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Graham CT, Gordon S, Kubes P. A historical perspective of Kupffer cells in the context of infection. Cell Tissue Res 2025; 400:121-136. [PMID: 39392500 DOI: 10.1007/s00441-024-03924-4] [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: 06/28/2024] [Accepted: 10/02/2024] [Indexed: 10/12/2024]
Abstract
The Kupffer cell was first discovered by Karl Wilhelm von Kupffer in 1876, labeling them as "Sternzellen." Since their discovery as the primary macrophages of the liver, researchers have gradually gained an in-depth understanding of the identity, functions, and influential role of Kupffer cells, particularly in infection. It is becoming clear that Kupffer cells perform important tissue-specific functions in homeostasis and disease. Stationary in the sinusoids of the liver, Kupffer cells have a high phagocytic capacity and are adept in clearing the bloodstream of foreign material, toxins, and pathogens. Thus, they are indispensable to host defense and prevent the dissemination of bacteria during infections. To highlight the importance of this cell, this review will explore the history of the Kupffer cell in the context of infection beginning with its discovery to the present day.
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Affiliation(s)
- Carolyn T Graham
- Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
| | - Siamon Gordon
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wenhua 1st Road Guishan Dist., Taoyuan, Taiwan
| | - Paul Kubes
- Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
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2
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Lawal MG, Samaila A, Basir R, Abd Aziz NAL, Alarabei AA, Abdullah MA, Majid RA, Nordin N, Hussain MK, Ismail EN. Suppression of 8-oxoguanine DNA glycosylase (OGG1) activity produced positive impacts on disease severity, survival, and histopathological features of mice infected with Plasmodium berghei. Exp Parasitol 2025; 272:108930. [PMID: 40088963 DOI: 10.1016/j.exppara.2025.108930] [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: 10/09/2024] [Revised: 01/12/2025] [Accepted: 03/10/2025] [Indexed: 03/17/2025]
Abstract
Malaria is a life-threatening disease, leading to significant morbidity and mortality. Malaria treatment remains a challenge due to its intricate pathophysiology and high levels of parasite resistance to many currently available antimalarial agents. Thus, there is an urgent need for more therapeutic strategies to combat the disease. OGG1 activity has been implicated in many inflammatory disease conditions, making suppressing OGG1 activity a potential target for therapeutic purposes. The current study aimed to determine the effect of suppressing OGG1 activity on the severity, survival, and histopathological features of P. berghei-infected mice. In this study, the effects of modulating OGG1 activity on parasitaemia development, disease progression, survival rate, and histopathological outcomes in major organs of Plasmodium berghei (P. berghei) infected mice were evaluated. A significant difference in the mean parasitaemia was observed between the Vehicle, TH5487-treated, and O8-treated mice (p < 0.001). Vehicle-treated mice exhibited markedly elevated mean percentage parasitaemia and succumbed to the infection earlier than TH5487 and O8-treated mice. The O8-treated mice showed the highest parasitaemia reduction of 39.60 ± 1.53 % compared to TH5487-treated mice. Histopathological examination revealed less severe pathological features associated with P. berghei infection in mice treated with OGG1 inhibitors than in vehicle-treated malaria mice. Significant differences were observed in the sequestration of PRBC, inflammation, hemozoin deposition, and architectural loss in mice treated with O8 and TH5487 compared to untreated malaria mice. The results of this study suggested that OGG1 suppression led to a decrease in parasitaemia and severity of the histopathological features in P. berghei-infected mice. The increased survival of treated malaria mice further supported this effect. These findings indicate that OGG1 suppression could be a potential therapeutic strategy during malaria.
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Affiliation(s)
- Mukhtar Gambo Lawal
- Department of Human Anatomy, Pharmacology Unit, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor Darul Ehsan, Malaysia; Department of Microbiology, Faculty of Natural & Applied Sciences, Umaru Musa Yar'adua University, P.M.B. 2218, Katsina State, Nigeria.
| | - Abdullahi Samaila
- Department of Human Anatomy, Pharmacology Unit, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor Darul Ehsan, Malaysia; Department of Pharmacology, College of Health Sciences, Umaru Musa Yar'adua University, P.M.B. 2218, Katsina State, Nigeria.
| | - Rusliza Basir
- Department of Human Anatomy, Pharmacology Unit, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor Darul Ehsan, Malaysia.
| | - Nur Aimi Liyana Abd Aziz
- Department of Human Anatomy, Pharmacology Unit, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor Darul Ehsan, Malaysia.
| | - Abdusalam Abdullah Alarabei
- Department of Human Anatomy, Pharmacology Unit, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor Darul Ehsan, Malaysia.
| | - Maizaton Atmadini Abdullah
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.
| | - Roslaini Abd Majid
- Department of Pre-clinical, Faculty of Medicine and Defence Health, National Defence University of Malaysia, Kuala Lumpur, 57000, Malaysia.
| | - Norshariza Nordin
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.
| | - Mohd Khairi Hussain
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.
| | - Elysha Nur Ismail
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.
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3
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Kaur A, Azeez GA, Thirunagari M, Fatima N, Anand A, Palvia AR, Yu AK. Association of Chronic Hepatitis B With Colorectal Cancer and Its Dual Impact on Colorectal Liver Metastasis: A Narrative Review. Cureus 2024; 16:e76079. [PMID: 39835087 PMCID: PMC11743875 DOI: 10.7759/cureus.76079] [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: 07/28/2024] [Accepted: 12/19/2024] [Indexed: 01/22/2025] Open
Abstract
Viral hepatitis B is infamous for being contracted in young adulthood and adolescence, as high-risk behaviors like unprotected sexual intercourse and intravenous drug abuse are common. Most infections caused by the hepatitis B virus (HBV) are cleared without any long-term sequelae, but some may persist and cause chronic hepatitis B (CHB). This chronicity may produce a state of prolonged inflammation and significantly increase the risk of developing colorectal adenomas (CRA) and colorectal carcinomas (CRC). The aim of this review is to deep-dive into the mechanisms by which CHB may predispose a patient to develop CRA and, more grimly, CRC. It also focuses on studying the influence of CHB on colorectal cancer liver metastases (CRLM). We conducted a comprehensive literature search using databases like PubMed and Google Scholar, focusing on studies that investigate the role of HBV in colorectal carcinogenesis and CRLM rates in patients suffering from CHB. Chronic inflammation, viral protein interactions with tumor suppressor genes, alteration of cellular pathways such as wingless-related integration site (Wnt) signaling, and extrahepatic accumulation of hepatitis B surface antigen (HBsAg) were the key mechanisms identified. Quite peculiarly, CHB, which is thought to increase the risk for CRA, seemed to protect against CRLM probably due to its sclerosing effect on the liver parenchyma and due to certain immune-mediated mechanisms that suppress tumor growth. Nonetheless, high viral count or the presence of hepatitis B envelope antigen (HBeAg) was found to increase the risk for CRLM, potentially due to increased angiogenesis in the liver. These findings provide convincing evidence that enhanced colonoscopic screening and stronger management protocols for patients suffering from it have the potential to reduce the risk of developing CRC and CRLM.
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Affiliation(s)
- Avneet Kaur
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Gibran A Azeez
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mounika Thirunagari
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Nazeefa Fatima
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Abhinav Anand
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Aadi R Palvia
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ann Kashmer Yu
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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Murrey MW, Ng IT, Pixley FJ. The role of macrophage migratory behavior in development, homeostasis and tumor invasion. Front Immunol 2024; 15:1480084. [PMID: 39588367 PMCID: PMC11586339 DOI: 10.3389/fimmu.2024.1480084] [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: 08/13/2024] [Accepted: 10/23/2024] [Indexed: 11/27/2024] Open
Abstract
Tumor-associated macrophages (TAMs) recapitulate the developmental and homeostatic behaviors of tissue resident macrophages (TRMs) to promote tumor growth, invasion and metastasis. TRMs arise in the embryo and colonize developing tissues, initially to guide tissue morphogenesis and then to form complex networks in adult tissues to constantly search for threats to homeostasis. The macrophage growth factor, colony-stimulating factor-1 (CSF-1), which is essential for TRM survival and differentiation, is also responsible for the development of the unique motility machinery of mature macrophages that underpins their ramified morphologies, migratory capacity and ability to degrade matrix. Two CSF-1-activated kinases, hematopoietic cell kinase and the p110δ catalytic isoform of phosphatidylinositol 3-kinase, regulate this machinery and selective inhibitors of these proteins completely block macrophage invasion. Considering tumors co-opt the invasive capacity of TAMs to promote their own invasion, these proteins are attractive targets for drug development to inhibit tumor progression to invasion and metastasis.
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Affiliation(s)
| | | | - Fiona J. Pixley
- Macrophage Biology and Cancer Laboratory, School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia
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5
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Diwan R, Gaytan SL, Bhatt HN, Pena-Zacarias J, Nurunnabi M. Liver fibrosis pathologies and potentials of RNA based therapeutics modalities. Drug Deliv Transl Res 2024; 14:2743-2770. [PMID: 38446352 DOI: 10.1007/s13346-024-01551-8] [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] [Accepted: 02/14/2024] [Indexed: 03/07/2024]
Abstract
Liver fibrosis (LF) occurs when the liver tissue responds to injury or inflammation by producing excessive amounts of scar tissue, known as the extracellular matrix. This buildup stiffens the liver tissue, hinders blood flow, and ultimately impairs liver function. Various factors can trigger this process, including bloodborne pathogens, genetic predisposition, alcohol abuse, non-steroidal anti-inflammatory drugs, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease. While some existing small-molecule therapies offer limited benefits, there is a pressing need for more effective treatments that can truly cure LF. RNA therapeutics have emerged as a promising approach, as they can potentially downregulate cytokine levels in cells responsible for liver fibrosis. Researchers are actively exploring various RNA-based therapeutics, such as mRNA, siRNA, miRNA, lncRNA, and oligonucleotides, to assess their efficacy in animal models. Furthermore, targeted drug delivery systems hold immense potential in this field. By utilizing lipid nanoparticles, exosomes, nanocomplexes, micelles, and polymeric nanoparticles, researchers aim to deliver therapeutic agents directly to specific biomarkers or cytokines within the fibrotic liver, increasing their effectiveness and reducing side effects. In conclusion, this review highlights the complex nature of liver fibrosis, its underlying causes, and the promising potential of RNA-based therapeutics and targeted delivery systems. Continued research in these areas could lead to the development of more effective and personalized treatment options for LF patients.
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Affiliation(s)
- Rimpy Diwan
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX, 79968, USA
| | - Samantha Lynn Gaytan
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Interdisciplinary Health Sciences, College of Health Sciences, The University of Texas El Paso, El Paso, Texas, 79968, USA
| | - Himanshu Narendrakumar Bhatt
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX, 79968, USA
| | - Jacqueline Pena-Zacarias
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Biological Sciences, College of Science, The University of Texas El Paso, El Paso, Texas, 79968, USA
| | - Md Nurunnabi
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA.
- Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX, 79968, USA.
- Department of Interdisciplinary Health Sciences, College of Health Sciences, The University of Texas El Paso, El Paso, Texas, 79968, USA.
- Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX, 79968, USA.
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Wang Q, Jia S, Wang Z, Chen H, Jiang X, Li Y, Ji P. Nanogene editing drug delivery systems in the treatment of liver fibrosis. Front Med (Lausanne) 2024; 11:1418786. [PMID: 39386741 PMCID: PMC11461213 DOI: 10.3389/fmed.2024.1418786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 09/09/2024] [Indexed: 10/12/2024] Open
Abstract
Liver fibrosis is a group of diseases that seriously affect the health of the world's population. Despite significant progress in understanding the mechanisms of liver fibrogenesis, the technologies and drugs used to treat liver fibrosis have limited efficacy. As a revolutionary genetic tool, gene editing technology brings new hope for treating liver fibrosis. Combining nano-delivery systems with gene editing tools to achieve precise delivery and efficient expression of gene editing tools that can be used to treat liver fibrosis has become a rapidly developing field. This review provides a comprehensive overview of the principles and methods of gene editing technology and commonly used gene editing targets for liver fibrosis. We also discuss recent advances in common gene editing delivery vehicles and nano-delivery formulations in liver fibrosis research. Although gene editing technology has potential advantages in liver fibrosis, it still faces some challenges regarding delivery efficiency, specificity, and safety. Future studies need to address these issues further to explore the potential and application of liver fibrosis technologies in treating liver fibrosis.
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Affiliation(s)
- Qun Wang
- College of Pharmacy and Chemistry & Chemical Engineering, Taizhou University, Taizhou, China
| | - Siyu Jia
- College of Pharmacy and Chemistry & Chemical Engineering, Taizhou University, Taizhou, China
| | - Zihan Wang
- College of Pharmacy and Chemistry & Chemical Engineering, Taizhou University, Taizhou, China
| | - Hui Chen
- College of Pharmacy and Chemistry & Chemical Engineering, Taizhou University, Taizhou, China
| | - Xinyi Jiang
- College of Pharmacy and Chemistry & Chemical Engineering, Taizhou University, Taizhou, China
| | - Yan Li
- Department of International Medicine, The Second Hospital of Dalian Medical University, Dalian, China
| | - Peng Ji
- College of Pharmacy and Chemistry & Chemical Engineering, Taizhou University, Taizhou, China
- Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
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Hou M, Liu L, Zhang Y, Pan Y, Ding N, Zhang Y. In vivo study of chelating agent-modified nano zero-valent iron: Biodistribution and toxicity in mice. WATER RESEARCH 2024; 257:121649. [PMID: 38718655 DOI: 10.1016/j.watres.2024.121649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 04/04/2024] [Accepted: 04/19/2024] [Indexed: 05/29/2024]
Abstract
In this study, the distribution and toxicity of nanoscale zero valent iron (nZVI) and nZVIs coated with citric acid and sodium tripolyphosphate (CA-nZVI and STPP-nZVI) in mice were investigated. nZVIs were primarily found in the livers and spleens, followed by the lungs, hearts, and kidneys. Histologic analysis revealed no significant histopathologic abnormalities or lesions in all organs except the liver at 14th d gavage. nZVIs did not have a noticeable impact on the body weight of the mice or the weight of their organs. Compared with the control group, there were no significant changes in hematology indexes in the nZVIs groups. However, the nZVIs groups exhibited varying levels of elevation in alanine aminotransferase, aspartate aminotransferase, and creatinine, suggesting liver and kidney inflammation in mice. The up-regulation of Nuclear Factor erythroid 2-Related Factor 2 and Heme oxygenase 1 in the nZVIs groups may be a response to nZVIs-induced oxidative stress. Immunohistochemical analysis confirmed the inflammatory response induced by the three nZVI groups. Chelating agents did not have a significant impact on the distribution or toxicity of nZVIs in mice. This study contributes to a comprehensive and detailed insight into nZVI toxicity in the environmental field.
