between hnRNPK and the E3 ubiquitin ligase TRIM25, which attenuates TRIM25-dependent hnRNPK ubiquitination and proteasomal destruction. In turn, the stabilization of hnRNPK through MEF enhances c-Myc expression by augmenting the translation c-Myc. Moreover, modulating the expression of MEF in shRNA-mediated knockdown and overexpression studies revealed that MEF expression is essential for colorectal cancer cell proliferation and survival, both in vitro and in vivo. From the clinical perspective, we show that MEF expression is differentially increased in colorectal cancer tissues compared to normal adjacent tissues. Further, correlations exist between MEF, c-Myc, and hnRNPK suggesting the MEF-c-Myc positive feedback loop is active in patients. Together these data demonstrate that MEF is a pivotal partner of the c-Myc network and propose MEF as a valuable therapeutic target for colorectal cancer.

Targeting high circDNA2v levels in colorectal cancer induces cellular senescence and elicits an anti-tumor secretome.

The efficacy of immunotherapy against colorectal cancer (CRC) is impaired by insufficient immune cell recruitment into the tumor microenvironment. Our study shows that targeting circDNA2v, a circular RNA commonly overexpressed in CRC, can be exploited to elicit cytotoxic T cell recruitment. circDNA2v functions through binding to IGF2BP3, preventing its ubiquitination, and prolonging the IGF2BP3 half-life, which in turn sustains mRNA levels of the protooncogene c-Myc. Targeting circDNA2v by gene silencing downregulates c-Myc to concordantly induce tumor cell senescence and the release of proinflammatory mediators. Production of CXCL10 and interleukin-9 by CRC cells is elicited through JAK-STAT1 signaling, in turn promoting the chemotactic and cytolytic activities of CD8+ T cells. Clinical evidence associates increased circDNA2v expression in CRC tissues with reductions in CD8+ T cell infiltration and worse outcomes. The regulatory relationship between circDNA2v, cellular senescence, and tumor-infiltrating lymphocytes thus provides a rational approach for improving immunotherapy in CRC.

Ruthenium(ii)-Arene Complex Triggers Immunogenic Ferroptosis for Reversing Drug Resistance.

Chemoresistance remains an arduous challenge in oncology, but ferroptosis shows potential for overcoming it by stimulating the immune system. Herein, a novel high-performance ruthenium(II)-based arene complex [Ru(η6-p-cym)(BTBpy)Cl] (RuBTB) is developed for ferroptosis-enhanced antitumor immunity and drug resistance reversal via glutathione (GSH) metabolism imbalance. RuBTB shows significantly enhanced antiproliferation activity against cisplatin (CDDP)-resistant lung cancer cells (A549R), with 26.35-fold better anticancer effects than CDDP. Immunogenic ferroptosis is induced by GSH depletion/glutathione peroxidase 4 (GPX4) inactivation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in RuBTB-treated cells. Mechanism studies indicate that RuBTB regulates ferroptosis and immune-related pathways, coordinating with GSH metabolism-mediated glutathione S-transferase (GST) inhibition to reverse drug resistance in platinum-combined therapy. Tumor vaccination experiments demonstrate the intensified antitumor effects endowed by highly immunogenic ferroptosis in vivo. This study provides the first example of a metal-arene complex for achieving satisfactory ferroptosis therapeutic effects with efficient immunogenicity to overcome drug resistance in metal-based immunochemotherapy.

Influence of extreme weather and meteorological anomalies on outbreaks of influenza A (H1N1).

Biological experiments and epidemiological evidence indicate that variations in environment have important effect on the occurrence and transmission of epidemic influenza. It is therefore important to understand the characteristic patterns of transmission for prevention of disease and reduction of disease burden. Based on case records, we analyzed the environmental characteristics including climate variables in Changsha, and then constructed a meteorological anomaly susceptive-infective-removal (SIR) model on the basis of the results of influenza A (H1N1) transmission. The results showed that the outbreak of influenza A (H1N1) in Changsha showed significant correlation with meteorological conditions; the spread of influenza was sensitive to meteorological anomalies, and that the outbreak of influenza A (H1N1) in Changsha was influenced by a combination of absolute humidity anomalous weather conditions, contact rates of the influenza patients and changes in population movements. These findings will provide helpful information regarding prevention strategies under different conditions, a fresh understanding of the emergence and re-emergence of influenza outbreaks, and a new perspective on the transmission dynamics of influenza.

FIT links c-Myc and P53 acetylation by recruiting RBBP7 during colorectal carcinogenesis.

