Clinical and Molecular Hepatology

Steatotic liver disease

Noninvasive markers: a double-edged sword that stratifies nonalcoholic steatohepatitis: Goh Eun Chung, Donghee Kim; Clin Mol Hepatol 2013;19(2):116-119.
Published online June 27, 2013; DOI: https://doi.org/10.3350/cmh.2013.19.2.116

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Apoptosis and diagnosis of nonalcoholic steatohepatitis: Chang Wook Kim, Chang Don Lee; Korean J Hepatol 2011;17(3):247-249.
Published online September 30, 2011; DOI: https://doi.org/10.3350/kjhep.2011.17.3.247

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Lacticaseibacillus paracsei HY7207 Alleviates Hepatic Steatosis, Inflammation, and Liver Fibrosis in Mice with Non-Alcoholic Fatty Liver Disease
Hyeon-Ji Kim, Hye-Jin Jeon, Dong-Gun Kim, Joo-Yun Kim, Jae-Jung Shim, Jae-Hwan Lee
International Journal of Molecular Sciences.2024; 25(18): 9870. CrossRef
15-Lipoxygenase metabolites of α-linolenic acid, [13-(S)-HPOTrE and 13-(S)-HOTrE], mediate anti-inflammatory effects by inactivating NLRP3 inflammasome
Naresh Kumar, Geetika Gupta, Kotha Anilkumar, Naireen Fatima, Roy Karnati, Gorla Venkateswara Reddy, Priyanka Voori Giri, Pallu Reddanna
Scientific Reports.2016;[Epub] CrossRef

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The effect of preconditioning on liver regeneration after hepatic resection in cirrhotic rats: Seon Ok Min, Sung Hoon Kim, Sang Woo Lee, Jin A Cho, Kyung Sik Kim; Korean J Hepatol 2011;17(2):139-147.
Published online June 23, 2011; DOI: https://doi.org/10.3350/kjhep.2011.17.2.139

Abstract
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Background/Aims

Ischemic preconditioning (IP) decreases severity of liver necrosis and has anti-apoptotic effects in previous studies using liver regeneration in normal rats. This study assessed the effect of IP on liver regeneration after hepatic resection in cirrhotic rats.

Methods

To induce liver cirrhosis, thioacetamide (300 mg/kg) was injected intraperitoneally into Sprague-Dawley rats twice per week for 16 weeks. Animals were divided into four groups: non-clamping (NC), total clamping (TC), IP, and intermittent clamping (IC). Ischemic injury was induced by clamping the left portal pedicle including the portal vein and hepatic artery. Liver enzymes alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured to assess liver damage. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining for apoptosis and proliferating cell nuclear antigen (PCNA) staining for cell replication were also performed.

Results

Day-1 ALT and AST were highest in IP, however, levels in NC and IC were comparably low on days 1-7. There was no significant correlation of AST or ALT with experimental groups (P=0.615 and P=0.186). On TUNEL, numbers of apoptotic cells at 100× magnification (cells/field) were 31.8±24.2 in NC, 69.0±72.3 in TC, 80.2±63.1 in IP, and 21.2±20.8 in IC (P<0.05). When regeneration capacity was assessed by PCNA staining, PCNA-positive cells (cells/field) at 400× were 3.4±6.0 in NC, 16.9±69 in TC, 17.0±7.8 in IP and 7.4±7.6 in IC (P<0.05).

Conclusions

Although regeneration capacity in IP is higher than IC, the liver is vulnerable to ischemic damage in cirrhotic rats. Careful consideration is needed in applying IP in the clinical setting.

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Liver ischemia-reperfusion injury: From trigger loading to shot firing
Eric Felli, Emanuele Felli, Edoardo M. Muttillo, Takeshi Urade, Giovanni G. Laracca, Valerio Giannelli, Simone Famularo, Bernard Geny, Giuseppe M. Ettorre, Krista Rombouts, Massimo Pinzani, Michele Diana, Jordi Gracia-Sancho
Liver Transplantation.2023; 29(11): 1226. CrossRef
Parenteral Solution of Nutritional Hepatotrophic Factors Improves Regeneration in Thioacetamide-induced Cirrhotic Livers after Partial Hepatectomy
Mauricio de Rosa Trotta, Dandara Murad Cajaiba, Osório Miguel Parra, Maria Lúcia Zaidan Dagli, Francisco Javier Hernandez-Blazquez
Toxicologic Pathology.2014; 42(2): 414. CrossRef

