Abstract
The occurrence of toxic metals in the aquatic environment is as caused by a variety of contaminations which makes difficulty in the concentration prediction. In this study, conventional ...methods of back-propagation neural network (BPNN) and nonlinear autoregressive network with exogenous inputs (NARX) were applied as benchmark models. Explanatory variables of Fe, pH, electrical conductivity, water temperature, river flow, nitrate nitrogen, and dissolved oxygen were used as different input combinations to forecast the long-term concentrations of As, Pb, and Zn. The wavelet transformation was applied to decompose the time series data, and then was integrated with conventional methods (as WNN and WNARX). The modelling performances of the hybrid models of WNN and WNARX were compared with the conventional models. All the given models were trained, validated, and tested by an 18-year data set and demonstrated based on the simulation results of a 2-year data set. Results revealed that the given models showed general good performances for the long-term prediction of the toxic metals of As, Pb, and Zn. The wavelet transform could enhance the long-term concentration predictions. However, it is not necessarily useful for each metal prediction. Therefore, different models with different inputs should be used for different metals predictions to achieve the best predictions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cervical cancer is the fourth most common cancer in women worldwide. Increasing evidence has shown that miRNAs are related to the progression of cervical cancer. However, the mechanisms that affect ...the prognosis of cancer are still largely unknown. In the present study, we sought to identify miRNAs associated with poor prognosis of patient with cervical cancer, as well as the possible mechanisms regulated by them. The miRNA expression profiles and relevant clinical information of patients with cervical cancer were obtained from The Cancer Genome Atlas (TCGA). The selection of prognostic miRNAs was carried out through an integrated bioinformatics approach. The most effective miRNAs with synergistic and additive effects were selected for validation through in vitro experiments. Three miRNAs (miR-216b-5p, miR-585-5p, and miR-7641) were identified as exhibiting good performance in predicting poor prognosis through additive effects analysis. The functional enrichment analysis suggested that not only pathways traditionally involved in cancer but also immune system pathways might be important in regulating the outcome of the disease. Our findings demonstrated that a synergistic combination of three miRNAs may be associated, through their regulation of specific pathways, with very poor survival rates for patients with cervical cancer.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
DNA N6-methyldeoxyadenosine (6mA) is rarely present in mammalian cells and its nuclear role remains elusive.
Here we show that hypoxia induces nuclear 6mA modification through a DNA ...methyltransferase, METTL4, in hypoxia-induced epithelial-mesenchymal transition (EMT) and tumor metastasis. Co-expression of METTL4 and 6mA represents a prognosis marker for upper tract urothelial cancer patients. By RNA sequencing and 6mA chromatin immunoprecipitation-exonuclease digestion followed by sequencing, we identify lncRNA RP11-390F4.3 and one novel HIF-1α co-activator, ZMIZ1, that are co-regulated by hypoxia and METTL4. Other genes involved in hypoxia-mediated phenotypes are also regulated by 6mA modification. Quantitative chromatin isolation by RNA purification assay shows the occupancy of lncRNA RP11-390F4.3 on the promoters of multiple EMT regulators, indicating lncRNA-chromatin interaction. Knockdown of lncRNA RP11-390F4.3 abolishes METTL4-mediated tumor metastasis. We demonstrate that ZMIZ1 is an essential co-activator of HIF-1α.
We show that hypoxia results in enriched 6mA levels in mammalian tumor cells through METTL4. This METTL4-mediated nuclear 6mA deposition induces tumor metastasis through activating multiple metastasis-inducing genes. METTL4 is characterized as a potential therapeutic target in hypoxic tumors.
Hypoxia-induced long noncoding RNAs (lncRNAs) have been shown to induce tumor metastasis. However, lncRNAs that are regulated by hypoxia/HIF-1α and subsequently control the expression of multiple ...epithelial-mesenchymal transition (EMT) regulators have not been identified. To identify such lncRNAs, analysis of RNA-sequencing datasets was performed. The lncRNA RP11-390F4.3 was shown to be induced by hypoxia and directly activated by HIF-1α. Overexpression of lncRNA RP11-390F4.3 induced EMT and metastasis. LncRNA RP11-390F4.3 was essential for hypoxia-induced EMT and metastasis. LncRNA RP11-390F4.3 overexpression induced the expression of multiple EMT regulators. This report demonstrates that LncRNA RP11-390F4.3 is induced by hypoxia/HIF-1α and is essential for hypoxia-induced EMT and metastasis via the activation of multiple EMT regulators.
