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Zhang S, Jahanbani F, Chander V, Kjellberg M, Liu M, Glass KA, Iu DS, Ahmed F, Li H, Maynard RD, Chou T, Cooper-Knock J, Zhang MJ, Thota D, Zeineh M, Grenier JK, Grimson A, Hanson MR, Snyder MP. Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.04.15.25325899. [PMID: 40321247 PMCID: PMC12047926 DOI: 10.1101/2025.04.15.25325899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/10/2025]
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, heterogeneous, and systemic disease defined by a suite of symptoms, including unexplained persistent fatigue, post-exertional malaise (PEM), cognitive impairment, myalgia, orthostatic intolerance, and unrefreshing sleep. The disease mechanism of ME/CFS is unknown, with no effective curative treatments. In this study, we present a multi-site ME/CFS whole-genome analysis, which is powered by a novel deep learning framework, HEAL2. We show that HEAL2 not only has predictive value for ME/CFS based on personal rare variants, but also links genetic risk to various ME/CFS-associated symptoms. Model interpretation of HEAL2 identifies 115 ME/CFS-risk genes that exhibit significant intolerance to loss-of-function (LoF) mutations. Transcriptome and network analyses highlight the functional importance of these genes across a wide range of tissues and cell types, including the central nervous system (CNS) and immune cells. Patient-derived multi-omics data implicate reduced expression of ME/CFS risk genes within ME/CFS patients, including in the plasma proteome, and the transcriptomes of B and T cells, especially cytotoxic CD4 T cells, supporting their disease relevance. Pan-phenotype analysis of ME/CFS genes further reveals the genetic correlation between ME/CFS and other complex diseases and traits, including depression and long COVID-19. Overall, HEAL2 provides a candidate genetic-based diagnostic tool for ME/CFS, and our findings contribute to a comprehensive understanding of the genetic, molecular, and cellular basis of ME/CFS, yielding novel insights into therapeutic targets. Our deep learning model also offers a potent, broadly applicable framework for parallel rare variant analysis and genetic prediction for other complex diseases and traits.
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Affiliation(s)
- Sai Zhang
- Department of Genetics, Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Department of Epidemiology, University of Florida, Gainesville, FL, USA
- Department of Biostatistics & Biomedical Engineering, Genetics Institute, McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Fereshteh Jahanbani
- Department of Genetics, Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Varuna Chander
- Department of Genetics, Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Martin Kjellberg
- Department of Genetics, Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Menghui Liu
- Department of Epidemiology, University of Florida, Gainesville, FL, USA
| | - Katherine A. Glass
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
| | - David S. Iu
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
| | - Faraz Ahmed
- Genomics Facility, Biotechnology Resource Center, Cornell University, Ithaca, NY, USA
| | - Han Li
- School of Mathematical Sciences and LPMC, Nankai University, Tianjin, China
| | - Rajan Douglas Maynard
- Department of Genetics, Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Tristan Chou
- Department of Genetics, Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Johnathan Cooper-Knock
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Martin Jinye Zhang
- Ray and Stephanie Lane Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA
| | - Durga Thota
- Department of Genetics, Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Michael Zeineh
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Jennifer K. Grenier
- Genomics Facility, Biotechnology Resource Center, Cornell University, Ithaca, NY, USA
| | - Andrew Grimson
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
| | - Maureen R. Hanson
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
| | - Michael P. Snyder
- Department of Genetics, Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA
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2
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Burov A, Rezvykh A, Vedernikova V, Belogurov A, Prassolov V, Spirin P, Funikov S, Morozov A, Karpov V. Caffeine modulates immunoproteasome activity and content in colorectal adenocarcinoma cells. Biochimie 2025; 235:1-13. [PMID: 40349826 DOI: 10.1016/j.biochi.2025.05.004] [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: 01/31/2025] [Revised: 04/30/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025]
Abstract
Proteasomes hydrolyze most intracellular proteins. Immunoproteasome is a form of proteasome implicated in inflammation, cancer and autoimmune diseases. Modulation of immunoproteasome activity is a promising approach against several pathologies. Using previously obtained reporter colorectal cancer cell lines, we tested how commonly used compounds including ibuprofen, acetylsalicylic acid, vitamin C, caffeine and others, affect immunoproteasome expression. Flow cytometry, qPCR and Western blot were used to evaluate immunoproteasome subunit expression. Proteasome activity was tested using fluorogenic substrates and the activity-based probe. Transcriptome analysis was performed to identify patterns of gene expression changes. Interestingly, caffeine was the only drug that stimulated modest reduction in quantity of immunoproteasomes. The effect of caffeine varied between cell lines and was stronger as a result of prolonged treatment. The reduction of immunoproteasome content in cells coincided with decreased expression of immunoproteasome subunits, genes encoding the Nrf3 transcription factor and a PAC4 proteasome assembly chaperone, as well as the reduced levels of oxidative stress. Caffeine did not affect the degradation of immunoproteasomes by autophagy. Obtained results uncover novel biological effects of caffeine, our data might help to optimize existing and develop new strategies for the treatment of colorectal cancer and several autoimmune diseases.
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Affiliation(s)
- Alexander Burov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991, Moscow, Russia
| | - Alexander Rezvykh
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991, Moscow, Russia
| | - Valeria Vedernikova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991, Moscow, Russia; Moscow Center for Advanced Studies, Kulakova Street 20, 123592, Moscow, Russia
| | - Alexey Belogurov
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street 16/10, 117997, Moscow, Russia; Department of Biological Chemistry, Russian University of Medicine, Ministry of Health of Russian Federation, Staromonetnyy Ln., 5, 119017, Moscow, Russia
| | - Vladimir Prassolov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991, Moscow, Russia
| | - Pavel Spirin
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991, Moscow, Russia
| | - Sergey Funikov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991, Moscow, Russia
| | - Alexey Morozov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991, Moscow, Russia.
| | - Vadim Karpov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991, Moscow, Russia
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Sawant P, Mathew A, Bensalel J, Gallego-Delgado J, Mandal P. Cancer Drug Bortezomib, a Proteasomal Inhibitor, Triggers Cytotoxicity in Microvascular Endothelial Cells via Multi-Organelle Stress. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.25.645304. [PMID: 40196627 PMCID: PMC11974872 DOI: 10.1101/2025.03.25.645304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Proteasomes maintain cellular homeostasis by degrading abnormal proteins, while cancer cells exploit them for survival, becoming a key chemotherapeutic target. Bortezomib (BTZ), a reversible proteasomal inhibitor, is a front-line treatment for multiple myeloma, mantle cell lymphoma, and non-small cell lung cancer. However, its efficacy is limited by severe side effects, including neurotoxicity and cardiovascular distress, with its toxicity mechanisms largely unexplored. Here, we discover that Bortezomib (BTZ), is cytotoxic to non-cancerous cells distinctly from Carfilzomib (CFZ), the second-line irreversible PI. BTZ or CFZ is administered intravenously, impacting blood vessel (vascular) endothelial cells. We used human pulmonary microvascular endothelial cells (HPMECs) to demonstrate that BTZ but not CFZ elicits endoplasmic reticulum (ER) stress, mitochondrial membrane compromise, mitochondrial reactive oxygen species (ROS) accumulation, and Caspase (CASP)9 activation (mediator of Intrinsic apoptosis) within fifteen hours of treatment. By twenty-four hours, BTZ-treated cells display cleavage of CASP8 (mediator of extrinsic apoptosis), activation of CASP3 (terminal executioner of apoptosis), cell-death and vascular barrier loss. Pan-caspase inhibitor zVAD significantly rescues BTZ-treated cells from cytotoxicity. Both BTZ and CFZ effectively kill MM cells. These findings reveal novel insights into fundamental signaling of regular cells where reversible inhibition of the proteasome dictates a unique cascade of stress distinct from irreversible inhibition. These harmful effects of BTZ emphasize the need to re- evaluate its use as a frontline chemotherapy for MM. Highlights Reversible proteasomal inhibitor Bortezomib is cytotoxic to non-cancerous, microvascular endothelial cellsIn endothelial cells, Bortezomib, but not irreversible inhibitor Carfilzomib, activates temporal cascade of caspases (Caspase-9, Caspase-8, Caspase-3) triggering apoptosisCaspase activation results from ER stress (via the IRE1α-CHOP) pathway and mitochondrial stress (ROS accumulation) independently from contribution from extrinsic signal via TNFBortezomib-dependent cytotoxicity compromises endothelial barrier potential.
