Regulation Of TGF Research Articles

Comparative performance of superior and inferior grains for quality parameters following diversified temperature during grain filling stage

The responses of rice quality including milling, appearance, and eating quality between superior (SG) and inferior grains (IG) to temperature during grain filling stage (TGF) remained poorly understood, especially for eating quality. Therefore, the regulation of TGF (17.6−30.4 °C) on quality of three indica hybrid varieties (IHs) was investigated by setting multiple sowing dates and the mechanism underlying taste difference was explored by monitoring chemical compositions, rapid visco analyser (RVA) profiles, and texture properties. Results suggested that TGF ranging from 23.3 to 25.2 °C could comprehensively improve the milling, appearance and eating quality of IHs, and the optimal TGF of SG was 2.3–4.2 °C lower than that of IG. Compared with chemical compositions and RVA profiles, texture properties were better for evaluating the eating quality of IHs. When TGF was higher than 24.0 °C, the taste value of IG was higher than that of SG mainly due to higher elasticity. The findings indicate that TGF had differential regulatory effects on SG and IG, which could provide a useful reference for cultivation of high-quality rice varieties under global climate change. Besides, the determination of texture properties was a reliable method for taste evaluating of IHs in the breeding process.

Hyperdry Human Amniotic Membrane as a Protective Dressing for Open Wounds With Exposed Bowel in Mice

IntroductionAn enteroatmospheric fistula forms when the exposed bowel is perforated with chronic enteric fistula formation. Currently, there is no established preventative method for this condition. Hyperdry (HD) amniotic membrane (AM) can promote early granulation tissue formation on the exposed viscera and is suitable for dressing intractable wounds as it possesses anti-inflammatory, antibacterial, and immunomodulatory properties. This study investigated whether HD-AM promotes early formation of blood vessel–containing granulation tissue for enteroatmospheric fistula treatment. MethodsAn experimental animal model of an open wound with exposed bowel was developed. A 15 × 20 mm wound was prepared on the abdomen of Institute of Cancer Research mice, and the HD-AM was placed. The mice were assigned to one of the following groups: HD-AM group, in which the stromal layer of the HD-AM was placed in contact with the exposed bowel; HD-AM UD group, in which the epithelial layer of the HD-AM was placed in contact with the exposed bowel; and the HD-AM (-) or control group, in which the HD-AM was not used. ResultsOn postoperative days 7 and 14, granulation tissue thickness significantly increased in the HD-AM and HD-AM UD groups compared with that in the HD-AM (-) group. Macrophages accumulated in the HD-AM epithelium only in the HD-AM group. During HD-AM contact, a subset of invading macrophages switched from M1 to M2 phenotype. ConclusionsHD-AM is a practical wound dressing with its scaffolding function, regulation of TGF β-1 and C-X-C motif chemokine 5 (CXCL-5), and ability to induce M1-to-M2 macrophage conversion.

OVOL1 inhibits breast cancer cell invasion by enhancing the degradation of TGF-\u03b2 type I receptor

Ovo-like transcriptional repressor 1 (OVOL1) is a key mediator of epithelial lineage determination and mesenchymal–epithelial transition (MET). The cytokines transforming growth factor-β (TGF-β) and bone morphogenetic proteins (BMP) control the epithelial–mesenchymal plasticity (EMP) of cancer cells, but whether this occurs through interplay with OVOL1 is not known. Here, we show that OVOL1 is inversely correlated with the epithelial–mesenchymal transition (EMT) signature, and is an indicator of a favorable prognosis for breast cancer patients. OVOL1 suppresses EMT, migration, extravasation, and early metastatic events of breast cancer cells. Importantly, BMP strongly promotes the expression of OVOL1, which enhances BMP signaling in turn. This positive feedback loop is established through the inhibition of TGF-β receptor signaling by OVOL1. Mechanistically, OVOL1 interacts with and prevents the ubiquitination and degradation of SMAD family member 7 (SMAD7), which is a negative regulator of TGF-β type I receptor stability. Moreover, a small-molecule compound 6-formylindolo(3,2-b)carbazole (FICZ) was identified to activate OVOL1 expression and thereby antagonizing (at least in part) TGF-β-mediated EMT and migration in breast cancer cells. Our results uncover a novel mechanism by which OVOL1 attenuates TGF-β/SMAD signaling and maintains the epithelial identity of breast cancer cells.

