|
1
|
Urlandini L, Leonetti AE, Conforti F, Perri A, Lofaro D, Antonucci G, Mandalà M, Bossio S, Di Agostino S, Rago V. Calorie-restriction treatment mitigates the aging in rat liver model. Biogerontology 2025; 26:108. [PMID: 40332584 PMCID: PMC12058891 DOI: 10.1007/s10522-025-10245-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 04/22/2025] [Indexed: 05/08/2025]
Abstract
The aging process promotes progressive impairment of homeostasis and the increase of the risk of disease and death. A major hallmark of the aging process is the systemic chronic inflammation which strongly contributes to the onset of aging-related diseases. In the liver, the aging condition drives the hepatocytes to develop a metabolic dysfunction-associated steatosis. Caloric restriction (CR) is a remarkable strategy to delay biological aging, occurring through several mechanisms. In this study we aimed to explore, employing an in vivo rat model, the impact of CR on aging-mediated liver inflammation markers. The experiments were performed on 14 male Sprague-Dawley rats (24 months old). At 18 months old, rats were allocated into two groups: the normal diet (ND) group was continued ad libitum diet, and the CR regimen group was fed a diet of the same chow restricted to 60% of the intake. All animals were sacrificed at 24 months old. Compared to the ND group, morphological examination of the liver revealed a lower level of fibrosis in the CR group, concomitantly with a reduced expression of key fibrotic markers, such as collagen I, fibronectin, and αSMA. Furthermore, CR improved the liver oxidative balance, as showed by the increased expression of two scavenging enzymes, SOD1/SOD. Moreover, we reported concomitant reduction of NLRP3 inflammasome signalling. Interestingly, CR significantly improved the signalling of key members of the nutrition-sensitizing affected by aging, AMPK/SIRT1/LKB1. Collectively our findings support the evidence on the metabolic benefits of CR about aging-related liver inflammation, by inducing a morphological improvement that mirrors the decrease in the expression of inflammatory molecular markers.
Collapse
Affiliation(s)
- L Urlandini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - A E Leonetti
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - F Conforti
- Pathology Unit, Annunziata Hospital, 87100, Cosenza, Italy
| | - A Perri
- Department of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Catanzaro, Italy
| | - D Lofaro
- University of Calabria, Department of Mathematics and Computer Science, Rende, 87036, Cosenza, Italy
| | - G Antonucci
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - M Mandalà
- Department of Biology, Ecology and Earth Science, University of Calabria, Rende, Italy
| | - S Bossio
- Department of Experimental and Clinical Medicine, Magna Græcia University of Catanzaro, Catanzaro, Italy
| | - S Di Agostino
- Department of Health Sciences, Magna Græcia University of Catanzaro, Catanzaro, Italy.
| | - V Rago
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
| |
Collapse
|
|
2
|
Ashmore-Harris C, Ayabe H, Yoshizawa E, Arisawa T, Takada Y, Takebe T, Fruhwirth GO. Gene editing enables non-invasive in vivo PET imaging of human induced pluripotent stem cell-derived liver bud organoids. Mol Ther Methods Clin Dev 2025; 33:101406. [PMID: 39927149 PMCID: PMC11803834 DOI: 10.1016/j.omtm.2025.101406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 01/06/2025] [Indexed: 02/11/2025]
Abstract
Human induced pluripotent stem cell (hiPSC)-derived liver cell therapies such as hepatocyte-like cells and liver organoids could provide unlimited therapeutic cells for clinical transplantation, but an inadequate understanding of their in vivo fate impedes translation. Whole body in vivo imaging could enable monitoring of transplanted cell survival and/or expansion non-invasively over time, permitting robust comparisons between emerging therapies to identify those most effective. The human sodium iodide symporter (hNIS) is a radionuclide reporter gene facilitating whole body in vivo cell tracking by positron emission tomography (PET). We gene-edited a clinical Good Manufacturing Practice-compliant hiPSC line at the AAVS1 safe harbor locus enabling constitutive expression of a hNIS-monomeric(m)GFP fusion reporter in hiPSCs and their differentiated progeny. We confirmed reporter integration did not impact pluripotency or differentiation capacity, and radiotracer uptake capacity was retained post-differentiation. In vivo trackable liver bud (LB) organoids were generated from traceable hNIS fused to monomeric GFP (hNIS-mGFP)-hiPSCs and transplanted into healthy and liver-injured mice. LB were imaged quantitatively by 18FBF4 --PET with imaging results confirmed histologically. We report, for the first time, hNIS-mGFP-hiPSC progeny retain differentiated function and PET trackability in vivo using LB. In vivo monitoring could accelerate regenerative cell therapy development by identifying efficacious candidate cells, successful engraftment/survival strategies and addressing safety concerns.
Collapse
Affiliation(s)
- Candice Ashmore-Harris
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, UK
- Imaging Therapies and Cancer Group, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London SE1 1UL, UK
- Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan
| | - Hiroaki Ayabe
- Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan
- Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
| | - Emi Yoshizawa
- Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan
| | - Tetsu Arisawa
- Department of Physiology, Graduate School of Medicine, Yokohama City University, Yokohama, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan
| | - Yuuki Takada
- Department of Physiology, Graduate School of Medicine, Yokohama City University, Yokohama, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan
| | - Takanori Takebe
- Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan
- Center for Stem Cell & Organoid Medicine (CuSTOM), Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA
- Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), and Division of Stem Cell and Organoid Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Gilbert O. Fruhwirth
- Imaging Therapies and Cancer Group, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London SE1 1UL, UK
| |
Collapse
|
|
3
|
Göring J, Schwarz C, Unger E, Quaas R, Hilger I. The Long-Term Impact of Polysaccharide-Coated Iron Oxide Nanoparticles on Inflammatory-Stressed Mice. J Xenobiot 2024; 14:1711-1728. [PMID: 39584956 PMCID: PMC11587046 DOI: 10.3390/jox14040091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/11/2024] [Accepted: 10/24/2024] [Indexed: 11/26/2024] Open
Abstract
Since iron oxide nanoparticles (IONPs) are expected to be important tools in medical care, patients with inflammatory diseases will be increasingly exposed to IONPs in the future. Here, we assessed the short- and long-term impact of polysaccharide (PS)-coated IONPs on mice with persistent systemic inflammation. To this end, PS-IONPs were synthetized by a core-shell method. Mice were regularly injected with sterile zymosan. PS-IONPs were administered intravenously. At specific nanoparticle injection post-observation times, the organ iron concentration was determined via atomic absorption spectrometry, the expression of NF-κB-related proteins using SDS-PAGE and immunoblotting, as well as body weight and haemograms. Finally, the mediator secretion in blood plasma was analysed using multiplexed ELISA. Our data show that PS-IONPs induce short-term changes of iron levels in distinct organs and of NF-κB p65 and p50, p100, COX-2s, and Bcl-2 protein expression in the liver of inflammatory stressed mice. In the long term, there was an attenuated expression of several NF-κB-related proteins and attenuated features of inflammatory-based anaemia in blood. PS-IONPs weakly influenced the blood cytokine levels. PS-IONPs are biocompatible, but given their short-term pro-inflammatory impact, they should prospectively be applied with caution in patients with inflammatory diseases of the liver.
Collapse
Affiliation(s)
- Julia Göring
- Experimental Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, D-07747 Jena, Germany; (J.G.)
| | - Claudia Schwarz
- Experimental Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, D-07747 Jena, Germany; (J.G.)
| | - Eric Unger
- Experimental Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, D-07747 Jena, Germany; (J.G.)
| | - Rainer Quaas
- Chemicell GmbH, Eresburgstrasse 22-23, D-12103 Berlin, Germany;
| | - Ingrid Hilger
- Experimental Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, D-07747 Jena, Germany; (J.G.)
| |
Collapse
|
|
4
|
Lu C, Li X, Fang C, Li C, Xu Y, Guo Y. Pretreatment of artesunate promoted hepatocyte proliferation by activating the PI3K/Akt/mTOR signaling pathway in mice. Acta Cir Bras 2024; 39:e394324. [PMID: 39476067 PMCID: PMC11506702 DOI: 10.1590/acb394324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 06/05/2024] [Indexed: 11/02/2024] Open
Abstract
PURPOSE Artesunate (ART) has been implicated in regulating the many processes of liver injury, but its roles in liver regeneration still need to be illustrated. METHODS In the present study, ART was used to pretreat hepatocyte cell line NCTC1469 to study the effect of ART on hepatocyte proliferation in vitro. Furthermore, the potency of ART as a regimen to promote liver regeneration and restore liver function was evaluated following partial hepatectomy (PH) on C57BL/6 mice. RESULTS ART concentration-dependently promoted hepatocyte proliferation and reduced apoptosis. Cell cycle and Ki-67 immunohistochemical analyses demonstrated that ART supplementation promoted the proliferation of hepatocytes and accelerated liver regeneration. Our results provided evidence that ART improved liver function in a dose-dependent manner, as indicated by decreased serum alanine aminotransferase, aspartate aminotransferase, and increased albumin, and hepatocyte growth factor levels in PH mice. Meanwhile, ART promoted the PI3K/Akt/mTOR signaling in NCTC1469 cells and liver tissue of PH mice. In addition, PI3K inhibitor LY294002 blocked the promotion effect of ART on hepatocyte proliferation and cell cycle progression. CONCLUSION ART promoted hepatocyte proliferation via activation of the PI3K/Akt/mTOR pathway, which was beneficial to liver regeneration of PH-induced liver injury.
Collapse
Affiliation(s)
- Changyou Lu
- The Affliated Traditional Chinese Medicine Hospital, Southwest Medical University – Department of Hepatobiliary and Pancreatic Surgery – Luzhou (Sichuan) – China
| | - Xinkai Li
- The Affliated Traditional Chinese Medicine Hospital, Southwest Medical University – Department of Hepatobiliary and Pancreatic Surgery – Luzhou (Sichuan) – China
| | - Chao Fang
- The Affliated Traditional Chinese Medicine Hospital, Southwest Medical University – Department of Hepatobiliary and Pancreatic Surgery – Luzhou (Sichuan) – China
| | - Chuntao Li
- The Affliated Traditional Chinese Medicine Hospital, Southwest Medical University – Department of Hepatobiliary and Pancreatic Surgery – Luzhou (Sichuan) – China
| | - Yunke Xu
- The Affliated Traditional Chinese Medicine Hospital, Southwest Medical University – Department of Hepatobiliary and Pancreatic Surgery – Luzhou (Sichuan) – China
| | - Yong Guo
- The Affliated Traditional Chinese Medicine Hospital, Southwest Medical University – Department of Hepatobiliary and Pancreatic Surgery – Luzhou (Sichuan) – China
| |
Collapse
|
|
5
|
Chen F, Hao T, Chen Q, Sun Y, Shen Y, Zhao Z, Du J, Li Y, Mai K, Ai Q. FABP1 induces lipogenesis by regulating the processing of SREBP1 in hepatocytes of large yellow croaker (Larimichthys crocea). FASEB J 2024; 38:e70036. [PMID: 39275940 DOI: 10.1096/fj.202401087rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 08/15/2024] [Accepted: 08/26/2024] [Indexed: 09/16/2024]
Abstract
Fatty acid-binding protein 1 (FABP1) plays an important role in regulating fatty acid metabolism in liver, which is a potential therapeutic target for diseases such as non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms are not well defined. Using complementary experimental models, we discovered FABP1 induction in hepatocytes as a primary mediator of lipogenesis when exposed to fatty acids, especially saturated fatty acids (SFAs). In the feeding trial, palm oil led to excess lipid accumulation in the liver of large yellow croaker (Larimichthys crocea), accompanied by significant induction of FABP1. In cultured cells, palmitic acid (PA), a kind of SFA, triggered the fabp1 expression and increased triglyceride (TG) contents. Knockdown of FABP1 dampened PA-induced TG accumulation through mitigated lipogenesis. The overexpression of FABP1 showed the opposite result. Furthermore, the inactivation of FABP1 led to induction in insulin-induced gene 1 (INSIG1) expression, which attenuated the processing of sterol regulatory element-binding protein 1 (SREBP1) by down-regulating the nuclear-localized SREBP1. These results revealed a previously unrecognized function of FABP1 in response to PA, providing additional evidence for targeting FABP1 in the treatment of NAFLD caused by SFA.
Collapse
Affiliation(s)
- Fan Chen
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, Qingdao, 266003, Shandong, People's Republic of China
| | - Tingting Hao
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, Qingdao, 266003, Shandong, People's Republic of China
| | - Qiang Chen
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, Qingdao, 266003, Shandong, People's Republic of China
| | - Yuning Sun
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, Qingdao, 266003, Shandong, People's Republic of China
| | - Yanan Shen
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, Qingdao, 266003, Shandong, People's Republic of China
| | - Zengqi Zhao
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, Qingdao, 266003, Shandong, People's Republic of China
| | - Jianlong Du
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, Qingdao, 266003, Shandong, People's Republic of China
| | - Yueru Li
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, Qingdao, 266003, Shandong, People's Republic of China
| | - Kangsen Mai
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, Qingdao, 266003, Shandong, People's Republic of China
| | - Qinghui Ai
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs), Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, Qingdao, 266003, Shandong, People's Republic of China
| |
Collapse
|
|
6
|
Tan Y, Wang Z, Guo R, Zhou X, Zhang W, Wu M, Guo C, Gao H, Sun X, Zhang Z, Gong T. Dual-Targeting Macrophages and Hepatic Stellate Cells by Modified Albumin Nanoparticles for Liver Cirrhosis Treatment. ACS APPLIED MATERIALS & INTERFACES 2024; 16:11239-11250. [PMID: 38395769 DOI: 10.1021/acsami.3c17670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2024]
Abstract
Hepatic cirrhosis has become a global public health concern with high mortality and currently lacks effective clinical treatment methods. Activation of hepatic stellate cells (HSCs) and the large number of macrophages infiltrating into the liver play a critical role in the development of liver cirrhosis. This study developed a novel modified nanoparticle system (SRF-CS-PSA NPs) in which Sorafenib (SRF) was encapsulated by palmitic acid-modified albumin (PSA) and further modified with chondroitin sulfate (CS). These modifications enabled the SRF-CS-PSA NPs to effectively target hepatic stellate cells (HSCs) and macrophages. SRF-CS-PSA NPs showed uniform particle size distribution of approximately 120 nm and high loading efficiency of up to 99.5% and can be taken up by HSCs and macrophages via CD44 and SR-A receptors, respectively. In a mouse model of liver cirrhosis, SRF-CS-PSA NPs demonstrated superior targeting and inhibition of HSCs and macrophages, effectively reversing the process of liver cirrhosis. Overall, our study demonstrates the potential of SRF-CS-PSA NPs as a targeted therapy for liver cirrhosis, with promising clinical applications.