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4
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Durán-Cristiano SC, de Diego-García L, Martín-Gil A, Carracedo G. The Role of the Ubiquitin System in Eye Diseases. Life (Basel) 2025; 15:504. [PMID: 40141848 PMCID: PMC11943997 DOI: 10.3390/life15030504] [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: 01/30/2025] [Revised: 03/11/2025] [Accepted: 03/19/2025] [Indexed: 03/28/2025] Open
Abstract
The ubiquitin-proteasome system (UPS) is a fundamental process that regulates various biological functions, including immune response, cell cycle, oxidative stress, migration, and cellular proliferation. This system is responsible for the degradation of proteins, while proteasomes play a significant role in mechanisms involved in health and human diseases. The participation of the UPS in immune response is particularly relevant, leading to the involvement of immunoproteasomes. This specialized proteasome is involved in the processing and presentation of antigenic peptides, making it crucial for proper immune function. Moreover, the impact of the UPS is considered essential in understanding several diseases, such as neurodegenerative disorders, infections, and vascular diseases. The dysregulation of the UPS may contribute to the pathogenesis of these conditions, highlighting its importance as a potential therapeutic target. Interestingly, the UPS is also related to ocular structures, playing a role in visual perception and ocular homeostasis. This involvement in the regulation of various ocular processes suggests its potential impact on both anterior and posterior eye pathologies. This review aims to discuss the general considerations of the UPS and provide information about its participation in anterior and posterior eye pathologies. By understanding its role in ocular health and disease, researchers and clinicians may explore novel therapeutic strategies targeting the UPS for the treatment of various eye conditions. In conclusion, the UPS is a crucial player in biological processes, with far-reaching implications in health and disease, including the anterior and posterior segments of the eye. Further research in this field may lead to the development of innovative therapies and a better understanding of the complex mechanisms underlying various eye disorders.
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Affiliation(s)
| | - Laura de Diego-García
- Department of Biochemistry and Molecular Biology, Faculty of Optics and Optometry, Universidad Complutense de Madrid, 28037 Madrid, Spain
| | - Alba Martín-Gil
- Department of Optometry and Vision, Faculty of Optics and Optometry, Universidad Complutense de Madrid, 28037 Madrid, Spain; (A.M.-G.); (G.C.)
| | - Gonzalo Carracedo
- Department of Optometry and Vision, Faculty of Optics and Optometry, Universidad Complutense de Madrid, 28037 Madrid, Spain; (A.M.-G.); (G.C.)
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5
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Goldberg K, Lobov A, Antonello P, Shmueli MD, Yakir I, Weizman T, Ulman A, Sheban D, Laser E, Kramer MP, Shteinvil R, Chen G, Ibraheem A, Sysoeva V, Fishbain-Yoskovitz V, Mohapatra G, Abramov A, Shimshi S, Ogneva K, Nandy M, Amidror S, Bootz-Maoz H, Kuo SH, Dezorella N, Kacen A, Javitt A, Lau GW, Yissachar N, Hayouka Z, Merbl Y. Cell-autonomous innate immunity by proteasome-derived defence peptides. Nature 2025; 639:1032-1041. [PMID: 40044870 PMCID: PMC11946893 DOI: 10.1038/s41586-025-08615-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 01/08/2025] [Indexed: 03/25/2025]
Abstract
For decades, antigen presentation on major histocompatibility complex class I for T cell-mediated immunity has been considered the primary function of proteasome-derived peptides1,2. However, whether the products of proteasomal degradation play additional parts in mounting immune responses remains unknown. Antimicrobial peptides serve as a first line of defence against invading pathogens before the adaptive immune system responds. Although the protective function of antimicrobial peptides across numerous tissues is well established, the cellular mechanisms underlying their generation are not fully understood. Here we uncover a role for proteasomes in the constitutive and bacterial-induced generation of defence peptides that impede bacterial growth both in vitro and in vivo by disrupting bacterial membranes. In silico prediction of proteome-wide proteasomal cleavage identified hundreds of thousands of potential proteasome-derived defence peptides with cationic properties that may be generated en route to degradation to act as a first line of defence. Furthermore, bacterial infection induces changes in proteasome composition and function, including PSME3 recruitment and increased tryptic-like cleavage, enhancing antimicrobial activity. Beyond providing mechanistic insights into the role of proteasomes in cell-autonomous innate immunity, our study suggests that proteasome-cleaved peptides may have previously overlooked functions downstream of degradation. From a translational standpoint, identifying proteasome-derived defence peptides could provide an untapped source of natural antibiotics for biotechnological applications and therapeutic interventions in infectious diseases and immunocompromised conditions.
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Affiliation(s)
- Karin Goldberg
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Arseniy Lobov
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Paola Antonello
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Merav D Shmueli
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Idan Yakir
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agricultural, Food & Environment, The Hebrew University of Jerusalem, Rehovot, Israel
| | - Tal Weizman
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Adi Ulman
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Daoud Sheban
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Einav Laser
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Matthias P Kramer
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Ronen Shteinvil
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Guoyun Chen
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Angham Ibraheem
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Vera Sysoeva
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | | | - Gayatree Mohapatra
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Anat Abramov
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Sandy Shimshi
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Kseniia Ogneva
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Madhurima Nandy
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Sivan Amidror
- The Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
- Bar-Ilan Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan, Israel
| | - Hadar Bootz-Maoz
- The Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
- Bar-Ilan Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan, Israel
| | - Shanny H Kuo
- Department of Pathobiology, University of Illinois, Urbana, IL, USA
| | - Nili Dezorella
- Electron Microscopy Unit, Weizmann Institute of Science, Rehovot, Israel
| | - Assaf Kacen
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Aaron Javitt
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
| | - Gee W Lau
- Department of Pathobiology, University of Illinois, Urbana, IL, USA
| | - Nissan Yissachar
- The Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
- Bar-Ilan Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan, Israel
| | - Zvi Hayouka
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agricultural, Food & Environment, The Hebrew University of Jerusalem, Rehovot, Israel
| | - Yifat Merbl
- Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel.
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Evangelakou Z, Schwaiger S, Gianniou DD, Trougakos IP, Stuppner H. Neolignan Kadsurenin F Modulates Proteostatic Pathways and Possesses Potent Anti-Inflammatory Properties. Chem Biodivers 2025; 22:e202401848. [PMID: 39578962 PMCID: PMC11908775 DOI: 10.1002/cbdv.202401848] [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: 07/29/2024] [Accepted: 11/06/2024] [Indexed: 11/24/2024]
Abstract
Kadsurenin F, a natural neolignan-type compound, has been described as a constituent of various members of the Lauraceae family such as Aniba spp. or Nectandra spp., but can also be found in various Piper species such as Piper kadsura Ohwi (Piperaceae). This species is traditionally used to treat asthma, rheumatic pain, arthritis, and digestive problems. Recently, several studies have highlighted the significant anti-inflammatory potential of P. kadsura extracts and secondary metabolites. Here, we report the isolation of kadsurenin F as an active component of P. kadsura. We found that kadsurenin F increases oxidative load and suppresses proteasome functionality in normal diploid human fibroblasts, and after administration in Drosophila flies. Moreover, kadsurenin F likely possesses anti-inflammatory properties, as apart from suppressing proteasome activity, it reversed inflammatory phenotypes and inhibited NO production in RAW 264.7 macrophage cells when administered in parallel with LPS. Our findings suggest that the kadsurenin F scaffold can be used for the development of novel highly bioactive proteasome inhibitors and/or anti-inflammatory compounds.