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Affiliation(s)
- Minhui Hou
- Tianjin Key Laboratory of Environmental Technology for Complex Trans-Media Pollution, College of Environmental Science and Engineering, Nankai University, Tianjin, 300350, China
| | - Linwei Liu
- Tianjin Key Laboratory of Environmental Technology for Complex Trans-Media Pollution, College of Environmental Science and Engineering, Nankai University, Tianjin, 300350, China
| | - Yuqing Zhang
- Tianjin Key Laboratory of Environmental Technology for Complex Trans-Media Pollution, College of Environmental Science and Engineering, Nankai University, Tianjin, 300350, China
| | - Yuwei Pan
- College of Biology and the Environment, Nanjing Forestry University, Nanjing, 210037, China
| | - Ning Ding
- Key Laboratory of Cleaner Production and Integrated Resource Utilization of China National Light Industry, Beijing Technology and Business University, Beijing, 100048, China
| | - Ying Zhang
- Tianjin Key Laboratory of Environmental Technology for Complex Trans-Media Pollution, College of Environmental Science and Engineering, Nankai University, Tianjin, 300350, China.
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Couto-Santos F, Guimarães-Ervilha LO, Carvalho RPR, Bastos DSS, Souza ACF, da Silva RC, de Oliveira LL, de Oliveira JA, Machado-Neves M. Impact of Early Arsenic Exposure on the Mineral Content and Oxidative Status of the Liver and Kidney of Pubescent and Adult Rats. Biol Trace Elem Res 2024; 202:1644-1655. [PMID: 37495827 DOI: 10.1007/s12011-023-03787-w] [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: 06/14/2023] [Accepted: 07/18/2023] [Indexed: 07/28/2023]
Abstract
This study evaluated the effect of prepubertal arsenic exposure in the liver and kidney of pubescent rats and their reversibility 30 days after arsenic withdrawal. Male pups of Wistar rats (21 days old) were divided into two groups (n = 20/group): control animals received filtered water, and exposed rats received 10 mg L-1 arsenic from postnatal day (PND) 21 to PND 51. The liver and kidney of 52 days old rats (n = 10/group) were examined to investigate the effects of arsenic on micromineral content, antioxidant enzyme activity, histology, and biochemistry parameters. The other animals were kept alive under free arsenic conditions until 82 days old and further analyzed by the same parameters. Our results revealed that 52-day-old rats increased arsenic content in their liver and arsenic and manganese in their kidney. In those animals, glycogen and zinc content and catalase activity were reduced in the liver, and the selenium content decreased in the kidney. Thirty days later, arsenic reduced the manganese and iron content and SOD and CAT activity in the liver of 82-day-old rats previously exposed to arsenic, while glycogen and selenium content decreased in their kidney. In contrast, PND 82 rats exhibited higher retention of copper in the liver, an increase in iron and copper content, and CAT and GST activity in the kidney. Significant histological alterations of liver and kidney tissues were not observed in rats of both ages. We conclude that arsenic-induced toxicity could alter differently the oxidative status and balance of trace elements in pubertal and adult rats, demonstrating that the metalloid can cause effects in adulthood.
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Affiliation(s)
- Felipe Couto-Santos
- Departmento de Biologia Geral, Universidade Federal de Viçosa, Av. P.H. Rolfs, s/n, DBG, Campus Universitário, Viçosa, Minas Gerais, 36570-900, Brazil
| | - Luiz Otávio Guimarães-Ervilha
- Departmento de Biologia Geral, Universidade Federal de Viçosa, Av. P.H. Rolfs, s/n, DBG, Campus Universitário, Viçosa, Minas Gerais, 36570-900, Brazil
| | - Renner Philipe Rodrigues Carvalho
- Departmento de Biologia Geral, Universidade Federal de Viçosa, Av. P.H. Rolfs, s/n, DBG, Campus Universitário, Viçosa, Minas Gerais, 36570-900, Brazil
| | - Daniel Silva Sena Bastos
- Departmento de Biologia Geral, Universidade Federal de Viçosa, Av. P.H. Rolfs, s/n, DBG, Campus Universitário, Viçosa, Minas Gerais, 36570-900, Brazil
| | - Ana Cláudia Ferreira Souza
- Departmento de Biologia Geral, Universidade Federal de Viçosa, Av. P.H. Rolfs, s/n, DBG, Campus Universitário, Viçosa, Minas Gerais, 36570-900, Brazil
- Departmento de Biologia Animal, Universidade Federal Rural do Rio de Janeiro, Seropédica, Rio de Janeiro, Brazil
| | - Renê Chagas da Silva
- Departmento de Física, Universidade Federal de Viçosa, Viçosa, Minas Gerais, Brazil
| | - Leandro Licursi de Oliveira
- Departmento de Biologia Geral, Universidade Federal de Viçosa, Av. P.H. Rolfs, s/n, DBG, Campus Universitário, Viçosa, Minas Gerais, 36570-900, Brazil
| | - Juraci Alves de Oliveira
- Departmento de Biologia Geral, Universidade Federal de Viçosa, Av. P.H. Rolfs, s/n, DBG, Campus Universitário, Viçosa, Minas Gerais, 36570-900, Brazil
| | - Mariana Machado-Neves
- Departmento de Biologia Geral, Universidade Federal de Viçosa, Av. P.H. Rolfs, s/n, DBG, Campus Universitário, Viçosa, Minas Gerais, 36570-900, Brazil.
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Mohammad-Rafiei F, Negahdari S, Tahershamsi Z, Gheibihayat SM. Interface between Resolvins and Efferocytosis in Health and Disease. Cell Biochem Biophys 2024; 82:53-65. [PMID: 37794303 DOI: 10.1007/s12013-023-01187-4] [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: 09/06/2023] [Accepted: 09/25/2023] [Indexed: 10/06/2023]
Abstract
Acute inflammation resolution acts as a vital process for active host response, tissue support, and homeostasis maintenance, during which resolvin D (RvD) and E (RvE) as mediators derived from omega-3 polyunsaturated fatty acids display specific and stereoselective anti-inflammations like restricting neutrophil infiltration and pro-resolving activities. On the other side of the coin, potent macrophage-mediated apoptotic cell clearance, namely efferocytosis, is essential for successful inflammation resolution. Further studies mentioned a linkage between efferocytosis and resolvins. For instance, resolvin D1 (RvD1), which is endogenously formed from docosahexaenoic acid within the inflammation resolution, thereby provoking efferocytosis. There is still limited information regarding the mechanism of action of RvD1-related efferocytosis enhancement at the molecular level. The current review article was conducted to explore recent data on how the efferocytosis process and resolvins relate to each other during the inflammation resolution in illness and health. Understanding different aspects of this connection sheds light on new curative approaches for medical conditions caused by defective efferocytosis and disrupted inflammation resolution.
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Affiliation(s)
- Fatemeh Mohammad-Rafiei
- Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Samira Negahdari
- Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran
| | - Zahra Tahershamsi
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Mohammad Gheibihayat
- Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Munich, Germany.
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10
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Zhao J, Ghallab A, Hassan R, Dooley S, Hengstler JG, Drasdo D. A liver digital twin for in silico testing of cellular and inter-cellular mechanisms in regeneration after drug-induced damage. iScience 2024; 27:108077. [PMID: 38371522 PMCID: PMC10869925 DOI: 10.1016/j.isci.2023.108077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 02/22/2023] [Accepted: 09/25/2023] [Indexed: 02/20/2024] Open
Abstract
This communication presents a mathematical mechanism-based model of the regenerating liver after drug-induced pericentral lobule damage resolving tissue microarchitecture. The consequence of alternative hypotheses about the interplay of different cell types on regeneration was simulated. Regeneration dynamics has been quantified by the size of the damage-induced dead cell area, the hepatocyte density and the spatial-temporal profile of the different cell types. We use deviations of observed trajectories from the simulated system to identify branching points, at which the systems behavior cannot be explained by the underlying set of hypotheses anymore. Our procedure reflects a successful strategy for generating a fully digital liver twin that, among others, permits to test perturbations from the molecular up to the tissue scale. The model simulations are complementing current knowledge on liver regeneration by identifying gaps in mechanistic relationships and guiding the system toward the most informative (lacking) parameters that can be experimentally addressed.
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Affiliation(s)
- Jieling Zhao
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Group SIMBIOTX, INRIA Saclay, 91120 Palaiseau, France
| | - Ahmed Ghallab
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt
| | - Reham Hassan
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt
| | - Steven Dooley
- Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Jan Georg Hengstler
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
| | - Dirk Drasdo
- Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), 44139 Dortmund, Germany
- Group SIMBIOTX, INRIA Saclay, 91120 Palaiseau, France
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11
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Ge J, Yue Y, Nie HY, Liu KG, Li H, Lin HG, Zhang T, Yan HF, Sun HW, Yang JW, Zhou JL, Cui Y. Simulated microgravity altered the gene expression profiles and inhibited the proliferation of Kupffer cells in the early phase by downregulating LMO2 and EZH2. LIFE SCIENCES IN SPACE RESEARCH 2024; 40:21-34. [PMID: 38245345 DOI: 10.1016/j.lssr.2023.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 09/30/2023] [Accepted: 11/08/2023] [Indexed: 01/22/2024]
Abstract
Microgravity is a primary challenge that need to overcome, when human travel to space. Our study provided evidence that Kupffer cells (KCs) are sensitive to simulated microgravity (SMG), and no similar research report has been found in the literature. Using transcriptome sequencing technology, it was showed that 631 genes were upregulated and 801 genes were downregulated in KCs after treatment under SMG for 3 days. The GO analysis indicated that the proliferation of KCs was affected when exposed to SMG for 3 days. CCK-8 assay confirmed that the proliferation of KCs was inhibited in the third day under the environment of SMG. Furthermore, we identified 8 key genes that affect the proliferation of KCs and predicted 2 transcription factors (TFs) that regulate the 8 key genes. Significantly, we found that microgravity could affect the expression of LMO2 and EZH2 to reduce the transcription of Racgap1, Ccna2, Nek2, Aurka, Plk1, Haus4, Cdc20, Bub1b, which resulting in the reduction in KCs proliferation. These finding suggested that the inhibition of KCs proliferation under microgravity may influence the homeostasis of liver, and LMO2 and EZH2 can be the targets in management of KCs' disturbance in the future practice of space medicine.
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Affiliation(s)
- Jun Ge
- Department of General Surgery, The 306th Hospital of PLA-Peking University Teaching Hospital, Beijing, 100101, China
| | - Yuan Yue
- Department of General Surgery, The 306th Hospital of PLA-Peking University Teaching Hospital, Beijing, 100101, China
| | - Hong-Yun Nie
- Department of General Surgery, The 306th Hospital of PLA-Peking University Teaching Hospital, Beijing, 100101, China
| | - Kai-Ge Liu
- Department of General Surgery, Strategic Support Force Medical Center, Beijing, 100101, China
| | - Hao Li
- Department of General Surgery, Strategic Support Force Medical Center, Beijing, 100101, China.
| | - Hai-Guan Lin
- Department of General Surgery, Strategic Support Force Medical Center, Beijing, 100101, China
| | - Tao Zhang
- Department of General Surgery, Strategic Support Force Medical Center, Beijing, 100101, China
| | - Hong-Feng Yan
- Department of General Surgery, Strategic Support Force Medical Center, Beijing, 100101, China
| | - Hong-Wei Sun
- Department of General Surgery, Strategic Support Force Medical Center, Beijing, 100101, China
| | - Jian-Wu Yang
- Department of General Surgery, Strategic Support Force Medical Center, Beijing, 100101, China
| | - Jin-Lian Zhou
- Department of Pathology, Strategic Support Force Medical Center, Beijing, 100101, China
| | - Yan Cui
- Department of General Surgery, The 306th Hospital of PLA-Peking University Teaching Hospital, Beijing, 100101, China; Department of General Surgery, Strategic Support Force Medical Center, Beijing, 100101, China.
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12
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Ortega-Ribera M, Babuta M, Szabo G. Sinusoidal cell interactions—From soluble factors to exosomes. SINUSOIDAL CELLS IN LIVER DISEASES 2024:23-52. [DOI: 10.1016/b978-0-323-95262-0.00002-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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13
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Shalaby N, Samocha-Bonet D, Kaakoush NO, Danta M. The Role of the Gastrointestinal Microbiome in Liver Disease. Pathogens 2023; 12:1087. [PMID: 37764895 PMCID: PMC10536540 DOI: 10.3390/pathogens12091087] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/14/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023] Open
Abstract
Liver disease is a major global health problem leading to approximately two million deaths a year. This is the consequence of a number of aetiologies, including alcohol-related, metabolic-related, viral infection, cholestatic and immune disease, leading to fibrosis and, eventually, cirrhosis. No specific registered antifibrotic therapies exist to reverse liver injury, so current treatment aims at managing the underlying factors to mitigate the development of liver disease. There are bidirectional feedback loops between the liver and the rest of the gastrointestinal tract via the portal venous and biliary systems, which are mediated by microbial metabolites, specifically short-chain fatty acids (SCFAs) and secondary bile acids. The interaction between the liver and the gastrointestinal microbiome has the potential to provide a novel therapeutic modality to mitigate the progression of liver disease and its complications. This review will outline our understanding of hepatic fibrosis, liver disease, and its connection to the microbiome, which may identify potential therapeutic targets or strategies to mitigate liver disease.