Collapse
Affiliation(s)
- Yulu Tan
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Zijun Wang
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Rui Guo
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Xueru Zhou
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Wei Zhang
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Mengying Wu
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Chenqi Guo
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Huile Gao
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Xun Sun
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Zhirong Zhang
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| | - Tao Gong
- Key Laboratory of Drug-Targeting & Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drugs & Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China
| |
Collapse
|
|
7
|
Coavoy-Sanchez SA, da Costa Marques LA, Costa SKP, Muscara MN. Role of Gasotransmitters in Inflammatory Edema. Antioxid Redox Signal 2024; 40:272-291. [PMID: 36974358 DOI: 10.1089/ars.2022.0089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
Abstract
Significance: Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are, to date, the identified members of the gasotransmitter family, which consists of gaseous signaling molecules that play central roles in the regulation of a wide variety of physiological and pathophysiological processes, including inflammatory edema. Recent Advances: Recent studies show the potential anti-inflammatory and antiedematogenic effects of NO-, CO-, and H2S-donors in vivo. In general, it has been observed that the therapeutical effects of NO-donors are more relevant when administered at low doses at the onset of the inflammatory process. Regarding CO-donors, their antiedematogenic effects are mainly associated with inhibition of proinflammatory mediators (such as inducible NO synthase [iNOS]-derived NO), and the observed protective effects of H2S-donors seem to be mediated by reducing some proinflammatory enzyme activities. Critical Issues: The most recent investigations focus on the interactions among the gasotransmitters under different pathophysiological conditions. However, the biochemical/pharmacological nature of these interactions is neither general nor fully understood, although specifically dependent on the site where the inflammatory edema occurs. Future Directions: Considering the nature of the involved mechanisms, a deeper knowledge of the interactions among the gasotransmitters is mandatory. In addition, the development of new pharmacological tools, either donors or synthesis inhibitors of the three gasotransmitters, will certainly aid the basic investigations and open new strategies for the therapeutic treatment of inflammatory edema. Antioxid. Redox Signal. 40, 272-291.
Collapse
Affiliation(s)
| | | | - Soraia Katia Pereira Costa
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil
| | - Marcelo Nicolas Muscara
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil
| |
Collapse
|
|
8
|
Leal F, Zeiringer S, Jeitler R, Costa PF, Roblegg E. A comprehensive overview of advanced dynamic in vitro intestinal and hepatic cell culture models. Tissue Barriers 2024; 12:2163820. [PMID: 36680530 PMCID: PMC10832944 DOI: 10.1080/21688370.2022.2163820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 12/22/2022] [Indexed: 01/22/2023] Open
Abstract
Orally administered drugs pass through the gastrointestinal tract before being absorbed in the small intestine and metabolised in the liver. To test the efficacy and toxicity of drugs, animal models are often employed; however, they are not suitable for investigating drug-tissue interactions and making reliable predictions, since the human organism differs drastically from animals in terms of absorption, distribution, metabolism and excretion of substances. Likewise, simple static in vitro cell culture systems currently used in preclinical drug screening often do not resemble the native characteristics of biological barriers. Dynamic models, on the other hand, provide in vivo-like cell phenotypes and functionalities that offer great potential for safety and efficacy prediction. Herein, current microfluidic in vitro intestinal and hepatic models are reviewed, namely single- and multi-tissue micro-bioreactors, which are associated with different methods of cell cultivation, i.e., scaffold-based versus scaffold-free.
Collapse
Affiliation(s)
- Filipa Leal
- BIOFABICS, Rua Alfredo Allen 455, 4200-135 Porto, Portugal
| | - Scarlett Zeiringer
- Department of Pharmaceutical Technology and Biopharmacy, University of Graz, Institute of Pharmaceutical Sciences, Universitaetsplatz 1, Graz, Austria
| | - Ramona Jeitler
- Department of Pharmaceutical Technology and Biopharmacy, University of Graz, Institute of Pharmaceutical Sciences, Universitaetsplatz 1, Graz, Austria
| | - Pedro F. Costa
- BIOFABICS, Rua Alfredo Allen 455, 4200-135 Porto, Portugal
| | - Eva Roblegg
- Department of Pharmaceutical Technology and Biopharmacy, University of Graz, Institute of Pharmaceutical Sciences, Universitaetsplatz 1, Graz, Austria
| |
Collapse
|
|
9
|
Sun C, Holstein DJF, Garcia-Cubero N, Moulla Y, Stroh C, Dietrich A, Schön MR, Gärtner D, Lohmann T, Dressler M, Stumvoll M, Blüher M, Kovacs P, Guiu-Jurado E. The Role of Phosphatidylethanolamine N-Methyltransferase ( PEMT) and Its Waist-Hip-Ratio-Associated Locus rs4646404 in Obesity-Related Metabolic Traits and Liver Disease. Int J Mol Sci 2023; 24:16850. [PMID: 38069170 PMCID: PMC10706059 DOI: 10.3390/ijms242316850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/21/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
In previous genome-wide association studies (GWAS), genetic loci associated with obesity and impaired fat distribution (FD) have been identified. In the present study, we elucidated the role of the PEMT gene, including the waist-hip-ratio-associated single nucleotide polymorphism rs4646404, and its influence on obesity-related metabolic traits. DNA from 2926 metabolically well-characterized subjects was used for genotyping. PEMT expression was analyzed in paired visceral (vis) and subcutaneous (sc) adipose tissue (AT) from a subset of 574 individuals. Additionally, PEMT expression was examined in vis, sc AT and liver tissue in a separate cohort of 64 patients with morbid obesity and liver disease. An in vitro Pemt knockdown was conducted in murine epididymal and inguinal adipocytes. Our findings highlight tissue-specific variations in PEMT mRNA expression across the three studied tissues. Specifically, vis PEMT mRNA levels correlated significantly with T2D and were implicated in the progression of non-alcoholic steatohepatitis (NASH), in contrast to liver tissue, where no significant associations were found. Moreover, sc PEMT expression showed significant correlations with several anthropometric- and metabolic-related parameters. The rs4646404 was associated with vis AT PEMT expression and also with diabetes-related traits. Our in vitro experiments supported the influence of PEMT on adipogenesis, emphasizing its role in AT biology. In summary, our data suggest that PEMT plays a role in regulating FD and has implications in metabolic diseases.
Collapse
Affiliation(s)
- Chang Sun
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - David J. F. Holstein
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - Natalia Garcia-Cubero
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - Yusef Moulla
- Clinic for Visceral, Transplantation and Thorax and Vascular Surgery, University Hospital Leipzig, 04103 Leipzig, Germany
| | - Christine Stroh
- Department of General, Abdominal and Pediatric Surgery, Municipal Hospital, 07548 Gera, Germany
| | - Arne Dietrich
- Clinic for Visceral, Transplantation and Thorax and Vascular Surgery, University Hospital Leipzig, 04103 Leipzig, Germany
| | - Michael R. Schön
- Städtisches Klinikum Karlsruhe, Clinic of Visceral Surgery, 76133 Karlsruhe, Germany
| | - Daniel Gärtner
- Städtisches Klinikum Karlsruhe, Clinic of Visceral Surgery, 76133 Karlsruhe, Germany
| | - Tobias Lohmann
- Municipal Clinic Dresden-Neustadt, 01129 Dresden, Germany
| | | | - Michael Stumvoll
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, 04103 Leipzig, Germany
| | - Matthias Blüher
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, 04103 Leipzig, Germany
| | - Peter Kovacs
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - Esther Guiu-Jurado
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
- Deutsches Zentrum für Diabetesforschung e.V., 85764 Neuherberg, Germany
| |
Collapse
|
|
10
|
Gao J, Bao M, Xing Y, Ding Y, Han T, Wen E, Liu J, Yue S, Wang R, Wang L, Liu J, Zhao S, Huang J, Liu E, Bai L. Mediator subunit MED1 deficiency prevents carbon tetrachloride-induced hepatic fibrosis in mice. Am J Physiol Gastrointest Liver Physiol 2023; 325:G418-G428. [PMID: 37668531 DOI: 10.1152/ajpgi.00076.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/17/2023] [Accepted: 08/22/2023] [Indexed: 09/06/2023]
Abstract
Mediator subunit mediator 1 (MED1) mediates ligand-dependent binding of the mediator coactivator complex to various nuclear receptors and plays a critical role in embryonic development, lipid and glucose metabolism, liver regeneration, and tumorigenesis. However, the precise role of MED1 in the development of liver fibrosis has been unclear. Here, we showed that MED1 expression was increased in livers from nonalcoholic steatohepatitis (NASH) patients and mice and positively correlated with transforming growth factor β (TGF-β) signaling and profibrotic factors. Upon treatment with carbon tetrachloride (CCl4), hepatic fibrosis was much less in liver-specific MED1 deletion (MED1ΔLiv) mice than in MED1fl/fl littermates. TGF-β/Smad2/3 signaling pathway was inhibited, and gene expression of fibrotic markers, including α-smooth muscle actin (α-SMA), collagen type 1 α 1 (Col1a1), matrix metalloproteinase-2 (Mmp2), and metallopeptidase inhibitor 1 (Timp1) were decreased in livers of MED1ΔLiv mice with CCl4 injection. Transcriptomic analysis revealed that the differentially expressed genes in livers of CCl4-administered MED1ΔLiv mice were enriched in the pathway of oxidoreductase activity, followed by robustly reduced oxidoreductase activity-related genes, such as Gm4756, Txnrd3, and Etfbkmt. More importantly, we found that the reduction of reactive oxygen species (ROS) in MED1 knockdown hepatocytes blocked the activation of TGF-β/Smad2/3 pathway and the expression of fibrotic genes in LX2 cells. These results indicate that MED1 is a positive regulator for hepatic fibrogenesis, and MED1 may be considered as a potential therapeutic target for the regression of liver fibrosis.NEW & NOTEWORTHY In this study, we present the first evidence that liver mediator 1 (MED1) deficiency attenuated carbon tetrachloride-induced hepatic fibrosis in mouse. The underlying mechanism is that MED1 deficiency reduces reactive oxygen species (ROS) production in hepatocytes, thus restricts the activation of TGF-β/Smad2/3 signaling pathway and fibrogenic genes expression in hepatic stellate cells (HSCs). These data suggest that MED1 is an essential regulator for hepatic fibrogenesis, and MED1 may be considered as a potential therapeutic target for liver fibrosis.
Collapse
Affiliation(s)
- Jie Gao
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
- School of Biological Science Technology and Engineering, Shaanxi University of Technology, Hanzhong, People's Republic of China
| | - Miaoye Bao
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Yuanming Xing
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Yiming Ding
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Tuo Han
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Ergang Wen
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Jun Liu
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Shaoyun Yue
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Rong Wang
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Ling Wang
- School of Biological Science Technology and Engineering, Shaanxi University of Technology, Hanzhong, People's Republic of China
| | - Junhui Liu
- Department of Clinical Laboratory, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Sihai Zhao
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Jiansheng Huang
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Enqi Liu
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| | - Liang Bai
- Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, People's Republic of China
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, People's Republic of China
| |
Collapse
|
|
11
|
Carlessi R, Denisenko E, Boslem E, Köhn-Gaone J, Main N, Abu Bakar NDB, Shirolkar GD, Jones M, Beasley AB, Poppe D, Dwyer BJ, Jackaman C, Tjiam MC, Lister R, Karin M, Fallowfield JA, Kendall TJ, Forbes SJ, Gray ES, Olynyk JK, Yeoh G, Forrest AR, Ramm GA, Febbraio MA, Tirnitz-Parker JE. Single-nucleus RNA sequencing of pre-malignant liver reveals disease-associated hepatocyte state with HCC prognostic potential. CELL GENOMICS 2023; 3:100301. [PMID: 37228755 PMCID: PMC10203275 DOI: 10.1016/j.xgen.2023.100301] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 01/27/2023] [Accepted: 03/17/2023] [Indexed: 05/27/2023]
Abstract
Current approaches to staging chronic liver diseases have limited utility for predicting liver cancer risk. Here, we employed single-nucleus RNA sequencing (snRNA-seq) to characterize the cellular microenvironment of healthy and pre-malignant livers using two distinct mouse models. Downstream analyses unraveled a previously uncharacterized disease-associated hepatocyte (daHep) transcriptional state. These cells were absent in healthy livers but increasingly prevalent as chronic liver disease progressed. Copy number variation (CNV) analysis of microdissected tissue demonstrated that daHep-enriched regions are riddled with structural variants, suggesting these cells represent a pre-malignant intermediary. Integrated analysis of three recent human snRNA-seq datasets confirmed the presence of a similar phenotype in human chronic liver disease and further supported its enhanced mutational burden. Importantly, we show that high daHep levels precede carcinogenesis and predict a higher risk of hepatocellular carcinoma development. These findings may change the way chronic liver disease patients are staged, surveilled, and risk stratified.
