Role of the epithelial-mesenchymal transition and its effects on embryonic stem cells

The epithelial-mesenchymal transition (EMT) is important for embryonic development and the formation of various tissues or organs. However, EMT dysfunction in normal cells leads to diseases, such as cancer or fibrosis. During the EMT, epithelial cells are converted into more invasive and active mesenchymal cells. E-box-binding proteins, including Snail, ZEB and helix-loop-helix family members, serve as EMT-activating transcription factors. These transcription factors repress the expression of epithelial markers, for example, E-cadherin, rearrange the cytoskeleton and promote the expression of mesenchymal markers, such as vimentin, fibronectin and other EMT-activating transcription factors. Signaling pathways that induce EMT, including transforming growth factor-beta, Wnt/glycogen synthase kinase-3beta, Notch and receptor tyrosine kinase signaling pathways, interact with each other for the regulation of this process. Although the mechanism(s) underlying EMT in cancer or embryonic development have been identified, the mechanism(s) in embryonic stem cells (ESCs) remain unclear. In this review, we describe the underlying mechanisms of important EMT factors, indicating a precise role for EMT in ESCs, and characterize the relationship between EMT and ESCs.

Development and application of neural stem cells for treating various human neurological diseases in animal models / 한국실험동물학회지

Stem cells derived from adult tissues or the inner cell mass (ICM) of embryos in the mammalian blastocyst (BL) stage are capable of self-renewal and have remarkable potential for undergoing lineage-specific differentiation under in vitro culturing conditions. In particular, neural stem cells (NSCs) that self-renew and differentiate into major cell types of the brain exist in the developing and adult central nervous system (CNS). The exact function and distribution of NSCs has been assessed, and they represent an interesting population that includes astrocytes, oligodendrocytes, and neurons. Many researchers have demonstrated functional recovery in animal models of various neurological diseases such as stroke, Parkinson's disease (PD), brain tumors, and metastatic tumors. The safety and efficacy of stem cell-based therapies (SCTs) are also being evaluated in humans. The therapeutic efficacy of NSCs has been shown in the brain disorder-induced animal models, and animal models may be well established to perform the test before clinical stage. Taken together, data from the literature have indicated that therapeutic NSCs may be useful for selectively treating diverse types of human brain diseases without incurring adverse effects.

Modulation of lipid metabolism by mixtures of protamine and chitooligosaccharide through pancreatic lipase inhibitory activity in a rat model / 한국실험동물학회지

Overweight and obesity are usually related with high fat and calorie intake, and seriously causative of lifestyle-related diseases such as cardiovascular disorders, arteriosclerosis, and colon cancer. In this study, we propose a novel dietary therapy against overweight and obesity using mixtures of protamine and chitooligosaccharide (COS), which are known to interrupt the lipid metabolism in the body. Protamine is a dietary protein originated from salmon reproductive organ, and COS is an oligosaccharide made from chitin or chitosan by chemical or enzymatic hydrolysis. In the enzyme activity analysis in vitro, protamine and COS strongly suppressed the activity of pancreatic lipase, which is the primary enzyme for the digestion and absorption of lipids in the intestine. In in vivo animal test, the mixtures of protamine and COS significantly reduced the serum levels of triglyceride (TG), total cholesterol (T-CHO), and low density lipoprotein-cholesterol (LDLC) and inhibited the accumulation of lipids in liver tissue of Sprague Dawley (SD) rats fed high fat diets. On the other hand, they increased fecal TG and T-CHO contents. From these alterations in lipid metabolism, we verified that protamine and COS mixtures could effectively interrupt the digestion and absorption of dietary lipids in the body by inhibiting pancreatic lipase activity. In addition, protamine and COS mixtures increased the serum level of high density lipoprotein-cholesterol (HDLC), responsible for removing cholesterol from cells and protecting atherosclerosis, and therefore decreased the potential risks of cardiovascular diseases by lowering values of the atherogenic index (AI) and cardiac risk factor (CRF). Taken together, we suggest protamine and COS mixtures as a prominent dietary therapy for the prevention of overweight, obesity, and further cardiovascular diseases related with hyperlipidemia.

