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Magnaporthe oryzae is one of the most destructive pathogens that threaten rice production around the world. Previous studies mainly focus on pathogenic mechanism of M. oryzae during infection on rice at leaf stage. However, the pathogenic mechanism of M. oryzae infection on panicle tissue is not well understood. In the present study, we performed RNA sequencing (RNA-seq) to study gene expression patterns of M. oryzae during infection at leaf stage and at panicle stage, respectively. The differentially expressed genes (DEGs) of M. oryzae in the infected leaf and panicle tissues were analyzed. Gene ontology (GO) enrichment analysis of DEGs revealed that M. oryzae genes involved in the biological processes were different at leaf and panicle stages. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of DEGs indicates that genes related to individual and important pathways may function at different infection stages. In particular, CAZymes carbohydrate esterases (CEs), carbohydrate-binding modules (CBMs), and glycoside hydrolases (GHs) may play important roles during M. oryzae infection on rice leaves, while glycosyltransferases (GTs) and GHs may play important roles during infection at rice panicle stage. Further analysis of effectors (BAS3, BAS113, BAS162, MoCDIP4, and MoHEG13) and their homologous genes suggest that they are involved in host defense suppression. Our findings provide insights into understanding the infection mechanisms of M. oryzae for rice leaf blast and panicle blast disease. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages M2 (TAM2), which are highly prevalent infiltrating immune cells in the stroma of pancreatic cancer (PC), have been found to induce an immunosuppressive tumor microenvironment, thus enhancing tumor initiation and progression. However, the immune therapy response and prognostic significance of regulatory genes associated with TAM2 in PC are currently unknown. Based on TCGA transcriptomic data and single-cell sequencing data from the GEO database, we identified TAM2-driven genes using the WGCNA algorithm. Molecular subtypes based on TAM2-driven genes were clustered using the ConsensusClusterPlus algorithm. The study constructed a prognostic model based on TAM2-driven genes through Lasso-COX regression analysis. A total of 178 samples obtained by accessing TCGA were accurately categorized into two molecular subtypes, including the high-TAM2 infiltration (HMI) cluster and the low-TAM2 infiltration (LMI) cluster. The HMI cluster exhibits a poor prognosis, a malignant tumor phenotype, immune-suppressive immune cell infiltration, resistance to immunotherapy, and a high number of genetic mutations, while the LMI cluster is the opposite. The prognostic model composed of six hub genes from TAM2-driven genes exhibits a high degree of accuracy in predicting the prognosis of patients with PC and serves as an independent risk factor. The induction of TAM2 was employed as a means of verifying these six gene expressions, revealing the significant up-regulation of BCAT1, BST2, and MERTK in TAM2 cells. In summary, the immunophenotype and prognostic model based on TAM2-driven genes offers a foundation for the clinical management of PC. The core TAM2-driven genes, including BCAT1, BST2, and MERTK, are involved in regulating tumor progression and TAM2 polarization, which are potential targets for PC therapy. [ABSTRACT FROM AUTHOR]

Taraxacum kok-saghyz Rodin (TKS) has great potential as an alternative natural-rubber (NR)-producing crop. The germplasm innovation of TKS still faces great challenges due to its self-incompatibility. Carbon-ion beam (CIB) irradiation is a powerful and non-species-specific physical method for mutation creation. Thus far, the CIB has not been utilized in TKS. To better inform future mutation breeding for TKS by the CIB and provide a basis for dose-selection, adventitious buds, which not only can avoid high levels of heterozygosity, but also further improve breeding efficiency, were irradiated here, and the dynamic changes of the growth and physiologic parameters, as well as gene expression pattern were profiled, comprehensively. The results showed that the CIB (5–40 Gy) caused significant biological effects on TKS, exhibiting inhibitory effects on the fresh weight and the number of regenerated buds and roots. Then,15 Gy was chosen for further study after comprehensive consideration. CIB-15 Gy resulted in significant oxidative damages (hydroxyl radical (OH•) generation activity, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity and malondialdehyde (MDA) content) and activated the antioxidant system (superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and ascorbate peroxidase (APX)) of TKS. Based on RNA-seq analysis, the number of differentially expressed genes (DEGs) peaked at 2 h after CIB irradiation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that DNA-replication-/repair- (mainly up-regulated), cell-death- (mainly up-regulated), plant-hormone- (auxin and cytokinin, which are related to plant morphogenesis, were mainly down-regulated), and photosynthesis- (mainly down-regulated) related pathways were involved in the response to the CIB. Furthermore, CIB irradiation can also up-regulate the genes involved in NR metabolism, which provides an alternative strategy to elevate the NR production in TKS in the future. These findings are helpful to understand the radiation response mechanism and further guide the future mutation breeding for TKS by the CIB. [ABSTRACT FROM AUTHOR]