Collapse
Affiliation(s)
- Rodrigo Carlessi
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Elena Denisenko
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Ebru Boslem
- Cellular & Molecular Metabolism Laboratory, Monash Institute of Pharmacological Sciences, Monash University, Parkville, VIC 3052, Australia
| | - Julia Köhn-Gaone
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
| | - Nathan Main
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
| | - N. Dianah B. Abu Bakar
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
| | - Gayatri D. Shirolkar
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
| | - Matthew Jones
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Aaron B. Beasley
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
| | - Daniel Poppe
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
- ARC Centre of Excellence in Plant Energy Biology, School of Molecular Sciences, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Benjamin J. Dwyer
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
| | - Connie Jackaman
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
| | - M. Christian Tjiam
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
- Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Nedlands, WA, Australia
| | - Ryan Lister
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
- ARC Centre of Excellence in Plant Energy Biology, School of Molecular Sciences, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Michael Karin
- Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Jonathan A. Fallowfield
- University of Edinburgh Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Timothy J. Kendall
- University of Edinburgh Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
- Edinburgh Pathology, University of Edinburgh, Edinburgh, UK
| | - Stuart J. Forbes
- Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Elin S. Gray
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
| | - John K. Olynyk
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
| | - George Yeoh
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Alistair R.R. Forrest
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Grant A. Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
| | - Mark A. Febbraio
- Cellular & Molecular Metabolism Laboratory, Monash Institute of Pharmacological Sciences, Monash University, Parkville, VIC 3052, Australia
| | - Janina E.E. Tirnitz-Parker
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
| |
Collapse
|
|
12
|
Clasen F, Nunes PM, Bidkhori G, Bah N, Boeing S, Shoaie S, Anastasiou D. Systematic diet composition swap in a mouse genome-scale metabolic model reveals determinants of obesogenic diet metabolism in liver cancer. iScience 2023; 26:106040. [PMID: 36844450 PMCID: PMC9947310 DOI: 10.1016/j.isci.2023.106040] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 09/08/2022] [Accepted: 01/20/2023] [Indexed: 01/26/2023] Open
Abstract
Dietary nutrient availability and gene expression, together, influence tissue metabolic activity. Here, we explore whether altering dietary nutrient composition in the context of mouse liver cancer suffices to overcome chronic gene expression changes that arise from tumorigenesis and western-style diet (WD). We construct a mouse genome-scale metabolic model and estimate metabolic fluxes in liver tumors and non-tumoral tissue after computationally varying the composition of input diet. This approach, called Systematic Diet Composition Swap (SyDiCoS), revealed that, compared to a control diet, WD increases production of glycerol and succinate irrespective of specific tissue gene expression patterns. Conversely, differences in fatty acid utilization pathways between tumor and non-tumor liver are amplified with WD by both dietary carbohydrates and lipids together. Our data suggest that combined dietary component modifications may be required to normalize the distinctive metabolic patterns that underlie selective targeting of tumor metabolism.
Collapse
Affiliation(s)
- Frederick Clasen
- Cancer Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK
| | - Patrícia M. Nunes
- Cancer Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Gholamreza Bidkhori
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK
| | - Nourdine Bah
- Bioinformatics and Biostatistics Science Technology Platform, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Stefan Boeing
- Bioinformatics and Biostatistics Science Technology Platform, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Saeed Shoaie
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK
- Science for Life Laboratory (SciLifeLab), KTH - Royal Institute of Technology, Tomtebodavägen 23, 171 65 Solna, Stockholm, Sweden
| | - Dimitrios Anastasiou
- Cancer Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| |
Collapse
|
|
13
|
Samsuzzaman M, Lee JH, Moon H, Lee J, Lee H, Lim Y, Park MG, Kim H, Kim SY. Identification of a potent NAFLD drug candidate for controlling T2DM-mediated inflammation and secondary damage in vitro and in vivo. Front Pharmacol 2022; 13:943879. [PMID: 36059993 PMCID: PMC9437277 DOI: 10.3389/fphar.2022.943879] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 07/15/2022] [Indexed: 11/25/2022] Open
Abstract
Accumulation of glucose/sugar results in the formation of reactive di-carbonyl compounds such as MGO and GO that interact with several amino acids and proteins to form toxic advanced glycation end products (AGEs). Induction of AGEs breakdown can control symptoms and severity in T2DM and other related complications like NAFLD where AGEs are the key players. Therefore, an AGE cross-link breaker has been suggested for preventing the onset/progression of NAFLD. In this study, we reported novel synthetic naphthalene-2-acyl thiazolium derivatives (KHAGs). Among synthesized KHAG derivatives, we observed that a novel KHAG-04, a 1,4-dimethoxynaphthalen-2-acyl thiazolium salt which is an analog of alagebrium, dramatically cleaves MGO/GO-AGE cross-links, and it also inhibited inflammation by lowering the level of nitric oxide production and IL-1β and TNF-α secretion in LPS and/or MGO-AGE–activated macrophage. Moreover, it also reduced FFA and MGO-AGE–induced lipogenesis in Hep-G2 cells. In mice, KHAG-04 significantly reduced the level of glyoxal in the liver, which was induced by DMC. Furthermore, KHAG-04 treatment significantly reduced blood glucose levels, lipid accumulation, and inflammation in the NAFLD/T2DM animal model. Novel KHAG-04–mediated induction of AGEs breakdown could be the possible reason for its anti-inflammatory, antihyperglycemic, and anti-lipidemic effects in cells and NAFLD in the T2DM animal model, respectively. Further research might explore the pharmacological efficacy and usefulness and consider the ability of this compound in the treatment strategy against various models of NAFLD in T2DM where MGO/GO-AGEs play a key role in the pathogenesis.
Collapse
Affiliation(s)
- Md Samsuzzaman
- College of Pharmacy, Gachon University, Incheon, South Korea
| | - Jae Hyuk Lee
- College of Pharmacy, Gachon University, Incheon, South Korea
| | - Hyejin Moon
- Department of Applied Chemistry and Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Seoul, Gyeonggi, South Korea
| | - Jisue Lee
- Department of Applied Chemistry and Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Seoul, Gyeonggi, South Korea
| | - Heaji Lee
- Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea
| | - Yunsook Lim
- Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea
| | | | - Hakwon Kim
- Department of Applied Chemistry and Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Seoul, Gyeonggi, South Korea
- *Correspondence: Hakwon Kim, ; Sun Yeou Kim,
| | - Sun Yeou Kim
- College of Pharmacy, Gachon University, Incheon, South Korea
- Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, South Korea
- *Correspondence: Hakwon Kim, ; Sun Yeou Kim,
| |
Collapse
|
|
14
|
Tiemeijer BM, Tel J. Hydrogels for Single-Cell Microgel Production: Recent Advances and Applications. Front Bioeng Biotechnol 2022; 10:891461. [PMID: 35782502 PMCID: PMC9247248 DOI: 10.3389/fbioe.2022.891461] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 05/09/2022] [Indexed: 12/12/2022] Open
Abstract
Single-cell techniques have become more and more incorporated in cell biological research over the past decades. Various approaches have been proposed to isolate, culture, sort, and analyze individual cells to understand cellular heterogeneity, which is at the foundation of every systematic cellular response in the human body. Microfluidics is undoubtedly the most suitable method of manipulating cells, due to its small scale, high degree of control, and gentle nature toward vulnerable cells. More specifically, the technique of microfluidic droplet production has proven to provide reproducible single-cell encapsulation with high throughput. Various in-droplet applications have been explored, ranging from immunoassays, cytotoxicity assays, and single-cell sequencing. All rely on the theoretically unlimited throughput that can be achieved and the monodispersity of each individual droplet. To make these platforms more suitable for adherent cells or to maintain spatial control after de-emulsification, hydrogels can be included during droplet production to obtain “microgels.” Over the past years, a multitude of research has focused on the possibilities these can provide. Also, as the technique matures, it is becoming clear that it will result in advantages over conventional droplet approaches. In this review, we provide a comprehensive overview on how various types of hydrogels can be incorporated into different droplet-based approaches and provide novel and more robust analytic and screening applications. We will further focus on a wide range of recently published applications for microgels and how these can be applied in cell biological research at the single- to multicell scale.
Collapse
Affiliation(s)
- B. M. Tiemeijer
- Laboratory of Immunoengineering, Department of Biomedical Engineering, TU Eindhoven, Eindhoven, Netherlands
- Institute of Complex Molecular Systems, TU Eindhoven, Eindhoven, Netherlands
| | - J. Tel
- Laboratory of Immunoengineering, Department of Biomedical Engineering, TU Eindhoven, Eindhoven, Netherlands
- Institute of Complex Molecular Systems, TU Eindhoven, Eindhoven, Netherlands
- *Correspondence: J. Tel,
| |
Collapse
|
|
15
|
Mandal S, Dey Bhowmik A, Mukhuty A, Kundu S, Truong KN, Rissanen K, Chattopadhyay A, Sahoo P. Reliable fluorescence technique to detect the antibiotic colistin, a possible environmental threat due to its overuse. Sci Rep 2022; 12:9307. [PMID: 35661822 PMCID: PMC9166777 DOI: 10.1038/s41598-022-13471-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/24/2022] [Indexed: 11/24/2022] Open
Abstract
Colistin, considered a drug of last resort as it is effective towards multidrug-resistant Gram-negative bacterial infections. Oral administration of colistin in the poultry industry is a common practice, not only to prevent and reduce bacterial infections, but also as a rapid-growth promoter. Long-term exposure to any antibiotic will eventually lead to the development of bacterial resistance towards all antibiotics through various mechanisms in the physiological system and environment. Chicken is the most consumed source of animal protein for humans throughout the world. In addition, the manure of poultry, containing traces of the used antibiotics, is being used in farming. Exposure to excess amounts of colistin causes a great concern not only to the humans but to the environment as a whole. In the present contribution, colistin has been detected in chicken hepatocyte cells through in vivo confocal microscopy. In addition, the amount of colistin in the chicken excrements has been estimated. A simple chemosensor NAF, a dye-based on napthaldehyde furfural, was developed for the detection of colistin, supplemented with experimental evidence and theoretical calculations.
Collapse
Affiliation(s)
- Saurodeep Mandal
- Department of Chemistry, Visva-Bharati, Santiniketan, West Bengal, 731235, India
| | - Arpan Dey Bhowmik
- Department of Zoology, Visva-Bharati, Santiniketan, West Bengal, 731235, India
| | - Alpana Mukhuty
- Department of Zoology, Visva-Bharati, Santiniketan, West Bengal, 731235, India
| | - Shampa Kundu
- Department of Chemistry, Visva-Bharati, Santiniketan, West Bengal, 731235, India
| | - Khai-Nghi Truong
- Department of Chemistry, University of Jyvaskyla, Survontie 9 B, P.O. Box 35, 40014, Jyvaskyla, Finland
| | - Kari Rissanen
- Department of Chemistry, University of Jyvaskyla, Survontie 9 B, P.O. Box 35, 40014, Jyvaskyla, Finland
| | | | - Prithidipa Sahoo
- Department of Chemistry, Visva-Bharati, Santiniketan, West Bengal, 731235, India.
| |
Collapse
|
|
16
|
Wang G, Wei W, Jiang Z, Jiang J, Han J, Zhang H, Hu J, Zhang P, Li X, Chen T, He J, Li Z, Lai J, Liang H, Ning C, Ye L. Talaromyces marneffei activates the AIM2-caspase-1/-4-GSDMD axis to induce pyroptosis in hepatocytes. Virulence 2022; 13:963-979. [PMID: 35639503 PMCID: PMC9176249 DOI: 10.1080/21505594.2022.2080904] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Talaromyces marneffei tends to induce systemic infection in immunocompromised individuals, which is one of the causes of the high mortality. The underlying molecular mechanisms of T.marneffei-induced abnormal liver function are still poorly understood. In this study, we found that T.marneffei-infected patients could develop abnormal liver function, evidenced by reduced albumin and increased levels of aspartate aminotransferase (AST) and AST/alanine aminotransferase (ALT). T. marneffei-infected mice exhibited similar characteristics. In vitro investigations showed that T.marneffei induced the death of AML-12 cells. Furthermore, we determined that T.marneffei infection induced pyroptosis in hepatocytes of C57BL/6J mice and AML-12 cells, demonstrated by the increase of AIM2, caspase-1/-4, Gasdermin D(GSDMD) and pyroptosis-related cytokines in T.marneffei-infected mice/cells. Importantly, cell death was markedly suppressed in the presence of VX765 (an inhibitor of caspase-1/-4). Furthermore, in the presence of VX765, T.marneffei-induced pyroptosis was blocked. Nevertheless, necroptosis and apoptosis were also detected in infected animal model at 14 days post-infection. In conclusion, T.marneffei induces pyroptosis in hepatocytes through activation of the AIM2-caspase-1/-4-GSDMD axis, which may be an important cause of liver damage, and other death pathways including necroptosis and apoptosis may also be involved in the later stage of infection.