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Affiliation(s)
- Nicholas Shalaby
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, St Vincent’s Healthcare Campus, Darlinghurst, NSW 2010, Australia
| | - Dorit Samocha-Bonet
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, St Vincent’s Healthcare Campus, Darlinghurst, NSW 2010, Australia
- Clinical Insulin Resistance Group, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
| | - Nadeem O. Kaakoush
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW 2033, Australia
| | - Mark Danta
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, St Vincent’s Healthcare Campus, Darlinghurst, NSW 2010, Australia
- Department of Gastroenterology and Hepatology, St Vincent’s Hospital, Darlinghurst, NSW 2010, Australia
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14
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Ono M, Watari S, Nishizawa-Higashi M, Konishi T, Takahashi Y, Saeki H, Joe GH. Water-soluble protein from walleye pollock ( Gadus chalcogrammus) suppresses lipopolysaccharide-induced inflammation by attenuating TLR4-MyD88 expression in macrophages. FOOD CHEMISTRY. MOLECULAR SCIENCES 2023; 6:100165. [PMID: 36891454 PMCID: PMC9988394 DOI: 10.1016/j.fochms.2023.100165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/27/2023] [Accepted: 02/03/2023] [Indexed: 02/09/2023]
Abstract
Water-soluble protein (WSP) from fish meat is abundant in the waste effluent generated via the surimi manufacturing process. This study investigated the anti-inflammatory effects and mechanisms of fish WSP using primary macrophages (MΦ) and animal ingestion. MΦ were treated with digested-WSP (d-WSP, 500 µg/mL) with or without lipopolysaccharide (LPS) stimulation. For the ingestion study, male ICR mice (5 weeks old) were fed 4% WSP for 14 days following LPS administration (4 mg/kg body weight). d-WSP decreased the expression of Tlr4, an LPS receptor. Additionally, d-WSP significantly suppressed the secretion of inflammatory cytokines, phagocytic ability, and Myd88 and Il1b expressions of LPS-stimulated macrophages. Furthermore, the ingestion of 4% WSP attenuated not only LPS-induced IL-1β secretion in the blood but also Myd88 and Il1b expressions in the liver. Thus, fish WSP decreases the expressions of the genes involved in the TLR4-MyD88 pathway in MΦ and the liver, thereby suppressing inflammation.
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Key Words
- 2Me, 2-mercaptoethanol
- Anti-inflammation
- Aq, aqua
- E. coli, Escherichia coli
- ELISA, Enzyme-linked immunosorbent assay
- FBS, Fetal bovine serum
- Fish water-soluble protein
- IL-1β, Interleukin 1 beta
- IL-6, Interleukin 6
- LBP, Lipopolysaccharide-binding protein
- LPS
- LPS, Lipopolysaccharide
- Macrophage
- MyD88
- MyD88, Myeloid differentiation primary response 88
- NCDs, Noncommunicable diseases
- NF-κB, Nuclear factor-kappa B
- NLRP3, NACHT, LRR, and PYD domain-containing protein 3
- PBS, Phosphate-buffered saline
- PCR, Polymerase chain reaction
- SDS, Sodium dodecyl sulfate
- TICAM-1, Toll-like receptor adaptor molecule 1
- TLR, Toll-like receptor
- TLR4
- TLR4, Toll-like receptor 4
- TNF-α, Tumor necrosis factor-alpha
- TNFR, Tumor necrosis factor receptor
- TRIF, TIR-domain–containing adapter-inducing interferon-beta
- WSP, Water-soluble protein
- d-WSP, digested water-soluble protein
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Affiliation(s)
- Masataka Ono
- Faculty of Fisheries Sciences, Hokkaido University, Minato 3, Hakodate, Hokkaido 041-8611, Japan
- Central Research Institute, Maruha Nichiro Corporation, 16-2, Wadai, Tsukuba, Ibaraki 300-4295, Japan
| | - Satomi Watari
- Faculty of Fisheries Sciences, Hokkaido University, Minato 3, Hakodate, Hokkaido 041-8611, Japan
| | - Mizuho Nishizawa-Higashi
- Central Research Institute, Maruha Nichiro Corporation, 16-2, Wadai, Tsukuba, Ibaraki 300-4295, Japan
| | - Tatsuya Konishi
- Central Research Institute, Maruha Nichiro Corporation, 16-2, Wadai, Tsukuba, Ibaraki 300-4295, Japan
| | - Yoshinori Takahashi
- Central Research Institute, Maruha Nichiro Corporation, 16-2, Wadai, Tsukuba, Ibaraki 300-4295, Japan
| | - Hiroki Saeki
- Faculty of Fisheries Sciences, Hokkaido University, Minato 3, Hakodate, Hokkaido 041-8611, Japan
| | - Ga-Hyun Joe
- Faculty of Fisheries Sciences, Hokkaido University, Minato 3, Hakodate, Hokkaido 041-8611, Japan
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15
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Shang LC, Wang M, Liu Y, Zhu X, Wang S. MSCs Ameliorate Hepatic IR Injury by Modulating Phenotypic Transformation of Kupffer Cells Through Drp-1 Dependent Mitochondrial Dynamics. Stem Cell Rev Rep 2023:10.1007/s12015-023-10566-6. [PMID: 37243829 DOI: 10.1007/s12015-023-10566-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/18/2023] [Indexed: 05/29/2023]
Abstract
BACKGROUND Hepatic ischemia and reperfusion (IR) injury, characterized by reactive oxygen species (ROS) production and immune disorders, leads to exogenous antigen-independent local inflammation and hepatocellular death. Mesenchymal stem cells (MSCs) have been shown to be immunomodulatory, antioxidative and contribute to liver regeneration in fulminant hepatic failure. We aimed to investigate the underlying mechanisms by which MSCs protect against liver IR injury in a mouse model. METHODS MSCs suspension was injected 30 min prior to hepatic warm IR. Primary kupffer cells (KCs) were isolated. Hepatic injury, inflammatory responses, innate immunity, KCs phenotypic polarization and mitochondrial dynamics were evaluated with or without KCs Drp-1 overexpression RESULTS: MSCs markedly ameliorated liver injury and attenuated inflammatory responses and innate immunity after liver IR injury. MSCs significantly restrained M1 phenotypic polarization but boosted M2 polarization of KCs extracted from ischemic liver, as demonstrated by lowered transcript levels of iNOS and IL-1β but raised transcript levels of Mrc-1 and Arg-1 combined with p-STAT6 up-regulation and p-STAT1 down-regulation. Moreover, MSCs inhibited KCs mitochondrial fission, as evidenced by decreased Drp1 and Dnm2 levels. We overexpressed Drp-1 in KCs which promote mitochondrial fission during IR injury. the regulation of MSCs towards KCs M1/M2 polarization was abrogated by Drp-1 overexpression after IR injury. Ultimately, in vivo Drp-1 overexpression in KCs hampered the therapeutic effects of MSCs against hepatic IR injury CONCLUSIONS: We revealed that MSCs facilitated M1-M2 phenotypic polarization through inhibiting Drp-1 dependent mitochondrial fission and further attenuated liver IR injury. These results add a new insight into regulating mechanisms of mitochondrial dynamics during hepatic IR injury and may offer novel opportunities for developing therapeutic targets to combat hepatic IR injury.
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Affiliation(s)
- Long-Cheng Shang
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu Province, China
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Man Wang
- Department of Hematology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yang Liu
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu Province, China
| | - Xinhua Zhu
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu Province, China.
| | - Shuai Wang
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu Province, China.
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
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16
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Shao M, Wang Y, Dong H, Wang L, Zhang X, Han X, Sang X, Bao Y, Peng M, Cao G. From liver fibrosis to hepatocarcinogenesis: Role of excessive liver H2O2 and targeting nanotherapeutics. Bioact Mater 2023; 23:187-205. [PMID: 36406254 PMCID: PMC9663332 DOI: 10.1016/j.bioactmat.2022.11.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 10/23/2022] [Accepted: 11/06/2022] [Indexed: 11/13/2022] Open
Abstract
Liver fibrosis and hepatocellular carcinoma (HCC) have been worldwide threats nowadays. Liver fibrosis is reversible in early stages but will develop precancerosis of HCC in cirrhotic stage. In pathological liver, excessive H2O2 is generated and accumulated, which impacts the functionality of hepatocytes, Kupffer cells (KCs) and hepatic stellate cells (HSCs), leading to genesis of fibrosis and HCC. H2O2 accumulation is associated with overproduction of superoxide anion (O2•−) and abolished antioxidant enzyme systems. Plenty of therapeutics focused on H2O2 have shown satisfactory effects against liver fibrosis or HCC in different ways. This review summarized the reasons of liver H2O2 accumulation, and the role of H2O2 in genesis of liver fibrosis and HCC. Additionally, nanotherapeutics targeting H2O2 were summarized for further consideration of antifibrotic or antitumor therapy.
Liver fibrosis and HCC are closely related because ROS induced liver damage and inflammation, especially over-cumulated H2O2. Excess H2O2 diffusion in pathological liver was due to increased metabolic rate and diminished cellular antioxidant systems. Freely diffused H2O2 damaged liver-specific cells, thereby leading to fibrogenesis and hepatocarcinogenesis. Nanotherapeutics targeting H2O2 are summarized for treatment of liver fibrosis and HCC, and also challenges are proposed.
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17
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Drummer C, Saaoud F, Jhala NC, Cueto R, Sun Y, Xu K, Shao Y, Lu Y, Shen H, Yang L, Zhou Y, Yu J, Wu S, Snyder NW, Hu W, Zhuo J‘J, Zhong Y, Jiang X, Wang H, Yang X. Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages. Front Immunol 2023; 14:1113883. [PMID: 36776889 PMCID: PMC9909353 DOI: 10.3389/fimmu.2023.1113883] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/06/2023] [Indexed: 01/27/2023] Open
Abstract
Introduction Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% of the population and is a leading cause of cirrhosis and hepatocellular carcinoma. NAFLD ranges from simple steatosis (non-alcoholic fatty liver) to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs) and monocyte-derived macrophages, act as key players in the progression of NAFLD. Caspases are a family of endoproteases that provide critical connections to cell regulatory networks that sense disease risk factors, control inflammation, and mediate inflammatory cell death (pyroptosis). Caspase-11 can cleave gasdermin D (GSDMD) to induce pyroptosis and specifically defends against bacterial pathogens that invade the cytosol. However, it's still unknown whether high fat diet (HFD)-facilitated gut microbiota-generated cytoplasmic lipopolysaccharides (LPS) activate caspase-11 and promote NAFLD. Methods To examine this hypothesis, we performed liver pathological analysis, RNA-seq, FACS, Western blots, Seahorse mitochondrial stress analyses of macrophages and bone marrow transplantation on HFD-induced NAFLD in WT and Casp11-/- mice. Results and Discussion Our results showed that 1) HFD increases body wight, liver wight, plasma cholesterol levels, liver fat deposition, and NAFLD activity score (NAS score) in wild-type (WT) mice; 2) HFD increases the expression of caspase-11, GSDMD, interleukin-1β, and guanylate-binding proteins in WT mice; 3) Caspase-11 deficiency decreases fat liver deposition and NAS score; 4) Caspase-11 deficiency decreases bone marrow monocyte-derived macrophage (MDM) pyroptosis (inflammatory cell death) and inflammatory monocyte (IM) surface GSDMD expression; 5) Caspase-11 deficiency re-programs liver transcriptomes and reduces HFD-induced NAFLD; 6) Caspase-11 deficiency decreases extracellular acidification rates (glycolysis) and oxidative phosphorylation (OXPHOS) in inflammatory fatty acid palmitic acid-stimulated macrophages, indicating that caspase-11 significantly contributes to maintain dual fuel bioenergetics-glycolysis and OXPHOS for promoting pyroptosis in macrophages. These results provide novel insights on the roles of the caspase-11-GSDMD pathway in promoting hepatic macrophage inflammation and pyroptosis and novel targets for future therapeutic interventions involving the transition of NAFLD to NASH, hyperlipidemia, type II diabetes, metabolic syndrome, metabolically healthy obesity, atherosclerotic cardiovascular diseases, autoimmune diseases, liver transplantation, and hepatic cancers.
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Affiliation(s)
- Charles Drummer
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Fatma Saaoud
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Nirag C. Jhala
- Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Ramon Cueto
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Yu Sun
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Keman Xu
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Ying Shao
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Yifan Lu
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Huimin Shen
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Ling Yang
- Department of Medical Genetics and Molecular Biochemistry, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Yan Zhou
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Temple Health, Philadelphia, PA, United States
| | - Jun Yu
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Sheng Wu
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Nathaniel W. Snyder
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Wenhui Hu
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Jia ‘Joe’ Zhuo
- Tulane Hypertension & Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States
| | - Yinghui Zhong
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, United States
| | - Xiaohua Jiang
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Hong Wang
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Xiaofeng Yang
- Centers of Cardiovascular Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
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18
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Zhu L, Gong P, Liu Y, Shi Y, Wang W, Zhang W, Hu Z, Li X. A retrospective case-series of influence of chronic hepatitis B on synchronous liver metastasis of colorectal cancer. Front Oncol 2023; 13:1109464. [PMID: 36910607 PMCID: PMC9995980 DOI: 10.3389/fonc.2023.1109464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 02/14/2023] [Indexed: 02/25/2023] Open
Abstract
Main point Our retrospective analysis of a large number of cases found in patients with primary colorectal cancer (CRC) carrying positive HBsAg inhibited the occurrence of synchronous liver metastases (SLM). However, liver cirrhosis caused by non-HBV factors promoted the occurrence of SLM. Objectives This study aimed to investigate the effect of HBV on the occurrence of synchronous liver metastases (SLM) of colorectal cancer (CRC). Methods Univariate and multivariate analyses were used to analyze the influence of clinical parameters on the occurrence of SLM. Results A total of 6, 020 patients with primary CRC were included in our study, of which 449 patients carrying HBsAg(+) accounted for 7.46%. 44 cases of SLM occurred in the HBsAg(+) group, accounting for 9.80%, which was much lower than 13.6% (758/5571) in the HBsAg(-) group (X=5.214, P=0.022). Among CRC patients with HBsAg(-), the incidence of SLM was 24.9% and 14.9% in the group with high APRI and FIB-4 levels, respectively, which were significantly higher than that in the compared groups (12.3% and 12.5%, all P<0.05). Compared with the control group, female patients, late-onset patients, and HBV-infective patients had lower risks of SLM (HR=0.737, 95%CI: 0.614-0.883, P<0.001; HR=0.752, 95%CI: 0.603-0.943, P=0.013; HR=0.682, 95%CI: 0.473-0.961, P=0.034). Conclusions The carriage of HBsAg(+) status inhibited the occurrence of SLM from CRC. HBV-causing liver cirrhosis did not further influence the occurrence of SLM, whereas non-HBV-factor cirrhosis promoted the occurrence of SLM. Nevertheless, this still required prospective data validation.
