Extracellular microvesicles that originated adipose tissue derived mesenchymal stem cells have the potential ability to improve rheumatoid arthritis on mice.

Introduction: Mesenchymal stem cells (MSCs) are promising therapeutic tools in regenerative medicine. In particularly adipose tissue derived MSC (AMSC) has powerful potential for the therapeutics of rheumatoid arthritis (RA) because these cells can control immune balance. RA systemically occurs autoimmune disease.

miR-27a ameliorates chemoresistance of breast cancer cells by disruption of reactive oxygen species homeostasis and impairment of autophagy.

In patients with breast cancer, primary chemotherapy often fails due to survival of chemoresistant breast cancer stem cells (BCSCs) which results in recurrence and metastasis of the tumor. However, the factors determining the chemoresistance of BCSCs have remained to be investigated. Here, we profiled a series of differentially expressed microRNAs (miRNAs) between parental adherent breast cancer cells and BCSC-mimicking mammosphere-derived cancer cells, and identified hsa-miR-27a as a negative regulator for survival and chemoresistance of BCSCs.

Novel form of miR-29b suppresses bleomycin-induced pulmonary fibrosis.

MicroRNA 29b (miR-29b) replacement therapy is effective for suppressing fibrosis in a mouse model. However, to develop clinical applications for miRNA mimics, the side effects of nucleic acid drugs have to be addressed. In this study, we focused on miRNA mimics in order to develop therapies for idiopathic pulmonary fibrosis.

Novel Types of Small RNA Exhibit Sequence- and Target-dependent Angiogenesis Suppression Without Activation of Toll-like Receptor 3 in an Age-related Macular Degeneration (AMD) Mouse Model.

RNA interference (RNAi) has become a powerful tool for suppressing gene expression in vitro and in vivo. A great deal of evidence has demonstrated the potential for the use of synthetic small interfering RNAs (siRNAs) as therapeutic agents. However, the application of siRNA to clinical medicine is still limited, mainly due to sequence-independent suppression of angiogenesis mediated by Toll-like receptor 3 (TLR3).

Adult-specific systemic over-expression reveals novel in vivo effects of the soluble forms of ActRIIA, ActRIIB and BMPRII.

Bone morphogenetic proteins (BMPs)/growth differentiation factors (GDFs), which belong to the TGF-beta superfamily, are pleiotropic factors that play a role in regulating the embryonic development and postnatal homeostasis of various organs and tissues by controlling cellular differentiation, proliferation and apoptosis. Conventional transgenic and knockout (KO) mouse approaches have provided only limited information regarding the in vivo functions of BMP signaling in adult animals due to the effects on prenatal development and the difficulty in manipulating multiligand signals simultaneously. We recently produced transgenic chimeric mice(Tg chimeras) in which the soluble IgG1-Fc fusion protein of three BMP type II receptors (ActRIIA, ActRIIB, BMPRII) was highly circulated (281-709 μg/ml), specifically in adult mouse blood.

Significant modulation of the hepatic proteome induced by exposure to low temperature in Xenopus laevis.

The African clawed frog, Xenopus laevis, is an ectothermic vertebrate that can survive at low environmental temperatures. To gain insight into the molecular events induced by low body temperature, liver proteins were evaluated at the standard laboratory rearing temperature (22°C, control) and a low environmental temperature (5°C, cold exposure). Using nano-flow liquid chromatography coupled with tandem mass spectrometry, we identified 58 proteins that differed in abundance.

Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells.

Despite the therapeutic potential of nucleic acid drugs, their clinical application has been limited in part by a lack of appropriate delivery systems. Exosomes or microvesicles are small endosomally derived vesicles that are secreted by a variety of cell types and tissues. Here, we show that exosomes can efficiently deliver microRNA (miRNA) to epidermal growth factor receptor (EGFR)-expressing breast cancer cells.

miR-92 is a key oncogenic component of the miR-17-92 cluster in colon cancer.

MicroRNAs (miRNAs) belong to a class of endogenously expressed non-coding small RNAs that function primarily as gene regulators. Growing evidence suggests that miRNAs play a significant role in tumor development, making them potential biomarkers for cancer diagnosis and prognosis. The miR-17-92 cluster has emerged as an important locus, being highly overexpressed in several cancers in association with cancer development and progression.

Trans-differentiation of a duodenal phenotype on duodenal transplantation of different normal tissues in F344 rats.

The mechanisms regulating stem cell differentiation and self-renewal are largely unknown. Our ultimate goal is to be able to regulate somatic stem cell differentiation and proliferation. In the present study the ability of trans-differentiation was studied when different normal tissue types were transplanted into the duodenum in rats.

Establishment of rat embryonic stem cells and making of chimera rats.

The rat is a reference animal model for physiological studies and for the analysis of multigenic human diseases such as hypertension, diabetes, neurological disorders, and cancer. The rats have long been used in extensive chemical carcinogenesis studies. Thus, the rat embryonic stem (rES) cell is an important resource for the study of disease models.

Possible application of human c-Ha-ras proto-oncogene transgenic rats in a medium-term bioassay model for carcinogens.