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Affiliation(s)
- Zoi Evangelakou
- Department of Cell Biology and BiophysicsFaculty of BiologyNational and Kapodistrian University of AthensAthens15784Greece
| | - Stefan Schwaiger
- Institute of Pharmacy/PharmacognosyUniversity of InnsbruckCCB, Innrain 80–826020InnsbruckAustria
| | - Despoina D. Gianniou
- Department of Cell Biology and BiophysicsFaculty of BiologyNational and Kapodistrian University of AthensAthens15784Greece
| | - Ioannis P. Trougakos
- Department of Cell Biology and BiophysicsFaculty of BiologyNational and Kapodistrian University of AthensAthens15784Greece
| | - Hermann Stuppner
- Institute of Pharmacy/PharmacognosyUniversity of InnsbruckCCB, Innrain 80–826020InnsbruckAustria
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Zhou Y, Chen Y, Xu M, Zhang Y, Wan X, Xia Y, Wang H, Zeng H. The effect of proteasome in heart transplantation: From mechanisms to therapeutic potential. Life Sci 2025; 364:123446. [PMID: 39920983 DOI: 10.1016/j.lfs.2025.123446] [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: 01/02/2025] [Revised: 01/25/2025] [Accepted: 02/03/2025] [Indexed: 02/10/2025]
Abstract
Heart transplantation is a critical treatment for end-stage heart failure. However, its clinical efficacy is hindered by some challenges, such as ischemia-reperfusion injury (IRI) and post-transplant rejection. These complications significantly contribute to graft dysfunction and compromise patient survival. Emerging evidence underscores the involvement of proteasome in the pathophysiology of both IRI and post-transplant rejection. Proteasome inhibition has demonstrated potential in attenuating IRI by limiting oxidative damage and apoptosis while also mitigating rejection through the regulation of adaptive and innate immune responses. Recent advances in the development of proteasome inhibitors, particularly in optimizing specificity and minimizing adverse effects, have further strengthened their prospects for clinical application. This review focuses on the roles of the proteasome and its inhibitors in heart transplantation, with an emphasis on their mechanisms and therapeutic applications in managing IRI and rejection.
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Affiliation(s)
- Ye Zhou
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Provincial Engineering Research Center of Vascular Interventional Therapy, Wuhan 430030, Hubei, China
| | - Yu Chen
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
| | - Mengyao Xu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Ying Zhang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Provincial Engineering Research Center of Vascular Interventional Therapy, Wuhan 430030, Hubei, China
| | - Xiaoning Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Yudong Xia
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hongjie Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Provincial Engineering Research Center of Vascular Interventional Therapy, Wuhan 430030, Hubei, China.
| | - Hesong Zeng
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Provincial Engineering Research Center of Vascular Interventional Therapy, Wuhan 430030, Hubei, China.
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8
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Górska E, Tylicka M, Kamińska J, Hermanowicz A, Matuszczak E, Ołdak Ł, Gorodkiewicz E, Karpińska E, Socha K, Kochanowicz J, Jakoniuk M, Homšak E, Koper-Lenkiewicz OM. 20S constitutive proteasome, 20S immunoproteasome, and cathepsin S are high-sensitivity and independent markers of immunological activity in relapsing-remitting type of multiple sclerosis. J Neurochem 2024; 168:2880-2892. [PMID: 38923513 DOI: 10.1111/jnc.16165] [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: 12/28/2023] [Revised: 05/10/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024]
Abstract
Research on the markers of autoimmune response in multiple sclerosis (MS) is still of great importance. The aim of our study was the evaluation of plasma 20S constitutive proteasome, 20S immunoproteasome, and cathepsin S concentrations as potential biomarkers of a relapsing-remitting type of MS (RRMS). Surface plasmon resonance imaging (SPRI) biosensors were used for the evaluation of protein concentrations. Plasma 20S constitutive proteasome, 20S immunoproteasome, and cathepsin S concentrations were significantly higher in RRMS patients compared to the control group. All three parameters were characterized by excellent usefulness in differentiating MS patients from healthy individuals (AUC equal to or close to 1.000). The plasma concentration of analyzed parameters was not correlated with severity of disability in the course of RRMS (EDSS value), the number of years from the first MS symptoms, the number of years from MS diagnosis, or the number of relapses within the 24-month observational period. Our study has shown that plasma concentrations of 20S constitutive proteasome, 20S immunoproteasome, and cathepsin S have promising potential in differentiating RRMS patients from healthy individuals. All of the analyzed parameters were found to be independent of the time of MS relapse and the severity of neurological symptoms. Hence, their potential as highly sensitive and independent circulating markers of RRMS suggests a stronger association with immunological activity (inflammatory processes) than with the severity of the disease.
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Affiliation(s)
- Ewelina Górska
- Neurological Private Practice, Bialystok, Poland
- Department of Pediatric Surgery, Medical University of Bialystok, Bialystok, Poland
- Bioanalysis Laboratory, Faculty of Chemistry, University of Bialystok, Bialystok, Poland
| | - Marzena Tylicka
- Department of Biophysics, Medical University of Bialystok, Bialystok, Poland
| | - Joanna Kamińska
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Bialystok, Poland
| | - Adam Hermanowicz
- Department of Pediatric Surgery, Medical University of Bialystok, Bialystok, Poland
| | - Ewa Matuszczak
- Department of Pediatric Surgery, Medical University of Bialystok, Bialystok, Poland
| | - Łukasz Ołdak
- Bioanalysis Laboratory, Faculty of Chemistry, University of Bialystok, Bialystok, Poland
| | - Ewa Gorodkiewicz
- Bioanalysis Laboratory, Faculty of Chemistry, University of Bialystok, Bialystok, Poland
| | - Elżbieta Karpińska
- Department of Bromatology, Medical University of Białystok, Białystok, Poland
| | - Katarzyna Socha
- Department of Bromatology, Medical University of Białystok, Białystok, Poland
| | - Jan Kochanowicz
- Department of Neurology, Medical University of Białystok, Białystok, Poland
| | - Marta Jakoniuk
- Department of Invasive Neurology, Medical University of Białystok, Białystok, Poland
| | - Evgenija Homšak
- Department for Laboratory Diagnostics, University Clinical Centre Maribor, Maribor, Slovenia
- Department for Clinical Biochemistry, Medical Faculty, University Maribor, Maribor, Slovenia
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Pelissier A, Laragione T, Gulko PS, Rodríguez Martínez M. Cell-specific gene networks and drivers in rheumatoid arthritis synovial tissues. Front Immunol 2024; 15:1428773. [PMID: 39161769 PMCID: PMC11330812 DOI: 10.3389/fimmu.2024.1428773] [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: 05/07/2024] [Accepted: 06/24/2024] [Indexed: 08/21/2024] Open
Abstract
Rheumatoid arthritis (RA) is a common autoimmune and inflammatory disease characterized by inflammation and hyperplasia of the synovial tissues. RA pathogenesis involves multiple cell types, genes, transcription factors (TFs) and networks. Yet, little is known about the TFs, and key drivers and networks regulating cell function and disease at the synovial tissue level, which is the site of disease. In the present study, we used available RNA-seq databases generated from synovial tissues and developed a novel approach to elucidate cell type-specific regulatory networks on synovial tissue genes in RA. We leverage established computational methodologies to infer sample-specific gene regulatory networks and applied statistical methods to compare network properties across phenotypic groups (RA versus osteoarthritis). We developed computational approaches to rank TFs based on their contribution to the observed phenotypic differences between RA and controls across different cell types. We identified 18 (fibroblast-like synoviocyte), 16 (T cells), 19 (B cells) and 11 (monocyte) key regulators in RA synovial tissues. Interestingly, fibroblast-like synoviocyte (FLS) and B cells were driven by multiple independent co-regulatory TF clusters that included MITF, HLX, BACH1 (FLS) and KLF13, FOSB, FOSL1 (B cells). However, monocytes were collectively governed by a single cluster of TF drivers, responsible for the main phenotypic differences between RA and controls, which included RFX5, IRF9, CREB5. Among several cell subset and pathway changes, we also detected reduced presence of Natural killer T (NKT) cells and eosinophils in RA synovial tissues. Overall, our novel approach identified new and previously unsuspected Key driver genes (KDG), TF and networks and should help better understanding individual cell regulation and co-regulatory networks in RA pathogenesis, as well as potentially generate new targets for treatment.
