• The Korean Journal of Physiology and Pharmacology
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• v.9 no.1
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• pp.1-8
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• 2005

Myotonic Dystrophies type 1 and 2 (DM1/2) are neuromuscular disorders which belong to a group of genetic diseases caused by unstable CTG triplet repeat (DM1) and CCTG tetranucleotide repeat (DM2) expansions. In DM1, CTG repeats are located within the 3' untranslated region of myotonin protein kinase (DMPK) gene on chromosome 19q. DM2 is caused by expansion of CCTG repeats located in the first intron of a gene coding for zinc finger factor 9 on chromosome 3q. The CTG and CCTG expansions are located in untranslated regions and are expressed as pre-mRNAs in nuclei (DM1 and DM2) and as mRNA in cytoplasm (DM1). Investigations of molecular alterations in DM1 discovered a new molecular mechanism responsible for this disease. Expansion of un-translated CUG repeats in the mutant DMPK mRNA disrupts biological functions of two CUG-binding proteins, CUGBP and MNBL. These proteins regulate translation and splicing of mRNAs coding for proteins which play a key role in skeletal muscle function. Expansion of CUG repeats alters these two stages of RNA metabolism in DM1 by titrating CUGBP1 and MNBL into mutant DMPK mRNA-protein complexes. Mouse models, in which levels of CUGBP1 and MNBL were modulated to mimic DM1, showed several symptoms of DM1 disease including muscular dystrophy, cataracts and myotonia. Mis-regulated levels of CUGBP1 in newborn mice cause a delay of muscle development mimicking muscle symptoms of congenital form of DM1 disease. Since expansion of CCTG repeats in DM2 is also located in untranslated region, it is predicted that DM2 mechanisms might be similar to those observed in DM1. However, differences in clinical phenotypes of DM1 and DM2 suggest some specific features in molecular pathways in both diseases. Recent publications suggest that number of pathways affected by RNA CUG and CCUG repeats could be larger than initially thought. Detailed studies of these pathways will help in developing therapy for patients affected with DM1 and DM2.

• Journal of Periodontal and Implant Science
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• v.50 no.5
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• pp.313-326
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• 2020

Purpose: This study was conducted to analyze specific RNA expression profiles in gingival tissue and saliva samples in periodontitis patients and healthy individuals, and to determine their correlations in light of the potential use of microarray-based analyses of saliva samples as a periodontal monitoring tool. Methods: Gingival tissue biopsies and saliva samples from 22 patients (12 with severe periodontitis and 10 with a healthy periodontium) were analyzed using transcriptomic microarray analysis. Differential gene expression was assessed, and pathway and clustering analyses were conducted for the samples. The correlations between the results for the gingival tissue and saliva samples were analyzed at both the gene and pathway levels. Results: There were 621 differentially expressed genes (DEGs; 320 upregulated and 301 downregulated) in the gingival tissue samples of the periodontitis group, and 154 DEGs (44 upregulated and 110 downregulated) in the saliva samples. Nine of these genes overlapped between the sample types. The periodontitis patients formed a distinct cluster group based on gene expression profiles for both the tissue and saliva samples. Database for Annotation, Visualization and Integrated Discovery analysis revealed 159 enriched pathways from the tissue samples of the periodontitis patients, as well as 110 enriched pathways In the saliva samples. Thirty-four pathways overlapped between the sample types. Conclusions: The present results indicate the possibility of using the salivary transcriptome to distinguish periodontitis patients from healthy individuals. Further work is required to enhance the extraction of available RNA from saliva samples.

• Journal of Ginseng Research
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• v.41 no.1
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• pp.78-84
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• 2017

Background: In the present study, metabolite profiles of ginsenosides Rk1 and Rg5 from red ginseng or red notoginseng in zebrafish were qualitatively analyzed with ultraperformance liquid chromatography/quadrupole-time-of-flight MS, and the possible metabolic were pathways proposed. Methods: After exposing to zebrafish for 24 h, we determined the metabolites of ginsenosides Rk1 and Rg5. The chromatography was accomplished on UPLC BEH C18 column using a binary gradient elution of 0.1% formic acetonitrile-0.1% formic acid water. The quasimolecular ions of compounds were analyzed in the negative mode. With reference to quasimolecular ions and MS2 spectra, by comparing with reference standards and matching the empirical molecular formula with that of known published compounds, and then the potential structures of metabolites of ginsenosides Rk1 and Rg5 were acquired. Results: Four and seven metabolites of ginsenoside Rk1 and ginsenoside Rg5, respectively, were identified in zebrafish. The mechanisms involved were further deduced to be desugarization, glucuronidation, sulfation, and dehydroxymethylation pathways. Dehydroxylation and loss of C-17 residue were also metabolic pathways of ginsenoside Rg5 in zebrafish. Conclusion: Loss of glucose at position C-3 and glucuronidation at position C-12 in zebrafish were regarded as the primary physiological processes of ginsenosides Rk1 and Rg5.