•Direct activation of lncRNA RP11-390F4.3 by hypoxia/HIF-1α.•Overexpression of lncRNA RP11-390F4.3 induces in vitro migration/invasion and in vivo metastasis.•lncRNA RP11-390F4.3 is essential for hypoxia-induced EMT.•Overexpression of lncRNA RP11-390F4.3 induces the expression of multiple EMT regulators.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
Metastasis is the end stage of renal cell carcinoma (RCC), and clear cell renal cell carcinoma (ccRCC) is the most common malignant subtype. The hypoxic microenvironment is a common feature ...in ccRCC and plays an essential role in the regulation of epithelial–mesenchymal transition (EMT). Accumulating evidence manifests that long non‐coding RNAs (lncRNAs) participate in RCC tumorigenesis and regulate hypoxia‐induced EMT. Here, we identified a lncRNA RP11‐367G18.1 induced by hypoxia, that was overexpressed in ccRCC tissues.
Methods
A total of 216 specimens, including 149 ccRCC tumor samples and 67 related normal kidney parenchyma tissue samples, were collected. To investigate the biological fucntions of RP11.367G18.1 in ccRCC, migration, invasion, soft agar colony formation, xenograft tumorigenicity assays, and tail vein and orthotopic metastatic mouse models were performed. The relationship between RP11‐367G18.1 and downstream signaling was analyzed utilizing reporter assay, RNA pull‐down, chromatin immunopreciptation, and chromatin isolation by RNA purification assays.
Results
Hypoxic conditions and overexpression of HIF‐1α increased the level of RP11‐367G18.1. RP11‐367G18.1 induced EMT and enhanced cell migration and invasion through variant 2. Inhibition of RP11‐367G18.1 variant 2 reversed hypoxia‐induced EMT phenotypes. An in vivo study revealed that RP11‐367G18.1 variant 2 was required for hypoxia‐induced tumor growth and metastasis in ccRCC. Mechanistically, RP11‐367G18.1 variant 2 interacted with p300 histone acetyltransferase to regulate lysine 16 acetylation on histone 4 (H4K16Ac), thus contributing to hypoxia‐regulated gene expression. Clinically, RP11‐367G18.1 variant 2 was upregulated in ccRCC tissues, particularly metastatic ccRCC tissues, and it is linked to poor overall survival.
Conclusion
These findings demonstrate the prognostic value and EMT‐promoting role of RP11‐367G18.1 and indicate that this lncRNA may provide a therapeutic target for ccRCC.
Hypoxia upregulated lncRNA RP11‐367G18.1 variant 2 which was associated with p300‐mediated chromatin modifying complex to activate H4K16Ac marks. RP11‐367G18.1 variant 2 increased the levels of H4K16Ac on the promoter of hypoxia‐regulated genes leading to EMT and tumor metastasis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Acute myocardial infarction (AMI) is defined as myocardial necrosis. Clinicians use the traditional Chinese patent medicine Yangxinkang Tablet (YXK) to treat chronic heart failure.
To explore the ...effects of YXK on heart injury following AMI and the underlying mechanisms.
The AMI model was produced in Wistar rats by permanent ligation of the left anterior descending coronary artery. Rats were divided into the following five groups: Sham (n = 6), MI (Model, n = 10), AICAR (AMPK agonist, 50 mg/kg/d, i.p., n = 10), Compound C (AMPK inhibitor, 10 mg/kg/d, i.p., n = 10), and YXK (0.72 g/kg/d, gavage, n = 10) groups. Cardiac function, cardiac fibrosis, apoptosis, and expression of p-AMPK, p-mTOR, and autophagy-related proteins was measured after 4 weeks of treatment after the successful modelling of the AMI.
Compared to MI group, both YXK and AMPK inhibitor improved cardiac dysfunction and reduced cardiac fibrosis (15.6 ± 2.3; 22.6 ± 4.6 vs. 34.6 ± 4.3%) and myocardial cell apoptosis (12 ± 3.67; 25.6 ± 6.8 vs. 54 ± 4.8%). Futhermore, YXK and AMPK inhibitor significantly decreased p-AMPK expression by 11.05% and 14.64%, LC3II/I by 25.08% and 35.28% and Beclin-1 by 66.71% and 33.85%, increased p-mTOR by 22.14% and 47.46% and p62 by 70.83% and 18.58%.
The underlying mechanism appears to include suppression of autophagy via inhibiting AMPK/mTOR signalling, suggesting that YXK may serve as a potentially effective Chinese herbal compound for suppressing cardiac fibrosis in heart injury.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
The hypoxia-responsive long non-coding RNA,
RP11-367G18.1
, has recently been reported to induce histone 4 lysine 16 acetylation (H4K16Ac) through its variant 2; however, the ...underlying molecular mechanism remains poorly understood.
Methods
RNA pull-down assay and liquid chromatography-tandem mass spectrometry were performed to identify
RP11-367G18.1
variant 2-binding partner. The molecular events were examined utilizing western blot analysis, real-time PCR, luciferase reporter assay, chromatin immunoprecipitation, and chromatin isolation by RNA purification assays. The migration, invasion, soft agar colony formation, and in vivo xenograft experiments were conducted to evaluate the impact of
RP11-367G18.1
variant 2–YY1 complex on tumor progression.
