• Title/Summary/Keyword: Liver dysfunction

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Study of hepatoprotective effect of Haegan-jeon through activation of nuclear factor erythroid 2-related factor 2 and optimization of herbal composition based on molecular mechanism (Nuclear factor erythroid 2-related factor 2 활성화를 통한 해간전(解肝煎)의 간세포 보호 효능 및 분자기전을 활용한 해간전(解肝煎) 구성 약물의 최적화 연구)

  • Kim, Jae Kwang;Jung, Ji Yun;Park, Sang Mi;Park, Chung A;Ku, Sae Kwang;Byun, Sung Hui;Cho, Il Je;Kim, Sang Chan
    • Herbal Formula Science
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    • v.26 no.3
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    • pp.207-221
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    • 2018
  • Objectives : Present study investigated hepatoprotective effect of Haegan-jeon extract (HE) and tried to elucidate molecular mechanism involved. According to molecular mechanism, present study optimized herbal composition of HE (op-HE) and compared in vitro and in vivo hepatoprotective effects of op-HE to HE. Methods : For in vitro experiments, HepG2 cells were exposed to arachidonic acid (AA, $10{\mu}M$) and iron ($5{\mu}M$) for inducing oxidative stress. Cell viability, GSH contents, $H_2O_2$ production, mitochondrial membrane potential, immunoblot and reporter gene assay were performed to investigate cytoprotective effects and responsible molecular mechanisms. For in vivo experiments, hepatoprotective effect of HE and op-HE were assessed on $CCl_4-induced$ liver injury mice model. Results : HE pretreatment prevented AA+iron-mediated hepatocytes apoptosis. In addition, AA+iron-induced mitochondrial dysfunction, $H_2O_2$ production, glutathione depletion were reduced by HE pretreatment. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation, antioxidant response element (ARE)-driven reporter gene activity, and antioxidant genes expression were increased by HE. Based on reporter gene and MTT assays, we found that op-HE consisting three medicinal herbs also significantly increased transactivation of Nrf2 and reduced the AA+iron-mediated cytotoxicity. Moreover, in $CCl_4-induced$ liver injury mice model, HE-op had an ability to ameliorate $CCl_4-mediated$ increases in serum alanine transferase and aspartate aminotransferase activity, hepatic degeneration, inflammatory cell infiltration, and collagen deposition. Hepatoprotective effects of op-HE were comparable to those of HE. Conclusions : Present study suggests that op-HE as well as HE exhibit hepatoprotective effect against oxidative stress-mediated liver injury via Nrf2 activation.

Effect of Ovariectomy and Genistein on Hepatic Mitochondrial Function (난소절제와 Genistein 투여가 간 미토콘드리아 기능에 미치는 영향)

  • Lee Young Min;Jung Myeong Ho;Lee Yeon Sook;Song Jihyun
    • Journal of Nutrition and Health
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    • v.37 no.9
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    • pp.786-793
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    • 2004
  • Women with menopause or rats with ovariectomy is associated with increased body weight, body fat and insulin resistance, which are components of metabolic syndrome. Increased prevalence of metabolic syndrome after menopause might be associated with mitochondrial dysfunction, since mitochondrial oxidative and phosphorylation activity is strongly correlated with insulin sensitivity. Although estradiol replacement prevents the metabolic syndrome, harmful effect of estradiol hampers the casual usage to prevent the metabolic syndrome. It has been reported that genistein has a mild estrogenic activity, decreases fat mass in mice and has an antidiabetic role in diabetic rats. Although insulin resistance is closely related to mitochondrial functions, there has not been yet any study in regard to the effect of dietary genistein on mitochondrial function in the insulin resistant female subjects induced by ovariectomy or similar situation. The present study investigated whether the supplementation of genistein in the high fat diet affected the mitochondrial function of high fat fed ovariectomized rats. Female Sprague Dawley rats (8 weeks old) were assigned to the following groups: sham-operated+ high fat diet (S, n=6); sham-operated + high fat diet with 0.1% genistein (S + G, n=7); ovariectomized + high fat diet (OVX, n=8); ovariectomized + high fat diet with 0.1% genistein (OVX+ G, n=8). Ovariectomy significantly increased body weight compared with S group. Genistein consumption in ovariectomized (OVX + G) rats decreased body weight gain compared with OVX rats. Liver weights were increased by ovariectomy. The hepatic mitochondrial protein density expressed as mg per g liver was lower in the OVX group than in the S group. However, OVX + G group showed the increased mitochondrial protein density similar to the level of S group. When mRNA levels of genes related to mitochondria such as peroxisome proliferator-activated receptor ${\gamma}$ coactivator 1 (PGC-1) and cytochrome c oxidase subunit III (COX III) were measured, there were decreases in the mRNA levels of PGC-1 and COX III in S + G, OVX and OVX + G group. The activity of cytochrome c oxidase was not different between groups. We could observe the decrease in succinate dehydrogenase (SDH) activity per g liver in OVX rats. Genistein supplement increased SDH activity. In conclusion, genistein supplementation to the OVX rats enhanced mitochondrial function by increasing mitochondrial protein density and SDH activity. The improvement in mitochondrial function by genistein can contribute to the improvement in metabolic syndrome.