Colorectal cancer (CRC) poses one of the most serious threats to human health worldwide, and abnormally expressed c-Myc and p53 are deemed the pivotal driving forces of CRC progression. In this study, we discovered that the lncRNA FIT, which was downregulated in CRC clinical samples, was transcriptionally suppressed by c-Myc in vitro and promoted CRC cell apoptosis by inducing FAS expression. FAS is a p53 target gene, and we found that FIT formed a trimer with RBBP7 and p53 that facilitated p53 acetylation and p53-mediated FAS gene transcription. Moreover, FIT was capable of retarding CRC growth in a mouse xenograft model, and FIT expression was positively correlated with FAS expression in clinical samples. Thus, our study elucidates the role of the lncRNA FIT in human colorectal cancer growth and provides a potential target for anti-CRC drugs.

[Study on the influence of landscape elements regarding on the transmission of hemorrhagic fever with renal syndrome in Changsha].

OBJECTIVE: To explore the influence of landscape elements on the transmission of hemorrhagic fever with renal syndrome (HFRS) in Changsha. METHODS: A total of 327 cases of HFRS diagnosed between year 2005 - 2009 were recruited in the study. Based on the demographic data, meteorological data and the data of second national land survey during the same period, a GIS landscape elements database of HFRS at the township scale of Changsha was established. Spatial-temporal cluster analysis methods were adopted to explore the influence of landscape elements on the spatial-temporal distribution of HFRS in Changsha during the year of 2005 - 2009. RESULTS: The annual incidences of HFRS in Changsha between year 2005 - 2009 were 1.16/100 000 (70 cases), 0.95/100 000 (58 cases), 1.40/100 000(87 cases), 0.75/100 000(47 cases) and 1.02/100 000(65 cases) respectively. The results of poisson regression model analysis of principal component showed that the incidence of HFRS was positively correlated with farmland area (M = 29.00 km2) and urban and rural area (M = 6.12 km2; incidence rate ratios (IRR) = 1.34, 95% CI: 1.27 - 1.41); but negatively correlated with forestland area (M = 39.00 km2; IRR = 0.67, 95% CI: 0.55 - 0.81) and garden plot area (M = 0.99 km2; IRR = 0.74, 95% CI: 0.63 - 0.86). A significant cluster of the spatial-temporal distribution of HFRS cases was found in the study. The primary cluster (28.9 N, 113.37 E, radius at 22.22 km, RR = 5.23, log likelihood ratio (LLR) = 51.61, P <0.01, 67 cases of HFRS and incidence at 4.4/100 000) was found between year 2006 and 2007; and the secondary cluster (28.2 N, 113.6 E, RR = 10.77, LLR = 16.01, P < 0.01, 11 cases of HFRS and the incidence at 10.6/100 000) was found between year 2008 and 2009. CONCLUSION: The landscape elements were found to be closely related to the prevalence and transmission of HFRS.

[Study on sensitivity of climatic factors on influenza A (H1N1) based on classification and regression tree and wavelet analysis].

OBJECTIVE: To analyze the periodicity of pandemic influenza A (H1N1) in Changsha in year 2009 and its correlation with sensitive climatic factors. METHODS: The information of 5439 cases of influenza A (H1N1) and synchronous meteorological data during the period between May 22th and December 31st in year 2009 (223 days in total) in Changsha city were collected. The classification and regression tree (CART) was employed to screen the sensitive climatic factors on influenza A (H1N1); meanwhile, cross wavelet transform and wavelet coherence analysis were applied to assess and compare the periodicity of the pandemic disease and its association with the time-lag phase features of the sensitive climatic factors. RESULTS: The results of CART indicated that the daily minimum temperature and daily absolute humidity were the sensitive climatic factors for the popularity of influenza A (H1N1) in Changsha. The peak of the incidence of influenza A (H1N1) was in the period between October and December (Median (M) = 44.00 cases per day), simultaneously the daily minimum temperature (M = 13°C) and daily absolute humidity (M = 6.69 g/m(3)) were relatively low. The results of wavelet analysis demonstrated that a period of 16 days was found in the epidemic threshold in Changsha, while the daily minimum temperature and daily absolute humidity were the relatively sensitive climatic factors. The number of daily reported patients was statistically relevant to the daily minimum temperature and daily absolute humidity. The frequency domain was mostly in the period of (16 ± 2) days. In the initial stage of the disease (from August 9th and September 8th), a 6-day lag was found between the incidence and the daily minimum temperature. In the peak period of the disease, the daily minimum temperature and daily absolute humidity were negatively relevant to the incidence of the disease. CONCLUSION: In the pandemic period, the incidence of influenza A (H1N1) showed periodic features; and the sensitive climatic factors did have a "driving effect" on the incidence of influenza A (H1N1).