Curcumin as Potential Adjuvant Therapy to Prevent Recurrence in Pterygium Excision.

Pterygium is a wing-shaped growth from the conjunctiva and fibrovascular tissue onto the surface of the cornea. It has a high postoperative recurrence rate (which can be as high as 89% and its severity may vary according to the approach adopted and the preoperative conditions). To reduce the postoperative recurrence rate, several surgical techniques have been developed. The pathophysiology of pterygium development is diverse, one of the main factors is the proliferative process initiated by the TGF-? mediator. One of the therapies developed to prevent pterygium recurrence is by targeting therapy on the proliferative pathway by adding pterygium surgery with adjuvant MMC therapy. MMC plays a role in inhibiting DNA synthesis, thereby reducing TGF-? expression and ultimately inhibiting cell proliferation. Although it can reduce the recurrence rate quite well, MMC has numbers of complications. Therefore, an agent is needed to suppress pterygium proliferation which is relatively safer. Curcumin is a compound derived from the tuber of Curcuma longa L. which includes polyphenols. Curcumin modulates proliferation by stimulating the formation of TGIF which is a negative regulator of TGF-? so that it can modulate proliferation.

Sp1-Like Protein KLF13 Acts as a Negative Feedback Regulator of TGF- β Signaling and Fibrosis

Sp1-Like Protein KLF13 Acts as a Negative Feedback Regulator of TGF- β Signaling and Fibrosis

LTBP4 affects renal fibrosis by influencing angiogenesis and altering mitochondrial structure

Transforming growth factor beta (TGFβ) signalling regulates extracellular matrix accumulation known to be essential for the pathogenesis of renal fibrosis; latent transforming growth factor beta binding protein 4 (LTBP4) is an important regulator of TGFβ activity. To date, the regulation of LTBP4 in renal fibrosis remains unknown. Herein, we report that LTBP4 is upregulated in patients with chronic kidney disease and fibrotic mice kidneys created by unilateral ureteral obstruction (UUO). Mice lacking the short LTBP4 isoform (Ltbp4S−/−) exhibited aggravated tubular interstitial fibrosis (TIF) after UUO, indicating that LTBP4 potentially protects against TIF. Transcriptomic analysis of human proximal tubule cells overexpressing LTBP4 revealed that LTBP4 influences angiogenic pathways; moreover, these cells preserved better mitochondrial respiratory functions and expressed higher vascular endothelial growth factor A (VEGFA) compared to wild-type cells under hypoxia. Results of the tube formation assay revealed that additional LTBP4 in human umbilical vein endothelial cell supernatant stimulates angiogenesis with upregulated vascular endothelial growth factor receptors (VEGFRs). In vivo, aberrant angiogenesis, abnormal mitochondrial morphology and enhanced oxidative stress were observed in Ltbp4S−/− mice after UUO. These results reveal novel molecular functions of LTBP4 stimulating angiogenesis and potentially impacting mitochondrial structure and function. Collectively, our findings indicate that LTBP4 protects against disease progression and may be of therapeutic use in renal fibrosis.

Negative regulation of TGF\u03b2-induced apoptosis by RAC1B enhances intestinal tumourigenesis

RAC1B is a tumour-related alternative splice isoform of the small GTPase RAC1, found overexpressed in a large number of tumour types. Building evidence suggests it promotes tumour progression but compelling in vivo evidence, demonstrating a role in driving tumour invasion, is currently lacking. In the present study, we have overexpressed RAC1B in a colorectal cancer mouse model with potential invasive properties. Interestingly, RAC1B overexpression did not trigger tumour invasion, rather it led to an acceleration of tumour initiation and reduced mouse survival. By modelling early stages of adenoma initiation we observed a reduced apoptotic rate in RAC1B overexpressing tumours, suggesting protection from apoptosis as a mediator of this phenotype. RAC1B overexpressing tumours displayed attenuated TGFβ signalling and functional analysis in ex vivo organoid cultures demonstrated that RAC1B negatively modulates TGFβ signalling and confers resistance to TGFβ-driven cell death. This work defines a novel mechanism by which early adenoma cells can overcome the cytostatic and cytotoxic effects of TGFβ signalling and characterises a new oncogenic function of RAC1B in vivo.