Collapse
Affiliation(s)
- Gang Wang
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Wudi Wei
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| | - Zhongsheng Jiang
- Department of Infectious Diseases, Liuzhou People's Hospital, Liuzhou, Guangxi, China
| | - Junjun Jiang
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Guangxi Collaborative Innovation Center for Biomedicine, Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Jing Han
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Guangxi Collaborative Innovation Center for Biomedicine, Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Hong Zhang
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Guangxi Collaborative Innovation Center for Biomedicine, Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Jiaguang Hu
- Department of Infectious Diseases, Liuzhou People's Hospital, Liuzhou, Guangxi, China
| | - Peng Zhang
- Department of Infectious Diseases, Liuzhou People's Hospital, Liuzhou, Guangxi, China
| | - Xu Li
- Department of Infectious Diseases, Liuzhou People's Hospital, Liuzhou, Guangxi, China
| | - Tao Chen
- Department of Infectious Diseases, Liuzhou People's Hospital, Liuzhou, Guangxi, China
| | - Jinhao He
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Guangxi Collaborative Innovation Center for Biomedicine, Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Zhen Li
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Guangxi Collaborative Innovation Center for Biomedicine, Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Jingzhen Lai
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Guangxi Collaborative Innovation Center for Biomedicine, Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Hao Liang
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Guangxi Collaborative Innovation Center for Biomedicine, Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Chuanyi Ning
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.,Nursing College, Guangxi Medical University, Nanning, Guangxi, China
| | - Li Ye
- Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China
| |
Collapse
|
|
17
|
scSPLAT, a scalable plate-based protocol for single cell WGBS library preparation. Sci Rep 2022; 12:5772. [PMID: 35388090 PMCID: PMC8986790 DOI: 10.1038/s41598-022-09798-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 03/29/2022] [Indexed: 11/11/2022] Open
Abstract
DNA methylation is a central epigenetic mark that has diverse roles in gene regulation, development, and maintenance of genome integrity. 5 methyl cytosine (5mC) can be interrogated at base resolution in single cells by using bisulfite sequencing (scWGBS). Several different scWGBS strategies have been described in recent years to study DNA methylation in single cells. However, there remain limitations with respect to cost-efficiency and yield. Herein, we present a new development in the field of scWGBS library preparation; single cell Splinted Ligation Adapter Tagging (scSPLAT). scSPLAT employs a pooling strategy to facilitate sample preparation at a higher scale and throughput than previously possible. We demonstrate the accuracy and robustness of the method by generating data from 225 single K562 cells and from 309 single liver nuclei and compare scSPLAT against other scWGBS methods.
Collapse
|
|
18
|
Deep proteomic profiling unveils arylsulfatase A as a non-alcoholic steatohepatitis inducible hepatokine and regulator of glycemic control. Nat Commun 2022; 13:1259. [PMID: 35273160 PMCID: PMC8913628 DOI: 10.1038/s41467-022-28889-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 02/10/2022] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, yet the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved. Using proteomic approaches, we interrogate hepatocyte protein secretion in two models of murine NASH to understand how liver-derived factors modulate lipid metabolism and insulin sensitivity in peripheral tissues. We reveal striking hepatokine remodelling that is associated with insulin resistance and maladaptive lipid metabolism, and identify arylsulfatase A (ARSA) as a hepatokine that is upregulated in NASH and type 2 diabetes. Mechanistically, hepatic ARSA reduces sulfatide content and increases lysophosphatidylcholine (LPC) accumulation within lipid rafts and suppresses LPC secretion from the liver, thereby lowering circulating LPC and lysophosphatidic acid (LPA) levels. Reduced LPA is linked to improvements in skeletal muscle insulin sensitivity and systemic glycemic control. Hepatic silencing of Arsa or inactivation of ARSA's enzymatic activity reverses these effects. Together, this study provides a unique resource describing global changes in hepatokine secretion in NASH, and identifies ARSA as a regulator of liver to muscle communication and as a potential therapeutic target for type 2 diabetes.
Collapse
|
|
19
|
Feasibility of Fetal Portal Venous System Ultrasound Assessment at the FT Anomaly Scan. Diagnostics (Basel) 2022; 12:diagnostics12020361. [PMID: 35204452 PMCID: PMC8871164 DOI: 10.3390/diagnostics12020361] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/13/2022] [Accepted: 01/29/2022] [Indexed: 02/04/2023] Open
Abstract
Objective: To investigate the feasibility of the first trimester (FT) ultrasound scan (US) for the evaluation of the fetal portal venous system (PVS) anatomy, and to evaluate the potential of microcopy for a proper pathology evaluation for the PVS in the FT. Methods: We evaluated the PVS in 200 scan examinations performed in FT pregnancy. Half of the cases were scanned by two operators with extensive experience in obstetric ultrasound—Group I, and the other half was evaluated by two sonographers with less experience—Group II. Second-trimester US and autopsy in terminated pregnancies were used as follow-up. The pathologic evaluation was supported by microscopy. Results: all PVS features were successfully assessed by transabdominal ultrasound (TAUS) in 27% of the Group I cases and 14% in Group II. These rates increased to 88% in Group I and in 72% in Group II, after rescanning and using transvaginal ultrasound (TVUS). The conditions that led to rescanning and TVUS were: BMI greater than 24 in 26% cases, unfavorable fetal position (12.32%), retroverted uterus (12.32%), abdominal scar (10.96%), fibroids (4.11%), and combinations of the above (34.23%). The L-shaped UV confluence was identified transabdominally in 91% in Group I and in 79% in Group II and increased to 98% and 95%, respectively, following reevaluations. Microscopy represented a useful audit in all FT investigated cases. Conclusions: At the end of the FT, the visualization of a normal L-shaped UV confluence, that excludes major PVS abnormalities, is achievable in approx. 80%, indifferently the examiners experience. The sonographers experience, pregnant women BMI, and uterine anomalies as fibroids or retroversion significantly affect the rate of visualization, and necessitates vaginal approach and reexamination. The FT pathology, the audit of the ultrasound findings can only be performed microscopically, with relatively little resources involved and good results.
Collapse
|
|
20
|
An age-structured model of hepatitis B viral infection highlights the potential of different therapeutic strategies. Sci Rep 2022; 12:1252. [PMID: 35075156 PMCID: PMC8786976 DOI: 10.1038/s41598-021-04022-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 12/10/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatitis B virus (HBV) is a global health threat, and its elimination by 2030 has been prioritised by the World Health Organisation. Here we present an age-structured model for the immune response to an HBV infection, which takes into account contributions from both cell-mediated and humoral immunity. The model has been validated using published patient data recorded during acute infection. It has been adapted to the scenarios of chronic infection, clearance of infection, and flare-ups via variation of the immune response parameters. The impacts of immune response exhaustion and non-infectious subviral particles on the immune response dynamics are analysed. A comparison of different treatment options in the context of this model reveals that drugs targeting aspects of the viral life cycle are more effective than exhaustion therapy, a form of therapy mitigating immune response exhaustion. Our results suggest that antiviral treatment is best started when viral load is declining rather than in a flare-up. The model suggests that a fast antibody production rate always leads to viral clearance, highlighting the promise of antibody therapies currently in clinical trials.
Collapse
|
|
21
|
Handin N, Mickols E, Ölander M, Rudfeldt J, Blom K, Nyberg F, Senkowski W, Urdzik J, Maturi V, Fryknäs M, Artursson P. Conditions for maintenance of hepatocyte differentiation and function in 3D cultures. iScience 2021; 24:103235. [PMID: 34746700 PMCID: PMC8551077 DOI: 10.1016/j.isci.2021.103235] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 08/02/2021] [Accepted: 10/04/2021] [Indexed: 12/15/2022] Open
Abstract
Spheroid cultures of primary human hepatocytes (PHH) are used in studies of hepatic drug metabolism and toxicity. The cultures are maintained under different conditions, with possible confounding results. We performed an in-depth analysis of the influence of various culture conditions to find the optimal conditions for the maintenance of an in vivo like phenotype. The formation, protein expression, and function of PHH spheroids were followed for three weeks in a high-throughput 384-well format. Medium composition affected spheroid histology, global proteome profile, drug metabolism and drug-induced toxicity. No epithelial-mesenchymal transition was observed. Media with fasting glucose and insulin levels gave spheroids with phenotypes closest to normal PHH. The most expensive medium resulted in PHH features most divergent from that of native PHH. Our results provide a protocol for culture of healthy PHH with maintained function - a prerequisite for studies of hepatocyte homeostasis and more reproducible hepatocyte research.
3D spheroid cultures were established in 384-well format Eight different media variants were used to optimize the 3D cultures Optimized William's medium was as good as expensive commercial medium The 3D cultures were used to study drug metabolism and toxicity
Collapse
Affiliation(s)
- Niklas Handin
- Department of Pharmacy, Uppsala University, 75123 Uppsala, Sweden
| | - Evgeniya Mickols
- Department of Pharmacy, Uppsala University, 75123 Uppsala, Sweden
| | - Magnus Ölander
- Department of Pharmacy, Uppsala University, 75123 Uppsala, Sweden
| | - Jakob Rudfeldt
- Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden
| | - Kristin Blom
- Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden
| | - Frida Nyberg
- Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden
| | - Wojciech Senkowski
- Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden.,Biotech Research & Innovation Centre (BRIC) and Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Jozef Urdzik
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Varun Maturi
- Department of Pharmacy, Uppsala University, 75123 Uppsala, Sweden
| | - Mårten Fryknäs
- Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden
| | - Per Artursson
- Department of Pharmacy, Uppsala University, 75123 Uppsala, Sweden
| |
Collapse
|
|
22
|
The immune niche of the liver. Clin Sci (Lond) 2021; 135:2445-2466. [PMID: 34709406 DOI: 10.1042/cs20190654] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 09/17/2021] [Accepted: 10/08/2021] [Indexed: 12/19/2022]
Abstract
The liver is an essential organ that is critical for the removal of toxins, the production of proteins, and the maintenance of metabolic homeostasis. Behind each liver functional unit, termed lobules, hides a heterogeneous, complex, and well-orchestrated system. Despite parenchymal cells being most commonly associated with the liver's primary functionality, it has become clear that it is the immune niche of the liver that plays a central role in maintaining both local and systemic homeostasis by propagating hepatic inflammation and orchestrating its resolution. As such, the immunological processes that are at play in healthy and diseased livers are being investigated thoroughly in order to understand the underpinnings of inflammation and the potential avenues for restoring homeostasis. This review highlights recent advances in our understanding of the immune niche of the liver and provides perspectives for how the implementation of new transcriptomic, multimodal, and spatial technologies can uncover the heterogeneity, plasticity, and location of hepatic immune populations. Findings from these technologies will further our understanding of liver biology and create a new framework for the identification of therapeutic targets.
Collapse
|
|
23
|
Connexin Expression Is Altered in Liver Development of Yotari ( dab1 -/-) Mice. Int J Mol Sci 2021; 22:ijms221910712. [PMID: 34639052 PMCID: PMC8509723 DOI: 10.3390/ijms221910712] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/26/2021] [Accepted: 09/29/2021] [Indexed: 01/05/2023] Open
Abstract
Disabled-1 (Dab1) protein is an intracellular adaptor of reelin signaling required for prenatal neuronal migration, as well as postnatal neurotransmission, memory formation and synaptic plasticity. Yotari, an autosomal recessive mutant of the mouse Dab1 gene is recognizable by its premature death, unstable gait and tremor. Previous findings are mostly based on neuronal abnormalities caused by Dab1 deficiency, but the role of the reelin signaling pathway in nonneuronal tissues and organs has not been studied until recently. Hepatocytes, the most abundant cells in the liver, communicate via gap junctions (GJ) are composed of connexins. Cell communication disruption in yotari mice was examined by analyzing the expression of connexins (Cxs): Cx26, Cx32, Cx37, Cx40, Cx43 and Cx45 during liver development at 13.5 and 15.5 gestation days (E13.5 and E15.5). Analyses were performed using immunohistochemistry and fluorescent microscopy, followed by quantification of area percentage covered by positive signal. Data are expressed as a mean ± SD and analyzed by one-way ANOVA. All Cxs examined displayed a significant decrease in yotari compared to wild type (wt) individuals at E13.5. Looking at E15.5 we have similar results with exception of Cx37 showing negligible expression in wt. Channels formation triggered by pathological stimuli, as well as propensity to apoptosis, was studied by measuring the expression of Pannexin1 (Panx1) and Apoptosis-inducing factor (AIF) through developmental stages mentioned above. An increase in Panx1 expression of E15.5 yotari mice, as well as a strong jump of AIF in both phases suggesting that yotari mice are more prone to apoptosis. Our results emphasize the importance of gap junction intercellular communication (GJIC) during liver development and their possible involvement in liver pathology and diagnostics where they can serve as potential biomarkers and drug targets.
Collapse
|
|
24
|
Pluta KD, Ciezkowska M, Wisniewska M, Wencel A, Pijanowska DG. Cell-based clinical and experimental methods for assisting the function of impaired livers – Present and future of liver support systems. Biocybern Biomed Eng 2021. [DOI: 10.1016/j.bbe.2021.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
25
|
Gök HN, Gül H, Gülfraz M, Asad MJ, Öztürk N, Şanal F, Orhan İE. Preclinical Study on the Hepatoprotective Effect of Pollen Extract of Pinus brutia Ten. (Red Pine) in Mice and Phenolic Acid Analysis. Turk J Pharm Sci 2021; 18:319-325. [PMID: 34157821 DOI: 10.4274/tjps.galenos.2020.47154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Objectives Many agents, including those from herbal sources, have been sought as preventives or cures for hepatotoxicity. The pollen of Pinus brutia Ten., known as red pine (Pinaceae), is used against liver diseases in Anatolian folk medicine. Materials and Methods In the current study, pollen ethanol extract of P. brutia was investigated for its possible hepatoprotective activity using a mouse model of CCl4-induced hepatotoxicity. Swiss albino mice were divided into five groups, and extract-treated groups were compared with a silymarin-treated group as the reference. The extract was tested at 100, 200, and 300 mg/kg (b.w.). Phenolic acids were analyzed using high-performance column chromatography (HPLC) in the extracts as pollens are usually known to be rich in phenolics. Results Our data revealed that the extract displayed the best hepatoprotection at a dose of 100 mg/kg when compared with silymarin (Legalon®), the reference drug. HPLC analysis indicated presence of protocatechuic acid (0.176 mg/g extract), p-hydroxybenzoic acid (0.001 mg/g extract), vanillic acid (VA) (0.537 mg/g extract), syringic acid (0.050 mg/g extract), and tr-cinnamic acid (0.310 mg/g extract), while the major phenolic acid was VA. Conclusion The outcomes of this study allow us to conclude that red pine pollen extract can serve as a promising hepatoprotective agent. Among the phenolic acids analyzed in the pollen extract, vanillic acid as the major one besides some other phenolic acids detected seems to be responsible for its remarkable hepatoprotective effect.