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Affiliation(s)
- Aurelien Pelissier
- Institute of Computational Life Sciences, Zürich University of Applied Sciences (ZHAW), Wädenswil, Switzerland
- AI for Scientific Discovery, IBM Research Europe, Rüschlikon, Switzerland
- Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
| | - Teresina Laragione
- Division of Rheumatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Percio S. Gulko
- Division of Rheumatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - María Rodríguez Martínez
- AI for Scientific Discovery, IBM Research Europe, Rüschlikon, Switzerland
- Department of Biomedical Informatics & Data Science, Yale School of Medicine, New Haven, CT, United States
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10
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Fernandes PMP, Guedes RA, Victor BL, Salvador JAR, Guedes RC. Decoding the secrets: how conformational and structural regulators inhibit the human 20S proteasome. Front Chem 2024; 11:1322628. [PMID: 38260042 PMCID: PMC10801056 DOI: 10.3389/fchem.2023.1322628] [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: 10/16/2023] [Accepted: 12/15/2023] [Indexed: 01/24/2024] Open
Abstract
Acquired resistance to drugs that modulate specific protein functions, such as the human proteasome, presents a significant challenge in targeted therapies. This underscores the importance of devising new methodologies to predict drug binding and potential resistance due to specific protein mutations. In this work, we conducted an extensive computational analysis to ascertain the effects of selected mutations (Ala49Thr, Ala50Val, and Cys52Phe) within the active site of the human proteasome. Specifically, we sought to understand how these mutations might disrupt protein function either by altering protein stability or by impeding interactions with a clinical administered drug. Leveraging molecular dynamics simulations and molecular docking calculations, we assessed the effect of these mutations on protein stability and ligand affinity. Notably, our results indicate that the Cys52Phe mutation critically impacts protein-ligand binding, providing valuable insights into potential proteasome inhibitor resistance.
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Affiliation(s)
- Pedro M. P. Fernandes
- Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal
| | - Romina A. Guedes
- Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal
| | - Bruno L. Victor
- BioISI─Biosystems & Integrative Sciences Institute, Faculty of Sciences, Universidade de Lisboa, Lisboa, Portugal
| | - Jorge A. R. Salvador
- Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | - Rita C. Guedes
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal
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11
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Tang B, Yang X. Clinical advances in immunotherapy for immune-mediated glomerular diseases. Clin Exp Med 2023; 23:4091-4105. [PMID: 37889398 PMCID: PMC10725396 DOI: 10.1007/s10238-023-01218-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 10/09/2023] [Indexed: 10/28/2023]
Abstract
BACKGROUND AND OBJECTIVE Due to the suboptimal therapeutic efficacy and potential adverse effects associated with traditional immunosuppressive medications, there has been an increasing emphasis on the development and utilization of immunotherapies. This paper aims to provide clinicians with valuable insights for selecting appropriate therapeutic approaches and contribute to the development of novel immunotherapeutic drugs. MAIN BODY This paper categorizes the immunotherapeutic drugs that are used for the treatment of immune-mediated glomerular diseases into three groups: immunotherapies targeting antigen-presenting cells (anti-CD80), immunotherapies targeting T/B cells (anti-CD20, anti-CD22, BAFF and APRIL inhibitors, CD40-CD40L inhibitors, proteasome inhibitors, Syk inhibitors, and Btk inhibitors), and immunotherapies targeting the complement system (C5 inhibitors, C5a/C5aR inhibitors, C3 inhibitors, MASP2 inhibitors, factor B inhibitors, and factor D inhibitors). The article then provides a comprehensive overview of advances related to these immunotherapeutic drugs in clinical research. CONCLUSION Certain immunotherapeutic drugs, such as rituximab, belimumab, and eculizumab, have exhibited notable efficacy in treating specific immune-mediated glomerular diseases, thereby providing novel therapeutic approaches for patients. Nonetheless, the efficacy of numerous immunotherapeutic drugs remains to be substantiated.
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Affiliation(s)
- Bihui Tang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Xiao Yang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
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12
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Pickett JR, Wu Y, Zacchi LF, Ta HT. Targeting endothelial vascular cell adhesion molecule-1 in atherosclerosis: drug discovery and development of vascular cell adhesion molecule-1-directed novel therapeutics. Cardiovasc Res 2023; 119:2278-2293. [PMID: 37595265 PMCID: PMC10597632 DOI: 10.1093/cvr/cvad130] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 06/14/2023] [Accepted: 07/04/2023] [Indexed: 08/20/2023] Open
Abstract
Vascular cell adhesion molecule-1 (VCAM-1) has been well established as a critical contributor to atherosclerosis and consequently as an attractive therapeutic target for anti-atherosclerotic drug candidates. Many publications have demonstrated that disrupting the VCAM-1 function blocks monocyte infiltration into the sub-endothelial space, which effectively prevents macrophage maturation and foam cell transformation necessary for atherosclerotic lesion formation. Currently, most VCAM-1-inhibiting drug candidates in pre-clinical and clinical testing do not directly target VCAM-1 itself but rather down-regulate its expression by inhibiting upstream cytokines and transcriptional regulators. However, the pleiotropic nature of these regulators within innate immunity means that optimizing dosage to a level that suppresses pathological activity while preserving normal physiological function is extremely challenging and oftentimes infeasible. In recent years, highly specific pharmacological strategies that selectively inhibit VCAM-1 function have emerged, particularly peptide- and antibody-based novel therapeutics. Studies in such VCAM-1-directed therapies so far remain scarce and are limited by the constraints of current experimental atherosclerosis models in accurately representing the complex pathophysiology of the disease. This has prompted the need for a comprehensive review that recounts the evolution of VCAM-1-directed pharmaceuticals and addresses the current challenges in novel anti-atherosclerotic drug development.
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Affiliation(s)
- Jessica R Pickett
- Queensland Micro- and Nanotechnology Centre (QMNC), Griffith University, West Creek Road, Nathan, QLD 4111, Australia
- School of Environment and Science, Griffith University, Kessels Road, Nathan, QLD 4111, Australia
| | - Yuao Wu
- Queensland Micro- and Nanotechnology Centre (QMNC), Griffith University, West Creek Road, Nathan, QLD 4111, Australia
| | - Lucia F Zacchi
- Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland, St. Lucia, QLD 4072, Australia
- School of Chemistry and Molecular Biosciences, the University of Queensland, St. Lucia, QLD 4072, Australia
| | - Hang T Ta
- Queensland Micro- and Nanotechnology Centre (QMNC), Griffith University, West Creek Road, Nathan, QLD 4111, Australia
- School of Environment and Science, Griffith University, Kessels Road, Nathan, QLD 4111, Australia
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13
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Malmhäll-Bah E, Andersson KM, Erlandsson MC, Silfverswärd ST, Pullerits R, Bokarewa MI. Metabolic signature and proteasome activity controls synovial migration of CDC42hiCD14 + cells in rheumatoid arthritis. Front Immunol 2023; 14:1187093. [PMID: 37662900 PMCID: PMC10469903 DOI: 10.3389/fimmu.2023.1187093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 07/31/2023] [Indexed: 09/05/2023] Open
Abstract
OBJECTIVE Activation of Rho-GTPases in macrophages causes inflammation and severe arthritis in mice. In this study, we explore if Rho-GTPases define the joint destination of pathogenic leukocytes, the mechanism by which they perpetuate rheumatoid arthritis (RA), and how JAK inhibition mitigates these effects. METHODS CD14+ cells of 136 RA patients were characterized by RNA sequencing and cytokine measurement to identify biological processes and transcriptional regulators specific for CDC42 hiCD14+ cells, which were summarized in a metabolic signature (MetSig). The effect of hypoxia and IFN-γ signaling on the metabolic signature of CD14+ cells was assessed experimentally. To investigate its connection with joint inflammation, the signature was translated into the single-cell characteristics of CDC42 hi synovial tissue macrophages. The sensitivity of MetSig to the RA disease activity and the treatment effect were assessed experimentally and clinically. RESULTS CDC42 hiCD14+ cells carried MetSig of genes functional in the oxidative phosphorylation and proteasome-dependent cell remodeling, which correlated with the cytokine-rich migratory phenotype and antigen-presenting capacity of these cells. Integration of CDC42 hiCD14+ and synovial macrophages marked with MetSig revealed the important role of the interferon-rich environment and immunoproteasome expression in the homeostasis of these pathogenic macrophages. The CDC42 hiCD14+ cells were targeted by JAK inhibitors and responded with the downregulation of immunoproteasome and MHC-II molecules, which disintegrated the immunological synapse, reduced cytokine production, and alleviated arthritis. CONCLUSION This study shows that the CDC42-related MetSig identifies the antigen-presenting CD14+ cells that migrate to joints to coordinate autoimmunity. The accumulation of CDC42 hiCD14+ cells discloses patients perceptive to the JAKi treatment.