MiR-2337 induces TGF-\u03b21 production in granulosa cells by acting as an endogenous small activating RNA

Transforming growth factor-β1 (TGF-β1) is essential for ovarian function and female fertility in mammals. Herein, we identified three completely linked variants, including two known variants referred to as c.1583A > G and c.1587A > G and the novel variant c.2074A > C in the porcine TGF-β1 3′-UTR. An important role of these variants in Yorkshire sow fertility was revealed. Variants c.1583A > G and c.1587A > G were located at the miRNA response element (MRE) of miR-2337 and affected miR-2337 regulation of TGF-β1 3′-UTR activity. Interestingly, miR-2337 induces, not reduces the transcription and production of TGF-β1 in granulosa cells (GCs). Mechanistically, miR-2337 enhances TGF-β1 promoter activity via the MRE motif in the core promoter region and alters histone modifications, including H3K4me2, H3K4me3, H3K9me2, and H3K9ac. In addition, miR-2337 controls TGF-β1-mediated activity of the TGF-β signaling pathway and GC apoptosis. Taken together, our findings identify miR-2337 as an endogenous small activating RNA (saRNA) of TGF-β1 in GCs, while miR-2337 is identified as a small activator of the TGF-β signaling pathway which is expected to be a new target for rescuing GC apoptosis and treating low fertility.

ZNF507 affects TGF-\u03b2 signaling via TGFBR1 and MAP3K8 activation in the progression of prostate cancer to an aggressive state

BackgroundThe progression of prostate cancer (PC) to the highly aggressive metastatic castration-resistant prostate cancer (mCRPC) or neuroendocrine prostate cancer (NEPC) is a fatal condition and the underlying molecular mechanisms are poorly understood. Here, we identified the novel transcriptional factor ZNF507 as a key mediator in the progression of PC to an aggressive state.MethodsWe analyzed ZNF507 expression in the data from various human PC database and high-grade PC patient samples. By establishment of ZNF507 knockdown and overexpression human PC cell lines, we assessed in vitro PC phenotype changes including cell proliferation, survival, migration and invasion. By performing microarray with ZNF507 knockdown PC cells, we profiled the gene clusters affected by ZNF507 knockdown. Moreover, ZNF507 regulated key signal was evaluated by dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Finally, we performed xenograft and in vivo metastasis assay to confirm the effect of ZNF507 knockdown in PC cells.ResultsWe found that ZNF507 expression was increased, particularly in the highly graded PC. ZNF507 was also found to be associated with metastatic PC of a high grade. Loss- or gain-of-function–based analysis revealed that ZNF507 promotes the growth, survival, proliferation, and metastatic properties of PC (e.g., epithelial-mesenchymal transition) by upregulating TGF-β signaling. Profiling of gene clusters affected by ZNF507 knockdown revealed that ZNF507 positively regulated the transcription of TGFBR1, MAP3K8, and FURIN, which in turn promoted the progression of PC to highly metastatic and aggressive state.ConclusionsOur findings suggest that ZNF507 is a novel key regulator of TGF-β signaling in the progression of malignant PC and could be a promising target for studying the development of advanced metastatic PCs.