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Affiliation(s)
- Lin Zhu
- Department of General Surgery, Tongji Hospital, Medical College of Tongji University, Shanghai, China
| | - Piqing Gong
- Department of Anorectal Surgery, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Ye Liu
- Department of Blood Transfusion, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Yunjie Shi
- Department of Anorectal Surgery, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Wenqiang Wang
- Department of General Surgery, Tongji Hospital, Medical College of Tongji University, Shanghai, China
| | - Wei Zhang
- Department of General Surgery, Tongji Hospital, Medical College of Tongji University, Shanghai, China
| | - Zhiqian Hu
- Department of General Surgery, Tongji Hospital, Medical College of Tongji University, Shanghai, China.,Department of Anorectal Surgery, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Xinxing Li
- Department of General Surgery, Tongji Hospital, Medical College of Tongji University, Shanghai, China
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Khodayari N, Oshins R, Aranyos AM, Duarte S, Mostofizadeh S, Lu Y, Brantly M. Characterization of hepatic inflammatory changes in a C57BL/6J mouse model of alpha1-antitrypsin deficiency. Am J Physiol Gastrointest Liver Physiol 2022; 323:G594-G608. [PMID: 36256438 DOI: 10.1152/ajpgi.00207.2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by a hepatic accumulation of mutant alpha-1 antitrypsin (ZAAT). Individuals with AATD are prone to develop a chronic liver disease that remains undiagnosed until late stage of the disease. Here, we sought to characterize the liver pathophysiology of a human transgenic mouse model for AATD with a manifestation of liver disease compared with normal transgenic mice model. Male and female transgenic mice for normal (Pi*M) and mutant variant (Pi*Z) human alpha-1 antitrypsin at 3 and 6 mo of age were subjected to this study. The progression of hepatic ZAAT accumulation, hepatocyte injury, steatosis, liver inflammation, and fibrotic features were monitored by performing an in vivo study. We have also performed a Next-Gene transcriptomic analysis of the transgenic mice liver tissue 16 h after lipopolysaccharide (LPS) administration to delineate liver inflammatory response in Pi*Z mice as compared with Pi*M. Our results show hepatic ZAAT accumulation, followed by hepatocyte ballooning and liver steatosis developed at 3 mo in Pi*Z mice compared with the mice carrying normal variant of human alpha-1 antitrypsin. We observed higher levels of hepatic immune cell infiltrations in both 3- and 6-mo-old Pi*Z mice compared with Pi*M as an indication of liver inflammation. Liver fibrosis was observed as accumulation of collagen in 6-mo-old Pi*Z liver tissues compared with Pi*M control mice. Furthermore, the transcriptomic analysis revealed a dysregulated liver immune response to LPS in Pi*Z mice compared with Pi*M. Of particular interest for translational work, this study aims to establish a mouse model of AATD with a strong manifestation of liver disease that will be a valuable in vivo tool to study the pathophysiology of AATD-mediated liver disease. Our data suggest that the human transgenic mouse model of AATD could provide a suitable model for the evaluation of therapeutic approaches and preventive reagents against AATD-mediated liver disease.NEW & NOTEWORTHY We have characterized a mouse model of human alpha-1 antitrypsin deficiency with a strong manifestation of liver disease that can be used as an in vivo tool to test preventive and therapeutic reagents. Our data explores the altered immunophenotype of alpha-1 antitrypsin-deficient liver macrophages and suggests a relationship between acute inflammation, immune response, and fibrosis.
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Affiliation(s)
- Nazli Khodayari
- Division of Pulmonary, Department of Medicine, University of Florida, Gainesville, Florida
| | - Regina Oshins
- Division of Pulmonary, Department of Medicine, University of Florida, Gainesville, Florida
| | - Alek M Aranyos
- Division of Pulmonary, Department of Medicine, University of Florida, Gainesville, Florida
| | - Sergio Duarte
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida
| | - Sayedamin Mostofizadeh
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida
| | - Yuanqing Lu
- Division of Pulmonary, Department of Medicine, University of Florida, Gainesville, Florida
| | - Mark Brantly
- Division of Pulmonary, Department of Medicine, University of Florida, Gainesville, Florida
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20
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Fodor M, Salcher S, Gottschling H, Mair A, Blumer M, Sopper S, Ebner S, Pircher A, Oberhuber R, Wolf D, Schneeberger S, Hautz T. The liver-resident immune cell repertoire - A boon or a bane during machine perfusion? Front Immunol 2022; 13:982018. [PMID: 36311746 PMCID: PMC9609784 DOI: 10.3389/fimmu.2022.982018] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/30/2022] [Indexed: 11/13/2022] Open
Abstract
The liver has been proposed as an important “immune organ” of the body, as it is critically involved in a variety of specific and unique immune tasks. It contains a huge resident immune cell repertoire, which determines the balance between tolerance and inflammation in the hepatic microenvironment. Liver-resident immune cells, populating the sinusoids and the space of Disse, include professional antigen-presenting cells, myeloid cells, as well as innate and adaptive lymphoid cell populations. Machine perfusion (MP) has emerged as an innovative technology to preserve organs ex vivo while testing for organ quality and function prior to transplantation. As for the liver, hypothermic and normothermic MP techniques have successfully been implemented in clinically routine, especially for the use of marginal donor livers. Although there is evidence that ischemia reperfusion injury-associated inflammation is reduced in machine-perfused livers, little is known whether MP impacts the quantity, activation state and function of the hepatic immune-cell repertoire, and how this affects the inflammatory milieu during MP. At this point, it remains even speculative if liver-resident immune cells primarily exert a pro-inflammatory and hence destructive effect on machine-perfused organs, or in part may be essential to induce liver regeneration and counteract liver damage. This review discusses the role of hepatic immune cell subtypes during inflammatory conditions and ischemia reperfusion injury in the context of liver transplantation. We further highlight the possible impact of MP on the modification of the immune cell repertoire and its potential for future applications and immune modulation of the liver.
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Affiliation(s)
- M. Fodor
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - S. Salcher
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - H. Gottschling
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A. Mair
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - M. Blumer
- Department of Anatomy and Embryology, Medical University of Innsbruck, Innsbruck, Austria
| | - S. Sopper
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - S. Ebner
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A. Pircher
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - R. Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - D. Wolf
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - S. Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - T. Hautz
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- *Correspondence: T. Hautz,
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21
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Mills JA, Liu F, Jarrett TR, Fletcher NL, Thurecht KJ. Nanoparticle based medicines: approaches for evading and manipulating the mononuclear phagocyte system and potential for clinical translation. Biomater Sci 2022; 10:3029-3053. [PMID: 35419582 DOI: 10.1039/d2bm00181k] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
For decades, nanomedicines have been reported as a potential means to overcome the limitations of conventional drug delivery systems by reducing side effects, toxicity and the non-ideal pharmacokinetic behaviour typically exhibited by small molecule drugs. However, upon administration many nanoparticles prompt induction of host inflammatory responses due to recognition and uptake by macrophages, eliminating up to 95% of the administered dose. While significant advances in nanoparticle engineering and consequent therapeutic efficacy have been made, it is becoming clear that nanoparticle recognition by the mononuclear phagocyte system (MPS) poses an impassable junction in the current framework of nanoparticle development. Hence, this has negative consequences on the clinical translation of nanotechnology with respect to therapeutic efficacy, systemic toxicity and economic benefit. In order to improve the translation of nanomedicines from bench-to-bedside, there is a requirement to either modify nanomedicines in terms of how they interact with intrinsic processes in the body, or modulate the body to be more accommodating for nanomedicine treatments. Here we provide an overview of the current standard for design elements of nanoparticles, as well as factors to consider when producing nanomedicines that have minimal MPS-nanoparticle interactions; we explore this landscape across the cellular to tissue and organ levels. Further, rather than designing materials to suit the body, a growing research niche involves modulating biological responses to administered nanomaterials. We here discuss how developing strategic methods of MPS 'pre-conditioning' with small molecule or biological drugs, as well as implementing strategic dosing regimens, such as 'decoy' nanoparticles, is essential to increasing nanoparticle therapeutic efficacy. By adopting such a perspective, we hope to highlight the increasing trends in research dedicated to improving nanomedicine translation, and subsequently making a positive clinical impact.
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Affiliation(s)
- Jessica A Mills
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia. .,Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD 4072, Australia.,ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australia
| | - Feifei Liu
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia. .,Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD 4072, Australia.,ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australia.,ARC Centre for Innovation in Biomedical Imaging Technology, Australia
| | - Thomas R Jarrett
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia. .,Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD 4072, Australia.,ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australia.,ARC Centre for Innovation in Biomedical Imaging Technology, Australia
| | - Nicholas L Fletcher
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia. .,Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD 4072, Australia.,ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australia
| | - Kristofer J Thurecht
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia. .,Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD 4072, Australia.,ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australia.,ARC Centre for Innovation in Biomedical Imaging Technology, Australia
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22
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Gupta A, Andresen JL, Manan RS, Langer R. Nucleic acid delivery for therapeutic applications. Adv Drug Deliv Rev 2021; 178:113834. [PMID: 34492233 DOI: 10.1016/j.addr.2021.113834] [Citation(s) in RCA: 173] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/25/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023]
Abstract
Recent medical advances have exploited the ability to address a given disease at the underlying level of transcription and translation. These treatment paradigms utilize nucleic acids - including short interfering RNA (siRNA), microRNA (miRNA), antisense oligonucleotides (ASO), and messenger RNA (mRNA) - to achieve a desired outcome ranging from gene knockdown to induced expression of a selected target protein. Towards this end, numerous strategies for encapsulation or stabilization of various nucleic acid structures have been developed in order to achieve intracellular delivery. In this review, we discuss several therapeutic applications of nucleic acids directed towards specific diseases and tissues of interest, in particular highlighting recent technologies which have reached late-stage clinical trials and received FDA approval.
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Affiliation(s)
- Akash Gupta
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA
| | - Jason L Andresen
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Rajith S Manan
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Robert Langer
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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23
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Al Ojaimi Y, Blin T, Lamamy J, Gracia M, Pitiot A, Denevault-Sabourin C, Joubert N, Pouget JP, Gouilleux-Gruart V, Heuzé-Vourc'h N, Lanznaster D, Poty S, Sécher T. Therapeutic antibodies - natural and pathological barriers and strategies to overcome them. Pharmacol Ther 2021; 233:108022. [PMID: 34687769 PMCID: PMC8527648 DOI: 10.1016/j.pharmthera.2021.108022] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 02/06/2023]
Abstract
Antibody-based therapeutics have become a major class of therapeutics with over 120 recombinant antibodies approved or under review in the EU or US. This therapeutic class has experienced a remarkable expansion with an expected acceleration in 2021-2022 due to the extraordinary global response to SARS-CoV2 pandemic and the public disclosure of over a hundred anti-SARS-CoV2 antibodies. Mainly delivered intravenously, alternative delivery routes have emerged to improve antibody therapeutic index and patient comfort. A major hurdle for antibody delivery and efficacy as well as the development of alternative administration routes, is to understand the different natural and pathological barriers that antibodies face as soon as they enter the body up to the moment they bind to their target antigen. In this review, we discuss the well-known and more under-investigated extracellular and cellular barriers faced by antibodies. We also discuss some of the strategies developed in the recent years to overcome these barriers and increase antibody delivery to its site of action. A better understanding of the biological barriers that antibodies have to face will allow the optimization of antibody delivery near its target. This opens the way to the development of improved therapy with less systemic side effects and increased patients' adherence to the treatment.
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Affiliation(s)
- Yara Al Ojaimi
- UMR 1253, iBrain, Inserm, 37000 Tours, France; University of Tours, 37000 Tours, France
| | - Timothée Blin
- University of Tours, 37000 Tours, France; UMR 1100, CEPR, Inserm, 37000 Tours, France
| | - Juliette Lamamy
- University of Tours, 37000 Tours, France; GICC, EA7501, 37000 Tours, France
| | - Matthieu Gracia
- Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier F-34298, France
| | - Aubin Pitiot
- University of Tours, 37000 Tours, France; UMR 1100, CEPR, Inserm, 37000 Tours, France
| | | | - Nicolas Joubert
- University of Tours, 37000 Tours, France; GICC, EA7501, 37000 Tours, France
| | - Jean-Pierre Pouget
- Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier F-34298, France
| | | | | | - Débora Lanznaster
- UMR 1253, iBrain, Inserm, 37000 Tours, France; University of Tours, 37000 Tours, France
| | - Sophie Poty
- Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier F-34298, France
| | - Thomas Sécher
- University of Tours, 37000 Tours, France; UMR 1100, CEPR, Inserm, 37000 Tours, France
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24
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Castro ANC, Díaz MC, Mendoza Torres GJ, Moreno Burgos B, Zanuzzi C, Illia MC, Lendez PA, Carril J, Ghezzi MD, Bodiola Diez JJ, Barbeito CG. Patterns of proliferation and cell differentiation during hepatic ontogeny in the alpaca. Tissue Cell 2021; 71:101589. [PMID: 34274592 DOI: 10.1016/j.tice.2021.101589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/28/2021] [Accepted: 06/29/2021] [Indexed: 10/21/2022]
Abstract
The liver has multiple functions that change throughout ontogeny. South American camelids (SAC) have unique characteristics related to adaptation to extreme environments and metabolism. However, the process of hepatic cell differentiation has not been studied in any SAC. We study the patterns of cell differentiation and proliferation in the liver of the alpaca at different times of the ontogeny, excluding the hematopoietic components. Immunohistochemical techniques were performed in 66 specimens, including embryos, fetuses, neonates and adults. Supplementary analyses were performed by lectinhistochemistry. The hepatocytic differentiation was performed by the identification of Hepatocyte (Clone: OCH1ES Dako®). It began in the specimens of 1.8-2.5 cm of crown to rump length (CRL), from Days 25-29 (ovulation = Day 0), continued during gestation and intensified towards its end. The cholangiocytic differentiation was performed by the identification of cytokeratin 7 (CK7, Dako®). It was manifested at the final of gestation (specimens of 28.4 cm CRL, from Day 223 onwards). Parenchymal cells underwent a process of gradual differentiation (differentiation of hepatocytes preceded that of cholangiocytes). Cell proliferation was observed along gestation using the nuclear proliferation antigen (PCNA) and Ki-67. Hepatic organogenesis in the alpacas shares similar differentiation and proliferation mechanisms with other altricial, but phylogenetically distant, species.