Collapse
Affiliation(s)
- Hasya Nazlı Gök
- Gazi University Faculty of Pharmacy, Department of Pharmacognosy, Ankara, Turkey
| | - Hina Gül
- PMAS Arid Agriculture University, Institute of Biochemistry and Biotechnology, Rawalpindi, Pakistan
| | - Muhammad Gülfraz
- PMAS Arid Agriculture University, Institute of Biochemistry and Biotechnology, Rawalpindi, Pakistan
| | - Muhammad Javaid Asad
- PMAS Arid Agriculture University, Institute of Biochemistry and Biotechnology, Rawalpindi, Pakistan
| | - Nilgün Öztürk
- Anadolu University Faculty of Pharmacy, Department of Pharmacognosy, Eskişehir, Turkey
| | - Fuat Şanal
- General Directorate of Forestry, Chairmanship of Inspection Committee, Ankara, Turkey
| | - İlkay Erdoğan Orhan
- Gazi University Faculty of Pharmacy, Department of Pharmacognosy, Ankara, Turkey
| |
Collapse
|
|
26
|
Clark AM, Allbritton NL, Wells A. Integrative microphysiological tissue systems of cancer metastasis to the liver. Semin Cancer Biol 2021; 71:157-169. [PMID: 32580025 PMCID: PMC7750290 DOI: 10.1016/j.semcancer.2020.06.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 06/10/2020] [Accepted: 06/10/2020] [Indexed: 02/07/2023]
Abstract
The liver is the most commonly involved organ in metastases from a wide variety of solid tumors. The use of biologically and cellularly complex liver tissue systems have shown that tumor cell behavior and therapeutic responses are modulated within the liver microenvironment and in ways distinct from the behaviors in the primary locations. These microphysiological systems have provided unexpected and powerful insights into the tumor cell biology of metastasis. However, neither the tumor nor the liver exist in an isolated tissue situation, having to function within a complete body and respond to systemic events as well as those in other organs. To examine the influence of one organ on the function of other tissues, microphysiological systems are being linked. Herein, we discuss extending this concept to tumor metastases by integrating complex models of the primary tumor with the liver metastatic environment. In addition, inflammatory organs and the immune system can be incorporated into these multi-organ systems to probe the effects on tumor behavior and cancer treatments.
Collapse
Affiliation(s)
- Amanda M Clark
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA; VA Pittsburgh Healthcare System, Pittsburgh, PA 15213, USA; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
| | - Nancy L Allbritton
- Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
| | - Alan Wells
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA; VA Pittsburgh Healthcare System, Pittsburgh, PA 15213, USA; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA
| |
Collapse
|
|
27
|
Ojima S, Okamura M, Osawa N, Tamura A, Yoshioka K, Kashimoto T, Haneda T, Ono HK, Hu DL. Characteristics of systemic infection and host responses in chickens experimentally infected with Salmonella enterica serovar Gallinarum biovar Gallinarum. J Vet Med Sci 2021; 83:1147-1154. [PMID: 34039786 PMCID: PMC8349805 DOI: 10.1292/jvms.21-0227] [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] [Indexed: 11/22/2022] Open
Abstract
Salmonella enterica serovar Gallinarum biovar Gallinarum (S. Gallinarum) is a host-specific pathogen causing systemic infection in poultry, which leads to significant economic losses due to high mortality. However, little is known about the dynamic process of systemic infection and pathogenic characteristics of S. Gallinarum in chickens. In the present study, we developed an oral infection model that reproduces the pathology of S. Gallinarum and clarified the host immune response of the infected chickens. Chickens at 20 days of age orally inoculated at a dose of 108 colony forming unit (CFU) showed typical clinical signs of fowl typhoid and died between 6 and 10 days post infection. The inoculated S. Gallinarum rapidly disseminated to multple organs and the bacterial counts increased in the liver and spleen at 3 days post infection. Pathological changes associated wirh inflammation in the liver and spleen became apparent at 4 days post infection, and increased expression of interferon (IFN)-γ and interleuikin (IL)-12 in the liver and spleen did not observed until 3 days post infection. These results indicate that S. Gallinarum rapidly spread to entire body through intestine, and the low-level of inflammatory responses in the liver during the early stage of infection may contribute to rapid, systemic dissemination of the bacteria. Our infection model and findings will contribute to the better understanding of the pathogenic mechanism of S. Gallinarum, and provide new insights into the prevention and control of fowl typhoid.
Collapse
Affiliation(s)
- Shinjiro Ojima
- Laboratory of Zoonoses, Kitasato University School of Veterinary Medicine, Towada, Aomori 034-8628, Japan
| | - Masashi Okamura
- Laboratory of Zoonoses, Kitasato University School of Veterinary Medicine, Towada, Aomori 034-8628, Japan.,Section of Applied Veterinary Sciences, Division of Veterinary Sciences, Department of Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555, Japan
| | - Nana Osawa
- Laboratory of Zoonoses, Kitasato University School of Veterinary Medicine, Towada, Aomori 034-8628, Japan
| | - Akiko Tamura
- Laboratory of Zoonoses, Kitasato University School of Veterinary Medicine, Towada, Aomori 034-8628, Japan
| | - Kazuki Yoshioka
- Laboratory of Veterinary Anatomy, Kitasato University School of Veterinary Medicine, Towada, Aomori 034-8628, Japan
| | - Takashige Kashimoto
- Laboratory of Veterinary Public Health, Kitasato University School of Veterinary Medicine, Towada, Aomori 034-8628, Japan
| | - Takeshi Haneda
- Laboratory of Microbiology, Kitasato University School of Pharmacy, Minato, Tokyo 108-8041, Japan
| | - Hisaya K Ono
- Laboratory of Zoonoses, Kitasato University School of Veterinary Medicine, Towada, Aomori 034-8628, Japan
| | - Dong-Liang Hu
- Laboratory of Zoonoses, Kitasato University School of Veterinary Medicine, Towada, Aomori 034-8628, Japan
| |
Collapse
|
|
28
|
Clark AM, Heusey HL, Griffith LG, Lauffenburger DA, Wells A. IP-10 (CXCL10) Can Trigger Emergence of Dormant Breast Cancer Cells in a Metastatic Liver Microenvironment. Front Oncol 2021; 11:676135. [PMID: 34123844 PMCID: PMC8190328 DOI: 10.3389/fonc.2021.676135] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 04/30/2021] [Indexed: 12/12/2022] Open
Abstract
Metastatic breast cancer remains a largely incurable and fatal disease with liver involvement bearing the worst prognosis. The danger is compounded by a subset of disseminated tumor cells that may lie dormant for years to decades before re-emerging as clinically detectable metastases. Pathophysiological signals can drive these tumor cells to emerge. Prior studies indicated CXCR3 ligands as being the predominant signals synergistically and significantly unregulated during inflammation in the gut-liver axis. Of the CXCR3 ligands, IP-10 (CXCL10) was the most abundant, correlated significantly with shortened survival of human breast cancer patients with metastatic disease and was highest in those with triple negative (TNBC) disease. Using a complex ex vivo all-human liver microphysiological (MPS) model of dormant-emergent metastatic progression, CXCR3 ligands were found to be elevated in actively growing populations of metastatic TNBC breast cancer cells whereas they remained similar to the tumor-free hepatic niche in those with dormant breast cancer cells. Subsequent stimulation of dormant breast cancer cells in the ex vivo metastatic liver MPS model with IP-10 triggered their emergence in a dose-dependent manner. Emergence was indicated to occur indirectly possibly via activation of the resident liver cells in the surrounding metastatic microenvironment, as stimulation of breast cancer cells with exogenous IP-10 did not significantly change their migratory, invasive or proliferative behavior. The findings reveal that IP-10 is capable of triggering the emergence of dormant breast cancer cells within the liver metastatic niche and identifies the IP-10/CXCR3 as a candidate targetable pathway for rational approaches aimed at maintaining dormancy.
Collapse
Affiliation(s)
- Amanda M. Clark
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
- Pittsburgh VA Medical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States
| | - Haley L. Heusey
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
- Pittsburgh VA Medical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, United States
| | - Linda G. Griffith
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Douglas. A. Lauffenburger
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Alan Wells
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
- Pittsburgh VA Medical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| |
Collapse
|
|
29
|
Abstract
Life expectancy, and longevity have been increasing in recent years. However, this is, in most cases, accompanied by age-related diseases. Thus, it became essential to better understand the mechanisms inherent to aging, and to establish biomarkers that characterize this physiological process. Among all biomolecules, lipids appear to be a good target for the study of these biomarkers. In fact, some lipids have already been associated with age-related diseases. With the development of analytical techniques such as Mass Spectrometry, and Nuclear Magnetic Resonance, Lipidomics has been increasingly used to study pathological, and physiological states of an organism. Thus, the study of serum, and plasma lipidome in centenarians, and elderly individuals without age-related diseases can be a useful tool for the identification of aging biomarkers, and to understand physiological aging, and longevity. This review focus on the importance of lipids as biomarkers of aging, and summarize the changes in the lipidome that have been associated with aging, and longevity.
Collapse
|
|
30
|
Sufleţel RT, Melincovici CS, Gheban BA, Toader Z, Mihu CM. Hepatic stellate cells - from past till present: morphology, human markers, human cell lines, behavior in normal and liver pathology. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY 2021; 61:615-642. [PMID: 33817704 PMCID: PMC8112759 DOI: 10.47162/rjme.61.3.01] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Hepatic stellate cell (HSC), initially analyzed by von Kupffer, in 1876, revealed to be an extraordinary mesenchymal cell, essential for both hepatocellular function and lesions, being the hallmark of hepatic fibrogenesis and carcinogenesis. Apart from their implications in hepatic injury, HSCs play a vital role in liver development and regeneration, xenobiotic response, intermediate metabolism, and regulation of immune response. In this review, we discuss the current state of knowledge regarding HSCs morphology, human HSCs markers and human HSC cell lines. We also summarize the latest findings concerning their roles in normal and liver pathology, focusing on their impact in fibrogenesis, chronic viral hepatitis and liver tumors.
Collapse
Affiliation(s)
- Rada Teodora Sufleţel
- Discipline of Histology, Department of Morphological Sciences, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania;
| | | | | | | | | |
Collapse
|
|
31
|
Relative DNA Methylation and Demethylation Efficiencies during Postnatal Liver Development Regulate Hepatitis B Virus Biosynthesis. J Virol 2021; 95:JVI.02148-20. [PMID: 33361417 DOI: 10.1128/jvi.02148-20] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 12/09/2020] [Indexed: 12/18/2022] Open
Abstract
Hepatitis B virus (HBV) transcription and replication increase progressively throughout postnatal liver development with maximal viral biosynthesis occurring at around 4 weeks of age in the HBV transgenic mouse model of chronic infection. Increasing viral biosynthesis is associated with a corresponding progressive loss of DNA methylation. The loss of DNA methylation is associated with increasing levels of 5-hydroxymethylcytosine (5hmC) residues which correlate with increased liver-enriched pioneer transcription factor Forkhead box protein A (FoxA) RNA levels, a rapid decline in postnatal liver DNA methyltransferase (Dnmt) transcripts, and a very modest reduction in ten-eleven translocation (Tet) methylcytosine dioxygenase expression. These observations are consistent with the suggestion that the balance between active HBV DNA methylation and demethylation is regulated by FoxA recruitment of Tet in the presence of declining Dnmt activity. These changes lead to demethylation of the viral genome during hepatocyte maturation with associated increases in viral biosynthesis. Consequently, manipulation of the relative activities of these two counterbalancing processes might permit the specific silencing of HBV gene expression with the loss of viral biosynthesis and the resolution of chronic HBV infections.IMPORTANCE HBV biosynthesis begins at birth and increases during early postnatal liver development in the HBV transgenic mouse model of chronic infection. The levels of viral RNA and DNA synthesis correlate with pioneer transcription factor FoxA transcript plus Tet methylcytosine dioxygenase-generated 5hmC abundance but inversely with Dnmt transcript levels and HBV DNA methylation. Together, these findings suggest that HBV DNA methylation during neonatal liver development is actively modulated by the relative contributions of FoxA-recruited Tet-mediated DNA demethylation and Dnmt-mediated DNA methylation activities. This mode of gene regulation, mediated by the loss of DNA methylation at hepatocyte-specific viral and cellular promoters, likely contributes to hepatocyte maturation during liver development in addition to the postnatal activation of HBV transcription and replication.
Collapse
|
|
32
|
Diamanti K, Inda Díaz JS, Raine A, Pan G, Wadelius C, Cavalli M. Single nucleus transcriptomics data integration recapitulates the major cell types in human liver. Hepatol Res 2021; 51:233-238. [PMID: 33119937 DOI: 10.1111/hepr.13585] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 10/02/2020] [Accepted: 10/20/2020] [Indexed: 12/13/2022]
Abstract
AIM The aim of this study was to explore the benefits of data integration from different platforms for single nucleus transcriptomics profiling to characterize cell populations in human liver. METHODS We generated single-nucleus RNA sequencing data from Chromium 10X Genomics and Drop-seq for a human liver sample. We utilized state of the art bioinformatics tools to undertake a rigorous quality control and to integrate the data into a common space summarizing the gene expression variation from the respective platforms, while accounting for known and unknown confounding factors. RESULTS Analysis of single nuclei transcriptomes from both 10X and Drop-seq allowed identification of the major liver cell types, while the integrated set obtained enough statistical power to separate a small population of inactive hepatic stellate cells that was not characterized in either of the platforms. CONCLUSIONS Integration of droplet-based single nucleus transcriptomics data enabled identification of a small cluster of inactive hepatic stellate cells that highlights the potential of our approach. We suggest single-nucleus RNA sequencing integrative approaches could be utilized to design larger and cost-effective studies.