Reduction in pericyte coverage leads to blood\u2013brain barrier dysfunction via endothelial transcytosis following chronic cerebral hypoperfusion

BackgroundChronic cerebral hypoperfusion (CCH) is the leading cause of cerebral small vessel disease (CSVD). CCH is strongly associated with blood–brain barrier (BBB) dysfunction and white matter lesions (WMLs) in CSVD. However, the effects of CCH on BBB integrity and components and the cellular and molecular mechanisms underlying the effects of BBB dysfunction remain elusive. Whether maintaining BBB integrity can reverse CCH-induced brain damage has also not been explored.MethodsIn this study, we established a rat model of CSVD via permanent bilateral common carotid artery occlusion (2VO) to mimic the chronic hypoperfusive state of CSVD. The progression of BBB dysfunction and components of the BBB were assessed using immunostaining, Western blotting, transmission electron microscopy (TEM) and RNA sequencing. We also observed the protective role of imatinib, a tyrosine kinase inhibitor, on BBB integrity and neuroprotective function following CCH. The data were analyzed using one-way or two-way ANOVA.ResultsWe noted transient yet severe breakdown of the BBB in the corpus callosum (CC) following CCH. The BBB was severely impaired as early as 1 day postoperation and most severely impaired 3 days postoperation. BBB breakdown preceded neuroinflammatory responses and the formation of WMLs. Moreover, pericyte loss was associated with BBB impairment, and the accumulation of serum protein was mediated by increased endothelial transcytosis in the CC. RNA sequencing also revealed increased transcytosis genes expression. BBB dysfunction led to brain damage through regulation of TGF-β/Smad2 signaling. Furthermore, imatinib treatment ameliorated serum protein leakage, oligodendrocyte progenitor cell (OPC) activation, endothelial transcytosis, microglial activation, and aberrant TGF-β/Smad2 signaling activation.ConclusionsOur results indicate that reduced pericyte coverage leads to increased BBB permeability via endothelial transcytosis. Imatinib executes a protective role on the BBB integrity via inhibition of endothelial transcytosis. Maintenance of BBB integrity ameliorates brain damage through regulation of TGF-β/Smad2 signaling following CCH; therefore, reversal of BBB dysfunction may be a promising strategy for CSVD treatment.

Elucidating the cellular mechanism for E2-induced dermal fibrosis

BackgroundBoth TGFβ and estradiol (E2), a form of estrogen, are pro-fibrotic in the skin. In the connective tissue disease, systemic sclerosis (SSc), both TGFβ and E2 are likely pathogenic. Yet the regulation of TGFβ in E2-induced dermal fibrosis remains ill-defined. Elucidating those regulatory mechanisms will improve the understanding of fibrotic disease pathogenesis and set the stage for developing potential therapeutics. Using E2-stimulated primary human dermal fibroblasts in vitro and human skin tissue ex vivo, we identified the important regulatory proteins for TGFβ and investigated the extracellular matrix (ECM) components that are directly stimulated by E2-induced TGFβ signaling.MethodsWe used primary human dermal fibroblasts in vitro and human skin tissue ex vivo stimulated with E2 or vehicle (ethanol) to measure TGFβ1 and TGFβ2 levels using quantitative PCR (qPCR). To identify the necessary cell signaling proteins in E2-induced TGFβ1 and TGFβ2 transcription, human dermal fibroblasts were pre-treated with an inhibitor of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway, U0126. Finally, human skin tissue ex vivo was pre-treated with SB-431542, a TGFβ receptor inhibitor, and ICI 182,780, an estrogen receptor α (ERα) inhibitor, to establish the effects of TGFβ and ERα signaling on E2-induced collagen 22A1 (Col22A1) transcription.ResultsWe found that expression of TGFβ1, TGFβ2, and Col22A1, a TGFβ-responsive gene, is induced in response to E2 stimulation. Mechanistically, Col22A1 induction was blocked by SB-431542 and ICI 182,780 despite E2 stimulation. Additionally, inhibiting E2-induced ERK/MAPK activation and early growth response 1 (EGR1) transcription prevents the E2-induced increase in TGFβ1 and TGFβ2 transcription and translation.ConclusionsWe conclude that E2-induced dermal fibrosis occurs in part through induction of TGFβ1, 2, and Col22A1, which is regulated through EGR1 and the MAPK pathway. Thus, blocking estrogen signaling and/or production may be a novel therapeutic option in pro-fibrotic diseases.