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Pro-apoptotic function of hepatitis B virus X protein: Kyun-Hwan Kim, Ph.D.; Korean J Hepatol 2010;16(2):112-122.
Published online June 25, 2010; DOI: https://doi.org/10.3350/kjhep.2010.16.2.112

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Infection of hepatitis B virus (HBV) is a main cause of liver diseases including hepatitis, cirrhosis and hepatocellular carcinoma (HCC). Among the HBV-encoded proteins, the HBV X protein (HBx) has been suspected to be strongly involved in HBV-associated liver pathogenesis. HBx, a virally encoded multifunctional regulator, has been shown to induce apoptosis, anti-apoptosis, proliferation, and transformation of cells depending on the cell lines, model systems used, assay protocols, and research groups. Among the several activities of HBx, the pro-apoptotic function of HBx will be discussed in this review. Given that the disruption of apoptosis pathway by HBx contributes to the liver pathogenesis, a better understanding of the molecular interference in the cellular pro-apoptotic networks by HBx will provide useful clues for the intervention in HBV-mediated liver diseases.

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Hepatitis B virus X gene differentially modulates cell cycle progression and apoptotic protein expression in hepatocyte versus hepatoma cell lines
C. H. Yang, M. Cho
Journal of Viral Hepatitis.2013; 20(1): 50. CrossRef
A natural mutation of the hepatitis B virus X gene affects cell cycle progression and apoptosis in Huh7 cells
Chang Hee Yang, Byung-Cheol Song, Moonjae Cho
Journal of the Korean Society for Applied Biological Chemistry.2012; 55(2): 229. CrossRef

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Down-regulation of survivin in growth inhibition of hepatoma cells induced by a selective cyclooxygenase-2 inhibitor: Il Han Song, M.D., Dong Woo Kim, M.D., Ki Chul Shin, M.D., Hyun Duk Shin, M.D., Se Young Yun, M.D., Suk Bae Kim, M.D., Jung Eun Shin, M.D., Hong Ja Kim, M.D., Eun Young Kim, M.D.; Korean J Hepatol 2008;14(3):351-359.
Published online September 30, 2008; DOI: https://doi.org/10.3350/kjhep.2008.14.3.351

Abstract
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Background/Aims
Cyclooxygenase-2 (COX-2) inhibitors reportedly inhibit the growth of hepatocellular carcinoma (HCC) via caspase-dependent or caspase-independent apoptosis, which is due to COX-2 being associated with hepatocarcinogenesis. Survivin is highly expressed in most human cancers, but the mechanism regulating survivin expression remains unclear. We investigated the regulatory expression of survivin in selective-COX-2-inhibitor-induced growth inhibition of hepatoma cells. Methods: After treatment with NS-398 (a selective COX-2 inhibitor) at various concentrations (10, 50, 100, 150, and 200 μM), the growth inhibition of Hep3B hepatoma cells was assessed by an MTT cell-viability assay, DNA fragmentation gel analysis, and flow cytometry. The expression of survivin transcript was analyzed by reverse-transcription polymerase chain reactions. Results: NS-398 inhibited the growth of hepatoma cells by an amount dependent on the concentration and the time since treatment. Apoptotic DNA ladder and flow-cytometry shifting to the sub-G1 phase were revealed in NS-398-induced growth inhibition of hepatoma cells. NS-398 suppressed the expression of the survivin gene in a concentration- and time-dependent manner. Conclusions: Survivin was down-regulated in the growth inhibition of hepatoma cells induced by a selective COX-2 inhibitor, NS-398, in a concentration- and time-dependent manner. These results suggest the therapeutic inhibition of COX-2 via suppression of survivin in HCC. (Korean J Hepatol 2008;14:351-359)

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Survivin gene expression increases gastric cancer cell lymphatic metastasis by upregulating vascular endothelial growth factor-C expression levels
JUNYAN ZHANG, ZHI ZHU, ZHE SUN, XUREN SUN, ZHENNING WANG, HUIMIAN XU
Molecular Medicine Reports.2014; 9(2): 600. CrossRef
Nimesulide inhibited the growth of hypopharyngeal carcinoma cells via suppressing Survivin expression
Tian Jia-Jun, Lu Su-Mei, Yu Liang, Ma Ju-Ke, Mu Ya-Kui, Wang Hai-Bo, Xu Wei
Head & Neck Oncology.2012;[Epub] CrossRef
Genotypic resistance to entecavir in chronic hepatitis B patients
Byeong Uk Kim, Ja Chung Goo, Byeong Chul Park, Soo Ok Kim, Sun Pyo Hong, Jee In Jeong, Hee Bok Chae, Seon Mee Park, Sei Jin Youn
The Korean Journal of Hepatology.2010; 16(2): 147. CrossRef
Anti-tumor mechanisms and regulation of survivin by selective cyclooxygenase-2 inhibitor
Jeong Won Jang
The Korean Journal of Hepatology.2008; 14(3): 305. CrossRef