Ena-VASP-like (EVL), a member of the Enabled/vasodilator stimulated phosphoprotein family, is functionally expressed in various cancers. This study explored the prognostic value and potential mechanism of EVL in pancreatic cancer (PC). RNA-seq obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to evaluate EVL expression differences, and clinical samples were collected for validation. The prognostic value of EVL was evaluated by survival data obtained from TCGA and clinical samples. The biological pathways involved in EVL were evaluated by functional enrichment analysis such as GO, KEGG, and GSEA. We used immune infiltration analysis to estimate the correlation between EVL and tumor-infiltrating immune cells (TICs). The expression of EVL is down-regulated in PC tissues, which is an independent factor affecting survival time. Survival analysis suggested EVL-high expression was associated with good prognosis in PC patients. The results of the enrichment analysis suggested that the biological function of EVL was closely related to the immune mechanism. Tumor immune infiltration analysis showed that high expression of EVL was accompanied by high levels of immune infiltration. Furthermore, EVL was strongly correlated with the content of immune cells such as CD8+ T cells, B cells, regulatory T cells, CD4+ Tem cells, and follicular Th cells. EVL is a potential independent prognostic marker and immunotherapy target for PC. Mechanistically, EVL may affect the prognosis by extensively promoting immune cell infiltration, including strengthening the anti-tumor immune response of CD8+ T cells. [ABSTRACT FROM AUTHOR]

This study aimed to identify novel differentially expressed genes in breast cancer and to explore the clinical value and the anti-tumor or oncogenic effects of the identified genes using bioinformatics analysis and in vitro experiments. The differentially expressed genes in breast cancer patients were identified using Gene Expression Omnibus (GEO) database with the cut-off criteria p < 0.05 and |logFC| > 1. The expression levels of palmdelphin (PALMD) and dermatopontin (DPT) in normal tissues and breast cancer tissues were evaluated based on GEPIA and UALCAN databases. PALMD and DPT expression levels in clinical subgroups of patients with breast cancer were analyzed to assess the association of PALMD and DPT expression with clinical characteristics. The prognostic and diagnostic values of PALMD and DPT in breast cancer were evaluated from Kaplan-Meier (K-M) survival curves and receiver operating characteristic (ROC) curves. Pearson's correlation coefficient was performed using LinkedOmics. KEGG pathway enrichment analysis was performed using DAVID. The protein levels were evaluated using western blot analysis. Cell proliferation was assessed using MTT and EdU assays. Two important genes, PALMD and DPT, were identified in breast cancer. The expression levels of PALMD and DPT were significantly lower in breast cancer tissues. The expression levels of PALMD were closely related to age, histological type, and T stage of breast cancer patients. The expression levels of DPT were closely related to age, histological type, T stage, N stage, estrogen receptor status, and progesterone receptor status of breast cancer patients. The K-M survival curves showed that PALMD or DPT was not an independent prognostic factor for breast cancer. The ROC curves showed that both PALMD and DPT had good diagnostic potential for breast cancer. KEGG pathway enrichment results showed that PI3K/Akt pathway was an important overlapping signaling for PALMD and DPT. Further studies proved that overexpression of PALMD and DPT inhibited proliferation in MCF-7 and MDA-MB-231 cells by suppressing the PI3K/Akt pathway. PALMD and DPT knockdown promoted proliferation in MCF-7 and MDA-MB-231 cells by activating the PI3K/Akt pathway. These results collectively suggested that PALMD and DPT might serve as potential diagnostic biomarkers and therapeutic targets for breast cancer. [ABSTRACT FROM AUTHOR]