SEPHS1 promotes SMAD2/3/4 expression and hepatocellular carcinoma cells invasion

BackgroundHepatocellular carcinoma (HCC) is one of the common cancers that are very aggressive. The secreted cytokine transforming growth factor-β (TGF-β) promotes cancer metastasis by multiple mechanisms such as epithelial-mesenchymal transition and immune evasion. The canonical TGF-β signaling is largely mediated by smooth muscle actin/mothers against decapentaplegic (SMAD) proteins. The current study aims to explore the regulation of TGF-β/SMAD signaling by selenophosphate synthetase 1 (SEPHS1).MethodsImmunohistochemistry was used to detect the expression of SEPHS1 in HCC and adjacent liver tissues. Western blotting and quantitative reverse-transcription PCR were used to detect the protein and mRNA levels in HCC cell lines. Cell migration and invasion were determined by transwell assay. Bioinformatic analysis was conducted to determine SEPHS1 expression in HCC and its correlation with the survival of HCC patients.ResultsHere we report that SEPHS1 is a positive regulator of SMAD proteins. SEPHS1 expression is up-regulated in HCC compared with adjacent liver tissues. SEPHS1 knockdown leads to decreased expression of SMAD2/3/4 and mesenchymal markers including snail, slug and N-cadherin in HCC cells. Furthermore, SEPHS1 knockdown results in a decrease in HCC cells migration and invasion, and suppresses the stimulation of HCC cells migration and invasion by TGF-β. Overexpression of SEPHS1 in HCC cells promotes cell invasion, which can be abrogated by SMAD3 knockdown. Lastly, higher expression of SEPHS1 is correlated with poor prognosis in HCC patients, as manifested by decreased overall survival and disease-free survival.ConclusionsSEPHS1 is a positive regulator of TGF-β/SMAD signaling that is up-regulated in HCC. Increased SEPHS1 expression may indicate poor prognosis for patients with HCC.

Epigenetic regulation of TGF-\u03b2-induced EMT by JMJD3/KDM6B histone H3K27 demethylase

Transforming growth factor-β (TGF-β) signaling pathways are well-recognized for their role in proliferation and epithelial–mesenchymal transition (EMT) of cancer cells, but much less is understood about their contribution to interactions with other signaling events. Recent studies have indicated that crosstalk between TGF-β and Ras signaling makes a contribution to TGF-β-mediated EMT. Here, we demonstrate that Jumonji domain containing-3 (JMJD3 also called KDM6B) promotes TGF-β-mediated Smad activation and EMT in Ras-activated lung cancer cells. JMJD3 in lung cancer patients was significantly increased and JMJD3 expression in lung tumor tissues was correlated with expression of K-Ras or H-Ras in particular, and its expression was regulated by Ras activity in lung cancer cells. JMJD3 promotes TGF-β-induced Smad activation and EMT in Ras-activated lung cancer cells through the induction of syntenin, a protein that regulates TGF-β receptor activation upon ligand binding. Tissue array and ChIP analysis revealed that JMJD3 epigenetically induces syntenin expression by directly regulating H3K27 methylation levels. Mechanical exploration identified a physical and functional association of JMJD3 with syntenin presiding over the TGF-β in Ras-activated lung cancer cells. Taken together, these findings provide new insight into the mechanisms by which JMJD3 promotes syntenin expression resulting in oncogenic Ras cooperation with TGF-β to promote EMT.

Transcriptional factor ATF3 promotes liver fibrosis via activating hepatic stellate cells

The excessive accumulation of extracellular matrix (ECM) is a key feature of liver fibrosis and the activated hepatic stellate cells (HSCs) are the major producer of ECM proteins. However, the precise mechanisms and target molecules that are involved in liver fibrosis remain unclear. In this study, we reported that activating transcription factor 3 (ATF3) was over-expressed in mice and human fibrotic livers, in activated HSCs and injured hepatocytes (HCs). Both in vivo and in vitro study have revealed that silencing ATF3 reduced the expression of pro-fibrotic genes and inhibited the activation of HSCs, thus alleviating the extent of liver fibrosis, indicating a potential protective role of ATF3 knockdown. However, ATF3 was not involved in either the apoptosis or proliferation of HCs. In addition, our data illustrated that increased nuclear localization of ATF3 promoted the transcription of fibrogenic genes and lnc-SCARNA10, which functioned as a novel positive regulator of TGF-β signaling in liver fibrogenesis by recruiting SMAD3 to the promoter of these genes. Interestingly, further study also demonstrated that lnc-SCARNA10 promoted the expression of ATF3 in a TGF-β/SMAD3-dependent manner, revealing a TGF-β/ATF3/lnc-SCARNA10 axis that contributed to liver fibrosis by activating HSCs. Taken together, our data provide a molecular mechanism implicating induced ATF3 in liver fibrosis, suggesting that ATF3 may represent a useful target in the development of therapeutic strategies for liver fibrosis.

Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by patchy scarring of the distal lung with limited therapeutic options and poor prognosis. Here, we show that conditional deletion of the ubiquitin ligase Nedd4-2 (Nedd4l) in lung epithelial cells in adult mice produces chronic lung disease sharing key features with IPF including progressive fibrosis and bronchiolization with increased expression of Muc5b in peripheral airways, honeycombing and characteristic alterations in the lung proteome. NEDD4-2 is implicated in the regulation of the epithelial Na+ channel critical for proper airway surface hydration and mucus clearance and the regulation of TGFβ signaling, which promotes fibrotic remodeling. Our data support a role of mucociliary dysfunction and aberrant epithelial pro-fibrotic response in the multifactorial disease pathogenesis. Further, treatment with the anti-fibrotic drug pirfenidone reduced pulmonary fibrosis in this model. This model may therefore aid studies of the pathogenesis and therapy of IPF.

MSX2 suppression through inhibition of TGF\u03b2 signaling enhances hematopoietic differentiation of human embryonic stem cells

BackgroundStrategies of generating functional blood cells from human pluripotent stem cells (hPSCs) remain largely unsuccessful due to the lack of a comprehensive understanding of hematopoietic development. Endothelial-to-hematopoietic transition (EHT) serves as the pivotal mechanism for the onset of hematopoiesis and is negatively regulated by TGF-β signaling. However, little is known about the underlying details of TGF-β signaling during EHT.MethodsIn this study, by applying genome-wide gene profiling, we identified muscle segment homeobox2 (MSX2) as a potential mediator of TGF-β signaling during EHT. We generated MSX2-deleted human embryonic stem cell (hESC) lines using the CRISPR/Cas9 technology and induced them to undergo hematopoietic differentiation. The role of MSX2 in hematopoiesis and functional regulation of TGFβ signaling in EHT was studied.ResultsWe identified MSX2 as a novel regulator of human hematopoiesis. MSX2 deletion promotes the production of hematopoietic cells from hESCs. Functional and bioinformatics studies further demonstrated that MSX2 deletion augments hematopoietic differentiation of hESCs by facilitating EHT. Mechanistically, MSX2 acts as a downstream target of TGFβ signaling to mediate its function during EHT.ConclusionsOur results not only improve the understanding of EHT, but may also provide novel insight into the efficient production of functional blood cells from hPSCs for regenerative medicine.

Role of SIX1 homeoprotein in the regulation of TGF[beta] pathway in anaplastic thyroid cancer

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Transcriptome analysis reveals autophagy as regulator of TGF\u03b2/Smad-induced fibrogenesis in trabecular meshwork cells

The trabecular meshwork (TM) is a specialized ocular tissue, which is responsible, together with the Schlemm’s canal (SC), for maintaining appropriate levels of intraocular pressure. Dysfunction of these tissues leads to ocular hypertension and increases the risk for developing glaucoma. Previous work by our laboratory revealed dysregulated autophagy in aging and in glaucomatous TM cells. In order to gain more insight in the role of autophagy in the TM pathophysiology, we have conducted transcriptome and functional network analyses of TM primary cells with silenced expression of the autophagy genes Atg5 and Atg7. Atg5/7-deficient TM cells showed changes in transcript levels of several fibrotic genes, including TGFβ2, BAMBI, and SMA. Furthermore, genetic and pharmacological inhibition of autophagy was associated with a parallel reduction in TGFβ-induced fibrosis, caused by a BAMBI-mediated reduced activation of Smad2/3 signaling in autophagy-deficient cells. At the same time, TGFβ treatment led to Smad2/3-dependent dysregulation of autophagy in TM cells, characterized by increased LC3-II levels and autophagic vacuoles content. Together, our results indicate a cross-talk between autophagy and TGFβ signaling in TM cells.