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Affiliation(s)
- Eric Malmhäll-Bah
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Karin M.E. Andersson
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Malin C. Erlandsson
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
- Rheumatology Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Sofia T. Silfverswärd
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Rille Pullerits
- Rheumatology Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Clinical Immunology and Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Maria I. Bokarewa
- Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
- Rheumatology Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden
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14
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Guedes RA, Grilo JH, Carvalho AN, Fernandes PMP, Ressurreição AS, Brito V, Santos AO, Silvestre S, Gallerani E, Gama MJ, Gavioli R, Salvador JAR, Guedes RC. New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies. Pharmaceuticals (Basel) 2023; 16:1096. [PMID: 37631011 PMCID: PMC10458307 DOI: 10.3390/ph16081096] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 07/26/2023] [Accepted: 07/31/2023] [Indexed: 08/27/2023] Open
Abstract
Cancer is a complex multifactorial disease whose pathophysiology involves multiple metabolic pathways, including the ubiquitin-proteasome system, for which several proteasome inhibitors have already been approved for clinical use. However, the resistance to existing therapies and the occurrence of severe adverse effects is still a concern. The purpose of this study was the discovery of novel scaffolds of proteasome inhibitors with anticancer activity, aiming to overcome the limitations of the existing proteasome inhibitors. Thus, a structure-based virtual screening protocol was developed using the structure of the human 20S proteasome, and 246 compounds from virtual databases were selected for in vitro evaluation, namely proteasome inhibition assays and cell viability assays. Compound 4 (JHG58) was shortlisted as the best hit compound based on its potential in terms of proteasome inhibitory activity and its ability to induce cell death (both with IC50 values in the low micromolar range). Molecular docking studies revealed that compound 4 interacts with key residues, namely with the catalytic Thr1, Ala20, Thr21, Lys33, and Asp125 at the chymotrypsin-like catalytic active site. The hit compound is a good candidate for additional optimization through a hit-to-lead campaign.
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Affiliation(s)
- Romina A. Guedes
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisboa, Portugal or (R.A.G.); (J.H.G.); (A.N.C.); (P.M.P.F.); (A.S.R.); (M.J.G.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal
- Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Jorge H. Grilo
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisboa, Portugal or (R.A.G.); (J.H.G.); (A.N.C.); (P.M.P.F.); (A.S.R.); (M.J.G.)
| | - Andreia N. Carvalho
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisboa, Portugal or (R.A.G.); (J.H.G.); (A.N.C.); (P.M.P.F.); (A.S.R.); (M.J.G.)
| | - Pedro M. P. Fernandes
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisboa, Portugal or (R.A.G.); (J.H.G.); (A.N.C.); (P.M.P.F.); (A.S.R.); (M.J.G.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal
- Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Ana S. Ressurreição
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisboa, Portugal or (R.A.G.); (J.H.G.); (A.N.C.); (P.M.P.F.); (A.S.R.); (M.J.G.)
| | - Vanessa Brito
- Health Sciences Research Centre (CICS-UBI), University of Beira Interior, 6200-506 Covilhã, Portugal; (V.B.); (A.O.S.); (S.S.)
| | - Adriana O. Santos
- Health Sciences Research Centre (CICS-UBI), University of Beira Interior, 6200-506 Covilhã, Portugal; (V.B.); (A.O.S.); (S.S.)
| | - Samuel Silvestre
- Health Sciences Research Centre (CICS-UBI), University of Beira Interior, 6200-506 Covilhã, Portugal; (V.B.); (A.O.S.); (S.S.)
| | - Eleonora Gallerani
- Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy;
| | - Maria João Gama
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisboa, Portugal or (R.A.G.); (J.H.G.); (A.N.C.); (P.M.P.F.); (A.S.R.); (M.J.G.)
| | - Riccardo Gavioli
- Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy;
| | - Jorge A. R. Salvador
- Center for Innovative Biomedicine and Biotechnology (CIBB), Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal
- Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Rita C. Guedes
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisboa, Portugal or (R.A.G.); (J.H.G.); (A.N.C.); (P.M.P.F.); (A.S.R.); (M.J.G.)
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15
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Farina N, Campochiaro C, Lescoat A, Benanti G, De Luca G, Khanna D, Dagna L, Matucci-Cerinic M. Drug development and novel therapeutics to ensure a personalized approach in the treatment of systemic sclerosis. Expert Rev Clin Immunol 2023; 19:1131-1142. [PMID: 37366065 DOI: 10.1080/1744666x.2023.2230370] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 06/23/2023] [Indexed: 06/28/2023]
Abstract
INTRODUCTION Systemic sclerosis (SSc) is a systemic disease encompassing autoimmunity, vasculopathy, and fibrosis. SSc is still burdened by high mortality and morbidity rates. Recent advances in understanding the pathogenesis of SSc have identified novel potential therapeutic targets. Several clinical trials have been subsequently designed to evaluate the efficacy of a number of new drugs. The aim of this review is to provide clinicians with useful information about these novel molecules. AREA COVERED In this narrative review, we summarize the available evidence regarding the most promising targeted therapies currently under investigation for the treatment of SSc. These medications include kinase inhibitors, B-cell depleting agents, and interleukin inhibitors. EXPERT OPINION Over the next five years, several new, targeted drugs will be introduced in clinical practice for the treatment of SSc. Such pharmacological agents will expand the existing pharmacopoeia and enable a more personalized and effective approach to patients with SSc. Thus, it will not only possible to target a specific disease domain, but also different stages of the disease.
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Affiliation(s)
- N Farina
- Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Hospital, Milan, Italy
| | - C Campochiaro
- Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - A Lescoat
- Department of Internal Medicine and Clinical Immunology, Rennes University Hospital, Rennes, France
| | - G Benanti
- Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - G De Luca
- Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - D Khanna
- Department of Internal Medicine, University of Michigan, Ann Arbor, USA
| | - L Dagna
- Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - M Matucci-Cerinic
- Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Hospital, Milan, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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16
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Kuiper JJ, Prinz JC, Stratikos E, Kuśnierczyk P, Arakawa A, Springer S, Mintoff D, Padjen I, Shumnalieva R, Vural S, Kötter I, van de Sande MG, Boyvat A, de Boer JH, Bertsias G, de Vries N, Krieckaert CL, Leal I, Vidovič Valentinčič N, Tugal-Tutkun I, El Khaldi Ahanach H, Costantino F, Glatigny S, Mrazovac Zimak D, Lötscher F, Kerstens FG, Bakula M, Viera Sousa E, Böhm P, Bosman K, Kenna TJ, Powis SJ, Breban M, Gul A, Bowes J, Lories RJ, Nowatzky J, Wolbink GJ, McGonagle DG, Turkstra F. EULAR study group on ‘MHC-I-opathy’: identifying disease-overarching mechanisms across disciplines and borders. Ann Rheum Dis 2023:ard-2022-222852. [PMID: 36987655 DOI: 10.1136/ard-2022-222852] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 01/25/2023] [Indexed: 03/29/2023]
Abstract
The ‘MHC-I (major histocompatibility complex class I)-opathy’ concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet’s disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.