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Affiliation(s)
- A N C Castro
- Laboratorio de Anatomía, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario (7000), Tandil, Buenos Aires, Argentina
| | - M C Díaz
- Laboratorio de Embriología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario (7000), Tandil, Buenos Aires, Argentina
| | - G J Mendoza Torres
- Laboratorio de Anatomía, Facultad de Veterinaria y Zootecnia, Universidad Peruana Cayetano Heredia, Av. Honorio Delgado 430, Distrito San Martín de Porres, Lima, Perú
| | - B Moreno Burgos
- Departamento de Patología Animal, Facultad de Veterinaria, Universidad de Zaragoza, Av. Miguel Servet 177, Zaragoza, España
| | - C Zanuzzi
- Laboratorio de Histología y Embriología Descriptiva, Experimental y Comparada. Facultad de Ciencias Veterinarias, CONICET, Universidad Nacional de La Plata, Calle 60 y 118, La Plata, 1900, Argentina
| | - M Carrica Illia
- Laboratorio de Anatomía, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario (7000), Tandil, Buenos Aires, Argentina
| | - P A Lendez
- Laboratorio de Anatomía, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario (7000), Tandil, Buenos Aires, Argentina
| | - J Carril
- Laboratorio de Histología y Embriología Descriptiva, Experimental y Comparada. Facultad de Ciencias Veterinarias, CONICET, Universidad Nacional de La Plata, Calle 60 y 118, La Plata, 1900, Argentina
| | - M D Ghezzi
- Laboratorio de Anatomía, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario (7000), Tandil, Buenos Aires, Argentina
| | - J J Bodiola Diez
- Departamento de Patología Animal, Facultad de Veterinaria, Universidad de Zaragoza, Av. Miguel Servet 177, Zaragoza, España
| | - C G Barbeito
- Laboratorio de Histología y Embriología Descriptiva, Experimental y Comparada. Facultad de Ciencias Veterinarias, CONICET, Universidad Nacional de La Plata, Calle 60 y 118, La Plata, 1900, Argentina.
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25
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Deprez J, Lajoinie G, Engelen Y, De Smedt SC, Lentacker I. Opening doors with ultrasound and microbubbles: Beating biological barriers to promote drug delivery. Adv Drug Deliv Rev 2021; 172:9-36. [PMID: 33705877 DOI: 10.1016/j.addr.2021.02.015] [Citation(s) in RCA: 130] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 02/01/2021] [Accepted: 02/17/2021] [Indexed: 12/13/2022]
Abstract
Apart from its clinical use in imaging, ultrasound has been thoroughly investigated as a tool to enhance drug delivery in a wide variety of applications. Therapeutic ultrasound, as such or combined with cavitating nuclei or microbubbles, has been explored to cross or permeabilize different biological barriers. This ability to access otherwise impermeable tissues in the body makes the combination of ultrasound and therapeutics very appealing to enhance drug delivery in situ. This review gives an overview of the most important biological barriers that can be tackled using ultrasound and aims to provide insight on how ultrasound has shown to improve accessibility as well as the biggest hurdles. In addition, we discuss the clinical applicability of therapeutic ultrasound with respect to the main challenges that must be addressed to enable the further progression of therapeutic ultrasound towards an effective, safe and easy-to-use treatment tailored for drug delivery in patients.
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Affiliation(s)
- J Deprez
- Ghent Research Group on Nanomedicines, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - G Lajoinie
- Physics of Fluids Group, MESA+ Institute for Nanotechnology and Technical Medical (TechMed) Center, University of Twente, P.O. Box 217, 7500 AE Enschede, Netherlands
| | - Y Engelen
- Ghent Research Group on Nanomedicines, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - S C De Smedt
- Ghent Research Group on Nanomedicines, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
| | - I Lentacker
- Ghent Research Group on Nanomedicines, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
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26
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Malta KK, Silva TP, Palazzi C, Neves VH, Carmo LAS, Cardoso SJ, Melo RCN. Changing our view of the Schistosoma granuloma to an ecological standpoint. Biol Rev Camb Philos Soc 2021; 96:1404-1420. [PMID: 33754464 DOI: 10.1111/brv.12708] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 12/27/2022]
Abstract
Schistosomiasis, a neglected parasitic tropical disease that has plagued humans for centuries, remains a major public health burden. A primary challenge to understanding schistosomiasis is deciphering the most remarkable pathological feature of this disease, the granuloma - a highly dynamic and self-organized structure formed by both host and parasite components. Granulomas are considered a remarkable example of how parasites evolved with their hosts to establish complex and intimate associations. However, much remains unclear regarding life within the granuloma, and strategies to restrain its development are still lacking. Here we explore current information on the hepatic Schistosoma mansoni granuloma in the light of Ecology and propose that this intricate structure acts as a real ecosystem. The schistosomal granuloma is formed by cells (biotic component), protein scaffolds, fibres, and chemical compounds (abiotic components) with inputs/outputs of energy and matter, as complex as in classical ecosystems. We review the distinct cell populations ('species') within the granuloma and examine how they integrate with each other and interact with their microenvironment to form a multifaceted cell community in different space-time frames. The colonization of the hepatic tissue to form granulomas is explained from the point of view of an ecological succession whereby a community is able to modify its physical environment, creating conditions and resources for ecosystem construction. Remarkably, the granuloma represents a dynamic evolutionary system that undergoes progressive changes in the 'species' that compose its community over time. In line with ecological concepts, we examine the granuloma not only as a place where a community of cells is settled (spatial niche or habitat) but also as a site in which the functional activities of these combined populations occur in an orchestrated way in response to microenvironmental gradients such as cytokines and egg antigens. Finally, we assert how the levels of organization of cellular components in a granuloma as conventionally defined by Cell Biology can fit perfectly into a hierarchical structure of biological systems as defined by Ecology. By rethinking the granuloma as an integrating and evolving ecosystem, we draw attention to the inner workings of this structure that are central to the understanding of schistosomiasis and could guide its future treatment.
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Affiliation(s)
- Kássia K Malta
- Laboratory of Cellular Biology, Department of Biology, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, São Pedro, Juiz de Fora, MG, 36036-900, Brazil.,Graduate Program in Biodiversity, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, São Pedro, Juiz de Fora, MG, 36036-900, Brazil
| | - Thiago P Silva
- Laboratory of Cellular Biology, Department of Biology, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, São Pedro, Juiz de Fora, MG, 36036-900, Brazil.,Graduate Program in Biodiversity, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, São Pedro, Juiz de Fora, MG, 36036-900, Brazil
| | - Cinthia Palazzi
- Laboratory of Cellular Biology, Department of Biology, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, São Pedro, Juiz de Fora, MG, 36036-900, Brazil.,Graduate Program in Cell Biology, Federal University of Minas Gerais, Belo Horizonte, Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG, 31270-901, Brazil
| | - Vitor H Neves
- Laboratory of Cellular Biology, Department of Biology, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, São Pedro, Juiz de Fora, MG, 36036-900, Brazil.,Graduate Program in Cell Biology, Federal University of Minas Gerais, Belo Horizonte, Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG, 31270-901, Brazil
| | - Lívia A S Carmo
- Laboratory of Cellular Biology, Department of Biology, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, São Pedro, Juiz de Fora, MG, 36036-900, Brazil.,Department of Medicine, Federal University of Alagoas, Rodovia AL-115, Bom Sucesso, Arapiraca, AL, 57309-005, Brazil
| | - Simone J Cardoso
- Graduate Program in Biodiversity, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, São Pedro, Juiz de Fora, MG, 36036-900, Brazil.,Laboratory of Plankton Ecology, Department of Zoology, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, São Pedro, Juiz de Fora, MG, 36036-900, Brazil
| | - Rossana C N Melo
- Laboratory of Cellular Biology, Department of Biology, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, São Pedro, Juiz de Fora, MG, 36036-900, Brazil.,Graduate Program in Biodiversity, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, São Pedro, Juiz de Fora, MG, 36036-900, Brazil.,Graduate Program in Cell Biology, Federal University of Minas Gerais, Belo Horizonte, Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG, 31270-901, Brazil
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27
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Zhang W, Liu Z, Xu X. Navigating immune cell immunometabolism after liver transplantation. Crit Rev Oncol Hematol 2021; 160:103227. [PMID: 33675906 DOI: 10.1016/j.critrevonc.2021.103227] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 12/18/2020] [Accepted: 01/16/2021] [Indexed: 11/15/2022] Open
Abstract
Liver transplantation (LT) is the most effective treatment for end-stage liver diseases. The immunometabolism microenvironment undergoes massive changes at the interface of immune functionalities and metabolic regulations after LT. These changes considerably modify post-transplant complications, and immune cells play an influential role in the hepatic immunometabolism microenvironment after LT. Therefore, adequate studies on the complex pathobiology of immune cells are critical to prevent post-transplant complications, and the interplay between cellular metabolism and immune function is evident. Furthermore, immune cells perform their specified functions, such as activation or differentiation, accompanied by alterations in metabolic pathways, such as metabolic reprogramming. This transformation remarkably affects post-transplant complications like rejection. By targeting different metabolic pathways, regulations of metabolism are employed to shape immune responses. These differences of metabolic pathways allow for selective regulation of immune responses to further develop effective therapies that prevent graft loss after LT. This review examines immune cells in the hepatic immunometabolism microenvironment after LT, summarizes possible mechanisms and potential prevention on rejection to acquire immune tolerance, and offers some insight into references for scientific research along with clinical treatment.
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Affiliation(s)
- Wenhui Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang University Cancer Center, Hangzhou 310058, China
| | - Zhikun Liu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang University Cancer Center, Hangzhou 310058, China.
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28
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Liu R, Kong W, Deng M, Lin G, Dai T, Ye L. Association between hepatitis B virus infection and colorectal liver metastasis: a meta-analysis. Bioengineered 2021; 12:736-744. [PMID: 33629626 PMCID: PMC8291855 DOI: 10.1080/21655979.2021.1890871] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The paper aims to assess the association between Hepatitis B Virus infection and colorectal liver metastasis by conducting a meta-analysis. The relevant studies were searched until 24 July 2020, Studies that assessed the correlation between HBV infection and CRLM were recruited. A random effects model was applied to calculate the odds ratio (OR) with 95% confidence interval (CI). All data analyses were performed by STATA 12.0 software. Ten studies involving 17529 participants were included in the study. The results shown that there was obvious association between HBV infection and CRLM (OR: 0.51, 95% CI: 0.28–0.91). The study type and case–control rate may be the main causes of heterogeneity. In addition, HBV infection had no association with extrahepatic metastasis or prognosis of patients with CRLM. Sensitivity analyses confirmed that the results were stable, and Egg’s test indicated that there was no publication bias. Patients with HBV infection have the reduced risk of CRLM.
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Affiliation(s)
- Rongqiang Liu
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Weihao Kong
- Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Mingbin Deng
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Guozhen Lin
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Tianxing Dai
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Linsen Ye
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Psaila AM, Vohralik EJ, Quinlan KGR. Shades of white: new insights into tissue-resident leukocyte heterogeneity. FEBS J 2021; 289:308-318. [PMID: 33513286 DOI: 10.1111/febs.15737] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 01/20/2021] [Accepted: 01/27/2021] [Indexed: 12/13/2022]
Abstract
Populations of white blood cells (leukocytes) have been found in tissues and organs across the body, in states of both health and disease. The role leukocytes play within these tissues is often highly contested. For many leukocytes, there are studies outlining pro-inflammatory destructive functions, while other studies provide clear evidence of anti-inflammatory homeostatic activities of leukocytes within the same tissue. We discuss how this functional dissonance can be explained by leukocyte heterogeneity. Although cell morphology and surface receptor profiles are excellent methods to segregate cell types, the true degree of leukocyte heterogeneity that exists can only be appreciated by studying the variable and dynamic gene expression profile. Unbiased single-cell RNA sequencing profiling of tissue-resident leukocytes is transforming the way we understand leukocytes across health and disease. Recent investigations into adipose tissue-resident leukocytes have revealed unprecedented levels of heterogeneity among populations of macrophages. We use this example to pose emerging questions regarding tissue-resident leukocytes and review what is currently known (and unknown) about the diversity of tissue-resident leukocytes within different organs.
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Affiliation(s)
- Annalise M Psaila
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, NSW, Australia
| | - Emily J Vohralik
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, NSW, Australia
| | - Kate G R Quinlan
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, NSW, Australia
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Endriß KJ, Meyerholz MM, Fischbach T, Brimmers L, Pfarrer C, Marth CD, Schmicke M. In vitro effects of Type I interferons (IFNτ and IFNα) on bovine hepatocytes cultured with or without Kupffer cells. Reprod Fertil Dev 2021; 33:305-317. [PMID: 33573713 DOI: 10.1071/rd20278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 12/17/2020] [Indexed: 12/12/2022] Open
Abstract
In cattle, maternal recognition of early pregnancy depends on the effects of the embryonic signal interferon (IFN)-τ. IFN-stimulated genes have been upregulated in the maternal liver during early pregnancy. In this study, primary hepatocyte cell culture models were evaluated for their suitability to test Type I IFN effects invitro. The expression of target genes (interferon-stimulated gene 15 (ISG-15), interferon-induced GTP-binding protein (MX-1), C-X-C motif chemokine 10 (CXCL-10), CXCL-5, insulin-like growth factor 1 (IGF-1), IGF binding protein 2 (IGFBP-2)) was measured using reverse transcription-quantitative polymerase chain reaction in hepatocytes from monoculture or in indirect coculture with Kupffer cells (HKCid) on Days 1, 2, 3 and 4 of culture (n=21 donor cows). Gene expression was also measured on Day 4 after challenging the cultures with recombinant IFNτ, IFNα, progesterone (P4), IFNτ+IFNα or IFNτ+P4 for 6h. A significant increase in the mRNA expression of target genes in hepatocytes was shown in response to stimulation with IFNτ. The Kupffer cells in coculture did not influence the effects of IFNτ in hepatocytes. In conclusion, primary bovine hepatocyte cultures are suitable for stimulation experiments with Type I IFNs and as an extrauterine model for embryo-maternal communication. The proposed endocrine action of IFNτ in the liver may affect maternal metabolism and immune function in the liver.