Enhanced survival of lethally irradiated mice given pegylated G-CSF, GM-CSF, and IL-11 with lisinopril via modulation of the hematopoietic cytokines TGF[Symbol]-1 and RANTES

Background and Hypothesis: 
 We have previously shown increased survival in mice given pegylated growth factors, G-CSF, GM-CSF, and IL-11 (triple combo, TC), with lisinopril compared to TC alone in the hematopoietic acute radiation syndrome (H-ARS). This experiment investigated the mechanism behind the survival benefit. We hypothesized lisinopril regulates inflammatory cytokines hence increasing quiescence of primitive bone marrow cells. 
 Experimental Design or Project Methods: 
 C57BL/6 mice were exposed to LD90/30 total body irradiation (TBI). The irradiated mice were given a TC injection on day 1, and lisinopril was administered in drinking water beginning on day 7. Mice were euthanized on day 10. Flow cytometry was used to analyze bone marrow cell cycle and Bioplex was used to analyze cytokines in bone marrow supernatant. 
 Results: 
 Treatment with TC+lisinopril significantly decreased the level of the pro-inflammatory cytokine RANTES compared with vehicle mice (Veh) and TC alone (TC+Liso vs. Veh: 3.6 vs. 7.8 pg/mL, p<0.01; TC+Liso vs. TC: 3.6 vs. 5.2 pg/ml, p<0.01). TC+lisinopril increases levels of the pro-quiescence cytokine TGF-[Symbol]1, compared with Veh and TC alone (TC+Liso vs. Veh: 92.8 vs. 45.6 pg/mL, p<0.05; TC+Liso vs. TC: 92.8 vs. 44.7 pg/ml, p<0.01). TC alone had lower percentages of quiescent Lin- primitive bone marrow cells (G0+G1) than non-irradiated (NI) mice (75.7 vs. 85.2%, p<0.05), whereas there is no difference between TC+Liso and NI mice (83.0 vs. 85.2%, p=0.44). 
 Conclusion and Potential Impact: 
 The increased survival of H-ARS mice given lisinopril might be due to the regulation of TGF-[Symbol]1 and RANTES levels in the bone marrow leading to quiescence of primitive bone marrow cells.

MiR-190 suppresses breast cancer metastasis by regulation of TGF-\u03b2-induced epithelial\u2013mesenchymal transition

BackgroundBreast cancer is the most common cancer among women worldwide and metastasis is the leading cause of death among patients with breast cancer. The transforming growth factor-β (TGF-β) pathway plays critical roles during breast cancer epithelial–mesenchymal transition (EMT) and metastasis. SMAD2, a positive regulator of TGF-β signaling, promotes breast cancer metastasis through induction of EMT.MethodsThe expression of miR-190 and SMAD2 in breast cancer tissues, adjacent normal breast tissues and cell lines were determined by RT-qPCR. The protein expression levels and localization were analyzed by western blotting and immunofluorescence. ChIP and dual-luciferase report assays were used to validate the regulation of ZEB1-miR-190-SMAD2 axis. The effect of miR-190 on breast cancer progression was investigated both in vitro and in vivo.ResultsmiR-190 down-regulation is required for TGF-β-induced EMT. miR-190 suppresses breast cancer metastasis both in vitro and in vivo by targeting SMAD2. miR-190 expression is down-regulated and inversely correlates with SMAD2 in breast cancer samples, and its expression level was associated with outcome in patients with breast cancer. Furthermore, miR-190 is transcriptionally regulated by ZEB1.ConclusionsOur data uncover the ZEB1-miR-190-SMAD2 axis and provide a mechanism to explain the TGF-β network in breast cancer metastasis.