Collapse
Affiliation(s)
- Klev Diamanti
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Juan Salvador Inda Díaz
- Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden
| | - Amanda Raine
- Science for Life Laboratory, Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden
| | - Gang Pan
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Claes Wadelius
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Marco Cavalli
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| |
Collapse
|
|
33
|
Ziemian S, Green C, Sourbron S, Jost G, Schütz G, Hines CD. Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T. NMR IN BIOMEDICINE 2021; 34:e4401. [PMID: 32851735 PMCID: PMC7757196 DOI: 10.1002/nbm.4401] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/11/2020] [Accepted: 08/13/2020] [Indexed: 06/11/2023]
Abstract
Quantitative mapping of gadoxetate uptake and excretion rates in liver cells has shown potential to significantly improve the management of chronic liver disease and liver cancer. Unfortunately, technical and clinical validation of the technique is currently hampered by the lack of data on gadoxetate relaxivity. The aim of this study was to fill this gap by measuring gadoxetate relaxivity in liver tissue, which approximates hepatocytes, in blood, urine and bile at magnetic field strengths of 1.41, 1.5, 3, 4.7 and 7 T. Measurements were performed ex vivo in 44 female Mrp2 knockout rats and 30 female wild-type rats who had received an intravenous bolus of either 10, 25 or 40 μmol/kg gadoxetate. T1 was measured at 37 ± 3°C on NMR instruments (1.41 and 3 T), small-animal MRI (4.7 and 7 T) and clinical MRI (1.5 and 3 T). Gadolinium concentration was measured with optical emission spectrometry or mass spectrometry. The impact on measurements of gadoxetate rate constants was determined by generalizing pharmacokinetic models to tissues with different relaxivities. Relaxivity values (L mmol-1 s-1 ) showed the expected dependency on tissue/biofluid type and field strength, ranging from 15.0 ± 0.9 (1.41) to 6.0 ± 0.3 (7) T in liver tissue, from 7.5 ± 0.2 (1.41) to 6.2 ± 0.3 (7) T in blood, from 5.6 ± 0.1 (1.41) to 4.5 ± 0.1 (7) T in urine and from 5.6 ± 0.4 (1.41) to 4.3 ± 0.6 (7) T in bile. Failing to correct for the relaxivity difference between liver tissue and blood overestimates intracellular uptake rates by a factor of 2.0 at 1.41 T, 1.8 at 1.5 T, 1.5 at 3 T and 1.2 at 4.7 T. The relaxivity values derived in this study can be used retrospectively and prospectively to remove a well-known bias in gadoxetate rate constants. This will promote the clinical translation of MR-based liver function assessment by enabling direct validation against reference methods and a more effective translation between in vitro findings, animal models and patient studies.
Collapse
Affiliation(s)
| | - Claudia Green
- MR & CT Contrast Media ResearchBayer AGBerlinGermany
| | - Steven Sourbron
- Department of Infection, Immunity and Cardiovascular DiseaseUniversity of SheffieldSheffieldUK
| | - Gregor Jost
- MR & CT Contrast Media ResearchBayer AGBerlinGermany
| | - Gunnar Schütz
- MR & CT Contrast Media ResearchBayer AGBerlinGermany
| | | |
Collapse
|
|
34
|
Extracellular vesicle release and uptake by the liver under normo- and hyperlipidemia. Cell Mol Life Sci 2021; 78:7589-7604. [PMID: 34665280 PMCID: PMC8629784 DOI: 10.1007/s00018-021-03969-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 09/03/2021] [Accepted: 10/05/2021] [Indexed: 02/07/2023]
Abstract
Liver plays a central role in elimination of circulating extracellular vesicles (EVs), and it also significantly contributes to EV release. However, the involvement of the different liver cell populations remains unknown. Here, we investigated EV uptake and release both in normolipemia and hyperlipidemia. C57BL/6 mice were kept on high fat diet for 20-30 weeks before circulating EV profiles were determined. In addition, control mice were intravenously injected with 99mTc-HYNIC-Duramycin labeled EVs, and an hour later, biodistribution was analyzed by SPECT/CT. In vitro, isolated liver cell types were tested for EV release and uptake with/without prior fatty acid treatment. We detected an elevated circulating EV number after the high fat diet. To clarify the differential involvement of liver cell types, we carried out in vitro experiments. We found an increased release of EVs by primary hepatocytes at concentrations of fatty acids comparable to what is characteristic for hyperlipidemia. When investigating EV biodistribution with 99mTc-labeled EVs, we detected EV accumulation primarily in the liver upon intravenous injection of mice with medium (326.3 ± 19.8 nm) and small EVs (130.5 ± 5.8 nm). In vitro, we found that medium and small EVs were preferentially taken up by Kupffer cells, and liver sinusoidal endothelial cells, respectively. Finally, we demonstrated that in hyperlipidemia, there was a decreased EV uptake both by Kupffer cells and liver sinusoidal endothelial cells. Our data suggest that hyperlipidema increases the release and reduces the uptake of EVs by liver cells. We also provide evidence for a size-dependent differential EV uptake by the different cell types of the liver. The EV radiolabeling protocol using 99mTc-Duramycin may provide a fast and simple labeling approach for SPECT/CT imaging of EVs biodistribution.
Collapse
|
|
35
|
Scholich A, Syga S, Morales-Navarrete H, Segovia-Miranda F, Nonaka H, Meyer K, de Back W, Brusch L, Kalaidzidis Y, Zerial M, Jülicher F, Friedrich BM. Quantification of nematic cell polarity in three-dimensional tissues. PLoS Comput Biol 2020; 16:e1008412. [PMID: 33301446 PMCID: PMC7755288 DOI: 10.1371/journal.pcbi.1008412] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 12/22/2020] [Accepted: 10/01/2020] [Indexed: 01/12/2023] Open
Abstract
How epithelial cells coordinate their polarity to form functional tissues is an open question in cell biology. Here, we characterize a unique type of polarity found in liver tissue, nematic cell polarity, which is different from vectorial cell polarity in simple, sheet-like epithelia. We propose a conceptual and algorithmic framework to characterize complex patterns of polarity proteins on the surface of a cell in terms of a multipole expansion. To rigorously quantify previously observed tissue-level patterns of nematic cell polarity (Morales-Navarrete et al., eLife 2019), we introduce the concept of co-orientational order parameters, which generalize the known biaxial order parameters of the theory of liquid crystals. Applying these concepts to three-dimensional reconstructions of single cells from high-resolution imaging data of mouse liver tissue, we show that the axes of nematic cell polarity of hepatocytes exhibit local coordination and are aligned with the biaxially anisotropic sinusoidal network for blood transport. Our study characterizes liver tissue as a biological example of a biaxial liquid crystal. The general methodology developed here could be applied to other tissues and in-vitro organoids.
Collapse
Affiliation(s)
- André Scholich
- Max Planck Institute for the Physics of Complex Systems, Dresden, Germany
| | - Simon Syga
- Max Planck Institute for the Physics of Complex Systems, Dresden, Germany
- Centre for Information Services and High Performance Computing, TU Dresden, Dresden, Germany
| | | | | | - Hidenori Nonaka
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Kirstin Meyer
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Walter de Back
- Centre for Information Services and High Performance Computing, TU Dresden, Dresden, Germany
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - Lutz Brusch
- Centre for Information Services and High Performance Computing, TU Dresden, Dresden, Germany
| | - Yannis Kalaidzidis
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Marino Zerial
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
- Center for Advancing Electronics Dresden, TU Dresden, Germany
- Cluster of Excellence Physics of Life, TU Dresden, Germany
| | - Frank Jülicher
- Max Planck Institute for the Physics of Complex Systems, Dresden, Germany
- Center for Advancing Electronics Dresden, TU Dresden, Germany
- Cluster of Excellence Physics of Life, TU Dresden, Germany
| | - Benjamin M. Friedrich
- Center for Advancing Electronics Dresden, TU Dresden, Germany
- Cluster of Excellence Physics of Life, TU Dresden, Germany
- Institute for Theoretical Physics, TU Dresden, Germany
| |
Collapse
|
|
36
|
Kimura T, Pydi SP, Pham J, Tanaka N. Metabolic Functions of G Protein-Coupled Receptors in Hepatocytes-Potential Applications for Diabetes and NAFLD. Biomolecules 2020; 10:1445. [PMID: 33076386 PMCID: PMC7602561 DOI: 10.3390/biom10101445] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/07/2020] [Accepted: 10/09/2020] [Indexed: 02/07/2023] Open
Abstract
G protein-coupled receptors (GPCRs) are cell surface receptors that mediate the function of extracellular ligands. Understanding how GPCRs work at the molecular level has important therapeutic implications, as 30-40% of the drugs currently in clinical use mediate therapeutic effects by acting on GPCRs. Like many other cell types, liver function is regulated by GPCRs. More than 50 different GPCRs are predicted to be expressed in the mouse liver. However, knowledge of how GPCRs regulate liver metabolism is limited. A better understanding of the metabolic role of GPCRs in hepatocytes, the dominant constituent cells of the liver, could lead to the development of novel drugs that are clinically useful for the treatment of various metabolic diseases, including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In this review, we describe the functions of multiple GPCRs expressed in hepatocytes and their role in metabolic processes.
Collapse
Affiliation(s)
- Takefumi Kimura
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20894, USA; (S.P.P.); (J.P.)
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Sai P. Pydi
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20894, USA; (S.P.P.); (J.P.)
| | - Jonathan Pham
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20894, USA; (S.P.P.); (J.P.)
| | - Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan;
- Research Center for Social Systems, Shinshu University, Matsumoto 390-8621, Japan
| |
Collapse
|
|
37
|
Wei QY, Xu YM, Lau ATY. Recent Progress of Nanocarrier-Based Therapy for Solid Malignancies. Cancers (Basel) 2020; 12:E2783. [PMID: 32998391 PMCID: PMC7600685 DOI: 10.3390/cancers12102783] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/16/2020] [Accepted: 09/21/2020] [Indexed: 02/05/2023] Open
Abstract
Conventional chemotherapy is still an important option of cancer treatment, but it has poor cell selectivity, severe side effects, and drug resistance. Utilizing nanoparticles (NPs) to improve the therapeutic effect of chemotherapeutic drugs has been highlighted in recent years. Nanotechnology dramatically changed the face of oncology by high loading capacity, less toxicity, targeted delivery of drugs, increased uptake to target sites, and optimized pharmacokinetic patterns of traditional drugs. At present, research is being envisaged in the field of novel nano-pharmaceutical design, such as liposome, polymer NPs, bio-NPs, and inorganic NPs, so as to make chemotherapy effective and long-lasting. Till now, a number of studies have been conducted using a wide range of nanocarriers for the treatment of solid tumors including lung, breast, pancreas, brain, and liver. To provide a reference for the further application of chemodrug-loaded nanoformulations, this review gives an overview of the recent development of nanocarriers, and the updated status of their use in the treatment of several solid tumors.
Collapse
Affiliation(s)
| | | | - Andy T. Y. Lau
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou 515041, Guangdong, China; (Q.-Y.W.); (Y.-M.X.)
| |
Collapse
|
|
38
|
Della Torre S. Non-alcoholic Fatty Liver Disease as a Canonical Example of Metabolic Inflammatory-Based Liver Disease Showing a Sex-Specific Prevalence: Relevance of Estrogen Signaling. Front Endocrinol (Lausanne) 2020; 11:572490. [PMID: 33071979 PMCID: PMC7531579 DOI: 10.3389/fendo.2020.572490] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 08/20/2020] [Indexed: 12/11/2022] Open
Abstract
There is extensive evidence supporting the interplay between metabolism and immune response, that have evolved in close relationship, sharing regulatory molecules and signaling systems, to support biological functions. Nowadays, the disruption of this interaction in the context of obesity and overnutrition underlies the increasing incidence of many inflammatory-based metabolic diseases, even in a sex-specific fashion. During evolution, the interplay between metabolism and reproduction has reached a degree of complexity particularly high in female mammals, likely to ensure reproduction only under favorable conditions. Several factors may account for differences in the incidence and progression of inflammatory-based metabolic diseases between females and males, thus contributing to age-related disease development and difference in life expectancy between the two sexes. Among these factors, estrogens, acting mainly through Estrogen Receptors (ERs), have been reported to regulate several metabolic pathways and inflammatory processes particularly in the liver, the metabolic organ showing the highest degree of sexual dimorphism. This review aims to investigate on the interaction between metabolism and inflammation in the liver, focusing on the relevance of estrogen signaling in counteracting the development and progression of non-alcoholic fatty liver disease (NAFLD), a canonical example of metabolic inflammatory-based liver disease showing a sex-specific prevalence. Understanding the role of estrogens/ERs in the regulation of hepatic metabolism and inflammation may provide the basis for the development of sex-specific therapeutic strategies for the management of such an inflammatory-based metabolic disease and its cardio-metabolic consequences.