Molecular Mechanisms and In Vivo Mouse Models of Skin Aging Associated with Dermal Matrix Alterations / 한국실험동물학회지

Skin is the most superficial body organ and plays an important role in protecting the body from environmental damage and in forming social relations. With the increase of the aging population in our society, dermatological and cosmetic concerns of skin aging are rapidly increasing. Skin aging is a complex process combined with intrinsic and extrinsic factors. Intrinsic or chronological skin aging results from the passage of time and is influenced by genetic factors. Extrinsic skin aging is mainly determined by UV irradiation, also called photoaging. These two types of aging processes are superimposed on sun-exposed skin, and have a common feature of causing dermal matrix alterations that mostly contribute to the formation of wrinkles, laxity, and fragility of aged skin. The dermal matrix contains extracellular matrix proteins such as collagen, elastin, and proteoglycans that confer the strength and resiliency of skin. Skin aging associated with dermal matrix alterations and atrophy can be caused by cellular senescence of dermal cells like fibroblasts, and decreased synthesis and accelerated degradation of dermal matrix components, especially collagen fibers. Both intrinsic aging and photoaging exert influence during each step of dermal matrix alteration via different mechanisms. Mouse models of skin aging have been extensively developed to elucidate intrinsic aging and photoaging processes, to validate in vitro biochemical data, and to test the effects of pharmacological tools for retarding skin aging because they have the advantages of being genetically similar to humans and are easily available.

Gene Alterations of Ovarian Cancer Cells Expressing Estrogen Receptors by Estrogen and Bisphenol A Using Microarray Analysis / 한국실험동물학회지

Since endocrine disrupting chemicals (EDCs) may interfere with the endocrine system(s) of our body and have an estrogenicity, we evaluated the effect(s) of bisphenol A (BPA) on the transcriptional levels of altered genes in estrogen receptor (ER)-positive BG-1 ovarian cancer cells by microarray and real-time polymerase-chain reaction. In this study, treatment with 17beta-estradiol (E2) or BPA increased mRNA levels of E2-responsive genes related to apoptosis, cancer and cell cycle, signal transduction and nucleic acid binding etc. In parallel with their microarray data, the mRNA levels of some altered genes including RAB31_MEMBER RAS ONCOGENE FAMILY (U59877), CYCLIN D1 (X59798), CYCLIN-DEPENDENT KINASE 4 (U37022), IGF-BINDING PROTEIN 4 (U20982), and ANTI-MULLERIAN HORMONE (NM_000479) were significantly induced by E2 or BPA in this cell model. These results indicate that BPA in parallel with E2 induced the transcriptional levels of E2-responsive genes in an estrogen receptor (ER)-positive BG-1 cells. In conclusion, these microarray and real-time polymerase-chain reaction results indicate that BPA, a potential weak estrogen, may have estrogenic effect by regulating E2-responsive genes in ER-positive BG-1 cells and BG-1 cells would be the best in vitro model to detect these estrogenic EDCs.

Gene Mutations in Animal Models: Do Tumor Suppressor Genes, brca1 and brca2, Play a Role in Ovarian Carcinogenesis? / 한국실험동물학회지

Ovarian cancer is the most lethal cause of death from gynecological malignancies in the Western world. Over 90% of human ovarian cancers arise in the ovarian surface epithelium (OSE). The OSE surrounding the ovary is simple mesothelium and squamous to flat-cubobidal mesothelial cells. This cell type of ovary has both epithelial and mesenchymal potential. Also OSE cells are regulated by many factors such as cytokines, growth factors, and multiple hormones. Nevertheless OSE function is poorly understood. In particular, ovarian cancers are closely related with hereditary predisposition. Hereditary ovarian tumors are commonly associated with mutations in tumor suppressor genes such as brca1 and brca2 genes. These genes play a role in maintenance of genome integrity, DNA repair, cell cycle control and apoptosis. Mutations in brca1 and/or brca2 may lead to carcinogenesis through distinct molecular pathways like estrogen-mediated proliferation, the presence of a p53 mutation, and the modulation of the activity of NF-kB. Especially the dysfunction of brca1 triggers the inactivation of p53 and a higher proportion of a p53 mutation is commonly linked to brca-linked ovarian tumorigenesis. The dysfunction of brca1 and/or brca2 can arise from multiple mechanisms in the regulation of both JNK and ERK1/2 signaling. For more effective diagnosis and therapy of ovarian cancer, the role of brca1 and/or brca2 in ovarian cancer has to be distinctively elucidated by the animal models in which the gene functions are deleted in mouse OSE cells and by the mechanisms by which these genes affect ovarian carcinogenesis.