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Anti-tumor mechanisms and regulation of survivin by selective cyclooxygenase-2 inhibitor: Jeong Won Jang; Korean J Hepatol 2008;14(3):305-308.
Published online September 30, 2008; DOI: https://doi.org/10.3350/kjhep.2008.14.3.305

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Analysis of polymorphic variants of the survivin promoter and p53 transcription factor in patients with genital endometriosis, type 1 diabetes mellitus and their combination
Nelly Y. Andreeva, Tatiana E. Ivaschenko, Maria I. Yarmolinskaya, Elena V. Misharina, Anna A. Shagina, Maria L. Sergeeva
Journal of obstetrics and women's diseases.2022; 71(2): 17. CrossRef
Survivin gene expression increases gastric cancer cell lymphatic metastasis by upregulating vascular endothelial growth factor-C expression levels
JUNYAN ZHANG, ZHI ZHU, ZHE SUN, XUREN SUN, ZHENNING WANG, HUIMIAN XU
Molecular Medicine Reports.2014; 9(2): 600. CrossRef
Relation between Cyclooxygenase-2 and Polo-like Kinase-1 in Non-Small Cell Lung Cancer
Kyu-Hwa Lee, Seok-Chul Yang
Tuberculosis and Respiratory Diseases.2009; 67(4): 303. CrossRef
Clinicopathologic significance of survivin expression in colorectal adenocarcinoma
Woong Na, Se Min Jang, Young Jin Jun, Young Soo Song, Ki‐Seok Jang, Kang Hong Lee, Kyeong Geun Lee, Hong Xiu Han, Seung Sam Paik
Basic and Applied Pathology.2009; 2(3): 94. CrossRef

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Analysis of Cell Proliferative Activity , p53 Protein Overexpression and Apoptosis in Hepatocellular Carcinoma and Surrounding Nontumorous Liver: So Dug Lim , Woo Ho Kim , Ja June Jang , Eun Sil Yu; Korean J Hepatol 1998;4(1):33-45.

Abstract
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Background/Aims
- Although the mechanism of hepatocellular carcinogenesis still remains to be clarified, it has been suggested that persistent hepatic necrosis and resultant irregular regeneration might cause genetic mutations, such as activation of protooncogenes, inactivation of tumor suppressor genes and modulation of apoptosis-related genes, finally leading to hepatocellular carcinoma (HCC). To elucidate the role of cell proliferative activity and apoptosis, a major mechanism of cell death, in hepatocellular carcinogenesis, we analyzed expression of proliferation cell nuclear antigen (PCNA), p53 protein and apoptotic cells in HCC and surrounding nonneoplastic hepatic parenchyma. Methods - We performed immunohistochemical staining to detect P CAN, p53 protein, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) method for the detection of apoptosis in 52 hepatocellular carcinomas and their adjacent nonneoplastic liver. We scored the expression of PCNA and p53, and apoptotic index by a 5 point scale' 0, 0%,1, 1-25%', 2, 25-50%, 3, 50-75%', 4, >76%, and analyzed the results with other clinicopathologic characteristics. Results: p53 protein was expressed in 42.3% of the HCC, but was not evident in nonneoplstic liver. P53 overexpression was correlated with the histologic grade of HCC (p<0.05). PCNA labelling indices (LI) of HCC were correlated with those of liver cell dysplasia and normal liver (p<0.05). Leading edges of HCCs showed higher proliferative activity than the central part of HCC. Four cases of HCCs with high TUNEL also showed high proliferative activity. There was no difference of the TUNEL between HCC and surrounding nonneoplastic liver. Expression of p53, PCNA LI and TUNEL had no relationship with clinicopathologic parameters including viral markers, aFP elevation, tumor size and underlying cirrhosis. Conclusion - p53 overexpression in HCC and absence of p53 mutation in nonneoplastic liver indicates the active participation of p53 in hepatocellular carcinogenesis. Invasiveness and metastatic potential appear to be related with the strong expression of PCNA, but apoptosis in HCC has no direct implication in hepatocellular carinogensis. (Korean J Hepatol 1998;8:33 45)

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Protective Effect of Cholesteryl Hemisuccinate on Fumonisin B1-Induced Apoptosis of Hepatocytes in the Rat Liver: Woo Sung Moon, M.D.1, 2, Chul Kyu Park, M.D.1, Myoung Jae Kang, M. D.1, 2, Dong Geun Lee, M.D.1, 2, Ho Yeul Choi, M.D.1, 2; Korean J Hepatol 1999;5(3):227-239.

Abstract
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Background/Aims
This study was aimed to examine if FB1 induced-hepatotoxicity involves apoptosis, and cholesteryl hemisuccinate (CS) pre-treatment would selectively interfere with FB1 induced-apoptosis of hepatocytes. Methods: Sprague-Dawley rats were intravenousely injected with FB1 (1.25 mg/kg/day) for two days, and were sacrificed at 3, 6, 12, 24 and 48 hours after injection. Another experiment group was composed of rats with pretreatment of CS (100 mg/kg/day, i.p.) before FB1 injection. Results: This study demonstrated that administration of hepatotoxic dose of FB1 to Sprague-Dawley rats resulted in liver injury leading to cell death by apoptosis. FB1-induced apoptosis was preceded by early elevation in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, and appearance of injured pre-apoptotic cells at 12 hours was followed by massive fragmentation and margination of heterochromatin at 24 hours. CS pre-treatment prior to FB1 injection ameliorated serum biochemistry and hepatic injury with apoptosis, demonstrated by histological, ultrastructural and TUNEL (terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling) methods. In addition, there was remarkable decrease in number of PCNA (proliferative cell nuclear antigen)-positive proliferating hepatocytes compared to that of FB1 treated group. Conclusion: This study suggests that apoptosis significantly contributes to FB1-induced hepatotoxicity in vivo, and pre-exposure of rat to CS prevents FB1-induced hepatic apoptosis and proliferation. (Korean J Hepatol 1999;5:227－239)

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The mRNA Expression of Tumor Necrosis Factor - Related Apoptosis - Inducing Ligand (TRAIL) and Its Receptors in Hepatocellular Carcinoma and Surrounding Liver Tissues: Saera Jung, M.D., Han Chu Lee, M.D., Hee Gon Song, M.D., Young-Hwa Chung, M.D., Yung Sang Lee, M.D., Ghil-Sook Yoon, M.D.*, Eunsil Yu, M.D.*, and Dong Jin Suh, M.D.; Korean J Hepatol 2001;7(3):273-280.

Abstract
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Background/Aims
TRAIL-induced apoptosis was believed to occur in tumor cell lines, while not in normal cells, which suggested that TRAIL might be safe as an antitumor therapy. Some authors advocate that this exclusive TRAIL-induced apoptosis depended on whether or not TRAIL-R3 mRNA was expressed. In this study we investigated the difference in the expression of TRAIL and its receptors mRNA between human hepatocellular carcinoma(HCC) and surrounding liver tissues.Methods:Intra-operative sampling of HCC and paired surrounding liver tissue was performed in 12 patients who underwent hepatic resection due to HCC. After RT-PCR, using total RNA extracts from the tissues, amplified RT-PCR, products were analyzed qualitatively for the expression of TRAIL and its receptors mRNA. Both tissues were compared semi-quantitatively for the expression of TRAIL-R3 mRNA with β-actin using the method of Nicoletti et al.Results:1)TRAIL mRNA was expressed in HCC and surrounding liver tissues in all cases. 2)TRAIL-R1, -R2, and -R3 mRNA were also expressed in HCC and surrounding liver tissues in all cases. 3)The ratio of the expression of TRAIL-R3 mRNA to β-actin mRNA was 0.22±0.15 in HCC and 0.34±0.21 in surrounding liver tissues(p=0.124, paired t-test). 4) TRAIL, TRAIL-R1, -R2 and -R3 mRNA were expressed in all HCC cases irrespective of the degree of tumor cell differentiation.Conclusions:TRAIL, TRAIL-R1, -R2, and TRAIL-R3 mRNA were expressed in all of the HCC and surrounding liver tissues. There was no quantitative difference in the expression of TRAIL-R3 mRNA between both tissues. (Korean J Hepatol 2001;7:273-280)

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Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis. Hepatology 2003;37: 87-95: Geun Youn Gwok , Jung Hwan Yoon; Korean J Hepatol 2003;9(2):145-146.