Strain-Driven Auto-Detachable Patterning of Flexible Electrodes.

Flexible electrodes that are multilayer, multimaterial, and conformal are pivotal for multifunctional wearable electronics. Traditional electronic circuits manufacturing requires substrate-supported transfer printing, which limits their multilayer integrity and device conformability on arbitrary surfaces. Herein, a "shrinkage-assisted patterning by evaporation" (SHAPE) method is reported, by employing evaporation-induced interfacial strain mismatch, to fabricate auto-detachable, freestanding, and patternable electrodes. The SHAPE method utilizes vacuum-filtration of polyaniline/bacterial cellulose (PANI/BC) ink through a masked filtration membrane to print high-resolution, patterned, and multilayer electrodes. The strong interlayer hydrogen bonding ensures robust multilayer integrity, while the controllable evaporative shrinking property of PANI/BC induces mismatch between the strains of the electrode and filtration membrane at the interface and thus autodetachment of electrodes. Notably, a 500-layer substrateless micro-supercapacitor fabricated using the SHAPE method exhibits an energy density of 350 mWh cm-2 at a power density of 40 mW cm-2 , 100 times higher than reported substrate-confined counterparts. Moreover, a digital circuit fabricated using the SHAPE method functions stably on a deformed glove, highlighting the broad wearable applications of the SHAPE method.

[The warning model and influence of climatic changes on hemorrhagic fever with renal syndrome in Changsha city].

OBJECTIVE: To realize the influence of climatic changes on the transmission of hemorrhagic fever with renal syndrome (HFRS), and to explore the adoption of climatic factors in warning HFRS. METHODS: A total of 2171 cases of HFRS and the synchronous climatic data in Changsha from 2000 to 2009 were collected to a climate-based forecasting model for HFRS transmission. The Cochran-Armitage trend test was employed to explore the variation trend of the annual incidence of HFRS. Cross-correlations analysis was then adopted to assess the time-lag period between the climatic factors, including monthly average temperature, relative humidity, rainfall and Multivariate Elño-Southern Oscillation Index (MEI) and the monthly HFRS cases. Finally the time-series Poisson regression model was constructed to analyze the influence of different climatic factors on the HFRS transmission. RESULTS: The annual incidence of HFRS in Changsha between 2000 - 2009 was 13.09/100 000 (755 cases), 9.92/100 000 (578 cases), 5.02/100 000 (294 cases), 2.55/100 000 (150 cases), 1.13/100 000 (67 cases), 1.16/100 000 (70 cases), 0.95/100 000 (58 cases), 1.40/100 000 (87 cases), 0.75/100 000 (47 cases) and 1.02/100 000 (65 cases), respectively. The incidence showed a decline during these years (Z = -5.78, P < 0.01). The results of Poisson regression model indicated that the monthly average temperature (18.00°C, r = 0.26, P < 0.01, 1-month lag period; IRR = 1.02, 95%CI: 1.00 - 1.03, P < 0.01), relative humidity (75.50%, r = 0.62, P < 0.01, 3-month lag period; IRR = 1.03, 95%CI: 1.02 - 1.04, P < 0.01), rainfall (112.40 mm, r = 0.25, P < 0.01, 6-month lag period; IRR = 1.01, 95CI: 1.01 - 1.02, P = 0.02), and MEI (r = 0.31, P < 0.01, 3-month lag period; IRR = 0.77, 95CI: 0.67 - 0.88, P < 0.01) were closely associated with monthly HFRS cases (18.10 cases). CONCLUSION: Climate factors significantly influence the incidence of HFRS. If the influence of variable-autocorrelation, seasonality, and long-term trend were controlled, the accuracy of forecasting by the time-series Poisson regression model in Changsha would be comparatively high, and we could forecast the incidence of HFRS in advance.

microRNA-21, via the HIF-1α/VEGF signaling pathway, is involved in arsenite-induced hepatic fibrosis through aberrant cross-talk of hepatocytes and hepatic stellate cells.