Collapse
Affiliation(s)
- Sara Della Torre
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| |
Collapse
|
|
39
|
Cooreman A, Van Campenhout R, Crespo Yanguas S, Gijbels E, Leroy K, Pieters A, Tabernilla A, Van Brantegem P, Annaert P, Cogliati B, Vinken M. Cholestasis Differentially Affects Liver Connexins. Int J Mol Sci 2020; 21:E6534. [PMID: 32906817 PMCID: PMC7116118 DOI: 10.3390/ijms21186534] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/26/2020] [Accepted: 09/05/2020] [Indexed: 12/11/2022] Open
Abstract
Connexins are goal keepers of tissue homeostasis, including in the liver. As a result, they are frequently involved in disease. The current study was set up to investigate the effects of cholestatic disease on the production of connexin26, connexin32 and connexin43 in the liver. For this purpose, bile duct ligation, a well-known trigger of cholestatic liver injury, was applied to mice. In parallel, human hepatoma HepaRG cell cultures were exposed to cholestatic drugs and bile acids. Samples from both the in vivo and in vitro settings were subsequently subjected to assessment of mRNA and protein quantities as well as to in situ immunostaining. While the outcome of cholestasis on connexin26 and connexin43 varied among experimental settings, a more generalized repressing effect was seen for connexin32. This has also been observed in many other liver pathologies and could suggest a role for connexin32 as a robust biomarker of liver disease and toxicity.
Collapse
Affiliation(s)
- Axelle Cooreman
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (A.C.); (R.V.C.); (S.C.Y.); (E.G.); (K.L.); (A.P.); (A.T.)
| | - Raf Van Campenhout
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (A.C.); (R.V.C.); (S.C.Y.); (E.G.); (K.L.); (A.P.); (A.T.)
| | - Sara Crespo Yanguas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (A.C.); (R.V.C.); (S.C.Y.); (E.G.); (K.L.); (A.P.); (A.T.)
| | - Eva Gijbels
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (A.C.); (R.V.C.); (S.C.Y.); (E.G.); (K.L.); (A.P.); (A.T.)
| | - Kaat Leroy
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (A.C.); (R.V.C.); (S.C.Y.); (E.G.); (K.L.); (A.P.); (A.T.)
| | - Alanah Pieters
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (A.C.); (R.V.C.); (S.C.Y.); (E.G.); (K.L.); (A.P.); (A.T.)
| | - Andrés Tabernilla
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (A.C.); (R.V.C.); (S.C.Y.); (E.G.); (K.L.); (A.P.); (A.T.)
| | - Pieter Van Brantegem
- Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, 3000 Leuven, Belgium; (P.V.B.); (P.A.)
| | - Pieter Annaert
- Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, 3000 Leuven, Belgium; (P.V.B.); (P.A.)
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo 05508-270, Brazil;
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (A.C.); (R.V.C.); (S.C.Y.); (E.G.); (K.L.); (A.P.); (A.T.)
| |
Collapse
|
|
40
|
Cai M, Shao W, Yu H, Hong Y, Shi L. Paeonol Inhibits Cell Proliferation, Migration and Invasion and Induces Apoptosis in Hepatocellular Carcinoma by Regulating miR-21-5p/KLF6 Axis. Cancer Manag Res 2020; 12:5931-5943. [PMID: 32765094 PMCID: PMC7381818 DOI: 10.2147/cmar.s254485] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 06/24/2020] [Indexed: 12/12/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common tumors with high mortality. MicroRNAs (miRNAs) were reported as crucial markers for the diagnosis of HCC. Paeonol exerted many pharmacological effects on tumor progression. This study aimed to elucidate the underlying molecular mechanism of paeonol in HCC progression. Methods Cell viability was determined by Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis was examined by flow cytometry. The levels of Cyclin D1, cyclin-dependent kinase 4 (CDK4), B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) were detected by Western blot assay. Cell migration and invasion were assessed by transwell assay. The levels of matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9) were measured by Western blot. The expression of miR-21-5p and kruppel-like factor 6 (KLF6) was detected by quantitative real-time PCR (qRT-PCR) or Western blot assay, respectively. Dual-luciferase reporter assay was performed to analyze the interaction between miR-21-5p and KLF6. The enrichment of miR-21-5p was determined by RNA pull-down assay. Xenograft assay was conducted to analyze tumor growth in vivo. Results The results demonstrated that cell viability of Hep3B and Huh-7 cells was inhibited, while cell apoptosis was promoted after treatment with paeonol. Transwell assay indicated that cell migration and invasion were blocked in paeonol-treated cells. Moreover, miR-21-5p expression was markedly decreased in paeonol-treated cells and its knockdown suppressed cell viability, migration and invasion, but contributed to cell apoptosis. MiR-21-5p targeted KLF6 and its silencing prominently elevated KLF6 level. Furthermore, the restoration experiment determined that miR-21-5p and KLF6 were antagonisms on cell viability, apoptosis, migration and invasion. Also, paeonol abated the decrease in KLF6 level caused by miR-21-5p up-regulation. Besides, paeonol suppressed tumor growth in vivo. Conclusion Paeonol impeded cell viability, migration and invasion and triggered apoptosis by regulating miR-21-5p/KLF6 axis in HCC cells. Xenograft assay confirmed that paeonol inhibited tumor growth through miR-21-5p/KLF6 axis in HCC in vivo.
Collapse
Affiliation(s)
- Miaoguo Cai
- Department of Medical Oncology, Luqiao Branch of Taizhou Hospital, Taizhou City, Zhejiang Province, People's Republic of China
| | - Wei Shao
- Department of Medical Oncology, Luqiao Branch of Taizhou Hospital, Taizhou City, Zhejiang Province, People's Republic of China
| | - Huijun Yu
- Department of Pediatric, Luqiao Branch of Taizhou Hospital, Taizhou City, Zhejiang Province, People's Republic of China
| | - Ye Hong
- Department of Medical Oncology, Luqiao Branch of Taizhou Hospital, Taizhou City, Zhejiang Province, People's Republic of China
| | - Lili Shi
- Department of Infection, Luqiao Branch of Taizhou Hospital, Taizhou City, Zhejiang Province, People's Republic of China
| |
Collapse
|
|
41
|
Ahmadi-Badejani R, Mosharaf-Dehkordi M, Ahmadikia H. An image-based geometric model for numerical simulation of blood perfusion within the liver lobules. Comput Methods Biomech Biomed Engin 2020; 23:987-1004. [PMID: 32594768 DOI: 10.1080/10255842.2020.1782389] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
An image-based numerical algorithm is presented for simulating blood flow through the liver tissue. First, a geometric model is constructed by applying image processing techniques on a real microscopic image of a liver tissue. Then, incompressible blood flow through liver lobules is simulated. Effects of tissue heterogeneity and deformity, presence/absence of the second central vein in a particular lobule, and apparent sinusoids density in the liver cross section on the blood flow are investigated. Numerical results indicate that the existence of thick low permeability vascular septum, high permeability sinusoids, and lobule tissue heterogeneity can considerably affect interlobular and intralobular blood flow.
Collapse
Affiliation(s)
- R Ahmadi-Badejani
- Department of Mechanical Engineering, Faculty of Engineering, University of Isfahan, Isfahan, Iran
| | - M Mosharaf-Dehkordi
- Department of Mechanical Engineering, Faculty of Engineering, University of Isfahan, Isfahan, Iran
| | - H Ahmadikia
- Department of Mechanical Engineering, Faculty of Engineering, University of Isfahan, Isfahan, Iran
| |
Collapse
|
|
42
|
Grabner GF, Fawzy N, Schreiber R, Pusch LM, Bulfon D, Koefeler H, Eichmann TO, Lass A, Schweiger M, Marsche G, Schoiswohl G, Taschler U, Zimmermann R. Metabolic regulation of the lysosomal cofactor bis(monoacylglycero)phosphate in mice. J Lipid Res 2020; 61:995-1003. [PMID: 32350080 PMCID: PMC7328040 DOI: 10.1194/jlr.ra119000516] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 04/23/2020] [Indexed: 01/02/2023] Open
Abstract
Bis(monoacylglycero)phosphate (BMP), also known as lysobisphosphatidic acid, is a phospholipid that promotes lipid sorting in late endosomes/lysosomes by activating lipid hydrolases and lipid transfer proteins. Changes in the cellular BMP content therefore reflect an altered metabolic activity of the endolysosomal system. Surprisingly, little is known about the physiological regulation of BMP. In this study, we investigated the effects of nutritional and metabolic factors on BMP profiles of whole tissues and parenchymal and nonparenchymal cells. Tissue samples were obtained from fed, fasted, 2 h refed, and insulin-treated mice, as well as from mice housed at 5°C, 22°C, or 30°C. These tissues exhibited distinct BMP profiles that were regulated by the nutritional state in a tissue-specific manner. Insulin treatment was not sufficient to mimic refeeding-induced changes in tissue BMP levels, indicating that BMP metabolism is regulated by other hormonal or nutritional factors. Tissue fractionation experiments revealed that fasting drastically elevates BMP levels in hepatocytes and pancreatic cells. Furthermore, we observed that the BMP content in brown adipose tissue strongly depends on housing temperatures. In conclusion, our observations suggest that BMP concentrations adapt to the metabolic state in a tissue- and cell-type-specific manner in mice. Drastic changes observed in hepatocytes, pancreatic cells, and brown adipocytes suggest that BMP plays a role in the functional adaption to nutrient starvation and ambient temperature.
Collapse
Affiliation(s)
- Gernot F Grabner
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Nermeen Fawzy
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Renate Schreiber
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Lisa M Pusch
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Dominik Bulfon
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Harald Koefeler
- Otto Loewi Research Center, and Center for Medical Research, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria
| | - Thomas O Eichmann
- Institute of Molecular Biosciences, University of Graz, Graz, Austria; Center for Explorative Lipidomics, BioTechMed-Graz, Graz, Austria
| | - Achim Lass
- Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria
| | - Martina Schweiger
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Gunther Marsche
- Division of Pharmacology, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria
| | | | - Ulrike Taschler
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Robert Zimmermann
- Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria. mailto:
| |
Collapse
|
|
43
|
Koç DÖ, Özhan Y, Acar ET, Bireroğlu N, Aslan F, Keğin M, Sipahi H. Serum Neopterin Levels and IDO Activity as Possible Markers for Presence and Progression of Hepatitis B. Pteridines 2020. [DOI: 10.1515/pteridines-2020-0010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Abstract
Chronic Hepatitis B virus (HBV) is still one of the major reasons for liver related mortality and morbidity all around the world. This study aimed to investigate the possible relationship between the immune system activation and presence, as well as progression, of hepatitis B infection by monitoring the tryptophan degradation and serum neopterin levels in patients with HBV. 110 patients with HBV and 23 healthy subjects were included in the study. The patients had significantly higher neopterin levels and increased kynurenine to tryptophan ratios, which were most probably due to enhanced indoleamine 2,3-dioxygenase (IDO) activity compared to healthy control. A strong positive correlation was found between neopterin levels and IDO activity in patient group. Neopterin levels and IDO activity were markedly increased in patients with histological activity index (HAI) ≥4 compared to HAI<4, and a significant correlation was found between neopterin and HAI. Moreover, there was a significant correlation between albumin levels and IDO activity in HBV patients. These findings suggest that tryptophan degradation results from IFN-γ-induced IDO activation, likewise depletion of albumin synthesis in HBV patients may result from diminished tryptophan availability. In conclusion, based on the study results, serum neopterin levels and IDO activity could provide additional immunological information for monitoring liver histological activity and can be used as prognostic markers in HBV disease.
Collapse
Affiliation(s)
- Deniz Öğütmen Koç
- Department of Gastroenterology , University of Health Sciences, Gaziosmanpaşa Training and Research Hospital , 34255, Gaziosmanpaşa, Istanbul , Turkey
| | - Yağmur Özhan
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy , Yeditepe University , 34755, Atasehir, Istanbul , Turkey
| | - Ebru Türköz Acar
- Department of Analytical Chemistry, Faculty of Pharmacy , Yeditepe University , 34755, Atasehir, Istanbul , Turkey
| | - Nilgün Bireroğlu
- Department of Biochemistry , University of Health Sciences, Gaziosmanpaşa Training and Research Hospital , 34255, Gaziosmanpaşa, Istanbul , Turkey
| | - Fatih Aslan
- Department of Internal Medicine , University of Health Sciences, Gaziosmanpaşa Training and Research Hospital , 34255, Gaziosmanpaşa, Istanbul , Turkey
| | - Murat Keğin
- Department of Surgery , University of Health Sciences, Gaziosmanpaşa Training and Research Hospital , 34255, Gaziosmanpaşa, Istanbul , Turkey
| | - Hande Sipahi
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy , Yeditepe University , 34755, Atasehir, Istanbul , Turkey
| |
Collapse
|
|
44
|
Karschau J, Scholich A, Wise J, Morales-Navarrete H, Kalaidzidis Y, Zerial M, Friedrich BM. Resilience of three-dimensional sinusoidal networks in liver tissue. PLoS Comput Biol 2020; 16:e1007965. [PMID: 32598356 PMCID: PMC7351228 DOI: 10.1371/journal.pcbi.1007965] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 07/10/2020] [Accepted: 05/19/2020] [Indexed: 12/19/2022] Open
Abstract
Can three-dimensional, microvasculature networks still ensure blood supply if individual links fail? We address this question in the sinusoidal network, a plexus-like microvasculature network, which transports nutrient-rich blood to every hepatocyte in liver tissue, by building on recent advances in high-resolution imaging and digital reconstruction of adult mice liver tissue. We find that the topology of the three-dimensional sinusoidal network reflects its two design requirements of a space-filling network that connects all hepatocytes, while using shortest transport routes: sinusoidal networks are sub-graphs of the Delaunay graph of their set of branching points, and also contain the corresponding minimum spanning tree, both to good approximation. To overcome the spatial limitations of experimental samples and generate arbitrarily-sized networks, we developed a network generation algorithm that reproduces the statistical features of 0.3-mm-sized samples of sinusoidal networks, using multi-objective optimization for node degree and edge length distribution. Nematic order in these simulated networks implies anisotropic transport properties, characterized by an empirical linear relation between a nematic order parameter and the anisotropy of the permeability tensor. Under the assumption that all sinusoid tubes have a constant and equal flow resistance, we predict that the distribution of currents in the network is very inhomogeneous, with a small number of edges carrying a substantial part of the flow-a feature known for hierarchical networks, but unexpected for plexus-like networks. We quantify network resilience in terms of a permeability-at-risk, i.e., permeability as function of the fraction of removed edges. We find that sinusoidal networks are resilient to random removal of edges, but vulnerable to the removal of high-current edges. Our findings suggest the existence of a mechanism counteracting flow inhomogeneity to balance metabolic load on the liver.