• Clinical and Experimental Reproductive Medicine
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• v.48 no.3
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• pp.211-220
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• 2021

Objective: The present study aimed to investigate the possibility that curcumin (CMN) protects against methotrexate (MTX)-induced testicular damage by affecting the phospho-p38 (p-p38) mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways. Methods: Eighteen male Wistar albino rats were randomly divided into three groups. The control group was given an intragastric administration of dimethyl sulfoxide (DMSO) daily for 14 days, the MTX group was given a single intraperitoneal dose of MTX (20 mg/kg) on the 11th day, and the MTX+CMN group was given intragastric CMN (100 mg/kg/day, dissolved in DMSO) for 14 days and a single intraperitoneal dose of MTX (20 mg/kg) on the 11th day. At the end of the experiment, all animals were sacrificed and the testicular tissues were removed for morphometry, histology, and immunohistochemistry. Body and testicular weights were measured. Results: Body weights, seminiferous tubule diameter, and germinal epithelium height significantly decreased in the MTX group compared to the control group. Whereas, the number of histologically damaged seminiferous tubules and interstitial space width significantly increased in the MTX group. In addition, the number of p-p38 MAPK immunopositive cells and the immunoreactivity of NF-κB also increased in the MTX group compared to the control group. CMN improved loss of body weight, morphometric values, and histological damage due to MTX. CMN also reduced the number of p-p38 MAPK immunopositive cells and the NF-κB immunoreactivity. Conclusion: CMN may reduce MTX-induced testicular damage by suppressing the p38 MAPK and NF-κB signaling pathways.

• Journal of Yeungnam Medical Science
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• v.37 no.4
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• pp.269-276
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• 2020

Fibrosis is characterized by excessive accumulation of extracellular matrix components. The fibrotic process ultimately leads to organ dysfunction and failure in chronic inflammatory and metabolic diseases such as pulmonary fibrosis, advanced kidney disease, and liver cirrhosis. Idiopathic pulmonary fibrosis (IPF) is a common form of progressive and chronic interstitial lung disease of unknown etiology. Pathophysiologically, the parenchyma of the lung alveoli, interstitium, and capillary endothelium becomes scarred and stiff, which makes breathing difficult because the lungs have to work harder to transfer oxygen and carbon dioxide between the alveolar space and bloodstream. The transforming growth factor beta (TGF-β) signaling pathway plays an important role in the pathogenesis of pulmonary fibrosis and scarring of the lung tissue. Recent clinical trials focused on the development of pharmacological agents that either directly or indirectly target kinases for the treatment of IPF. Therefore, to develop therapeutic targets for pulmonary fibrosis, it is essential to understand the key factors involved in the pathogenesis of pulmonary fibrosis and the underlying signaling pathway. The objective of this review is to discuss the role of kinase signaling cascades in the regulation of either TGF-β-dependent or other signaling pathways, including Rho-associated coiled-coil kinase, c-jun N-terminal kinase, extracellular signal-regulated kinase 5, and p90 ribosomal S6 kinase pathways, and potential therapeutic targets in IPF.

• Genomics & Informatics
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• v.12 no.1
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• pp.35-41
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• 2014

Single-nucleotide polymorphisms (SNPs) have been emerging out of the efforts to research human diseases and ethnic disparities. A semantic network is needed for in-depth understanding of the impacts of SNPs, because phenotypes are modulated by complex networks, including biochemical and physiological pathways. We identified ethnicity-specific SNPs by eliminating overlapped SNPs from HapMap samples, and the ethnicity-specific SNPs were mapped to the UCSC RefGene lists. Ethnicity-specific genes were identified as follows: 22 genes in the USA (CEU) individuals, 25 genes in the Japanese (JPT) individuals, and 332 genes in the African (YRI) individuals. To analyze the biologically functional implications for ethnicity-specific SNPs, we focused on constructing a semantic network model. Entities for the network represented by "Gene," "Pathway," "Disease," "Chemical," "Drug," "ClinicalTrials," "SNP," and relationships between entity-entity were obtained through curation. Our semantic modeling for ethnicity-specific SNPs showed interesting results in the three categories, including three diseases ("AIDS-associated nephropathy," "Hypertension," and "Pelvic infection"), one drug ("Methylphenidate"), and five pathways ("Hemostasis," "Systemic lupus erythematosus," "Prostate cancer," "Hepatitis C virus," and "Rheumatoid arthritis"). We found ethnicity-specific genes using the semantic modeling, and the majority of our findings was consistent with the previous studies - that an understanding of genetic variability explained ethnicity-specific disparities.