Long-term exposure to arsenic, a widely distributed environmental toxicant, may result in damage to various organs, including the liver. Mice exposed chronically to arsenite developed hepatic damage, inflammation, and fibrosis, as well as increased levels of microRNA-21 (miR-21) and hypoxia-inducible factor (HIF)-1α. The levels of miR-21 and HIF-1α were also enhanced in primary hepatocytes and L-02 cells exposed to arsenite. The culture media from these cells induced the activation of hepatic stellate cells (HSCs), as demonstrated by up-regulation of the protein levels of α-smooth muscle actin (α-SMA) and collagen1A2 (COL1A2) and by increased activity in gel contractility assays. For L-02 cells, knockdown of miR-21 blocked the arsenite-induced up-regulation of HIF-1α and vascular endothelial growth factor (VEGF), which prevented the activation of LX-2 cells induced by medium from arsenite-exposed L-02 cells. However, these effects were reversed by down-regulation of von Hippel Lindau protein (pVHL). In arsenite-treated L-02 cells, miR-21 knockdown elevated the levels of ubiquitination and accelerated the degradation of HIF-1α via pVHL. In the livers of miR-21-/- mice exposed chronically to arsenite, there were less hepatic damage, lower fibrosis, lower levels of HIF-1α and VEGF, and higher levels of pVHL than for wild-type mice. In summary, we propose that miR-21, acting via the HIF-1α/VEGF signaling pathway, is involved in arsenite-induced hepatic fibrosis through mediating aberrant cross-talk of hepatocytes and HSCs. The findings provide evidence relating to the pathogenesis of hepatic fibrosis induced by exposure to arsenic.

MicroRNA-15b in extracellular vesicles from arsenite-treated macrophages promotes the progression of hepatocellular carcinomas by blocking the LATS1-mediated Hippo pathway.

Arsenic, a human carcinogen, causes various human cancers, including those of the skin, lung, and liver. Hepatocellular carcinomas (HCCs), which have high mortality, are common malignancies worldwide. Tumor-associated macrophages (TAMs), which are considered to be similar to M2-polarized macrophages, promote tumor invasion and progression. Small non-coding RNAs (miRNAs) regulate expression of genes involved in progression of various malignancies. Extracellular vesicles (EVs), as mediators of cell communication, pass specific miRNAs directly from TAMs to tumor cells, promoting tumor pathogenesis and metastasis. In HCCs, large tumor suppressor kinase 1 (LATS1), functions as a tumor suppressor. However, the molecular mechanism by which miRNA modulates LATS1 expression in HCCs remains unclear. The results show that exposure to arsenite, increased miR-15b levels and induced M2 polarization of THP-1 cells. Elevated levels of miR-15b were transferred from arsenite-treated-THP-1 (As-THP-1) cells to HCC cells via miR-15b in EVs inhibited activation of the Hippo pathway by targeting LATS1, and was involved in promoting the proliferation, migration, and invasion of HCC cells. In conclusion, miR-15b in EVs from As-THP-1 cells is transferred to HCC cells, in which it targets and downregulates LATS1 expression and promotes the proliferation, migration, and invasion of HCC cells.

LncRNA H19-mediated M2 polarization of macrophages promotes myofibroblast differentiation in pulmonary fibrosis induced by arsenic exposure.

Arsenic is a potent toxicant, and long-term exposure to inorganic arsenic causes lung damage. M2 macrophages play an important role in the pathogenesis of pulmonary fibrosis. However, the potential connections between arsenic and M2 macrophages in the development of pulmonary fibrosis are elusive. C57BL/6 mice were fed with drinking water containing 0, 10 and 20 ppm arsenite for 12 months. We have found that, in lung tissues of mice, arsenite, a biologically active form of arsenic, elevated H19, c-Myc, and Arg1; decreased let-7a; and caused pulmonary fibrosis. For THP-1 macrophages (THP-M) and bone-marrow-derived macrophages (BMDMs), 8 µM arsenite increased H19, c-Myc, and Arg1; decreased let-7a; and induced M2 polarization of macrophages, which caused secretion of the fibrogenic cytokine, TGF-ß1. Down-regulation of H19 or up-regulation of let-7a reversed the arsenite-induced M2 polarization of macrophages. Arsenite-treated THP-M and BMDMs co-cultured with MRC-5 cells or primary lung fibroblasts (PLFs) elevated levels of p-SMAD2/3, SMAD4, α-SMA, and collagen I in lung fibroblasts and resulted in the activation of lung fibroblasts. Knockout of H19 or up-regulation of let-7a in macrophages reversed the effects. The results indicated that H19 functioned as an miRNA sponge for let-7a, which was involved in arsenite-induced M2 polarization of macrophages and induced the myofibroblast differentiation phenotype by regulation of c-Myc. In the sera of arseniasis patients, levels of hydroxyproline and H19 were higher, and levels of let-7a were lower than levels in the controls. These observations elucidate a possible mechanism for arsenic exposure-induced pulmonary fibrosis.