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Affiliation(s)
- Kai Josef Endriß
- University of Veterinary Medicine Hanover, Clinic for Cattle, Endocrinology, Bischofsholer Damm 15, 30539 Hanover, Germany
| | - Marie Margarete Meyerholz
- Clinic for Ruminants with Ambulatory and Herd Health Services, Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-University Munich, Sonnenstraße 16, 85764 Oberschleißheim, Germany
| | - Teresa Fischbach
- University of Veterinary Medicine Hanover, Clinic for Cattle, Endocrinology, Bischofsholer Damm 15, 30539 Hanover, Germany
| | - Lutz Brimmers
- University of Veterinary Medicine Hanover, Clinic for Cattle, Endocrinology, Bischofsholer Damm 15, 30539 Hanover, Germany
| | - Christiane Pfarrer
- University of Veterinary Medicine Hanover, Anatomy, Bischofsholer Damm 15, 30539 Hanover, Germany
| | - Christina Deborah Marth
- Melbourne Veterinary School, The University of Melbourne, 250 Princes Highway, Werribee, Vic. 3030, Australia
| | - Marion Schmicke
- University of Veterinary Medicine Hanover, Clinic for Cattle, Endocrinology, Bischofsholer Damm 15, 30539 Hanover, Germany; and Martin-Luther University Halle-Wittenberg, Faculty of Natural Sciences III, Institute of Agricultural and Nutritional Sciences, Animal Health Management, Theodor-Lieser-Straße 11, 06120 Halle, Germany; and Corresponding author.
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31
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Li Y, Li S, Duan X, Yang C, Xu M, Chen L. Macrophage Phenotypes and Hepatitis B Virus Infection. J Clin Transl Hepatol 2020; 8:424-431. [PMID: 33447526 PMCID: PMC7782119 DOI: 10.14218/jcth.2020.00046] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 08/20/2020] [Accepted: 09/06/2020] [Indexed: 12/14/2022] Open
Abstract
Globally, hepatitis B virus (HBV) infection and its related liver diseases account for 780,000 deaths every year. Outcomes of HBV infection depend on the interaction between the virus and host immune system. It is becoming increasingly apparent that Kupffer cells (KCs), the largest population of resident and monocyte-derived macrophages in the liver, contribute to HBV infection in various aspects. These cells play an important role not only in the anti-HBV immunity including virus recognition, cytokine production to directly inhibit viral replication and recruitment and activation of other immune cells involved in virus clearance but also in HBV outcome and progression, such as persistent infection and development of end-stage liver diseases. Since liver macrophages play multiple roles in HBV infection, they are directly targeted by HBV to benefit its life cycle. In the present review, we briefly outline the current advances of research of macrophages, especially the studies of their phenotypes, in chronic HBV infection.
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Affiliation(s)
- Yujia Li
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, Sichuan, China
| | - Shilin Li
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, Sichuan, China
| | - Xiaoqiong Duan
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, Sichuan, China
| | - Chunhui Yang
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, Sichuan, China
| | - Min Xu
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, Sichuan, China
| | - Limin Chen
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, Sichuan, China
- Toronto General Research Institute, University of Toronto, Toronto, ON M5G 1L6, Canada
- Correspondence to: Limin Chen, Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Peking Union Medical College, 26 Huacai Street, Chengdu, Sichuan 610052, China. Tel: +86-28-61648530, E-mail: or
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Al-Dhamin Z, Liu LD, Li DD, Zhang SY, Dong SM, Nan YM. Therapeutic efficiency of bone marrow-derived mesenchymal stem cells for liver fibrosis: A systematic review of in vivo studies. World J Gastroenterol 2020; 26:7444-7469. [PMID: 33384547 PMCID: PMC7754546 DOI: 10.3748/wjg.v26.i47.7444] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/31/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Although multiple drugs are accessible for recovering liver function in patients, none are considered efficient. Liver transplantation is the mainstay therapy for end-stage liver fibrosis. However, the worldwide shortage of healthy liver donors, organ rejection, complex surgery, and high costs are prompting researchers to develop novel approaches to deal with the overwhelming liver fibrosis cases. Mesenchymal stem cell (MSC) therapy is an emerging alternative method for treating patients with liver fibrosis. However, many aspects of this therapy remain unclear, such as the efficiency compared to conventional treatment, the ideal MSC sources, and the most effective way to use it. Because bone marrow (BM) is the largest source for MSCs, this paper used a systematic review approach to study the therapeutic efficiency of MSCs against liver fibrosis and related factors. We systematically searched multiple published articles to identify studies involving liver fibrosis and BM-MSC-based therapy. Analyzing the selected studies showed that compared with conventional treatment BM-MSC therapy may be more efficient for liver fibrosis in some cases. In contrast, the cotreatment presented a more efficient way. Nevertheless, BM-MSCs are lacking as a therapy for liver fibrosis; thus, this paper also reviews factors that affect BM-MSC efficiency, such as the implementation routes and strategies employed to enhance the potential in alleviating liver fibrosis. Ultimately, our review summarizes the recent advances in the BM-MSC therapy for liver fibrosis. It is grounded in recent developments underlying the efficiency of BM-MSCs as therapy, focusing on the preclinical in vivo experiments, and comparing to other treatments or sources and the strategies used to enhance its potential while mentioning the research gaps.
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Affiliation(s)
- Zaid Al-Dhamin
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Ling-Di Liu
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Dong-Dong Li
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Si-Yu Zhang
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Shi-Ming Dong
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Yue-Min Nan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
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Bhandari S, Li R, Simón-Santamaría J, McCourt P, Johansen SD, Smedsrød B, Martinez-Zubiaurre I, Sørensen KK. Transcriptome and proteome profiling reveal complementary scavenger and immune features of rat liver sinusoidal endothelial cells and liver macrophages. BMC Mol Cell Biol 2020; 21:85. [PMID: 33246411 PMCID: PMC7694354 DOI: 10.1186/s12860-020-00331-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Accepted: 11/18/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs; liver resident macrophages) form the body's most effective scavenger cell system for the removal of harmful blood-borne substances, ranging from modified self-proteins to pathogens and xenobiotics. Controversies in the literature regarding the LSEC phenotype pose a challenge when determining distinct functionalities of KCs and LSECs. This may be due to overlapping functions of the two cells, insufficient purification and/or identification of the cells, rapid dedifferentiation of LSECs in vitro, or species differences. We therefore characterized and quantitatively compared expressed gene products of freshly isolated, highly pure LSECs (fenestrated SE-1/FcγRIIb2+) and KCs (CD11b/c+) from Sprague Dawley, Crl:CD (SD), male rats using high throughput mRNA-sequencing and label-free proteomics. RESULTS We observed a robust correlation between the proteomes and transcriptomes of the two cell types. Integrative analysis of the global molecular profile demonstrated the immunological aspects of LSECs. The constitutive expression of several immune genes and corresponding proteins of LSECs bore some resemblance with the expression in macrophages. LSECs and KCs both expressed high levels of scavenger receptors (SR) and C-type lectins. Equivalent expression of SR-A1 (Msr1), mannose receptor (Mrc1), SR-B1 (Scarb1), and SR-B3 (Scarb2) suggested functional similarity between the two cell types, while functional distinction between the cells was evidenced by LSEC-specific expression of the SRs stabilin-1 (Stab1) and stabilin-2 (Stab2), and the C-type lectins LSECtin (Clec4g) and DC-SIGNR (Clec4m). Many immune regulatory factors were differentially expressed in LSECs and KCs, with one cell predominantly expressing a specific cytokine/chemokine and the other cell the cognate receptor, illustrating the complex cytokine milieu of the sinusoids. Both cells expressed genes and proteins involved in antigen processing and presentation, and lymphocyte co-stimulation. CONCLUSIONS Our findings support complementary and partly overlapping scavenging and immune functions of LSECs and KCs. This highlights the importance of including LSECs in studies of liver immunity, and liver clearance and toxicity of large molecule drugs and nano-formulations.
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Affiliation(s)
- Sabin Bhandari
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Ruomei Li
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Jaione Simón-Santamaría
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Peter McCourt
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Steinar Daae Johansen
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway.,Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | - Bård Smedsrød
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway.
| | | | - Karen Kristine Sørensen
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
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Zarate MA, Wesolowski SR, Nguyen LM, De Dios RK, Wilkening RB, Rozance PJ, Wright CJ. In utero inflammatory challenge induces an early activation of the hepatic innate immune response in late gestation fetal sheep. Innate Immun 2020; 26:549-564. [PMID: 32538259 PMCID: PMC7556190 DOI: 10.1177/1753425920928388] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/20/2020] [Accepted: 04/26/2020] [Indexed: 12/15/2022] Open
Abstract
Chorioamnionitis is associated with inflammatory end-organ damage in the fetus. Tissues in direct contact with amniotic fluid drive a pro-inflammatory response and contribute to this injury. However, due to a lack of direct contact with the amniotic fluid, the liver contribution to this response has not been fully characterized. Given its role as an immunologic organ, we hypothesized that the fetal liver would demonstrate an early innate immune response to an in utero inflammatory challenge. Fetal sheep (131 ± 1 d gestation) demonstrated metabolic acidosis and high cortisol and norepinephrine values within 5 h of exposure to intra-amniotic LPS. Likewise, expression of pro-inflammatory cytokines increased significantly at 1 and 5 h of exposure. This was associated with NF-κB activation, by inhibitory protein IκBα degradation, and nuclear translocation of NF-κB subunits (p65/p50). Corroborating these findings, LPS exposure significantly increased pro-inflammatory innate immune gene expression in fetal sheep hepatic macrophages in vitro. Thus, an in utero inflammatory challenge induces an early hepatic innate immune response with systemic metabolic and stress responses. Within the fetal liver, hepatic macrophages respond robustly to LPS exposure. Our results demonstrate that the fetal hepatic innate immune response must be considered when developing therapeutic approaches to attenuate end-organ injury associated with in utero inflammation.
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Affiliation(s)
- Miguel A Zarate
- Section of Neonatology, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Stephanie R Wesolowski
- Section of Neonatology, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Leanna M Nguyen
- Section of Neonatology, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Robyn K De Dios
- Section of Neonatology, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Randall B Wilkening
- Section of Neonatology, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Paul J Rozance
- Section of Neonatology, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Clyde J Wright
- Section of Neonatology, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO 80045, USA
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Teng KY, Barajas JM, Hu P, Jacob ST, Ghoshal K. Role of B Cell Lymphoma 2 in the Regulation of Liver Fibrosis in miR-122 Knockout Mice. BIOLOGY 2020; 9:biology9070157. [PMID: 32650615 PMCID: PMC7408427 DOI: 10.3390/biology9070157] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/25/2020] [Accepted: 07/02/2020] [Indexed: 12/12/2022]
Abstract
MicroRNA-122 (miR-122) has been identified as a marker of various liver injuries, including hepatitis- virus-infection-, alcoholic-, and non-alcoholic steatohepatitis (NASH)-induced liver fibrosis. Here, we report that the extracellular miR-122 from hepatic cells can be delivered to hepatic stellate cells (HSCs) to modulate their proliferation and gene expression. Our published Argonaute crosslinking immunoprecipitation (Ago-CLIP) data identified several pro-fibrotic genes, including Ctgf, as miR-122 targets in mice livers. However, treating Ctgf as a therapeutic target failed to rescue the fibrosis developed in the miR-122 knockout livers. Alternatively, we compared the published datasets of human cirrhotic livers and miR-122 KO livers, which revealed upregulation of BCL2, suggesting its potential role in regulating fibrosis. Notably, ectopic miR-122 expression inhibited BCL2 expression in human HSC (LX-2) cells). Publicly available ChIP-seq data in human hepatocellular cancer (HepG2) cells and mice livers suggested miR-122 could regulate BCL2 expression indirectly through c-MYC, which was confirmed by siRNA-mediated depletion of c-MYC in Hepatocellular Carcinoma (HCC) cell lines. Importantly, Venetoclax, a potent BCL2 inhibitor approved for the treatment of leukemia, showed promising anti-fibrotic effects in miR-122 knockout mice. Collectively, our data demonstrate that miR-122 suppresses liver fibrosis and implicates anti-fibrotic potential of Venetoclax.
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Affiliation(s)
- Kun-Yu Teng
- Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, OH 43210, USA;
- Department of Pathology, The Ohio State University, Columbus, OH 43210, USA; (J.M.B.); (S.T.J.)
- Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA;
| | - Juan M. Barajas
- Department of Pathology, The Ohio State University, Columbus, OH 43210, USA; (J.M.B.); (S.T.J.)
- Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA;
| | - Peng Hu
- Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA;
| | - Samson T. Jacob
- Department of Pathology, The Ohio State University, Columbus, OH 43210, USA; (J.M.B.); (S.T.J.)
- Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA;
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210, USA
| | - Kalpana Ghoshal
- Department of Pathology, The Ohio State University, Columbus, OH 43210, USA; (J.M.B.); (S.T.J.)