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Affiliation(s)
- Jonas Jw Kuiper
- Department of Ophthalmology, Center for Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Jörg C Prinz
- University Hospital, department of Dermatology and Allergy, Ludwig Maximilians University Munich, Munchen, Germany
| | - Efstratios Stratikos
- Laboratory of Biochemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Piotr Kuśnierczyk
- Laboratory of Immunogenetics and Tissue Immunology, Institute of Immunology and Experimental Therapy Ludwik Hirszfeld Polish Academy of Sciences, Wroclaw, Poland
| | - Akiko Arakawa
- University Hospital, department of Dermatology and Allergy, Ludwig Maximilians University Munich, Munchen, Germany
| | | | - Dillon Mintoff
- Department of Dermatology, Mater Dei Hospital, Msida, Malta
- Department of Pathology, University of Malta Faculty of Medicine and Surgery, Msida, Malta
| | - Ivan Padjen
- Division of Clinical Immunology and Rheumatology, University Hospital Centre Zagreb Department of Internal Medicine, Zagreb, Croatia
- University of Zagreb School of Medicine, Zagreb, Croatia
| | - Russka Shumnalieva
- Clinic of Rheumatology, Department of Rheumatology, Medical University of Sofia, Sofia, Bulgaria
| | - Seçil Vural
- School of Medicine, Department of Dermatology, Koç University, Istanbul, Turkey
| | - Ina Kötter
- Clinic for Rheumatology and Immunology, Bad Bramdsted Hospital, Bad Bramstedt, Germany
- Division of Rheumatology and Systemic Inflammatory Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marleen G van de Sande
- University of Amsterdam, Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Institute for Infection & Immunity, Amsterdam UMC Location AMC, Amsterdam, The Netherlands
- Amsterdam Rheumatology and Immunology Center (ARC) | Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Ayşe Boyvat
- Department of Dermatology, Ankara University Faculty of Medicine, Ankara, Turkey
| | - Joke H de Boer
- Department of Ophthalmology, Center for Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - George Bertsias
- Department of Rheumatology and Clinical Immunology, University of Crete School of Medicine, Iraklio, Greece
- Laboratory of Autoimmunity-Inflammation, Institute of Molecular Biology and Biotechnology, Heraklion, Greece
| | - Niek de Vries
- University of Amsterdam, Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Institute for Infection & Immunity, Amsterdam UMC Location AMC, Amsterdam, The Netherlands
- Amsterdam Rheumatology and Immunology Center (ARC) | Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Charlotte Lm Krieckaert
- Amsterdam Rheumatology and immunology Center (ARC)| Reade, Amsterdam, The Netherlands
- Department of Rheumatology, Reade Hoofdlocatie Dr Jan van Breemenstraat, Amsterdam, The Netherlands
| | - Inês Leal
- Department of Ophthalmology, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisboa, Portugal
- Centro de Estudeos das Ciencias da Visão, Universidade de Lisboa Faculdade de Medicina, Lisboa, Portugal
| | - Nataša Vidovič Valentinčič
- University Eye Clinic, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Ilknur Tugal-Tutkun
- Department of Ophthalmology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Hanane El Khaldi Ahanach
- Departement of Ophthalmology, Amsterdam UMC Location AMC, Amsterdam, The Netherlands
- Department of Ophthalmology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
| | - Félicie Costantino
- Service de Rheumatology, Hospital Ambroise-Pare, Boulogne-Billancourt, France
- Infection & Inflammation, UMR 1173, Inserm, UVSQ, University Paris-Saclay, Montigny-le-Bretonneux, France
| | - Simon Glatigny
- Infection & Inflammation, UMR 1173, Inserm, UVSQ/Université Paris Saclay, Montigny-le-Bretonneux, France
- Laboratoire d'Excellence Inflamex, Paris, France
| | | | - Fabian Lötscher
- Department of Rheumatology and Immunology, Inselspital University Hospital Bern, University of Bern, Bern, Switzerland
| | - Floor G Kerstens
- Amsterdam Rheumatology and immunology Center (ARC)| Reade, Amsterdam, The Netherlands
- Department of Rheumatology, Reade Hoofdlocatie Dr Jan van Breemenstraat, Amsterdam, The Netherlands
| | - Marija Bakula
- Division of Clinical Immunology and Rheumatology, University Hospital Centre Zagreb Department of Internal Medicine, Zagreb, Croatia
| | - Elsa Viera Sousa
- Rheumatology Research Unit Molecular João Lobo Antunes, University of Lisbon Medical Faculty, Lisboa, Portugal
- Rheumatology DepartmentSanta Maria Centro Hospital, Academic Medical Centre of Lisbon, Lisboa, Portugal
| | - Peter Böhm
- Patientpartner, German League against Rheumatism, Bonn, Germany
| | - Kees Bosman
- Patientpartner, Nationale Vereniging ReumaZorg, Nijmegen, The Netherlands
| | - Tony J Kenna
- Translational Research Institute, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Simon J Powis
- School of Medicine, University of St Andrews School of Medicine, St Andrews, UK
| | - Maxime Breban
- Service de Rheumatology, Hospital Ambroise-Pare, Boulogne-Billancourt, France
- Infection & Inflammation, UMR 1173, Inserm, UVSQ, University Paris-Saclay, Montigny-le-Bretonneux, France
| | - Ahmet Gul
- Division of Rheumatology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
| | - John Bowes
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Center, The University of Manchester, Manchester, UK
- NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester University NHS Foundation Trust, Manchester, UK
| | - Rik Ju Lories
- Department of Rheumatology, KU Leuven University Hospitals Leuven, Leuven, Belgium
- Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Johannes Nowatzky
- Department of Medicine, Division of Rheumatology, NYU Langone Behçet's Disease Program, NYU Langone Ocular Rheumatology Program, New York University Grossman School of Medicine, New York University, New York, New York, USA
- Department of Pathology, New York University Grossman School of Medicine, New York, New York, USA
| | - Gerrit Jan Wolbink
- Amsterdam Rheumatology and immunology Center (ARC)| Reade, Amsterdam, The Netherlands
- Department Immunopathology, Sanquin Research, Amsterdam, The Netherlands
| | - Dennis G McGonagle
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
- NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Franktien Turkstra
- Amsterdam Rheumatology and immunology Center (ARC)| Reade, Amsterdam, The Netherlands
- Department of Rheumatology, Reade Hoofdlocatie Dr Jan van Breemenstraat, Amsterdam, The Netherlands
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17
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Qureshi N, Desousa J, Siddiqui AZ, Morrison DC, Qureshi AA. Reprograming of Gene Expression of Key Inflammatory Signaling Pathways in Human Peripheral Blood Mononuclear Cells by Soybean Lectin and Resveratrol. Int J Mol Sci 2022; 23:12946. [PMID: 36361735 PMCID: PMC9659230 DOI: 10.3390/ijms232112946] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/17/2022] [Accepted: 10/20/2022] [Indexed: 02/03/2025] Open
Abstract
Inflammation is linked to several human diseases like microbial infections, cancer, heart disease, asthma, diabetes, and neurological disorders. We have shown that the prototype inflammatory agonist LPS modulates the activity of Ubiquitin-Proteasome System (UPS) and regulates transcription factors such as NF-κB, leading to inflammation, tolerance, hypoxia, autophagy, and apoptosis of cells. We hypothesized that proteasome modulators resveratrol and soybean lectin would alter the gene expression of mediators involved in inflammation-induced signaling pathways, when administered ex vivo to human peripheral blood mononuclear blood cells (PBMCs) obtained from normal healthy controls. To test this hypothesis, analysis of RNA derived from LPS-treated human PBMCs, with or without resveratrol and soybean lectin, was carried out using Next Generation Sequencing (NGS). Collectively, the findings described herein suggest that proteasome modulators, resveratrol (proteasome inhibitor) and lectins (proteasome activator), have a profound capacity to modulate cytokine expression in response to proteasome modulators, as well as expression of mediators in multiple signaling pathways in PBMCs of control subjects. We show for the first-time that resveratrol downregulates expression of mediators involved in several key signaling pathways IFN-γ, IL-4, PSMB8 (LMP7), and a subset of LPS-induced genes, while lectins induced IFN-γ, IL-4, PSMB8, and many of the same genes as LPS that are important for innate and adaptive immunity. These findings suggest that inflammation may be influenced by common dietary components and this knowledge may be used to prevent or reverse inflammation-based diseases.
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Affiliation(s)
- Nilofer Qureshi
- Department of Biomedical Sciences, Shock/Trauma Research Center, School of Medicine, University of Missouri, 2411 Holmes Street, Kansas City, MO 64108, USA
- Pharmacology/Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Julia Desousa
- Department of Biomedical Sciences, Shock/Trauma Research Center, School of Medicine, University of Missouri, 2411 Holmes Street, Kansas City, MO 64108, USA
- Pharmacology/Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Adeela Z. Siddiqui
- Department of Biomedical Sciences, Shock/Trauma Research Center, School of Medicine, University of Missouri, 2411 Holmes Street, Kansas City, MO 64108, USA
| | - David C. Morrison
- Department of Biomedical Sciences, Shock/Trauma Research Center, School of Medicine, University of Missouri, 2411 Holmes Street, Kansas City, MO 64108, USA
| | - Asaf A. Qureshi
- Department of Biomedical Sciences, Shock/Trauma Research Center, School of Medicine, University of Missouri, 2411 Holmes Street, Kansas City, MO 64108, USA
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18
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Iglesias M, Brennan DC, Larsen CP, Raimondi G. Targeting inflammation and immune activation to improve CTLA4-Ig-based modulation of transplant rejection. Front Immunol 2022; 13:926648. [PMID: 36119093 PMCID: PMC9478663 DOI: 10.3389/fimmu.2022.926648] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
For the last few decades, Calcineurin inhibitors (CNI)-based therapy has been the pillar of immunosuppression for prevention of organ transplant rejection. However, despite exerting effective control of acute rejection in the first year post-transplant, prolonged CNI use is associated with significant side effects and is not well suited for long term allograft survival. The implementation of Costimulation Blockade (CoB) therapies, based on the interruption of T cell costimulatory signals as strategy to control allo-responses, has proven potential for better management of transplant recipients compared to CNI-based therapies. The use of the biologic cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig is the most successful approach to date in this arena. Following evaluation of the BENEFIT trials, Belatacept, a high-affinity version of CTLA4-Ig, has been FDA approved for use in kidney transplant recipients. Despite its benefits, the use of CTLA4-Ig as a monotherapy has proved to be insufficient to induce long-term allograft acceptance in several settings. Multiple studies have demonstrated that events that induce an acute inflammatory response with the consequent release of proinflammatory cytokines, and an abundance of allograft-reactive memory cells in the recipient, can prevent the induction of or break established immunomodulation induced with CoB regimens. This review highlights advances in our understanding of the factors and mechanisms that limit CoB regimens efficacy. We also discuss recent successes in experimentally designing complementary therapies that favor CTLA4-Ig effect, affording a better control of transplant rejection and supporting their clinical applicability.
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Affiliation(s)
- Marcos Iglesias
- Vascularized and Composite Allotransplantation (VCA) Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Giorgio Raimondi, ; Marcos Iglesias,
| | - Daniel C. Brennan
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Christian P. Larsen
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States
| | - Giorgio Raimondi
- Vascularized and Composite Allotransplantation (VCA) Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Giorgio Raimondi, ; Marcos Iglesias,
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Gene Ontology Analysis Highlights Biological Processes Influencing Non-Response to Anti-TNF Therapy in Rheumatoid Arthritis. Biomedicines 2022; 10:biomedicines10081808. [PMID: 36009355 PMCID: PMC9404936 DOI: 10.3390/biomedicines10081808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/22/2022] [Accepted: 07/26/2022] [Indexed: 11/20/2022] Open
Abstract
Anti-TNF therapy has significantly improved disease control in rheumatoid arthritis, but a fraction of rheumatoid arthritis patients do not respond to anti-TNF therapy or lose response over time. Moreover, the mechanisms underlying non-response to anti-TNF therapy remain largely unknown. To date, many single biomarkers of response to anti-TNF therapy have been published but they have not yet been analyzed as a system of interacting nodes. The aim of our study is to systematically elucidate the biological processes underlying non-response to anti-TNF therapy in rheumatoid arthritis using the gene ontologies of previously published predictive biomarkers. Gene networks were constructed based on published biomarkers and then enriched gene ontology terms were elucidated in subgroups using gene ontology software tools. Our results highlight the novel role of proteasome-mediated protein catabolic processes (p = 2.91 × 10−15) and plasma lipoproteins (p = 4.55 × 10−11) in anti-TNF therapy response. The results of our gene ontology analysis help elucidate the biological processes underlying non-response to anti-TNF therapy in rheumatoid arthritis and encourage further study of the highlighted processes.
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20
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Pereira M, Vale N. Saquinavir: From HIV to COVID-19 and Cancer Treatment. Biomolecules 2022; 12:biom12070944. [PMID: 35883499 PMCID: PMC9313067 DOI: 10.3390/biom12070944] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/01/2022] [Accepted: 07/04/2022] [Indexed: 11/25/2022] Open
Abstract
Saquinavir was the first protease inhibitor developed for HIV therapy, and it changed the standard of treatment for this disease to a combination of drugs that ultimately led to increased survival of this otherwise deadly condition. Inhibiting the HIV protease impedes the virus from maturing and replicating. With this in mind, since the start of the COVID-19 outbreak, the research for already approved drugs (mainly antivirals) to repurpose for treatment of this disease has increased. Among the drugs tested, saquinavir showed promise in silico and in vitro in the inhibition of the SARS-CoV-2 main protease (3CLpro). Another field for saquinavir repurposing has been in anticancer treatment, in which it has shown effects in vitro and in vivo in several types of cancer, from Kaposi carcinoma to neuroblastoma, demonstrating cytotoxicity, apoptosis, inhibition of cell invasion, and improvement of radiosensibility of cancer cells. Despite the lack of follow-up in clinical trials for cancer use, there has been a renewed interest in this drug recently due to COVID-19, which shows similar pharmacological pathways and has developed superior in silico models that can be translated to oncologic research. This could help further testing and future approval of saquinavir repurposing for cancer treatment.
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Affiliation(s)
- Mariana Pereira
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal;
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Nuno Vale
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal;
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- Correspondence:
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21
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Black RM, Flaman LL, Lindblom K, Chubinskaya S, Grodzinsky AJ, Önnerfjord P. Tissue catabolism and donor-specific dexamethasone response in a human osteochondral model of post-traumatic osteoarthritis. Arthritis Res Ther 2022; 24:137. [PMID: 35689293 PMCID: PMC9185927 DOI: 10.1186/s13075-022-02828-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 05/22/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Post-traumatic osteoarthritis (PTOA) does not currently have clinical prognostic biomarkers or disease-modifying drugs, though promising candidates such as dexamethasone (Dex) exist. Many challenges in studying and treating this disease stem from tissue interactions that complicate understanding of drug effects. We present an ex vivo human osteochondral model of PTOA to investigate disease effects on cartilage and bone homeostasis and discover biomarkers for disease progression and drug efficacy. METHODS Human osteochondral explants were harvested from normal (Collins grade 0-1) ankle talocrural joints of human donors (2 female, 5 male, ages 23-70). After pre-equilibration, osteochondral explants were treated with a single-impact mechanical injury and TNF-α, IL-6, and sIL-6R ± 100 nM Dex for 21 days and media collected every 2-3 days. Chondrocyte viability, tissue DNA content, and glycosaminoglycan (sGAG) percent loss to the media were assayed and compared to untreated controls using a linear mixed effects model. Mass spectrometry analysis was performed for both cartilage tissue and pooled culture medium, and the statistical significance of protein abundance changes was determined with the R package limma and empirical Bayes statistics. Partial least squares regression analyses of sGAG loss and Dex attenuation of sGAG loss against proteomic data were performed. RESULTS Injury and cytokine treatment caused an increase in the release of matrix components, proteases, pro-inflammatory factors, and intracellular proteins, while tissue lost intracellular metabolic proteins, which was mitigated with the addition of Dex. Dex maintained chondrocyte viability and reduced sGAG loss caused by injury and cytokine treatment by 2/3 overall, with donor-specific differences in the sGAG attenuation effect. Biomarkers of bone metabolism had mixed effects, and collagen II synthesis was suppressed with both disease and Dex treatment by 2- to 5-fold. Semitryptic peptides associated with increased sGAG loss were identified. Pro-inflammatory humoral proteins and apolipoproteins were associated with lower Dex responses. CONCLUSIONS Catabolic effects on cartilage tissue caused by injury and cytokine treatment were reduced with the addition of Dex in this osteochondral PTOA model. This study presents potential peptide biomarkers of early PTOA progression and Dex efficacy that can help identify and treat patients at risk of PTOA.