Abstract: Clear cell renal cell carcinoma (ccRCC) is a common urological malignancy. Our previous study has indicated that the protein tyrosine phosphatase receptor type delta (PTPRD) gene may play a role. To determine the effect of PTPRD genetic polymorphisms on ccRCC occurrence and progression, a total of 377 ccRCC cases and 754 matched controls were enrolled in the study. DNA sequencing and genotyping, and immunohistochemistry were conducted to test the associations of genotypes with ccRCC risk and PTPRD expression level in somatic tissues. The C allele of PTPRD rs2279776 was associated with a higher risk of ccRCC (per allele OR=1.23, P =0.03). Patients without distant metastasis at the time of surgery were followed for a median of 33.1months. Overall survival was not different between different rs2279776 genotype groups (P =0.30). The C allele was associated with a higher percentage of negative immunostaining in adjacent normal renal tissues (P =0.02). PTPRD rs2279776 SNP may be a novel genetic risk factor of ccRCC. [Copyright &y& Elsevier]

Abstract: We explored the potential involvement of FoxO3a activation in erythroid and granulocytic differentiation for Ph+ cells of chronic myeloid leukemia blast crisis (CML BC). We demonstrate that FoxO3a activation in CML blast crisis (BC) cells by overexpressing FoxO3a leads to the maturation of CML BC cells. Hemoglobin production significantly increased upon FoxO3a activation in CML BC cells. FoxO3a activation upregulated erythroid surface protein (glycophorin A, GPA), but did not significantly modulate granulocytic markers (CD11b). Additionally, FoxO3a activation reduced the mRNA and protein expression of Tal1. Similar results were observed in cells that were given nilotinib. Our results indicate that FoxO3a activation may promote erythroid differentiation of BC cells via down-regulating Tal1 expression. [Copyright &y& Elsevier]

S. cerevisiae -derived-beta- d -glucan (S. cerevisiae -BG) is a natural polysaccharide with various biological effects. The present study was to investigate the protective effect of S. cerevisiae -BG on the injury induced by high linear-energy-transfer (LET) carbon ion irradiation and to reveal the protective mechanisms. Female mice were orally administrated with S. cerevisiae -BG before irradiation. 30-day survival of 6 Gy irradiated-mice was monitored. The damage and recovery of hematopoietic system were evaluated after 2 Gy irradiation, cytokines in plasma were detected, transcriptomics of bone marrow mononuclear cells (BMMNCs) were detected and analyzed. The mortality results showed that S. cerevisiae -BG could prolong the survival of mice exposed to 6 Gy. The results of BMMNCs injury analysis showed that S. cerevisiae -BG could reduce the ROS level, mitigate DNA damage and apoptosis. S. cerevisiae -BG increased the plasma radioprotective cytokines level in irradiated mice. Transcriptomics analysis revealed that S. cerevisiae -BG modulated the gene expression in BMMNCs of irradiated mice, 256 genes were significantly up-regulated and 97 genes were significantly down-regulated. Gene function and Gene Ontology analysis indicated the key genes related to hematopoiesis and immunity. Pathway analysis revealed that these up-regulated genes mainly focus on PI3K-Akt pathway and down-regulated genes mainly focus on MAPK pathway. These data contribute to understanding the molecular mechanisms of the radioprotective effect of S. cerevisiae -BG. • S. cerevisiae -BG prolonged the survival of carbon ion irradiated mice. • S. cerevisiae -BG ameliorates carbon ion irradiation-induced murine myelosuppression. • S. cerevisiae -BG affected transcriptomic response of radiotoxicity in bone marrow. • S. cerevisiae -BG mainly regulated PI3K-Akt and MAPK pathway for radioprotection. [ABSTRACT FROM AUTHOR]