Results
In this study, RNA sequencing data revealed that hypoxia and
RP11-367G18.1
variant 2 co-regulated genes were enriched in tumor-related pathways. YY1 was identified as an
RP11-367G18.1
variant 2-binding partner that activates the H4K16Ac mark. YY1 was upregulated under hypoxic conditions and served as a target gene for hypoxia-inducible factor-1α.
RP11-367G18.1
variant 2 colocalized with YY1 and H4K16Ac in the nucleus under hypoxic conditions. Head and neck cancer tissues had higher levels of
RP11-367G18.1
and YY1 which were associated with poor patient outcomes.
RP11-367G18.1
variant 2–YY1 complex contributes to hypoxia-induced epithelial–mesenchymal transition, cell migration, invasion, and tumorigenicity. YY1 regulated hypoxia-induced genes dependent on
RP11-367G18.1
variant 2.
Conclusions
RP11-367G18.1
variant 2–YY1 complex mediates the tumor-promoting effects of hypoxia, suggesting that this complex can be targeted as a novel therapeutic strategy for cancer treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Nerve growth factor (NGF) promotes axonal growth in PC12 cells primarily by regulating the RTK-RAS-MEK-ERK pathway. Panaxydol, a polyacetylene isolated from Panax notoginseng, can mimic the effects ...of NGF. Panaxydol promotes neurite outgrowth in PC12 cells, but its molecular mechanism remains unclear. Indeed, although alkynol compounds such as panaxydol can increase intracellular cyclic adenosine 3',5'-monophosphate (cAMP) levels and the ERK inhibitor U0126 inhibits alkynol-induced axonal growth, how pathways downstream of cAMP activate ERK have not been investigated. This study observed the molecular mechanism of panaxydol-, NGF- and forskolin-induced PC12 cell axon growth using specific signaling pathway inhibitors. The results demonstrated that although the RTK inhibitor SU5416 obviously inhibited the growth-promoting effect of NGF, it could not inhibit the promoting effect of panaxydol on axonal growth of PC12 cells. The adenylate cyclase inhibitor SQ22536 and cAMP-dependent protein kinase inhibitor RpcAMPS could suppress the promoting effect of forskolin and panaxydol on axonal growth. The ERK inhibitor U0126 inhibited axonal growth induced by all three factors. However, the PKA inhibitor H89 inhibited the promoting effect of forskolin on axonal growth but could not suppress the promoting effect of panaxydol. A western blot assay was used to determine the effects of stimulating factors and inhibitors on ERK phosphorylation levels. The results revealed that NGF activates the ERK pathway through tyrosine receptors to induce axonal growth of PC12 cells. In contrast, panaxydol and forskolin increased cellular cAMP levels and were inhibited by adenylyl cyclase inhibitors. The protein kinase A inhibitor H89 completely inhibited forskolin-induced axonal outgrowth and ERK phosphorylation, but could not inhibit panaxydol-induced axonal growth and ERK phosphorylation. These results indicated that panaxydol promoted axonal growth of PC12 cells through different pathways downstream of cAMP. Considering that exchange protein directly activated by cAMP 1 (Epac1) plays an important role in mediating cAMP signaling pathways, RNA interference experiments targeting the Epac1 gene were employed. The results verified that Epac1 could mediate the axonal growth signaling pathway induced by panaxydol. These findings suggest that compared with NGF and forskolin, panaxydol elicits axonal growth through the cAMP-Epac1-Rap1-MEK-ERK-CREB pathway, which is independent of PKA.
Long noncoding RNAs (lncRNAs) are noncoding RNAs with length greater than 200 nt. The biological roles and mechanisms mediated by lncRNAs have been extensively investigated. Hypoxia is a proven ...microenvironmental factor that promotes solid tumor metastasis. Epithelial-mesenchymal transition (EMT) is one of the major mechanisms induced by hypoxia to contribute to metastasis. Many lncRNAs have been shown to be induced by hypoxia and their roles have been delineated. In this review, we focus on the hypoxia-inducible lncRNAs that interact with protein/protein complex and chromatin/epigenetic factors, and the mechanisms that contribute to metastasis. The role of a recently discovered lncRNA RP11-390F4.3 in hypoxia-induced EMT is discussed. Whole genome approaches to delineating the association between lncRNAs and histone modifications are discussed. Other topics related to hypoxia-induced tumor progression but require further investigation are also mentioned. The clinical significance and treatment strategy targeted against lncRNAs are discussed. The review aims to identify suitable lncRNA targets that may provide feasible therapeutic venues for hypoxia-involved cancers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP