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Karnawat K, Parthasarathy R, Sakhrie M, Karthik H, Krishna KV, Balachander GM. Building in vitro models for mechanistic understanding of liver regeneration in chronic liver diseases. J Mater Chem B 2024; 12:7669-7691. [PMID: 38973693 DOI: 10.1039/d4tb00738g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/09/2024]
Abstract
The liver has excellent regeneration potential and attains complete functional recovery from partial hepatectomy. The regenerative mechanisms malfunction in chronic liver diseases (CLDs), which fuels disease progression. CLDs account for 2 million deaths per year worldwide. Pathophysiological studies with clinical correlation have shown evidence of deviation of normal regenerative mechanisms and its contribution to fueling fibrosis and disease progression. However, we lack realistic in vitro models that can allow experimental manipulation for mechanistic understanding of liver regeneration in CLDs and testing of candidate drugs. In this review, we aim to provide the framework for building appropriate organotypic models for dissecting regenerative responses in CLDs, with the focus on non-alcoholic steatohepatitis (NASH). By drawing parallels with development and hepatectomy, we explain the selection of critical components such as cells, signaling, and, substrate-driven biophysical cues to build an appropriate CLD model. We highlight the organoid-based organotypic models available for NASH disease modeling, including organ-on-a-chip and 3D bioprinted models. With the focus on bioprinting as a fabrication method, we prescribe building in vitro CLD models and testing schemes for exploring the regenerative responses in the bioprinted model.
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Affiliation(s)
- Khushi Karnawat
- School of Biomedical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi-221005, India.
| | - Rithika Parthasarathy
- School of Biomedical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi-221005, India.
| | - Mesevilhou Sakhrie
- School of Biomedical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi-221005, India.
| | - Harikeshav Karthik
- School of Biomedical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi-221005, India.
| | - Konatala Vibhuvan Krishna
- School of Biomedical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi-221005, India.
| | - Gowri Manohari Balachander
- School of Biomedical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi-221005, India.
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Dwivedi DK, Jena GB. Dimethyl fumarate-mediated Nrf2/ARE pathway activation and glibenclamide-mediated NLRP3 inflammasome cascade inhibition alleviate type II diabetes-associated fatty liver in rats by mitigating oxidative stress and inflammation. J Biochem Mol Toxicol 2023; 37:e23357. [PMID: 36999408 DOI: 10.1002/jbt.23357] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 12/21/2022] [Accepted: 03/20/2023] [Indexed: 04/01/2023]
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) is much higher in patients with type II diabetes (T2D). Inflammasomes are multimolecular complexes reported to involve inflammatory conditions. The nuclear factor (erythroid-derived 2)-like factor 2/antioxidant responsive element (Nrf2/ARE) pathway is an important regulator of antioxidant status in cells. Antidiabetic drug glibenclamide (GLB) is reported as NACHT, leucine-rich repeat, and pyrin domain domains-containing protein 3 (NLRP3) inflammasome inhibitor, whereas anti-multiple sclerosis drug dimethyl fumarate (DMF) is reported as an Nrf2/ARE pathway activator. Both GLB and DMF possess anti-inflammatory and antioxidant properties, therefore, the hypothesis was made to look into the alone as well as the combination potential of GLB, DMF, and GLB + DMF, against NAFLD in diabetic rats. This study was aimed to investigate (1) the involvement of NLRP3 inflammasome and Nrf2/ARE signaling in diabetes-associated NAFLD (2) the effect of GLB, DMF, GLB + DMF, and metformin (MET) interventions on NLRP3 inflammasome and Nrf2/ARE signaling in diabetes-associated NAFLD. The rats were injected with streptozotocin (STZ) 35 mg/kg and fed a high-fat diet (HFD) for 17 consecutive weeks to induce diabetic NAFLD. The oral treatment of GLB 0.5 mg/kg/day, DMF 25 mg/kg/day, their combination and MET 200 mg/kg/day, were provided from the 6th to the 17th week. Treatment with GLB, DMF, GLB + DMF, and MET significantly alleviated HFD + STZ-induced plasma glucose, triglycerides, cholesterol, %HbA1c, hepatic steatosis, NLRP3, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain, CARD, caspase-1, interleukin-1β (IL-1β), nuclear factor-κB (NF-κB), Nrf2, superoxide dismutase 1, catalase, IGF 1, heme oxygenase 1, receptor for the advanced glycation end product (RAGE), and collagen-1 in diabetic rats. Further, a mechanistic molecular study employing other specific NLRP3 inhibitors and Nrf2 activators will significantly contribute to the development of novel therapy for fatty liver diseases.
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Affiliation(s)
- Durgesh K Dwivedi
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, India
| | - G B Jena
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, India
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Jia W, Yang Z, Zhang X, Dong Y, Jia X, Zhou J. Shear wave elastography and pulsed doppler for breast lesions: Similar diagnostic performance and positively correlated stiffness and blood flow resistance. Eur J Radiol 2022; 147:110149. [PMID: 35007981 DOI: 10.1016/j.ejrad.2021.110149] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 12/11/2021] [Accepted: 12/30/2021] [Indexed: 12/24/2022]
Abstract
PURPOSE To compare the diagnostic performance of shear wave elastography (SWE) and pulsed Doppler ultrasound in breast lesions, and to explore whether the quantitative SWE parameters correlated with pulsed Doppler ultrasound parameters. MATERIALS AND METHODS Seventy-nine patients with 79 breast lesions who had undergone conventional ultrasound, pulsed Doppler ultrasound and SWE examination were included. All of them underwent core needle biopsy or surgery within one week. Parameters including Emax (the maximum elastic modulus), Emean (mean elastic modulus), Emin (minimum elastic modulus), Esd (elastic modulus standard deviation), and RI (resistive index), PI (pulsatility index), PSV (peak systolic velocity) and EDV (end diastolic velocity) were obtained for statistical analysis. RESULTS Almost all SWE parameters were significantly different between benign and malignant breast lesions (P＜0.05). There was no significant difference between Esd and PI (P＞0.05), which had the best AUC among SWE and vascular parameters respectively (0.877 vs. 0.871). Emax showed a moderate correlation with PI (P = 0.000, r = 0.552) and RI (P = 0.000, r = 0.544), and Esd moderately correlated with PI (P = 0.000, r = 0.567) and RI (P = 0.000, r = 0.546). For the benign group, no parameters showed any significant correlation (P＞0.05), while for the malignant group, Emax and Esd also significantly correlated with PI or RI. CONCLUSIONS SWE and pulsed Doppler ultrasound had similar diagnostic efficacy for breast lesions. SWE and pulsed Doppler parameters were significantly correlated in breast lesions, especially in malignant ones, indicating the potential association between elastographic and vascular characteristics of breast tumors.
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Affiliation(s)
- WanRu Jia
- Department of Ultrasound, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - ZhiFang Yang
- Department of Ultrasound, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - XiaoXiao Zhang
- Department of Ultrasound, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - YiJie Dong
- Department of Ultrasound, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - XiaoHong Jia
- Department of Ultrasound, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
| | - JianQiao Zhou
- Department of Ultrasound, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
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Gestation Food Restriction and Refeeding Compensate Maternal Energy Status and Alleviate Metabolic Consequences in Juvenile Offspring in a Rabbit Model. Nutrients 2021; 13:nu13020310. [PMID: 33499108 PMCID: PMC7912334 DOI: 10.3390/nu13020310] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 12/12/2022] Open
Abstract
Nutritional status during gestation can influence mother and offspring metabolism. Undernutrition in pregnancy affects women in both western and developing countries, and it is associated with a high prevalence of chronic diseases in later life. The present work was conducted in the rabbit model, as a longitudinal study, to examine the effect of food restriction during early and mid-gestation, and re-feeding ad libitum until the end of pregnancy on metabolic status and body reserves of mother and, its association with development and metabolism of fetuses and female offspring to the juvenile stage. Little changes in live body weight (LBW), compensatory feed intake, similar body reserves, and metabolism were observed in dams. Placenta biometry and efficiency were slightly affected, but fetal BW and phenotype were not modified. However, hyperinsulinemia, insulin resistance, and hypertriglyceridemia were demonstrated in pre-term fetuses. In the juvenile period, these changes were not evidenced, and a similar pattern of growth and serum metabolic parameters in offspring of food-restricted mothers were found, except in serum aminotransferases levels, which increased. These were associated with higher liver fibrosis. Maternal food restriction in the early and mid-pregnancy followed by re-feeding in our rabbit model established a compensatory energy status in dams and alleviated potential long-term consequences in growth and metabolism in the offspring, even if fetal metabolism was altered.
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Duval F, Cruz-Vega DE, González-Gamboa I, González-Garza MT, Ponz F, Sánchez F, Alarcón-Galván G, Moreno-Cuevas JE. Detection of Autoantibodies to Vascular Endothelial Growth Factor Receptor-3 in Bile Duct Ligated Rats and Correlations with a Panel of Traditional Markers of Liver Diseases. DISEASE MARKERS 2016; 2016:6597970. [PMID: 27212785 PMCID: PMC4860220 DOI: 10.1155/2016/6597970] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 04/05/2016] [Indexed: 12/14/2022]
Abstract
There is a need for new noninvasive biomarkers (NIBMs) able to assess cholestasis and fibrosis in chronic cholestatic liver diseases (CCLDs). Tumorigenesis can arise from CCLDs. Therefore, autoantibodies to tumor-associated antigens (TAA) may be early produced in response to abnormal self-antigen expression caused by cholestatic injury. Vascular endothelial growth factor receptor-3 (VEGFR-3) has TAA potential since it is involved in cholangiocytes and lymphatic vessels proliferations during CCLDs. This study aims to detect autoantibodies directed at VEGFR-3 during bile duct ligation- (BDL-) induced cholestatic injury in rat sera and investigate whether they could be associated with traditional markers of liver damage, cholestasis, and fibrosis. An ELISA was performed to detect anti-VEGFR-3 autoantibodies in sera of rats with different degree of liver injury and results were correlated with aminotransferases, total bilirubin, and the relative fibrotic area. Mean absorbances of anti-VEGFR-3 autoantibodies were significantly increased from week one to week five after BDL. The highest correlation was observed with total bilirubin (R (2) = 0.8450, P = 3.04e - 12). In conclusion, anti-VEGFR-3 autoantibodies are early produced during BDL-induced cholestatic injury, and they are closely related to cholestasis, suggesting the potential of anti-VEGFR-3 autoantibodies as NIBMs of cholestasis in CCLDs and justifying the need for further investigations in patients with CCLD.
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Affiliation(s)
- Florent Duval
- Catedra de Terapia Celular, Escuela de Medicina, Tecnológico de Monterrey, Avenida Morones Prieto 3000 Pte., 64710 Monterrey, NL, Mexico
| | - Delia Elva Cruz-Vega
- Catedra de Terapia Celular, Escuela de Medicina, Tecnológico de Monterrey, Avenida Morones Prieto 3000 Pte., 64710 Monterrey, NL, Mexico
| | - Ivonne González-Gamboa
- Centro de Biotecnología y Genómica de Plantas (CBGP), UPM-INIA, Campus de Montegancedo, Autovía M40, Km 38, Pozuelo de Alarcón, 28223 Madrid, Spain
| | - María Teresa González-Garza
- Catedra de Terapia Celular, Escuela de Medicina, Tecnológico de Monterrey, Avenida Morones Prieto 3000 Pte., 64710 Monterrey, NL, Mexico
| | - Fernando Ponz
- Centro de Biotecnología y Genómica de Plantas (CBGP), UPM-INIA, Campus de Montegancedo, Autovía M40, Km 38, Pozuelo de Alarcón, 28223 Madrid, Spain
| | - Flora Sánchez
- Centro de Biotecnología y Genómica de Plantas (CBGP), UPM-INIA, Campus de Montegancedo, Autovía M40, Km 38, Pozuelo de Alarcón, 28223 Madrid, Spain
| | - Gabriela Alarcón-Galván
- Servicio de Anatomía Patológica y Citopatología, Hospital Universitario “Dr. José Eleuterio González”, Universidad Autónoma de Nuevo León, Madero y Dr. Aguirre Pequeño, 64460 Monterrey, NL, Mexico
| | - Jorge E. Moreno-Cuevas
- Catedra de Terapia Celular, Escuela de Medicina, Tecnológico de Monterrey, Avenida Morones Prieto 3000 Pte., 64710 Monterrey, NL, Mexico
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Normal and Fibrotic Rat Livers Demonstrate Shear Strain Softening and Compression Stiffening: A Model for Soft Tissue Mechanics. PLoS One 2016; 11:e0146588. [PMID: 26735954 PMCID: PMC4703410 DOI: 10.1371/journal.pone.0146588] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 12/18/2015] [Indexed: 12/19/2022] Open
Abstract
Tissues including liver stiffen and acquire more extracellular matrix with fibrosis. The relationship between matrix content and stiffness, however, is non-linear, and stiffness is only one component of tissue mechanics. The mechanical response of tissues such as liver to physiological stresses is not well described, and models of tissue mechanics are limited. To better understand the mechanics of the normal and fibrotic rat liver, we carried out a series of studies using parallel plate rheometry, measuring the response to compressive, extensional, and shear strains. We found that the shear storage and loss moduli G’ and G” and the apparent Young's moduli measured by uniaxial strain orthogonal to the shear direction increased markedly with both progressive fibrosis and increasing compression, that livers shear strain softened, and that significant increases in shear modulus with compressional stress occurred within a range consistent with increased sinusoidal pressures in liver disease. Proteoglycan content and integrin-matrix interactions were significant determinants of liver mechanics, particularly in compression. We propose a new non-linear constitutive model of the liver. A key feature of this model is that, while it assumes overall liver incompressibility, it takes into account water flow and solid phase compressibility. In sum, we report a detailed study of non-linear liver mechanics under physiological strains in the normal state, early fibrosis, and late fibrosis. We propose a constitutive model that captures compression stiffening, tension softening, and shear softening, and can be understood in terms of the cellular and matrix components of the liver.
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Enomoto M, Morikawa H, Tamori A, Kawada N. Noninvasive assessment of liver fibrosis in patients with chronic hepatitis B. World J Gastroenterol 2014; 20:12031-12038. [PMID: 25232240 PMCID: PMC4161791 DOI: 10.3748/wjg.v20.i34.12031] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 02/09/2014] [Accepted: 04/15/2014] [Indexed: 02/06/2023] Open
Abstract
Infection with hepatitis B virus is an important health problem worldwide: it affects more than 350 million people and is a leading cause of liver-related morbidity, accounting for 1 million deaths annually. Hepatic fibrosis is a consequence of the accumulation of extracellular matrix components in the liver. An accurate diagnosis of liver fibrosis is essential for the management of chronic liver disease. Liver biopsy has been considered the gold standard for diagnosing disease, grading necroinflammatory activity, and staging fibrosis. However, liver biopsy is unsuitable for repeated evaluations because it is invasive and can cause major complications, including death. Several noninvasive evaluations have been introduced for the assessment of liver fibrosis: serum biomarkers, combined indices or scores, and imaging techniques including transient elastography, acoustic radiation force impulse, real-time tissue elastography, and magnetic resonance elastography. Here, we review the recent progress of noninvasive assessment of liver fibrosis in patients with chronic hepatitis B. Most noninvasive evaluations for liver fibrosis have been validated first in patients with chronic hepatitis C, and later in those with chronic hepatitis B. The establishment of a noninvasive assessment of liver fibrosis is urgently needed to aid in the management of this leading cause of chronic liver disease.
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Cocciolillo S, Parruti G, Marzio L. CEUS and Fibroscan in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. World J Hepatol 2014; 6:496-503. [PMID: 25068001 PMCID: PMC4110541 DOI: 10.4254/wjh.v6.i7.496] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Revised: 06/12/2014] [Accepted: 06/27/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine intra-hepatic blood flow and liver stiffness in patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) using contrast-enhanced ultrasound and fibroscan.
METHODS: This prospective study included 15 patients with NAFLD, 17 patients with NASH and 16 healthy controls. In each patient, real-time ultrasound was used to locate the portal vein (PV) and the right liver lobe, and 5 mL of SonoVue® was then injected intravenous in a peripheral vein of the left arm over a 4-s span. Digital recording was performed for 3 min thereafter. The recording was subsequently retrieved to identify an area of interest in the PV area and in the right liver parenchyma (LP) to assess the blood flow by processing the data using dedicated software (Qontrast®, Bracco, Italy). The following parameters were evaluated: percentage of maximal contrast activity (Peak%), time to peak (TTP, s), regional blood volume (RBV, cm3), regional blood flow (RBF, cm3/s) and mean transit time (MTT, s). At 24-48 h post-injection, liver stiffness was evaluated using Fibroscan and measured in kPa. The statistical evaluation was performed using Student’s t test.
RESULTS: In the PV, the Peak%, RBV and RBF were significantly reduced in the NAFLD and NASH patients compared with the controls (Peak%: NAFLD 26.3 ± 6.6, NASH 28.1 ± 7.3 vs controls 55.8 ± 9.9, P < 0.001; RBV: NAFLD 4202.3 ± 3519.7, NASH 3929.8 ± 1941.3 vs controls 7473 ± 3281, P < 0.01; RBF: NAFLD 32.5 ± 10.8, NASH 32.7 ± 12.1 vs controls 73.1 ± 13.9, P < 0.001). The TTP in the PV was longer in both patient groups but reached statistical significance only in the NASH patients compared with the controls (NASH 79.5 ± 37.8 vs controls 43.2 ± 30, P < 0.01). In the LP, the Peak%, RBV and RBF were significantly reduced in the NAFLD and NASH patients compared with the controls (Peak%: NAFLD 43.2 ± 7.3, NASH 41.7 ± 7.7 vs controls 56.6 ± 6.3, P < 0.001; RBV: NAFLD 4851.5 ± 2009, NASH 5069.4 ± 2292.5 vs controls 6922.9 ± 2461.5, P < 0.05; RBF: NAFLD 55.7 ± 10.1, NASH 54.5 ± 12.1 vs controls 75.9 ± 10.5, P < 0.001). The TTP was longer in both patient groups but did not reach statistical significance. The MTT in both the PV and LP in the NAFLD and NASH patients was not different from that in the controls. Liver stiffness was significantly increased relative to the controls only in the NASH patients (NASH: 6.4 ± 2.2 vs controls 4.6 ± 1.5, P < 0.05).
CONCLUSION: Blood flow derangement within the liver present not only in NASH but also in NAFLD suggests that a vascular flow alteration precedes liver fibrosis development.
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Motoyama H, Komiya T, Thuy LTT, Tamori A, Enomoto M, Morikawa H, Iwai S, Uchida-Kobayashi S, Fujii H, Hagihara A, Kawamura E, Murakami Y, Yoshizato K, Kawada N. Cytoglobin is expressed in hepatic stellate cells, but not in myofibroblasts, in normal and fibrotic human liver. J Transl Med 2014; 94:192-207. [PMID: 24296877 DOI: 10.1038/labinvest.2013.135] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2013] [Revised: 09/20/2013] [Accepted: 10/04/2013] [Indexed: 12/16/2022] Open
Abstract
Cytoglobin (CYGB) is ubiquitously expressed in the cytoplasm of fibroblastic cells in many organs, including hepatic stellate cells. As yet, there is no specific marker with which to distinguish stellate cells from myofibroblasts in the human liver. To investigate whether CYGB can be utilized to distinguish hepatic stellate cells from myofibroblasts in normal and fibrotic human liver, human liver tissues damaged by infection with hepatitis C virus (HCV) and at different stages of fibrosis were obtained by liver biopsy. Immunohistochemistry was performed on histological sections of liver tissues using antibodies against CYGB, cellular retinol-binding protein-1 (CRBP-1), α-smooth muscle actin (α-SMA), thymocyte differentiation antigen 1 (Thy-1), and fibulin-2 (FBLN2). CYGB- and CRBP-1-positive cells were counted around fibrotic portal tracts in histological sections of the samples. The expression of several of the proteins listed above was examined in cultured mouse stellate cells. Quiescent stellate cells, but not portal myofibroblasts, expressed both CYGB and CRBP-1 in normal livers. In fibrotic and cirrhotic livers, stellate cells expressed both CYGB and α-SMA, whereas myofibroblasts around the portal vein expressed α-SMA, Thy-1, and FBLN2, but not CYGB. Development of the fibrotic stage was positively correlated with increases in Sirius red-stained, α-SMA-positive, and Thy-1-positive areas, whereas the number of CYGB- and CRBP-1-positive cells decreased with fibrosis development. Primary cultured mouse stellate cells expressed cytoplasmic CYGB at day 1, whereas they began to express α-SMA at the cellular margins at day 4. Thy-1 was undetectable throughout the culture period. In human liver tissues, quiescent stellate cells are CYGB positive. When activated, they also become α-SMA positive; however, they are negative for Thy-1 and FBLN2. Thus, CYGB is a useful marker with which to distinguish stellate cells from portal myofibroblasts in the damaged human liver.
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Affiliation(s)
- Hiroyuki Motoyama
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Tohru Komiya
- Department of Biological Function, Faculty of Science, Osaka City University, Osaka, Japan
| | - Le Thi Thanh Thuy
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Akihiro Tamori
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Hiroyasu Morikawa
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Shuji Iwai
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | | | - Hideki Fujii
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Atsushi Hagihara
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Etsushi Kawamura
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Yoshiki Murakami
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Katsutoshi Yoshizato
- 1] Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan [2] PhoenixBio, Higashihiroshima, Hiroshima, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
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Yarpuzlu B, Ayyildiz M, Tok OE, Aktas RG, Basdogan C. Correlation between the mechanical and histological properties of liver tissue. J Mech Behav Biomed Mater 2014; 29:403-16. [DOI: 10.1016/j.jmbbm.2013.09.016] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Revised: 09/11/2013] [Accepted: 09/13/2013] [Indexed: 12/24/2022]
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Sun S, Song Z, Cotler SJ, Cho M. Biomechanics and functionality of hepatocytes in liver cirrhosis. J Biomech 2013; 47:2205-10. [PMID: 24262849 DOI: 10.1016/j.jbiomech.2013.10.050] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 10/21/2013] [Accepted: 10/26/2013] [Indexed: 12/13/2022]
Abstract
Cirrhosis is a life-threatening condition that is generally attributed to overproduction of collagen fibers in the extracellular matrix that mechanically stiffens the liver. Chronic liver injury due to causes including viral hepatitis, inherited and metabolic liver diseases and external factors such as alcohol abuse can result in the development of cirrhosis. Progression of cirrhosis leads to hepatocellular dysfunction. While extensive studies to understand the complexity underlying liver fibrosis have led to potential application of anti-fibrotic drugs, no such FDA-approved drugs are currently available. Additional studies of hepatic fibrogenesis and cirrhosis primarily have focused on the extracellular matrix, while hepatocyte biomechanics has received limited attention. The role of hepatocyte biomechanics in liver cirrhosis remains elusive, and how the cell stiffness is correlated with biological functions of hepatocytes is also unknown. In this study, we demonstrate that the biomechanical properties of hepatocytes are correlated with their functions (e.g., glucose metabolism), and that hepatic dysfunction can be restored through modulation of the cellular biomechanics. Furthermore, our results indicate the hepatocyte functionality appears to be regulated through a crosstalk between the Rho and Akt signaling. These novel findings may lead to biomechanical intervention of hepatocytes and the development of innovative tissue engineering for clinical treatment to target liver cells rather than exclusively focusing on the extracellular matrix alone in liver cirrhosis.
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Affiliation(s)
- Shan Sun
- Department of Bioengineering, University of Illinois at Chicago, Chicago, IL 60607, United States
| | - Zhenyuan Song
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, United States
| | - Scott J Cotler
- Division of Hepatology, Loyola University Medical Center, Maywood, IL 60153, United States
| | - Michael Cho
- Department of Bioengineering, University of Illinois at Chicago, Chicago, IL 60607, United States.
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Yokoo T, Tang A, Sirlin CB. Imaging of NAFLD. NON‐ALCOHOLIC FATTY LIVER DISEASE 2013:93-111. [DOI: 10.1002/9781118556153.ch9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Tarantino G. Is Assessing the Presence of NASH by Liver Histology or Surrogate Markers Always Advisable? HEPATITIS MONTHLY 2013; 13:e7560. [PMID: 23610586 PMCID: PMC3631528 DOI: 10.5812/hepatmon.7560] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Accepted: 09/28/2012] [Indexed: 12/11/2022]
Affiliation(s)
- Giovanni Tarantino
- Department of Clinical and Experimental Medicine, School of Naples, Federico II University Medical, Naples, Italy
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Cobbold JFL, Patel D, Taylor-Robinson SD. Assessment of inflammation and fibrosis in non-alcoholic fatty liver disease by imaging-based techniques. J Gastroenterol Hepatol 2012; 27:1281-92. [PMID: 22432836 DOI: 10.1111/j.1440-1746.2012.07127.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Non-alcoholic fatty liver disease (NALFD) is a burgeoning global health problem, and the assessment of disease severity remains a clinical challenge. Conventional imaging and clinical blood tests are frequently unable to determine disease activity (the degree of inflammatory change) and fibrotic severity, while the applicability of histological examination of liver biopsy is limited. Imaging platforms provide liver-specific structural information, while newer applications of these technologies non-invasively exploit the physical and chemical characteristics of liver tissue in health and disease. In this review, conventional and newer imaging-based techniques for the assessment of inflammation and fibrosis in NAFLD are discussed in terms of diagnostic accuracy, radio-pathological correlations, and practical considerations. In particular, recent clinical studies of ultrasound (US)-based and magnetic resonance elastography techniques are evaluated, while the potential of contrast-enhanced US and magnetic resonance spectroscopy techniques is discussed. The development and application of these techniques is starting to reduce the clinical need for liver biopsy, to produce surrogate end-points for interventional and observational clinical studies, and through this, to provide new insights into the natural history of NAFLD.
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