Abstract The plant-pathogenic fungus Ustilaginoidea virens (Cooke) Takah causes rice false smut (RFS), which is responsible for significant quantitative and qualitative losses in rice industry. Propiconazole is a triazole fungicide which belongs to Demethylation inhibitors (DMIs). It is used to control RFS in China. We previously screened 158 isolates of U. virens collected in the fields in 2015 in Jiangsu province of China, and found two of them were highly resistant to propiconazole (named 82 and 88, respectively). In this study, we have analyzed the physiological and biochemical characters of six field-sensitive isolates and the two field-resistant isolates, including mycelial growth and cell wall integrity. We found there was cross-resistance between different DMIs fungicides, but was no cross-resistance between DMIs and QoIs fungicides. We also analyzed the fitness, and found the pathogenicity in 88 was stronger than the field-sensitive isolates, but was completely lost in 82. Sequence analyses of CYP51 and the 1000-bp upstream of CYP51 coding region showed no mutation in 82 compared to the field-sensitive strains, but two more bases CC were identified at 154-bp upstream of the coding region in the field-resistant isolate 88. Moreover, the expression of CYP51 gene in all tested isolates was significantly induced by propiconazole. However, the up-regulation expression level in both 82 and 88 was much higher than that in the field-sensitive isolates. We also found propiconazole could inhibit the ergosterol biosynthesis in the field-sensitive isolates, but stimulated it in both field-resistant isolates 82 and 88. Given the high level of U. virens developing propiconazole resistance and the good fitness of the field-resistant isolate 88, the resistance of U. virens to DMIs must be monitored and managed in rice fields. Graphical abstract Unlabelled Image Highlights • Two propiconazole -resistant isolates were screened in the field. • Propiconazole has no cross-resistance with QoIs fungicides. • The field-resistant isolate 88 did not reduced fitness and virulence. • The resistance to propiconazole of U. • Virens was associated with increased expression of CYP51 gene. [ABSTRACT FROM AUTHOR]

To investigate the role and mechanism of microRNAs (miRNAs) in fibrotic processes involved in the pathology of systemic sclerosis (SSc). R language and bioinformatics methods were used to identify differential miRNAs and mRNAs and analyze their biological functions. Transfection experiments were performed to evaluate the function and regulatory mechanism of miR-27a-3p in vitro. Levels of fibrosis-related genes, SPP1 and cell proliferation were assessed. MiR-27a-3p is reduced both in SSc lung and skin tissues. Overexpression of miR-27a-3p significantly inhibited fibrosis-related genes expression and protein abundance and cell proliferation, whereas inhibition of miR-27a-3p significantly enhanced these phenomena. Moreover, miR-27a-3p exerts its anti-fibrosis effect by negatively regulating SPP1 and ERK signal, more prominent in fibroblasts. Our findings show that miR-27a-3p regulates a common mechanism in the process of SSc skin and lung fibrosis. MiR-27a-3p/SPP1/ERK1/2 axis may be an important target for delaying the progression of SSc fibrosis. • MiRNAs play a vital role in the fibrosis process of SSc. • MiR-27a-3p is involved in the process of SSc skin and lung tissue fibrosis. • MiR-27a-3p exerts its anti-fibrosis effect by negatively regulating SPP1-ERK axis. • MiR-27a-3p-SPP1-ERK1/2 regulatory axis is a potential therapeutic target for SSc. [ABSTRACT FROM AUTHOR]

A large proportion of mutants with altered pigment features have been obtained via exposure to heavy-ion beams, a technique that is efficient for trait improvement in the breeding of plants and algae. However, little is known about the underlying mechanisms by which the photosynthetic pigments are altered by heavy-ion irradiation. In our study, the photosynthetic characteristics of progenies from carbon-ion irradiated Selenastrum capricornutum were investigated. Five progenies deficient in chlorophyll a were isolated after carbon-ion exposure. Photosynthetic characteristics, photoprotection capacity and gene expression of the light-harvesting complex in these progenies were further characterized by the measurement of chlorophyll fluorescence parameters (Fv/Fm, ФPSII, NPQ, ETR), the de-epoxidation state of the xanthophyll cycle, the amount of lutein and quantitative real-time PCR. High maximum quantum yield of photosystem II at day 10 and high thermal dissipation ability were observed in progenies #23 and #37 under normal culture condition. Progenies #18, #19 and #20 showed stronger resistance against high levels of light steps than the control group (612–1077 μmol photons m -2 s -1, p< 0.05). The progenies #20 and #23 exhibited strong photoprotection by thermal dissipation and quenching of 3Chl* after 24 h of high light treatment. The mRNA levels of Lhcb5, Lhcbm5 and Lhcbm1 of the light-harvesting complex revealed markedly differential expression in the five progenies irradiated by carbon-ion beams. This work indicates that photosynthetic efficiency, photoprotection ability and the expression of light-harvesting antennae in unicellular green algae can be markedly influenced by irradiation. To our knowledge, this is the first report on changes in the photosynthetic pigments of green algae after treatment with carbon-ion beams. [ABSTRACT FROM AUTHOR]