• Toxicological Research
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• v.25 no.2
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• pp.85-92
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• 2009

4,4'-Methylenedianiline (MDA) is an aromatic amine that is widely used in the industrial synthetic process. Genotoxic MDA forms DNA adducts in the liver and is known to induce liver damage in human and rats. To elucidate the molecular mechanisms associated with MDA-induced hepatotoxicity, we have identified genes differentially expressed by microarray approach. BALB/c male mice were treated once daily with MDA (20 mg/kg) up to 7 days via intraperitoneal injection (i.p.) and hepatic damages were revealed by histopathological observation and elevation of serum marker enzymes such as AST, ALT, ALP, cholesterol, DBIL, and TBIL. Microarray analysis showed that 952 genes were differentially expressed in the liver of MDA-treated mice and their biological functions and canonical pathways were further analyzed using Ingenuity Pathways Analysis (IPA). Toxicological functional analysis showed that genes related to hepatotoxicity such hyperplasia/hyperproliferation (Timp1), necrosis/cell death (Cd14, Mt1f, Timp1, and Pmaip1), hemorrhaging (Mt1f), cholestasis (Akr1c3, Hpx, and Slc10a2), and inflammation (Cd14 and Hpx) were differentially expressed in MDA-treated group. This gene expression profiling should be useful for elucidating the genetic events associated with aromatic amine-induced hepatotoxicity and for discovering the potential biomarkers for hepatotoxicity.

• Clinical and Experimental Pediatrics
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• v.48 no.6
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• pp.580-587
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• 2005

New evidence is emerging that airway smooth muscle(ASM) may act as an immunomodulatory cell by providing pro-inflammatory cytokines and chemokines, polypeptide growth factors, extracellular matrix proteins, cell adhesion receptors and co-stimulatory molecules. ASM can promote the formation of the interstitial extracellular matrix, and potentially contribute to the alterations within the extracellular matrix in asthma. In addition, extracellular matrix components can alter the proliferative, survival, and cytoskeletal synthetic function of ASM cells through integrin-directed signaling. Increased ASM mass is one of the most important features of the airway wall remodeling process in asthma. Three different mechanisms may contribute to the increased ASM mass : cell proliferation, increased migration and decreased rate of apoptosis. The major signaling pathways of cell proliferation activated by ASM mitogens are those dependent on extracellular signal-regulated kinase and phosphoinositide 3'-kinase. The key signaling mechanisms of cell migration have been identified as the p38 mitogen-activated protein kinase and the p21-activated kinase 1 pathways. ASM cells contain ${\beta}2$-adrenergic receptors and glucocorticoid receptors. They may represent a key target for ${\beta}2$-adrenergic receptor agonist/corticosteroid interactions which have antiproliferative activity against a broad spectrum of mitogens.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.4
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• pp.1643-1647
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• 2016

Since their discovery in 1940, it has been well established that gangliosides are associated with a number of biological pathways and cellular processes such as growth, differentiation and toxin uptake. Gangliosides are glycosphingolipids containing neuraminic acid which are expressed on the plasma membrane of cells particularly in the nervous system. Heterogeneity and structural variation in the carbohydrate chains of gangliosides contributes to unique features of each of these molecules. Thirty five years ago it was discovered that aberrant glycosylation occurs in a variety of human cancers, including aberrant glycosylation of gangliosides. Ganglioside expression in terms of quality and quantity varies in different cancers and different roles may be played. Gangliosides, by affecting the immune system, including esxpression of cytokines and adhesion molecules, may inhibit anti-tumor mechanisms, as well as having direct impact on angiogenesis, cell movement and metastasis. It should be noted that different kinds of gangliosides do not all act by the same mechanisms.

• Archives of Pharmacal Research
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• v.29 no.1
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• pp.1-15
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• 2006

Vascular endothelial cell injury or dysfunction has been implicated in the onset and' progression of cardiovascular diseases including atherosclerosis. A number of previous studies have demonstrated that the pro-oxidative and pro-inflammatory pathways within vascular endothelium play an important role in the initiation and progression of atherosclerosis, Recent evidence has provided compelling evidence to indicate that interleukin-4 (IL-4) can induce proc inflammatory environment via oxidative stress-mediated up-regulation of inflammatory mediators such as cytokine, chemokine, and adhesion molecules in vascular endothelial cells. In addition, apoptotic cell death within vascular endothelium has been hypothesized to be involved in the development of atherosclerosis. Emerging evidence has demonstrated that IL-4 can induce apoptosis of human vascular endothelial cells through the caspase-3-dependent pathway, suggesting that IL-4 can increase endothelial cell turnover by accelerated apoptosis, the event which may cause the dysfunction of the vascular endothelium. These studies will have a high probability of revealing new directions that lead to the development of clinical strategies toward the prevention and/or treatment for individuals with inflammatory vascular diseases including atherosclerosis.