Collapse
Affiliation(s)
| | - André Scholich
- Max Planck Institute for the Physics of Complex Systems, Dresden, Germany
| | - Jonathan Wise
- cfaed, TU Dresden, Dresden, Germany
- Univ. Grenoble Alpes, CNRS, LPMMC, Grenoble, France
| | | | - Yannis Kalaidzidis
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Marino Zerial
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
- Cluster of Excellence ‘Physics of Life’, TU Dresden, Dresden, Germany
| | - Benjamin M. Friedrich
- cfaed, TU Dresden, Dresden, Germany
- Cluster of Excellence ‘Physics of Life’, TU Dresden, Dresden, Germany
| |
Collapse
|
|
45
|
Ríos-López DG, Aranda-López Y, Sosa-Garrocho M, Macías-Silva M. La plasticidad del hepatocito y su relevancia en la fisiología y la patología hepática. TIP REVISTA ESPECIALIZADA EN CIENCIAS QUÍMICO-BIOLÓGICAS 2020. [DOI: 10.22201/fesz.23958723e.2020.0.225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
El hígado es uno de los principales órganos encargados de mantener la homeostasis en vertebrados, además de poseer una gran capacidad regenerativa. El hígado está constituido por diversos tipos celulares que de forma coordinada contribuyen para que el órgano funcione eficientemente. Los hepatocitos representan el tipo celular principal de este órgano y llevan a cabo la mayoría de sus actividades; además, constituyen una población heterogénea de células epiteliales con funciones especializadas en el metabolismo. El fenotipo de los hepatocitos está controlado por diferentes vías de señalización, como la vía del TGFβ/Smads, la ruta Hippo/YAP-TAZ y la vía Wnt/β-catenina, entre otras. Los hepatocitos son células que se encuentran normalmente en un estado quiescente, aunque cuentan con una plasticidad intrínseca que se manifiesta en respuesta a diversos daños en el hígado; así, estas células reactivan su capacidad proliferativa o cambian su fenotipo a través de procesos celulares como la transdiferenciación o la transformación, para contribuir a mantener la homeostasis del órgano en condiciones saludables o desarrollar diversas patologías.
Collapse
|
|
46
|
Sun X, Harris EN. New aspects of hepatic endothelial cells in physiology and nonalcoholic fatty liver disease. Am J Physiol Cell Physiol 2020; 318:C1200-C1213. [PMID: 32374676 DOI: 10.1152/ajpcell.00062.2020] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The liver is the central metabolic hub for carbohydrate, lipid, and protein metabolism. It is composed of four major types of cells, including hepatocytes, endothelial cells (ECs), Kupffer cells, and stellate cells. Hepatic ECs are highly heterogeneous in both mice and humans, representing the second largest population of cells in liver. The majority of them line hepatic sinusoids known as liver sinusoidal ECs (LSECs). The structure and biology of LSECs and their roles in physiology and liver disease were reviewed recently. Here, we do not give a comprehensive review of LSEC structure, function, or pathophysiology. Instead, we focus on the recent progress in LSEC research and other hepatic ECs in physiology and nonalcoholic fatty liver disease and other hepatic fibrosis-related conditions. We discuss several current areas of interest, including capillarization, scavenger function, autophagy, cellular senescence, paracrine effects, and mechanotransduction. In addition, we summarize the strengths and weaknesses of evidence for the potential role of endothelial-to-mesenchymal transition in liver fibrosis.
Collapse
Affiliation(s)
- Xinghui Sun
- Department of Biochemistry, University of Nebraska-Lincoln, Beadle Center, Lincoln, Nebraska.,Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, Nebraska.,Nebraska Center for the Prevention of Obesity Diseases through Dietary Molecules, University of Nebraska-Lincoln, Lincoln, Nebraska
| | - Edward N Harris
- Department of Biochemistry, University of Nebraska-Lincoln, Beadle Center, Lincoln, Nebraska.,Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, Nebraska.,Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
| |
Collapse
|
|
47
|
Debnath T, Mallarpu CS, Chelluri LK. Development of Bioengineered Organ Using Biological Acellular Rat Liver Scaffold and Hepatocytes. Organogenesis 2020; 16:61-72. [PMID: 32362216 DOI: 10.1080/15476278.2020.1742534] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The increasing demand for organs for transplantation necessitates the development of substitutes to meet the structural and physiological functions. Tissue decellularization and recellularization aids in retaining the three-dimensional integrity, biochemical composition, tissue ultra-structure, and mechanical behavior, which makes them functionally suitable for organ transplantation. Herein, we attempted to rebuild functional liver grafts in small animal model (Wistar rat) with a potential of translation. A soft approach was adopted using 0.1% SDS (Sodium Dodecyl Sulfate) for decellularization and primary hepatocytes were used as a potential cell source for recellularization. The decellularization process was evaluated and confirmed using histology, DNA content, ultra-structure analysis. The resultant scaffold was re-seeded with the rat hepatocytes and their biocompatibility was assessed by its metabolic functions and gene expression. The structural components of the Extracellular matrix (ECM) (Laminins, Collagen type I, Reticulins) were conserved and the liver cell-specific proteins like CK-18, alpha-fetoprotein, albumin were expressed in the recellularized scaffold. The functionality and metabolic activity of the repopulated scaffold were evident from the albumin and urea production. Expression of Cytokeratin-19 (CK-19), Glucose 6-Phosphatase (G6P), Albumin, Gamma Glutamyl Transferase (GGT) genes has distinctly confirmed the translational signals after the repopulation process. Our study clearly elucidates that the native extracellular matrix of rat liver can be utilized as a scaffold for effective recellularization for whole organ regeneration.
Collapse
Affiliation(s)
- Tanya Debnath
- Stem Cell Unit, Global Medical Education & Research Foundation , Hyderabad, India
| | | | | |
Collapse
|
|
48
|
Cavalli M, Diamanti K, Pan G, Spalinskas R, Kumar C, Deshmukh AS, Mann M, Sahlén P, Komorowski J, Wadelius C. A Multi-Omics Approach to Liver Diseases: Integration of Single Nuclei Transcriptomics with Proteomics and HiCap Bulk Data in Human Liver. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2020; 24:180-194. [PMID: 32181701 PMCID: PMC7185313 DOI: 10.1089/omi.2019.0215] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The liver is the largest solid organ and a primary metabolic hub. In recent years, intact cell nuclei were used to perform single-nuclei RNA-seq (snRNA-seq) for tissues difficult to dissociate and for flash-frozen archived tissue samples to discover unknown and rare cell subpopulations. In this study, we performed snRNA-seq of a liver sample to identify subpopulations of cells based on nuclear transcriptomics. In 4282 single nuclei, we detected, on average, 1377 active genes and we identified seven major cell types. We integrated data from 94,286 distal interactions (p < 0.05) for 7682 promoters from a targeted chromosome conformation capture technique (HiCap) and mass spectrometry proteomics for the same liver sample. We observed a reasonable correlation between proteomics and in silico bulk snRNA-seq (r = 0.47) using tissue-independent gene-specific protein abundancy estimation factors. We specifically looked at genes of medical importance. The DPYD gene is involved in the pharmacogenetics of fluoropyrimidine toxicity and some of its variants are analyzed for clinical purposes. We identified a new putative polymorphic regulatory element, which may contribute to variation in toxicity. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and we investigated all known risk genes. We identified a complex regulatory landscape for the SLC2A2 gene with 16 candidate enhancers. Three of them harbor somatic motif breaking and other mutations in HCC in the Pan Cancer Analysis of Whole Genomes dataset and are candidates to contribute to malignancy. Our results highlight the potential of a multi-omics approach in the study of human diseases.
Collapse
Affiliation(s)
- Marco Cavalli
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Klev Diamanti
- Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
| | - Gang Pan
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Rapolas Spalinskas
- Science for Life Laboratory, Division of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Chanchal Kumar
- Translational Science and Experimental Medicine, Early Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- Karolinska Institutet/AstraZeneca Integrated CardioMetabolic Center (KI/AZ ICMC), Department of Medicine, Novum, Huddinge, Sweden
| | - Atul Shahaji Deshmukh
- Novo Nordisk Foundation Center for Protein Research, Proteomics Program, Clinical Proteomics Group, Copenhagen, Denmark
| | - Matthias Mann
- Novo Nordisk Foundation Center for Protein Research, Proteomics Program, Clinical Proteomics Group, Copenhagen, Denmark
| | - Pelin Sahlén
- Science for Life Laboratory, Division of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Jan Komorowski
- Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
- Institute of Computer Science, Polish Academy of Sciences, Warszawa, Poland
| | - Claes Wadelius
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| |
Collapse
|
|
49
|
Sällberg M, Pasetto A. Liver, Tumor and Viral Hepatitis: Key Players in the Complex Balance Between Tolerance and Immune Activation. Front Immunol 2020; 11:552. [PMID: 32292409 PMCID: PMC7119224 DOI: 10.3389/fimmu.2020.00552] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 03/10/2020] [Indexed: 12/12/2022] Open
Abstract
Liver cancer is the third most common cause of cancer related death in the World. From an epidemiological point of view the risk factors associated to primary liver cancer are mainly viral hepatitis infection and alcohol consumption. Even though there is a clear correlation between liver inflammation, cirrhosis and cancer, other emerging liver diseases (like fatty liver) could also lead to liver cancer. Moreover, the liver is the major site of metastasis from colon, breast, ovarian and other cancers. In this review we will address the peculiar status of the liver as organ that has to balance between tolerance and immune activation. We will focus on macrophages and other key cellular components of the liver microenvironment that play a central role during tumor progression. We will also discuss how current and future therapies may affect the balance toward immune activation.
Collapse
Affiliation(s)
- Matti Sällberg
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Anna Pasetto
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
50
|
Liang WQ, Zhang KC, Li H, Cui JX, Xi HQ, Li JY, Cai AZ, Liu YH, Zhang W, Zhang L, Wei B, Chen L. Preoperative albumin levels predict prolonged postoperative ileus in gastrointestinal surgery. World J Gastroenterol 2020; 26:1185-1196. [PMID: 32231422 PMCID: PMC7093316 DOI: 10.3748/wjg.v26.i11.1185] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/20/2020] [Accepted: 02/21/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Prolonged postoperative ileus (PPOI) is a prolonged state of "pathological" gastrointestinal (GI) tract dysmotility. There are relatively few studies examining the influence of preoperative nutritional status on the development of PPOI in patients who underwent GI surgery. The association between preoperative albumin and PPOI has not been fully studied. We hypothesized that preoperative albumin may be an independent indicator of PPOI. AIM To analyze the role of preoperative albumin in predicting PPOI and to establish a nomogram for clinical risk evaluation. METHODS Patients were drawn from a prospective hospital registry database of GI surgery. A total of 311 patients diagnosed with gastric or colorectal cancer between June 2016 and March 2017 were included. Potential predictors of PPOI were analyzed by univariate and multivariable logistic regression analyses, and a nomogram for quantifying the presence of PPOI was developed and internally validated. RESULTS The overall PPOI rate was 21.54%. Advanced tumor stage and postoperative opioid analgesic administration were associated with PPOI. Preoperative albumin was an independent predictor of PPOI, and an optimal cutoff value of 39.15 was statistically calculated. After adjusting multiple variables, per unit or per SD increase in albumin resulted in a significant decrease in the incidence of PPOI of 8% (OR = 0.92, 95%CI: 0.85-1.00, P = 0.046) or 27% (OR = 0.73, 95%CI: 0.54-0.99, P = 0.046), respectively. Patients with a high level of preoperative albumin (≥ 39.15) tended to experience PPOI compared to those with low levels (< 39.15) (OR = 0.43, 95%CI: 0.24-0.78, P = 0.006). A nomogram for predicting PPOI was developed [area under the curve (AUC) = 0.741] and internally validated by bootstrap resampling (AUC = 0.725, 95%CI: 0.663-0.799). CONCLUSION Preoperative albumin is an independent predictive factor of PPOI in patients who underwent GI surgery. The nomogram provided a model to screen for early indications in the clinical setting.
Collapse
Affiliation(s)
- Wen-Quan Liang
- Department of General Surgery & Institute of General Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Ke-Cheng Zhang
- Department of General Surgery & Institute of General Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Hua Li
- Department of Surgical Oncology, Xing Tai People's Hospital, Xingtai 054001, Hebei Province China
| | - Jian-Xin Cui
- Department of General Surgery & Institute of General Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Hong-Qing Xi
- Department of General Surgery & Institute of General Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Ji-Yang Li
- Department of General Surgery & Institute of General Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Ai-Zhen Cai
- Department of General Surgery & Institute of General Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Yu-Hua Liu
- Institute of Army Hospital Management, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Wang Zhang
- Department of General Surgery & Institute of General Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Lan Zhang
- Department of General Surgery & Institute of General Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Bo Wei
- Department of General Surgery & Institute of General Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Lin Chen
- Department of General Surgery & Institute of General Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| |
Collapse
|