Twist, a highly conserved basic Helix-Loop-Helix transcription factor, functions as a major regulator of epithelial-mesenchymal transition (EMT) and tumor metastasis. In different cell models, signaling pathways such as TGF-β, MAPK/ERK, WNT, AKT, JAK/STAT, Notch, and P53 have also been shown to play key roles in the EMT process, yet little is known about the signaling pathways regulated by Twist in tumor cells. Using iTRAQ-labeling combined with 2D LC–MS/MS analysis, we identified 194 proteins with significant changes of expression in MCF10A-Twist cells. These proteins reportedly play roles in EMT, cell junction organization, cell adhesion, and cell migration and invasion. ECM–receptor interaction, MAPK, PI3K/AKT, P53 and WNT signaling were found to be aberrantly activated in MCF10A-Twist cells. Ingenuity Pathways Analysis showed that integrin β1 (ITGB1) acts as a core regulator in linking integrin-linked kinase (ILK), Focal-adhesion kinase (FAK), MAPK/ERK, PI3K/AKT, and WNT signaling. Increased Twist and ITGB1 are associated with breast tumor progression. Twist transcriptionally regulates ITGB1 expression. Over-expression of ITGB1 or Twist in MCF10A led to EMT, activation of FAK/ILK, MAPK/ERK, PI3K/AKT, and WNT signaling. Knockdown of Twist or ITGB1 in BT549 and Hs578T cells decreased activity of FAK, ILK, and their downstream signaling, thus specifically impeding EMT and cell invasion. Knocking down ILK or inhibiting FAK, MAPK/ERK, or PI3K/AKT signaling also suppressed Twist-driven EMT and cell invasion. Thus, the Twist-ITGB1-FAK/ILK pathway and their downstream signaling network dictate the Twist-induced EMT process in human mammary epithelial cells and breast cancer cells. [ABSTRACT FROM AUTHOR]

Background Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a widely expressed multi-functional adhesion molecule reported to serve as a serum biomarker in several types of cancer. However, the serum CEACAM1 expression in breast cancer is unclear. We investigated the serum concentrations of CEACAM1 in patients with breast cancer and determine the potential of serum CEACAM1 as a breast cancer biomarker. Methods Serum specimens were obtained from 33 patients with breast cancer, 30 patients with benign breast diseases and 34 healthy donors. The serum CEACAM1 concentrations were examined by an enzyme-linked immunosorbent assay (ELISA). Results The serum CEACAM1 concentrations in the malignant group (532 ng/ml) were significantly higher than those of the benign group (423 ng/ml) and healthy control group (386 ng/ml) (both p < 0.001). Based on univariable logistic regression, serum CEACAM1 concentrations significantly predicted breast cancer versus normal controls or benign breast diseases. Area under receiver operating characteristic curve (ROC) for serum CEACAM1 was 0.925(95% CI: 0.866–0.984). The optimal cut-off concentration of CEACAM1 was 475.82 ng/ml for discriminating breast cancer from normal controls. Conclusion Serum concentrations of CEACAM1 may serve as a useful indicator for the presence of breast cancer. [ABSTRACT FROM AUTHOR]