With the aim of developing a medium-term assay for screening of environmental carcinogens, we exposed mammary carcinogen sensitive human c-Ha-ras proto-oncogene transgenic (Hras128) rats to various carcinogens, including compounds that do not normally induce mammary tumors. Seven-week-old Hras128 rats and wild-type littermates received administrations of 3-methylcholanthrene (3-MC), benzo[a]pyrene (B[a]P), anthracene, pyrene, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), dimethylarsinic acid (DMA), diethylnitrosamine (DEN) or azoxymethane (AOM) and were sacrificed at week 12 (females) (at week 10 for the 3-MC group) or week 20 (males). Female Hras128 rats receiving NNK, DEN, or DMA showed a significant increase in mammary tumor incidence and/or multiplicity compared to the respective values with olive oil or deionized distilled water (DDW) vehicles.

Differentiation of a hepatic phenotype after heterotropic transplantation of heart, kidney, brain, and skin tissues into liver in F344 rats.

While organ-specific stem cells with roles in tissue injury repair have been documented, their pathogenic significance in diseases and the factors potentially responsible for their activation remain largely unclear. In the present study, heart, kidney, brain, and skin samples from F344 transgenic rats carrying the GFP gene were transplanted into normal F344 rat liver one day after an intraperitoneal injection (i.p.

Possible enhancing activity of diacylglycerol on 4-nitroquinoline 1-oxide induced carcinogenesis of the tongue in human c-Ha-ras proto-oncogene transgenic rats.

1,2-diacylglycerol (1,2-DAG) is involved in cell proliferation as an activator of protein kinase C (PKC) and has been shown to stimulate growth of cancer cells, raising the possibility of a role in tumor promotion. Ingested DAG oil, containing 70% 1,3-DAG and 30% 1,2-DAG, is digested and considered to be safe as edible oil. However, DAG may directly contact with oral cavity mucosa in undigested form.

Ductal origin of pancreatic adenocarcinomas induced by conditional activation of a human Ha-ras oncogene in rat pancreas.

Pancreatic ductal adenocarcinoma is one of the most debilitating malignancies in humans. Currently, radiation and chemotherapy are ineffective, with median survival times after treatment of <12 months. Animal models that reflect the human condition and can be used to explore screening and therapeutic approaches are clearly desirable.

MOZ is essential for maintenance of hematopoietic stem cells.

Monocytic leukemia zinc-finger protein (MOZ), a MYST family histone acetyltransferase, is involved in the chromosome translocations associated with acute myeloid leukemia. MOZ acts as a transcriptional coactivator for AML1, which is essential for establishment of definitive hematopoiesis. To investigate the roles of MOZ in normal hematopoiesis, we generated MOZ-null mice.

High susceptibility of human c-Ha-ras proto-oncogene transgenic rats to carcinogenesis: a cancer-prone animal model.

Transgenic animals carrying human c-Ha-ras proto-oncogene, v-Ha-ras transgenic mice, pim-1 transgenic mice and several knockout mice deficient of tumor suppressor genes, such as p53, have been shown to exhibit increased carcinogen susceptibility. As a result, studies into practical application and medium-term screening of environmental carcinogens are under way. Given the advantages of rat models characterized by larger organ size, abundant information regarding preneoplasias and virus-free constitution, we have concentrated on the generation of transgenic rats bearing copies of the human c-Ha-ras proto-oncogene and shown the Hras128 strain to be extremely sensitive to the induction of mammary carcinomas, and to a lesser extent, lesions in the urinary bladder, esophagus and skin.

Preferential mammary carcinogenic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in human c-Ha-ras proto-oncogene transgenic rats.

In order to clarify the susceptibility of the Hras128 rat harboring copies of the human c-Ha-ras proto-oncogene to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), Hras128 rats were intragastically treated with 100 mg/kg PhIP 8 times (females) or 80 mg/kg PhIP 10 times (males) over a 9-week period, then sacrificed at weeks 12 and 30. Multiple mammary tumors of adenocarcinoma type were induced in all females, while 83% of treated males developed adenocarcinomas, sarcomas and transitional carcinosarcomas, as evidenced by casein and vimentin immunoreactivity. All tumors examined had mutations in the c-Ha-ras transgene, while the endogenous rat c-Ha-ras gene was intact.

Rapid induction of skin and mammary tumors in human c-Ha-ras proto-oncogene transgenic rats by treatment with 7,12-dimethylbenz[a]anthracene followed by 12-O-tetradecanoylphorbol 13-acetate.

We have established a transgenic rat line carrying 3 copies of the human c-Ha-ras proto-oncogene with its own promoter region (Jcl/SD-TgN(HrasGen)128Ncc) (Hras128 rat), expression being detectable in almost all organs. We have already demonstrated that the rat is highly sensitive to mammary, esophagus and bladder carcinogenesis. In the present study, male and female transgenic and wild-type littermates were topically treated with 2.

Terminal endbuds and acini as the respective major targets for chemical and sporadic carcinogenesis in the mammary glands of human c-Ha-ras protooncogene transgenic rats.

A rat strain carrying the human c-Ha-ras protooncogene, established by our laboratory, is highly susceptible to mammary chemical carcinogens. The transgenic rats exhibit increased number of terminal endbuds (TEBs) at the tips of developing ducts in the mammary gland compared to non-transgenic littermates. Confocal microscopy revealed the level of active mitogen-activated protein kinase to be elevated in these TEBs, and a close correlation between their numbers and tumorigenic response initiated by 7,12-dimethylbenz[a]anthracene was confirmed.