Abstract
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최근 간섬유화의 resolution phase에서 활성화된 간 성상세포(hepatic stellate cell)의 수가 줄어드는 기전으로 세포사멸(apoptosis)가 중요한 역할을 담당함이 알려지고 있다. 이러한 사실은 활성화된 간 성상세포가 휴지기에 있을 때보다 세포사멸을 일으키는 자극에 더 민감하다는 것을 암시한다. 이미 다른 종류의 세포들이 휴지 상태보다 활성화된 상태에서 TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)에 의한 세포사멸에 더 민감하다는 사실이 알려진 바 있기 때문에 본 연구자들은 이번 연구에서 점진적인 활성화 단계를 거치는 간 성상세포에서 단계별 TRAIL 사망 수용체(death receptor)의 발현과 TRAIL에 의한 세포 독성에 대한 민감도를 밝히고자 하였다. 자연적으로 불멸화된 인간 간 성상세포주인 LX-2 세포를 14일간 플라스틱 용기에서 배양하며 분석한 결과, 14일 후 간 성상세포 활성화의 지표인 α-smooth muscle actin (α-SMA)과 β-crystalline의 messenger RNA (mRNA)의 양이 각각 7배와 5배 증가하였으며, 같은 기간동안 TRAIL-R1/DR4와 TRAIL-R2/DR5 mRNA 발현은 각각 18배와 17.6배 증가하였다. 양적으로 보았을 때에는 TRAIL-R2/DR5의 발현이 TRAIL-R1/ DR4보다 103배 높았다. 아울러 TRAIL-R2/DR5 단백 발현과 TRAIL 유도 세포사멸에 대한 민감플라스틱 용기에서 활성화 과정을 거치는 동안 도에서도 동일한 양상의 변화가 관찰되었으며, 설치류의 간으로부터 일차배양한 간 성상세포 역시 유사한 변화를 보였다. 결론적으로 간 성상세포는 활성화되어감에 따라 TRAIL-R2/DR5 발현이 증가하고 TRAIL 유도 세포사멸에 민감해짐을 알 수 있었다. 따라서 임상적으로 TRAIL-R2/DR5 agonist가 생체 내에서 선택적으로 간 성상세포의 세포사멸을 유도하여 간섬유화를 줄이는데 유용하게 이용될 수 있을 것으로 기대된다.

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Topics Related to Hepatocellular Carcinoma: Il Han Song; Korean J Hepatol 2004;10(2):174-176.

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Prostaglandin A₂ Induces Caspase-independent Apoptosis in Hepatocellular Carcinoma Cells: Ho Shik Kim , Jae Chun Shim , Ju Youn Choi , Hyang Shuk Rhim , In Kyung Kim; Korean J Hepatol 2005;11(1):72-79.

Abstract
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Background/Aims
Prostaglandin (PG) A2 has been reported to inhibit the growth of hepatocellular carcinoma cells via activation of apoptosis, although the molecular mechanisms involved have not been clarified, yet. To investigate the mechanism of the PGA₂-induced apoptosis, we analyzed the activation of caspases during the apoptosis of hepatoma cell lines. Methods: Induction of apoptosis by PGA₂ in hepatoma cell lines, Hep 3B and Hep G2, was assessed by DAPI staining of nuclei and agarose gel electrophoresis of genomic DNA. The involvement of caspases was analyzed by immunoblot analysis of poly ADP-ribose polymerase (PARP) and by checking the effect of caspase inhibitors on PGA₂-induced apoptosis. Results: PGA₂ inhibited the growth of Hep 3B and Hep G2 cells, accompanying nuclear condensation and fragmentation, and genomic DNA laddering, which are the hallmarks of apoptosis. The PARP was not cleaved during the apoptosis of Hep 3B and Hep G2 cells and caspase inhibitors such as z-VAD-Fmk and z-DEVD-Fmk exerted no effect on the PGA₂-induced apoptosis. Conclusions: These results suggest that PGA₂ induces apoptosis in Hep 3B and Hep G2 cells via caspase-independent pathway. (Korean J Hepatol 2005;11:72-79)

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Cerulein Pancreatitis: Oxidative Stress, Inflammation, and Apoptosis: Hye Young Kim; Korean J Hepatol 2008;12(2):74-80.

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Cerulein pancreatitis is similar to human edematous pancreatitis, manifesting with dysregulation of digestive enzyme production and cytoplasmic vacuolization, the death of acinar cells, edema formation, and infiltration of inflammatory cells into the pancreas. Reactive oxygen species are involved in nuclear factor-κB activation, cytokine expression, apoptosis and pathogenesis of pancreatitis. There is recent evidence that cerulein activates NADPH oxidase, which is a major source of reactive oxygen species during inflammation and apoptosis in pancreatic acinar cells. In addition, the Janus kinase/signal transducer and activator of transcription pathway has been suggested as being involved in inflammatory signaling in the pancreas. This review discusses the involvement of oxidative stress in inflammation and apoptosis in pancreatic acinar cells stimulated with cerulein as an in vitro model of pancreatitis.