Background Recent evidence suggested that ClC-3, encoding Cl − channel or Cl − /H + antiporter, plays a critical role in regulation of a variety of physiological functions. However, remarkably little is known about whether ClC-3 is involved in atherosclerosis. This study aims to establish the involvement and direct role of ClC-3 in atherogenesis and underlying mechanisms by using ClC-3 and ApoE double null mice. Methods and results After a 16-week western-type high-fat diet, the ClC-3 +/+ ApoE −/− mice developed widespread atherosclerotic lesions in aorta. However, the lesion size was significantly reduced in aorta of ClC-3 −/− ApoE −/− mice. Compared with the ClC-3 +/+ controls, there was significantly decreased ox-LDL binding and uptake in isolated peritoneal macrophages from ClC-3 −/− mice. Moreover, the expression of scavenger receptor SR-A, but not CD36, was significantly decreased in both ClC-3 −/− peritoneal macrophages and aortic lesions from ClC-3 −/− ApoE −/− mice. These findings were further confirmed in ox-LDL-treated RAW264.7 macrophages, which showed that silence of ClC-3 inhibited SR-A expression, ox-LDL accumulation and foam cell formation, whereas overexpression of ClC-3 produced the opposite effects. In addition, ClC-3 siRNA significantly inhibited, whereas ClC-3 overexpression increased, the phosphorylation of JNK/p38 MAPK in ox-LDL-treated RAW264.7 foam cells. Pretreatment with JNK or p38 inhibitor abolished ClC-3-induced increase in SR-A expression and ox-LDL uptake. Finally, the increased JNK/p38 phosphorylation and SR-A expression induced by ClC-3 could be mimicked by reduction of [Cl − ] i by low Cl − solution. Conclusions Our findings demonstrated that ClC-3 deficiency inhibits atherosclerotic lesion development, possibly via suppression of JNK/p38 MAPK dependent SR-A expression and foam cell formation. [ABSTRACT FROM AUTHOR]

Eosinophils (EOS) quantity, active state, peroxidase activity (POX), and HLA-DR expression in bone marrow of 176 Auto-Immune-Related Hematocytopenia (AIRH) patients were analyzed. Immunofluorescent staining (IF) is performed to observe the expression of immunizing molecules on EOS. In serum of AIRH patients the levels of IL-4, IL-5, IL-6, IL-12, IL-17, and IFN-γwere increased but there was no significance on IL-2 level. In marrow of AIRH, activated EOS expressed POX, and other molecules, it played various cell-mediated immunity injury roles to hemocyte. EOS might be possessed with multiple immunological fuctions, it playes an important immune effect in AIRH autoimmune pathological processes. [ABSTRACT FROM AUTHOR]

Objective: KCa3.1 channel participates in many important cellular functions. This study planned to investigate the potential involvement of KCa3.1 channel in premature senescence, myofibroblast phenotype transition and proliferation of mesangial cells. Methods & Materials: Rat mesangial cells were cultured together with TGF-β1 (2 ng/ml) and TGF-β1 (2 ng/ml) + TRAM-34 (16 nM) separately for specified times from 0 min to 60 min. The cells without treatment served as controls. The location of KCa3.1 channels in mesangial cells was determined with Confocal laser microscope, the cell cycle of mesangial cells was assessed with flow cytometry, the protein and mRNA expression of KCa3.1, α-smooth muscle actin (α-SMA) and fibroblast-specific protein-1 (FSP-1) were detected with Western blot and RT-PCR. One-way analysis of variance (ANOVA) and Student-Newman-Keuls-q test (SNK-q) were used to do statistical analysis. Statistical significance was considered at P<0.05. Results: Kca3.1 channels were located in the cell membranes and/or in the cytoplasm of mesangial cells. The percentage of cells in G0-G1 phase and the expression of Kca3.1, α-SMA and FSP-1 were elevated under the induction of TGF-β1 when compared to the control and decreased under the induction of TGF-β1+TRAM-34 when compared to the TGF-β1 induced (P<0.05 or P<0.01). Conclusion: Targeted disruption of KCa3.1 inhibits TGF-β1-induced premature aging, myofibroblast-like phenotype transdifferentiation and proliferation of mesangial cells. [ABSTRACT FROM AUTHOR]

Background: Mechanism of radioresistance in rectal carcinoma remains largely unknown. We aimed to evaluate the predictive role of ATP-binding cassette subfamily C member 4 (ABCC4) in locally advanced rectal carcinoma and explore possible molecular mechanisms by which ABCC4 confers the resistance to neoadjuvant radiotherapy. Methods: The expression of ABCC4 and P53 mutant in biopsy tissue specimens from 121 locally advanced rectal carcinoma patients was examined using immunohistochemistry. The factors contributing to 3-year overall survival and disease-free survival were evaluated using the Kaplan-Meier method and Cox proportional hazard model. Lentivirus-mediated small hairpin RNA was applied to inhibit ABCC4 expression in colorectal carcinoma cell line RKO, and investigate the radiosensitivity in xenograft model. Intracellular cyclic adenosine monophosphate concentration and cell cycle distribution following irradiation were detected. Results: High expression of ABCC4 and p53 mutant in pretreated tumors, poor pathological response, and high final tumor staging were significant factors independently predicted an unfavorable prognosis of locally advanced rectal carcinoma patients after neoadjuvant radiotherapy. Down-regulation of ABCC4 expression significantly enhanced irradiation-induced suppression of tumor growth in xenograft model. Furthermore, down-regulation of ABCC4 expression enhanced intracellular cyclic adenosine monophosphate production and noticeable deficiency of G1-S phase checkpoint in cell cycle following irradiation. Conclusions: Our study suggests that ABCC4 serves as a novel predictive biomarker that is responsible for the radioresistance and predicts a poor prognosis for locally advanced rectal carcinoma after neoadjuvant radiotherapy. [ABSTRACT FROM AUTHOR]

Aims We have previously demonstrated that ClC-3 chloride channel activity and expression are significantly increased in remodelled cerebral vessels of hypertensive rats. This study aims to examine whether this channel directly regulates cerebrovascular remodelling during hypertension by using ClC-3−/− mice. Methods and results After DOCA-salt treatment, medial cross-sectional area, media thickness, and media–lumen ratio of the basilar artery of ClC-3+/+ mice were significantly increased, accompanied by reduced lumen diameter, indicating apparent vascular remodelling. The vascular ultrastructure of ClC-3+/+ hypertensive mice by electron microscopy revealed obvious disarray of SMCs and extracellular matrix accumulation. Immunofluorescence analysis showed that fibronectin was overexpressed in ClC-3+/+ DOCA-salt mice. All of these vascular structure alterations were prevented in ClC-3−/− mice despite DOCA-salt treatment. However, propranolol, which reduced blood pressure as effectively as ClC-3 deficiency, failed to prevent basilar artery from remodelling. The vascular structure injury in ClC-3+/+ hypertensive mice was accompanied by significantly increased expression of matrix metalloproteinase (MMP)-2, membrane-type (MT)1-MMP, and tissue inhibitor of metalloproteinase (TIMP)-2, which was inhibited by ClC-3 knockout. Additionally, the increase in transforming growth factor (TGF)-β1 level in serum, as well as phosphorylation of Smad3 at serine 423/425 in basilar artery, induced by DOCA-salt, was markedly prevented in ClC-3−/− mice. Conclusion Our findings suggest that ClC-3 deficiency attenuates cerebrovascular remodelling possibly via the suppression of MMPs/TIMP expression and TGF-β1/Smad3 signalling pathway in this hypertension. [ABSTRACT FROM AUTHOR]

Background: Transforming growth factor-β1 (TGF-β1) is a polypeptide member of the transforming growth factor β superfamily of cytokines and performs many cellular functions. Its overexpression may lead to renal fibrosis. Aim: This study planed to investigate the effects of TGF-β1 on the cell cycle and phenotype of mesangial cells. Methods: Rat mesangial cells were cultured together with different concentrations (0, 1, 2, 5, and 10 ng/mL) of TGF-β1 for specified times from 0 min to 72 h. 0 ng/mL TGF-β1 and 0 min served as controls. Cell cycles were assessed by flow cytometry and α-smooth muscle actin expression (α-SMA) protein expression by western blot analysis. All data were presented as Mean ± SD. Statistical analysis was performed by using one-way analysis of variance and correlation analysis. Results were considered significant at p < 0.05. Results: After 15 min of co-culture with different concentrations of TGF-β1, the percentage of mesangial cells in G0/G1 phase was significantly elevated compared to the control ( p < 0.05). 12 h co-culture induced cell hyperplasia, 24 h co-culture obvious up-regulation of α-SMA ( p < 0.01) and one or two cells' myofibroblast phenotype transition, and 36 h co-culture several cells' phenotype transition. Correlation analysis prompted that the TGF-β1-induced premature aging was time-dependent ( p < 0.01). Conclusion: TGF-β1 may induce mesangial cells' premature senescence and myofibroblast-like phenotype transformation time-dependently, which may contribute to the development of early stage of glomerulosclerosis. [ABSTRACT FROM AUTHOR]