Bibliographical study on the Jiu Qi(九氣) shown at Ju Tong Lun(擧痛論) in Shao Wen(素問) Huang Ti Nei Ching(黃帝內經) (${\ll}$소문(素問).거통론(擧痛論)${\gg}$에 나타난 구기(九氣)에 대(對)한 고찰(考察))

  • Kim, Bo-Kyung
    • Journal of Oriental Neuropsychiatry
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    • v.11 no.1
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    • pp.145-167
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    • 2000
  • Jiu Qi(九氣) was shown at Ju Tong Lun(擧痛論) in Shao Wen(素問) Huang Ti Nei Ching(黃帝內經), and is nine important factors that affect the function of human body. Jiu Qi concludes endogenous, exogenous, non-endo-exogenous factors. I do the bibliographical study on the Jiu Qi, the results were as follows; 1. The Qi of Jiu Qi has two opposite meanings. one is genuine vital energy(正氣), and the other is the factors causing abnormal state in vital energy. Jiu Qi is nine factors concluding coldness-heat(exogenous factors). six emotional factors(endogenous factor), overworking(non -endo-exogenous factor). 2. Anger may lead to abnormal rising of vital energy. Anger causes Qi of the liver to go perversely upward, and perverted flow of exuberant Qi of the liver lead to dysfunction of the spleen, so resulted in hematemesis, diarrhea, indigestion. 3. Joy can promote the harmony of vital energy and blood, so do the circulation of nutrient and defensive energy in physiological state. But an excessive joy may lead to the sluggishness of vital energy. 4. The lung keeps the pathway of air unconstructed, disseminates vital energy, cleanses the inspired air and keeps vital energy flowing downward. Sorrow affects on the function of the lung and the heart, so could result in obstruction of the circulation of nutrient and defensive energy. An excessive sorrow after stagnation may lead to the consumption of vital energy. 5. Fear makes vital energy and essence of the kidney sink to inward and downside, makes Yang-Qi can't go upward, so causes obstruction of triple wanner. An excessive fear can obstructs the ascending of Yang-Qi, so may lead to the abnormal falling of vital energy. 6. Coldness makes the sweat pore be contracted, so obstructs the circulation of triple warmer, causes sluggishness of defensive energy or Qi of the internal organ. 7. Heat makes the sweat pore be open, much amount of sweat is excreted with Yang-Qi, defensive energy, vital energy. Heat may consume vital energy. 8. Sudden fright affects on spirits of the heart and liver, causes disorder of the mental faculties and separation of blood and vital energy. Fright may lead to disorder of Qi. 9. Overwork concludes overfatigue and exhaustion caused by intemperance in sexual life. Overwork renders vital energy consumed, and hence results in lassitude and listlessness. 10. Thinking affects on the function of the heart and the spleen. Over thinking may lead to depression of vital energy. Through the bibliographical study on Jiu Qi, I got smallest amount of it, and this must be more investigated correlating with clinical study.

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The Metabolic Effects of FGF21: From Physiology to Pharmacology (생리, 약학적 관점에서 fibroblast growth factor 21 (FGF21)의 대사 효과 고찰)

  • Song, Parkyong
    • Journal of Life Science
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    • v.30 no.7
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    • pp.640-650
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    • 2020
  • Fibroblast growth factor 21 (FGF21) is an atypical member of the FGF protein family which is highly synthesized in the liver, pancreas, and adipose tissue. Depending on the expression tissue, FGF21 uses endo- or paracrine features to regulate several metabolic pathways including glucose metabolism and energy homeostasis. Different physiologically stressful conditions such as starvation, a ketogenic diet, extreme cold, and mitochondrial dysfunction are known to induce FGF21 synthesis in various tissues to exert either adaptive or defensive mechanisms. More specifically, peroxisome proliferator-activated receptor gamma and peroxisome proliferator-activated receptor alpha control FGF21 expression in adipose tissue and liver, respectively. In addition, the pharmacologic administration of FGF21 has been reported to decrease the body weight and improve the insulin sensitivity and lipoprotein profiles of obese mice and type 2 diabetes patients meaning that FGF21 has attracted huge interest as a therapeutic agent for type 2 diabetes, obesity, and non-alcoholic fatty liver disease. However, understanding FGF21 remains complicated due to the paradoxical condition of its tissue-dependent expression. For example, nutrient deprivation largely increases hepatic FGF21 levels whereas adipose tissue-derived FGF21 is increased under feeding condition. This review discusses the issues of interest that have arisen from existing publications, including the tissue-specific function of FGF21 and its action mechanism. We also summarize the current stage of a clinical trial using several FGF21 analogs.

Protective Effect of Phosphatidylcholine on Lipopolysaccharide-Induced Acute Inflammation in Multiple Organ Injury

  • Jung, Yoon Yang;Nam, Yunsung;Park, Yong Seol;Lee, Ho Sung;Hong, Soon Auck;Kim, Beom Keun;Park, Eon Sub;Chung, Yoon Hee;Jeong, Ji Hoon
    • The Korean Journal of Physiology and Pharmacology
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    • v.17 no.3
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    • pp.209-216
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    • 2013
  • Soybean polyunsaturated phosphatidylcholine (PC) is thought to exert anti-inflammatory activities and has potent effects in attenuating acute renal failure and liver dysfunction. The aim of this study was to investigate the effects of PC in protecting multiple organ injury (MOI) from lipopolysaccharide (LPS). Six groups of rats (N=8) were used in this study. Three groups acted as controls and received only saline, hydrocortisone (HC, 6 mg/kg, i.v.) or PC (600 mg/kg, i.p.) without LPS (15 mg/kg, i.p.) injections. Other 3 groups, as the test groups, were administered saline, HC or PC in the presence of LPS. Six hours after the LPS injection, blood and organs (lung, liver and kidney) were collected from each group to measure inflammatory cytokines and perform histopathology and myeloperoxidase (MPO) assessment. Serum cytokines (TNF-${\alpha}$, IL-6 and IL-10) and MPO activities were significantly increased, and significant histopathological changes in the organs were observed by LPS challenge. These findings were significantly attenuated by PC or HC. The treatment with PC or HC resulted in a significant attenuation on the increase in serum levels of TNF-${\alpha}$ and IL-6, pro-inflammatory cytokines, while neither PC nor HC significantly attenuated serum levels of IL-10, anti-inflammatory cytokine. In the organs, the enhanced infiltration of neutrophils and expression of ED2 positive macrophage were attenuated by PC or HC. Inductions of MPO activity were also significantly attenuated by PC or HC. From the findings, we suggest that PC may be a functional material for its use as an anti-inflammatory agent.

Short Bowel Syndrome as the Leading Cause of Intestinal Failure in Early Life: Some Insights into the Management

  • Goulet, Olivier;Nader, Elie Abi;Pigneur, Benedicte;Lambe, Cecile
    • Pediatric Gastroenterology, Hepatology & Nutrition
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    • v.22 no.4
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    • pp.303-329
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    • 2019
  • Intestinal failure (IF) is the critical reduction of the gut mass or its function below the minimum needed to absorb nutrients and fluids required for adequate growth in children. Severe IF requires parenteral nutrition (PN). Pediatric IF is most commonly due to congenital or neonatal intestinal diseases or malformations divided into 3 groups: 1) reduced intestinal length and consequently reduced absorptive surface, such as in short bowel syndrome (SBS) or extensive aganglionosis; 2) abnormal development of the intestinal mucosa such as congenital diseases of enterocyte development; 3) extensive motility dysfunction such as chronic intestinal pseudo-obstruction syndromes. The leading cause of IF in childhood is the SBS. In clinical practice the degree of IF may be indirectly measured by the level of PN required for normal or catch up growth. Other indicators such as serum citrulline have not proven to be highly reliable prognostic factors in children. The last decades have allowed the development of highly sophisticated nutrient solutions consisting of optimal combinations of macronutrients and micronutrients as well as guidelines, promoting PN as a safe and efficient feeding technique. However, IF that requires long-term PN may be associated with various complications including infections, growth failure, metabolic disorders, and bone disease. IF Associated Liver Disease may be a limiting factor. However, changes in the global management of IF pediatric patients, especially since the setup of intestinal rehabilitation centres did change the prognosis thus limiting "nutritional failure" which is considered as a major indication for intestinal transplantation (ITx) or combined liver-ITx.

Enrichment of Short-Chain Ceramides and Free Fatty Acids in the Skin Epidermis, Liver, and Kidneys of db/db Mice, a Type 2 Diabetes Mellitus Model

  • Kim, Minjeong;Jeong, Haengdueng;Lee, Buhyun;Cho, Yejin;Yoon, Won Kee;Cho, Ahreum;Kwon, Guideock;Nam, Ki Taek;Ha, Hunjoo;Lim, Kyung-Min
    • Biomolecules & Therapeutics
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    • v.27 no.5
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    • pp.457-465
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    • 2019
  • Patients with diabetes mellitus (DM) often suffer from diverse skin disorders, which might be attributable to skin barrier dysfunction. To explore the role of lipid alterations in the epidermis in DM skin disorders, we quantitated 49 lipids (34 ceramides, 14 free fatty acids (FFAs), and cholesterol) in the skin epidermis, liver, and kidneys of db/db mice, a Type 2 DM model, using UPLC-MS/MS. The expression of genes involved in lipid synthesis was also evaluated. With the full establishment of hyperglycemia at the age of 20 weeks, remarkable lipid enrichment was noted in the skin of the db/db mice, especially at the epidermis and subcutaneous fat bed. Prominent increases in the ceramides and FFAs (>3 fold) with short or medium chains ($LXR{\alpha}/{\beta}$ and $PPAR{\gamma}$, nuclear receptors promoting lipid synthesis, lipid synthesis enzymes such as elongases 1, 4, and 6, and fatty acid synthase and stearoyl-CoA desaturase were highly expressed in the skin and livers of the db/db mice. Collectively, our study demonstrates an extensive alteration in the skin and systemic lipid profiles of db/db mice, which could contribute to the development of skin disorders in DM.

Heterogenous Clinical Manifestations in Adult Patients with Late Diagnosis of Glycogen Storage Disease type Ia (성인기에 진단된 당원병 제 Ia형의 다양한 임상 양상)

  • Kim, Yoo-Mi;Cheon, Chong Kun;Kim, Gu-Hwan;Yoo, Han-Wook
    • Journal of The Korean Society of Inherited Metabolic disease
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    • v.15 no.1
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    • pp.9-17
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    • 2015
  • Glycogen storage disease (GSD) type Ia is rare inborn metabolic disorder, caused by glucose-6-phosphatase deficiency. It characterized by hepatomegaly, hypoglycemia, lactic acidosis, hypertriglyceridemia, and hyperuricemia and it is usually manifested in the infantile period. In addition, it is also associated with growth failure, pubertal delay, anemia, platelet dysfunction, osteopenia, and pulmonary hypertension. Hepatocellular adenoma and renal dysfunction are frequent late complications. Delayed diagnosis and inappropriate therapy lead to many complications such as growth failure, osteoporosis, refractory gout, renal failure, hepatocellular carcinoma (HCC), and pulmonary hypertension. Here, two Korean sisters diagnosed with GSD Ia, aged 33 and 36 respectively, were described and compared to recent articles about four adults with late diagnosis of GSD Ia. One sister had typical manifestations of GSD Ia including short stature (height, 145 cm), multiple hepatic adenoma, chronic kidney disease stage IV, and severe osteoporosis, whereas the older sister had normal stature (162 cm), one tiny hepatic nodule, and normal renal function. Direct sequencing of G6PC in two sisters identified a homozygous splicing mutation, c.645G>T, which is a prevalent mutation in Korea. Interestingly, our cases and four adults from recent reports had asymptomatic mild hypoglycemia and various manifestations including renal failure, HCC, fatty liver, or uncontrolled hyperlipidemia. These adult cases represent not only heterogenous phenotype to genotype within family members with GSD Ia but also long-term complications such as gouty arthritis, renal failure, and osteoporosis in untreated adult GSD Ia patients. In addition, lactic academia and hypertriglyceridemia are good markers of GSD Ia to distinguish from metabolic disease.

A Case of Interstitial Pneumonitis Caused by Leflunomide (Leflunomide에 의한 약물유발 간질성 폐렴 1예)

  • Lee, Jung Hwa;Cheon, Won Seok;Seo, Young Il;Eom, Kwang-Seok;Jang, Seung Hun;Bahn, Joon-Woo;Kim, Dong-Gyu;Jung, Ki-Suck
    • Tuberculosis and Respiratory Diseases
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    • v.58 no.1
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    • pp.83-88
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    • 2005
  • Leflunomide is a new disease modifying anti rheumatic drug (DMARD) for the treatment of active rheumatoid arthritis. Its mechanism of action differs from other DMARDs in that it inhibits the de novo pyrimidine synthesis by inhibiting dihydroorotate dehydrogenase and therefore prevents the proliferation of activated lymphocytes. As it has been prescribed worldwide, there is a great deal of much concerns regarding its potential adverse effects. Because leflunomide has an active metabolite with a long elimination half-life of approximately 2 weeks, serious adverse reactions may occur even after the leflunomide treatment has been stopped. The profile of serious reactions includes liver dysfunction, hematological disorders, severe skin reactions and respiratory dysfunction. Respiratory dysfunctions with leflunomide therapy are very rare and its incidence is lower than that of methotrexate therapy. However, there are reports in Japan showing that 5 patients died of interstitial pneumonitis and another 11 patients developed serious lung complications associated with leflunomide. This suggests the possibility of fatal respiratory toxicity of leflunomide. There are no reports of interstitial pneumonitis associated with leflunomide in Korea. We report a case of a 62-year old woman who developed interstitial pneumonitis, which might have been induced by leflunomide during the treatment of rheumatoid arthritis.

Developmental Roles of D-bifunctional Protein-A Zebrafish Model of Peroxisome Dysfunction

  • Kim, Yong-Il;Bhandari, Sushil;Lee, Joon No;Yoo, Kyeong-Won;Kim, Se-Jin;Oh, Gi-Su;Kim, Hyung-Jin;Cho, Meyoung;Kwak, Jong-Young;So, Hong-Seob;Park, Raekil;Choe, Seong-Kyu
    • Molecules and Cells
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    • v.37 no.1
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    • pp.74-80
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    • 2014
  • The peroxisome is an intracellular organelle that responds dynamically to environmental changes. Various model organisms have been used to study the roles of peroxisomal proteins in maintaining cellular homeostasis. By taking advantage of the zebrafish model whose early stage of embryogenesis is dependent on yolk components, we examined the developmental roles of the D-bifunctional protein (Dbp), an essential enzyme in the peroxisomal ${\beta}$-oxidation. The knockdown of dbp in zebrafish phenocopied clinical manifestations of its deficiency in human, including defective craniofacial morphogenesis, growth retardation, and abnormal neuronal development. Overexpression of murine Dbp rescued the morphological phenotypes induced by dbp knockdown, indicative of conserved roles of Dbp during zebrafish and mammalian development. Knockdown of dbp impaired normal development of blood, blood vessels, and most strikingly, endoderm-derived organs including the liver and pancreas - a phenotype not reported elsewhere in connection with peroxisome dysfunction. Taken together, our results demonstrate for the first time that zebrafish might be a useful model animal to study the role of peroxisomes during vertebrate development.