- Comprehensive Cancer Center, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA;
- Correspondence: ; Tel.: +614-292-8865; Fax: +614-688-4245
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Folate Receptor β (FRβ) Expression in Tissue-Resident and Tumor-Associated Macrophages Associates with and Depends on the Expression of PU.1. Cells 2020; 9:cells9061445. [PMID: 32532019 PMCID: PMC7349916 DOI: 10.3390/cells9061445] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 06/02/2020] [Accepted: 06/08/2020] [Indexed: 02/07/2023] Open
Abstract
As macrophages exhibit a huge functional plasticity under homeostasis and pathological conditions, they have become a therapeutic target for chronic inflammatory diseases. Hence, the identification of macrophage subset-specific markers is a requisite for the development of macrophage-directed therapeutic interventions. In this regard, the macrophage-specific Folate Receptor β (FRβ, encoded by the FOLR2 gene) has been already validated as a target for molecular delivery in cancer as well as in macrophage-targeting therapeutic strategies for chronic inflammatory pathologies. We now show that the transcriptome of human macrophages from healthy and inflamed tissues (tumor; rheumatoid arthritis, RA) share a significant over-representation of the “anti-inflammatory gene set”, which defines the gene profile of M-CSF-dependent IL-10-producing human macrophages (M-MØ). More specifically, FOLR2 expression has been found to strongly correlate with the expression of M-MØ-specific genes in tissue-resident macrophages, tumor-associated macrophages (TAM) and macrophages from inflamed synovium, and also correlates with the presence of the PU.1 transcription factor. In fact, PU.1-binding elements are found upstream of the first exon of FOLR2 and most M-MØ-specific- and TAM-specific genes. The functional relevance of PU.1 binding was demonstrated through analysis of the proximal regulatory region of the FOLR2 gene, whose activity was dependent on a cluster of PU.1-binding sequences. Further, siRNA-mediated knockdown established the importance of PU.1 for FOLR2 gene expression in myeloid cells. Therefore, we provide evidence that FRβ marks tissue-resident macrophages as well as macrophages within inflamed tissues, and its expression is dependent on PU.1.
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Cheng Z, Abrams ST, Toh J, Wang SS, Downey C, Ge X, Yu Q, Yu W, Wang G, Toh CH. Complexes between C-Reactive Protein and Very Low Density Lipoprotein Delay Bacterial Clearance in Sepsis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 204:2712-2721. [PMID: 32269097 DOI: 10.4049/jimmunol.1900962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 02/19/2020] [Indexed: 11/19/2022]
Abstract
C-reactive protein (CRP) can increase up to 1000-fold in blood and form complexes with very low density lipoproteins (VLDL). These complexes are associated with worse outcomes for septic patients, and this suggests a potential pathological role in sepsis. Complex formation is heightened when CRP is over 200 mg/l and levels are associated with the severity of sepsis and blood bacterial culture positivity. Using a mouse bacteremia model, blood bacterial clearance can be delayed by i.v. injection of CRP-VLDL complexes. Complexes are more efficiently taken up by activated U937 cells in vitro and Kupffer cells in vivo than VLDL alone. Both in vitro-generated and naturally occurring CRP-VLDL complexes reduce phagocytosis of bacteria by activated U937 cells. Fcγ and scavenger receptors are involved and a competitive mechanism for clearance of CRP-VLDL complexes and bacteria is demonstrated. Interaction of phosphocholine groups on VLDL with CRP is the major driver for complex formation and phosphocholine can disrupt the complexes to reverse their inhibitory effects on phagocytosis and bacterial clearance. Increased formation of CRP-VLDL complexes is therefore harmful and could be a novel target for therapy in sepsis.
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Affiliation(s)
- Zhenxing Cheng
- Medical School, Southeast University, Nanjing 210009, China
| | - Simon T Abrams
- Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, United Kingdom
| | - Julien Toh
- Wirral University Teaching Hospital NHS Foundation Trust, Upton, Wirral CH49 5PE, United Kingdom
| | - Susan S Wang
- Royal London Hospital, Whitechapel, London E1 1FR, United Kingdom; and
| | - Colin Downey
- Royal Liverpool University Hospital, University of Liverpool, Liverpool L7 8XP, United Kingdom
| | - Xiaoling Ge
- Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, United Kingdom
| | - Qian Yu
- Medical School, Southeast University, Nanjing 210009, China
| | - Weiping Yu
- Medical School, Southeast University, Nanjing 210009, China
| | - Guozheng Wang
- Medical School, Southeast University, Nanjing 210009, China;
- Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, United Kingdom
| | - Cheng-Hock Toh
- Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, United Kingdom
- Royal Liverpool University Hospital, University of Liverpool, Liverpool L7 8XP, United Kingdom
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Woitok MM, Zoubek ME, Doleschel D, Bartneck M, Mohamed MR, Kießling F, Lederle W, Trautwein C, Cubero FJ. Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease. Cell Death Dis 2020; 11:343. [PMID: 32393755 PMCID: PMC7214425 DOI: 10.1038/s41419-020-2571-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 02/17/2020] [Accepted: 02/18/2020] [Indexed: 11/25/2022]
Abstract
Lipid-based RNA nanocarriers have been recently accepted as a novel therapeutic option in humans, thus increasing the therapeutic options for patients. Tailored nanomedicines will enable to treat chronic liver disease (CLD) and end-stage liver cancer, disorders with high mortality and few treatment options. Here, we investigated the curative potential of gene therapy of a key molecule in CLD, the c-Jun N-terminal kinase-2 (Jnk2). Delivery to hepatocytes was achieved using a lipid-based clinically employable siRNA formulation that includes a cationic aminolipid to knockdown Jnk2 (named siJnk2). After assessing the therapeutic potential of siJnk2 treatment, non-invasive imaging demonstrated reduced apoptotic cell death and improved hepatocarcinogenesis was evidenced by improved liver parenchyma as well as ameliorated markers of hepatic damage, reduced fibrogenesis in 1-year-old mice. Strikingly, chronic siJnk2 treatment reduced premalignant nodules, indicative of tumor initiation. Furthermore, siJnk2 treatment led to a significant activation of the immune cell compartment. In conclusion, Jnk2 knockdown in hepatocytes ameliorated hepatitis, fibrogenesis, and initiation of hepatocellular carcinoma (HCC), and hence might be a suitable therapeutic option, to define novel molecular targets for precision medicine in CLD.
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Affiliation(s)
| | - Miguel Eugenio Zoubek
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.,Department of Toxicology and Pharmacology, School of Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Centre Maastricht University, Maastricht, The Netherlands
| | - Dennis Doleschel
- Institute for Experimental and Molecular Imaging, University Hospital RWTH Aachen, Aachen, Germany
| | - Matthias Bartneck
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Mohamed Ramadan Mohamed
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.,Department of Therapeutic Chemistry, National Research Centre, 12622, Cairo, Egypt
| | - Fabian Kießling
- Institute for Experimental and Molecular Imaging, University Hospital RWTH Aachen, Aachen, Germany
| | - Wiltrud Lederle
- Institute for Experimental and Molecular Imaging, University Hospital RWTH Aachen, Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
| | - Francisco Javier Cubero
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany. .,Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain. .,12 de Octubre Health Research Institute (imas12), Madrid, Spain.
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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.
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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
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Gandahi NS, Gandahi JA, Yang P, Tarique I, Vistro WA, Haseeb A, Huang Y, Yu L, Bai X, Chen Q. Ultrastructural Evidence of Melanomacrophagic Centers and Lipofuscin in the Liver of Zebrafish ( Denio rerio). Zebrafish 2020; 17:83-90. [PMID: 32125963 DOI: 10.1089/zeb.2019.1826] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Melanomacrophagic centers (MMCs) were studied in the liver of zebrafish using transmission electron microscope (TEM). The MMCs were located in the space of Disse (SD), and their pseudopodia protruded into the lumen of sinusoids. The degree of extension of body structure of MMCs in the SD was determined by the size of the phagocytosed content. An irregular or amoeboid nucleus was present. Vacuoles were occasionally present, both, in endothelium and MMCs. The cytoplasm of MMCs showed several engulfed structures. The most common structure was the presence of mitochondria of small to giant size and distorted shape with inconspicuous cristae. The product of mitochondrial degeneration accompanied by lysosomes contributed to the formation of lipofuscins. Besides, changes were also observed in rough endoplasmic reticulum (rER), the Golgi complex, and lysosomes. Occasionally, small to large fragments of the erythrocytes were found in the cytoplasm of MMCs. The rER encompassed the mitochondria and lipid droplets forming a membrane-like structure. Golgi complex were dilated. Lysosomes fused with such membrane-bound structures contributed to the formation of the lipofuscin. The results provide evidence of the role of liver-resident MMCs of zebrafish in phagocytosis of damaged organelles, clearance of the worn-out erythrocytes, and lipofuscin formation.
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Affiliation(s)
- Noor Samad Gandahi
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Jameel Ahmed Gandahi
- Department of Anatomy and Histology, Faculty of Animal Husbandry and Veterinary Science, Sindh Agriculture University, Tandojam, Pakistan
| | - Ping Yang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Imran Tarique
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Waseem Ali Vistro
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Abdul Haseeb
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Yufei Huang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Liang Yu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Xuebing Bai
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Qiusheng Chen
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
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41
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Cheng D, Morsch M, Shami GJ, Chung RS, Braet F. Observation and characterisation of macrophages in zebrafish liver. Micron 2020; 132:102851. [PMID: 32092694 DOI: 10.1016/j.micron.2020.102851] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 02/12/2020] [Accepted: 02/12/2020] [Indexed: 01/22/2023]
Abstract
Kupffer cells are liver-resident macrophages that play an important role in mediating immune-related functions in mammals and humans. They are well-known for their capacity to phagocytose large amounts of waste complexes, cell debris, microbial particles and even malignant cells. Location, appearance and functional aspects are important features used to identify these characteristic cells of the liver sinusoid. To-date, there is limited information on the occurrence of macrophages in zebrafish liver. Therefore, we aimed to characterise the ultrastructural and functional aspects of liver-associated macrophages in the zebrafish model by taking advantage of the latest advances in zebrafish genetics and multimodal correlative imaging. Herein, we report on the occurrence of macrophages within the zebrafish liver exhibiting conventional ultrastructural features (e.g. presence of pseudopodia, extensive lysosomal apparatus, a phagolysosome and making up ∼3% of the liver volume). Intriguingly, these cells were not located within the sinusoidal vascular bed of hepatic tissue but instead resided between hepatocytes and lacked phagocytic function. While our results demonstrated the presence and structural similarities with liver macrophages from other experimental models, their functional characteristics were distinctly different from Kupffer cells that have been described in rodents and humans. These findings illustrate that the innate immune system of the zebrafish liver has some distinctly different characteristics compared to other animal experimental models. This conclusion underpins our call for future studies in order to have a better understanding of the physiological role of macrophages residing between the parenchymal cells of the zebrafish liver.
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Affiliation(s)
- Delfine Cheng
- School of Medical Sciences (Discipline of Anatomy and Histology) - The Bosch Institute, The University of Sydney, NSW 2006, Australia.
| | - Marco Morsch
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.
| | - Gerald J Shami
- School of Medical Sciences (Discipline of Anatomy and Histology) - The Bosch Institute, The University of Sydney, NSW 2006, Australia.
| | - Roger S Chung
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.
| | - Filip Braet
- School of Medical Sciences (Discipline of Anatomy and Histology) - The Bosch Institute, The University of Sydney, NSW 2006, Australia; Australian Centre for Microscopy & Microanalysis, The University of Sydney, NSW 2006, Australia; Charles Perkins Centre (Cellular Imaging Facility), The University of Sydney, NSW 2006, Australia.
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Dou L, Shi X, He X, Gao Y. Macrophage Phenotype and Function in Liver Disorder. Front Immunol 2020; 10:3112. [PMID: 32047496 PMCID: PMC6997484 DOI: 10.3389/fimmu.2019.03112] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 12/20/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatic macrophages are a remarkably heterogeneous population consisting of self-renewing tissue-resident phagocytes, termed Kupffer cells (KCs), and recruited macrophages derived from peritoneal cavity as well as the bone marrow. KCs are located in the liver sinusoid where they scavenge the microbe from the portal vein to maintain liver homeostasis. Liver injury may trigger hepatic recruitment of peritoneal macrophages and monocyte-derived macrophages. Studies describing macrophage accumulation have shown that hepatic macrophages are involved in the initiation and progression of various liver diseases. They act as tolerogenic antigen-presenting cells to inhibit T-cell activation by producing distinct sets of cytokines, chemokines, and mediators to maintain or resolve inflammation. Furthermore, by releasing regenerative growth factors, matrix metalloproteinase arginase, they promote tissue repair. Recent experiments found that KCs and recruited macrophages may play different roles in the development of liver disease. Given that hepatic macrophages are considerably plastic populations, their phenotypes and functions are likely switching along disease progression. In this review, we summarize current knowledge about the role of tissue-resident macrophages and recruited macrophages in pathogenesis of alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), viral hepatitis, and hepatocellular carcinoma (HCC).
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Affiliation(s)
- Lang Dou
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaomin Shi
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoshun He
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yifang Gao
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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43
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Fornaguera C, Guerra‐Rebollo M, Lázaro MÁ, Cascante A, Rubio N, Blanco J, Borrós S. In Vivo Retargeting of Poly(beta aminoester) (OM-PBAE) Nanoparticles is Influenced by Protein Corona. Adv Healthc Mater 2019; 8:e1900849. [PMID: 31478348 DOI: 10.1002/adhm.201900849] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 07/28/2019] [Indexed: 12/29/2022]
Abstract
One of the main bottlenecks in the translation of nanomedicines from research to clinics is the difficulty in designing nanoparticles actively vectorized to the target tissue, a key parameter to ensure efficacy and safety. In this group, a library of poly(beta aminoester) polymers is developed, and it is demonstrated that adding specific combinations of terminal oligopeptides (OM-PBAE), in vitro transfection is cell selective. The current study aims to actively direct the nanoparticles to the liver by the addition of a targeting molecule. To achieve this objective, retinol, successfully attached to OM-PBAE, is selected as hepatic targeting moiety. It is demonstrated that organ biodistribution is tailored, achieving the desired liver accumulation. Regarding cell type transfection, antigen presenting cells in the liver are those showing the highest transfection. Thanks to proteomics studies, organ but not cellular biodistribution can be explained by the formation of differential protein coronas. Therefore, organ biodistribution is governed by differential protein corona formed when retinol is present, while cellular biodistribution is controlled by the end oligopeptides type. In summary, this work is a proof of concept that demonstrates the versatility of these OM-PBAE nanoparticles, in terms of the modification of the biodistribution of OM-PBAE nanoparticles adding active targeting moieties.
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Affiliation(s)
- Cristina Fornaguera
- Grup d'Enginyeria de Materials (Gemat)Institut Químic de Sarrià (IQS)Ramon Llull University (URL) Via Augusta 390 08017 Barcelona Spain
| | - Marta Guerra‐Rebollo
- Grup d'Enginyeria de Materials (Gemat)Institut Químic de Sarrià (IQS)Ramon Llull University (URL) Via Augusta 390 08017 Barcelona Spain
| | | | - Anna Cascante
- Sagetis‐Biotech SL Via Augusta 390 08017 Barcelona Spain
| | - Núria Rubio
- Grup de Terapia CellularInstitut de Química Avançada de Catalunya (IQAC‐CSIC) C/Jordi Girona 28‐26 08034 Barcelona Spain
| | - Jerónimo Blanco
- Grup de Terapia CellularInstitut de Química Avançada de Catalunya (IQAC‐CSIC) C/Jordi Girona 28‐26 08034 Barcelona Spain
| | - Salvador Borrós
- Grup d'Enginyeria de Materials (Gemat)Institut Químic de Sarrià (IQS)Ramon Llull University (URL) Via Augusta 390 08017 Barcelona Spain
- Sagetis‐Biotech SL Via Augusta 390 08017 Barcelona Spain
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44
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Wesolowski R, Sharma N, Reebel L, Rodal MB, Peck A, West BL, Marimuthu A, Severson P, Karlin DA, Dowlati A, Le MH, Coussens LM, Rugo HS. Phase Ib study of the combination of pexidartinib (PLX3397), a CSF-1R inhibitor, and paclitaxel in patients with advanced solid tumors. Ther Adv Med Oncol 2019; 11:1758835919854238. [PMID: 31258629 PMCID: PMC6589951 DOI: 10.1177/1758835919854238] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 05/01/2019] [Indexed: 12/22/2022] Open
Abstract
Purpose: To evaluate the safety, recommended phase II dose (RP2D) and efficacy of pexidartinib, a colony stimulating factor receptor 1 (CSF-1R) inhibitor, in combination with weekly paclitaxel in patients with advanced solid tumors. Patients and Methods: In part 1 of this phase Ib study, 24 patients with advanced solid tumors received escalating doses of pexidartinib with weekly paclitaxel (80 mg/m2). Pexidartinib was administered at 600 mg/day in cohort 1. For subsequent cohorts, the dose was increased by ⩽50% using a standard 3+3 design. In part 2, 30 patients with metastatic solid tumors were enrolled to examine safety, tolerability and efficacy of the RP2D. Pharmacokinetics and biomarkers were also assessed. Results: A total of 51 patients reported ≥1 adverse event(s) (AEs) that were at least possibly related to either study drug. Grade 3–4 AEs, including anemia (26%), neutropenia (22%), lymphopenia (19%), fatigue (15%), and hypertension (11%), were recorded in 38 patients (70%). In part 1, no maximum tolerated dose was achieved and 1600 mg/day was determined to be the RP2D. Of 38 patients evaluable for efficacy, 1 (3%) had complete response, 5 (13%) partial response, 13 (34%) stable disease, and 17 (45%) progressive disease. No drug–drug interactions were found. Plasma CSF-1 levels increased 1.6- to 53-fold, and CD14dim/CD16+ monocyte levels decreased by 57–100%. Conclusions: The combination of pexidartinib and paclitaxel was generally well tolerated. RP2D for pexidartinib was 1600 mg/day. Pexidartinib blocked CSF-1R signaling, indicating potential for mitigating macrophage tumor infiltration.
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Affiliation(s)
- Robert Wesolowski
- Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, 1800 Cannon Dr 1250 Lincoln Tower Columbus, OH, 43210, USA
| | | | - Laura Reebel
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | | | | | | | | | | | | | | | - Mai H Le
- Plexxikon Inc. Berkeley, CA, USA
| | | | - Hope S Rugo
- University of California San Francisco, CA, USA
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45
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Miarka L, Hauser C, Helm O, Holdhof D, Beckinger S, Egberts JH, Gundlach JP, Lenk L, Rahn S, Mikulits W, Trauzold A, Sebens S. The Hepatic Microenvironment and TRAIL-R2 Impact Outgrowth of Liver Metastases in Pancreatic Cancer after Surgical Resection. Cancers (Basel) 2019; 11:cancers11060745. [PMID: 31146405 PMCID: PMC6627672 DOI: 10.3390/cancers11060745] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 05/26/2019] [Indexed: 12/12/2022] Open
Abstract
Most patients with pancreatic ductal adenocarcinoma (PDAC) undergoing curative resection relapse within months, often with liver metastases. The hepatic microenvironment determines induction and reversal of dormancy during metastasis. Both tumor growth and metastasis depend on the Tumor necrosis factor (TNF)-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2). This study investigated the interplay of TRAIL-R2 and the hepatic microenvironment in liver metastases formation and the impact of surgical resection. Although TRAIL-R2-knockdown (PancTu-I shTR2) decreased local relapses and number of macroscopic liver metastases after primary tumor resection in an orthotopic PDAC model, the number of micrometastases was increased. Moreover, abdominal surgery induced liver inflammation involving activation of hepatic stellate cells (HSCs) into hepatic myofibroblasts (HMFs). In coculture with HSCs, proliferation of PancTu-I shTR2 cells was significantly lower compared to PancTu-I shCtrl cells, an effect still observed after switching coculture from HSC to HMF, mimicking surgery-mediated liver inflammation and enhancing cell proliferation. CXCL-8/IL-8 blockade diminished HSC-mediated growth inhibition in PancTu-I shTR2 cells, while Vascular Endothelial Growth Factor (VEGF) neutralization decreased HMF-mediated proliferation. Overall, this study points to an important role of TRAIL-R2 in PDAC cells in the interplay with the hepatic microenvironment during metastasis. Resection of primary PDAC seems to induce liver inflammation, which might contribute to outgrowth of liver metastases.
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Affiliation(s)
- Lauritz Miarka
- Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Arnold-Heller-Str. 3, Building 17, 24105 Kiel, Germany.
| | - Charlotte Hauser
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel, 24105 Kiel, Germany.
| | - Ole Helm
- Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Arnold-Heller-Str. 3, Building 17, 24105 Kiel, Germany.
| | - Dörthe Holdhof
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
- Department, Research Institute Children's Cancer Center Hamburg, 20251 Hamburg, Germany.
| | - Silje Beckinger
- Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Arnold-Heller-Str. 3, Building 17, 24105 Kiel, Germany.
| | - Jan-Hendrik Egberts
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel, 24105 Kiel, Germany.
| | - Jan-Paul Gundlach
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel, 24105 Kiel, Germany.
| | - Lennart Lenk
- Department of Pediatrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Schwanenweg 20, 24105 Kiel, Germany.
| | - Sascha Rahn
- Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Arnold-Heller-Str. 3, Building 17, 24105 Kiel, Germany.
| | - Wolfgang Mikulits
- Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
| | - Anna Trauzold
- Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Arnold-Heller-Str. 3, Building 17, 24105 Kiel, Germany.
- Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel, 24105 Kiel, Germany.
| | - Susanne Sebens
- Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Arnold-Heller-Str. 3, Building 17, 24105 Kiel, Germany.
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46
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Nanomedicines for cancer therapy: current status, challenges and future prospects. Ther Deliv 2019; 10:113-132. [DOI: 10.4155/tde-2018-0062] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The emergence of nanomedicine as an innovative and promising alternative technology shows many advantages over conventional cancer therapies and provides new opportunities for early detection, improved treatment, and diagnosis of cancer. Despite the cancer nanomedicines’ capability of delivering chemotherapeutic agents while providing lower systemic toxicity, it is paramount to consider the cancer complexity and dynamics for bridging the translational bench-to-bedside gap. It is important to conduct appropriate investigations for exploiting the tumor microenvironment, and achieving a more comprehensive understanding of the fundamental biological processes in cancer and their roles in modulating nanoparticle–protein interactions, blood circulation, and tumor penetration. This review provides an overview of the current cancer nanomedicines, the major challenges, and the future opportunities in this research area.
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47
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2-Methoxyestradiol attenuates liver fibrosis in mice: implications for M2 macrophages. Naunyn Schmiedebergs Arch Pharmacol 2018; 392:381-391. [PMID: 30535572 DOI: 10.1007/s00210-018-1577-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 10/31/2018] [Indexed: 02/06/2023]
Abstract
Liver fibrosis is a major health problem worldwide due to its serious complications including cirrhosis and liver cancer. 2-Methoxyestradiol (2-ME) is an end metabolite of estradiol with anti-proliferative, antioxidant, and anti-inflammatory activities. However, the protective role of 2-ME in liver fibrosis has not been fully investigated. The aim of this study was to determine the protective effect of 2-ME in carbon tetrachloride (CCl4)-induced liver fibrosis in mice. Animals were injected intraperitoneally with CCl4 twice weekly for 6 weeks. 2-ME 50 mg/kg or 100 mg/kg was administrated intraperitoneally every day over the same period. Our data showed that 2-ME reduced the extent of liver toxicity and fibrosis due to CCl4 exposure. It restored the elevated serum liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels and ameliorated oxidative status. In addition, 2-ME significantly reduced collagen deposition and alpha-smooth muscle actin (α-SMA) protein expressions. Furthermore, 2-ME markedly lowered macrophage infiltration and macrophage alternative activation marker chitinase-like molecules (CHI3L3/YM1). The results of this study indicate an important protective activity of 2-ME in liver fibrosis and highlight the role of macrophage recruitment and alternative activation as a possible target.
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48
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Zhou H, Oh S, Kim JE, Zou F, Hwang DY, Lee J. In Vivo Study of Spiky Fe3O4@Au Nanoparticles with Different Branch Lengths: Biodistribution, Clearance, and Biocompatibility in Mice. ACS APPLIED BIO MATERIALS 2018; 2:163-170. [DOI: 10.1021/acsabm.8b00505] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
| | - Sangjin Oh
- Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 46241, Republic of Korea
| | - Ji Eun Kim
- Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang 50463, Republic of Korea
| | | | - Dae Youn Hwang
- Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang 50463, Republic of Korea
| | - Jaebeom Lee
- Department of Chemistry, Chungnam National University, Daejeon 34134, Republic of Korea
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Fabregat I, Caballero-Díaz D. Transforming Growth Factor-β-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis. Front Oncol 2018; 8:357. [PMID: 30250825 PMCID: PMC6139328 DOI: 10.3389/fonc.2018.00357] [Citation(s) in RCA: 250] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 08/13/2018] [Indexed: 12/11/2022] Open
Abstract
The Transforming Growth Factor-beta (TGF-β) family plays relevant roles in the regulation of different cellular processes that are essential for tissue and organ homeostasis. In the case of the liver, TGF-β signaling participates in different stages of disease progression, from initial liver injury toward fibrosis, cirrhosis and cancer. When a chronic injury takes place, mobilization of lymphocytes and other inflammatory cells occur, thus setting the stage for persistence of an inflammatory response. Macrophages produce profibrotic mediators, among them, TGF-β, which is responsible for activation -transdifferentiation- of quiescent hepatic stellate cells (HSC) to a myofibroblast (MFB) phenotype. MFBs are the principal source of extracellular matrix protein (ECM) accumulation and prominent mediators of fibrogenesis. TGF-β also mediates an epithelial-mesenchymal transition (EMT) process in hepatocytes that may contribute, directly or indirectly, to increase the MFB population. In hepatocarcinogenesis, TGF-β plays a dual role, behaving as a suppressor factor at early stages, but contributing to later tumor progression, once cells escape from its cytostatic effects. As part of its potential pro-tumorigenic actions, TGF-β induces EMT in liver tumor cells, which increases its pro-migratory and invasive potential. In parallel, TGF-β also induces changes in tumor cell plasticity, conferring properties of a migratory tumor initiating cell (TIC). The main aim of this review is to shed light about the pleiotropic actions of TGF-β that explain its effects on the different liver cell populations. The cross-talk with other signaling pathways that contribute to TGF-β effects, in particular the Epidermal Growth Factor Receptor (EGFR), will be presented. Finally, we will discuss the rationale for targeting the TGF-β pathway in liver pathologies.
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Affiliation(s)
- Isabel Fabregat
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute, Barcelona, Spain.,Department of Physiological Sciences, School of Medicine, University of Barcelona, Barcelona, Spain.,Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Barcelona, Spain
| | - Daniel Caballero-Díaz
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute, Barcelona, Spain.,Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Barcelona, Spain
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Lian M, Selmi C, Gershwin ME, Ma X. Myeloid Cells and Chronic Liver Disease: a Comprehensive Review. Clin Rev Allergy Immunol 2018; 54:307-317. [PMID: 29313221 DOI: 10.1007/s12016-017-8664-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Myeloid cells play a major role in the sensitization to liver injury, particularly in chronic inflammatory liver diseases with a biliary or hepatocellular origin, and the interplay between myeloid cells and the liver may explain the increased incidence of hepatic osteodystrophy. The myeloid cell-liver axis involves several mature myeloid cells as well as immature or progenitor cells with the complexity of the liver immune microenvironment aggravating the mist of cell differentiation. The unique positioning of the liver at the junction of the peripheral and portal circulation systems underlines the interaction of myeloid cells and hepatic cells and leads to immune tolerance breakdown. We herein discuss the scenarios of different chronic liver diseases closely modulated by myeloid cells and illustrate the numerous potential targets, the understanding of which will ultimately steer the development of solid immunotherapeutic regimens. Ultimately, we are convinced that an adequate modulation of the liver microenvironment to modify the functional and quantitative characteristics of myeloid cells will be a successful approach to treating chronic liver diseases of different etiologies.
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Affiliation(s)
- Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Carlo Selmi
- Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy.,BIOMETRA Department, University of Milan, Milan, Italy
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China.
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