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Affiliation(s)
- Rebecca Mae Black
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
| | - Lisa L Flaman
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Karin Lindblom
- Rheumatology and Molecular Skeletal Biology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden
| | - Susan Chubinskaya
- Departments of Pediatrics, Orthopedic Surgery and Medicine (Section of Rheumatology), Rush University Medical Center, Chicago, IL, USA
| | - Alan J Grodzinsky
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Patrik Önnerfjord
- Rheumatology and Molecular Skeletal Biology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden
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22
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B cells in autoimmune hepatitis: bystanders or central players? Semin Immunopathol 2022; 44:411-427. [PMID: 35488094 PMCID: PMC9256567 DOI: 10.1007/s00281-022-00937-5] [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] [Received: 02/24/2022] [Accepted: 04/07/2022] [Indexed: 02/07/2023]
Abstract
B cells are central for the adaptive immune system to mount successful immune responses not only as antibody producers but also as regulators of cellular immunity. These multifaceted features are also reflected in autoimmunity where autoreactive B cells can fuel disease by production of cytotoxic autoantibodies, presentation of autoantigens to autoreactive T cells, and secretion of cytokines and chemokines that either promote detrimental immune activation or impair regulatory T and B cells. The role of B cells and autoantibodies in autoimmune hepatitis (AIH) have been controversially discussed, with typical autoantibodies and hypergammaglobulinemia indicating a key role, while strong HLA class II association suggests T cells as key players. In this review, we summarize current knowledge on B cells in AIH and how different B cell subpopulations may drive AIH progression beyond autoantibodies. We also discuss recent findings of B cell-directed therapies in AIH.
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23
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Novel treatment strategies for acetylcholine receptor antibody-positive myasthenia gravis and related disorders. Autoimmun Rev 2022; 21:103104. [PMID: 35452851 DOI: 10.1016/j.autrev.2022.103104] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 04/18/2022] [Indexed: 11/21/2022]
Abstract
The presence of autoantibodies directed against the muscle nicotinic acetylcholine receptor (AChR) is the most common cause of myasthenia gravis (MG). These antibodies damage the postsynaptic membrane of the neuromuscular junction and cause muscle weakness by depleting AChRs and thus impairing synaptic transmission. As one of the best-characterized antibody-mediated autoimmune diseases, AChR-MG has often served as a reference model for other autoimmune disorders. Classical pharmacological treatments, including broad-spectrum immunosuppressive drugs, are effective in many patients. However, complete remission cannot be achieved in all patients, and 10% of patients do not respond to currently used therapies. This may be attributed to production of autoantibodies by long-lived plasma cells which are resistant to conventional immunosuppressive drugs. Hence, novel therapies specifically targeting plasma cells might be a suitable therapeutic approach for selected patients. Additionally, in order to reduce side effects of broad-spectrum immunosuppression, targeted immunotherapies and symptomatic treatments will be required. This review presents established therapies as well as novel therapeutic approaches for MG and related conditions, with a focus on AChR-MG.
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24
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Modulating the Ubiquitin–Proteasome System: A Therapeutic Strategy for Autoimmune Diseases. Cells 2022; 11:cells11071093. [PMID: 35406655 PMCID: PMC8997991 DOI: 10.3390/cells11071093] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/20/2022] [Accepted: 03/22/2022] [Indexed: 12/12/2022] Open
Abstract
Multiple sclerosis (MS) is an autoimmune, neurodegenerative disease associated with the central nervous system (CNS). Autoimmunity is caused by an abnormal immune response to self-antigens, which results in chronic inflammation and tissue death. Ubiquitination is a post-translational modification in which ubiquitin molecules are attached to proteins by ubiquitinating enzymes, and then the modified proteins are degraded by the proteasome system. In addition to regulating proteasomal degradation of proteins, ubiquitination also regulates other cellular functions that are independent of proteasomal degradation. It plays a vital role in intracellular protein turnover and immune signaling and responses. The ubiquitin–proteasome system (UPS) is primarily responsible for the nonlysosomal proteolysis of intracellular proteins. The 26S proteasome is a multicatalytic adenosine-triphosphate-dependent protease that recognizes ubiquitin covalently attached to particular proteins and targets them for degradation. Damaged, oxidized, or misfolded proteins, as well as regulatory proteins that govern many essential cellular functions, are removed by this degradation pathway. When this system is affected, cellular homeostasis is altered, resulting in the induction of a range of diseases. This review discusses the biochemistry and molecular biology of the UPS, including its role in the development of MS and proteinopathies. Potential therapies and targets involving the UPS are also addressed.
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25
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Immunoproteasome Activity in Chronic Lymphocytic Leukemia as a Target of the Immunoproteasome-Selective Inhibitors. Cells 2022; 11:cells11050838. [PMID: 35269460 PMCID: PMC8909520 DOI: 10.3390/cells11050838] [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] [Received: 01/27/2022] [Revised: 02/21/2022] [Accepted: 02/22/2022] [Indexed: 12/21/2022] Open
Abstract
Targeting proteasome with proteasome inhibitors (PIs) is an approved treatment strategy in multiple myeloma that has also been explored pre-clinically and clinically in other hematological malignancies. The approved PIs target both the constitutive and the immunoproteasome, the latter being present predominantly in cells of lymphoid origin. Therapeutic targeting of the immunoproteasome in cells with sole immunoproteasome activity may be selectively cytotoxic in malignant cells, while sparing the non-lymphoid tissues from the on-target PIs toxicity. Using activity-based probes to assess the proteasome activity profile and correlating it with the cytotoxicity assays, we identified B-cell chronic lymphocytic leukemia (B-CLL) to express predominantly immunoproteasome activity, which is associated with high sensitivity to approved proteasome inhibitors and, more importantly, to the immunoproteasome selective inhibitors LU005i and LU035i, targeting all immunoproteasome active subunits or only the immunoproteasome β5i, respectively. At the same time, LU102, a proteasome β2 inhibitor, sensitized B-CLL or immunoproteasome inhibitor-inherently resistant primary cells of acute myeloid leukemia, B-cell acute lymphoblastic leukemia, multiple myeloma and plasma cell leukemia to low doses of LU035i. The immunoproteasome thus represents a novel therapeutic target, which warrants further testing with clinical stage immunoproteasome inhibitors in monotherapy or in combinations.
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26
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Roberti A, Chaffey LE, Greaves DR. NF-κB Signaling and Inflammation-Drug Repurposing to Treat Inflammatory Disorders? BIOLOGY 2022; 11:372. [PMID: 35336746 PMCID: PMC8945680 DOI: 10.3390/biology11030372] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/12/2022] [Accepted: 02/15/2022] [Indexed: 12/15/2022]
Abstract
NF-κB is a central mediator of inflammation, response to DNA damage and oxidative stress. As a result of its central role in so many important cellular processes, NF-κB dysregulation has been implicated in the pathology of important human diseases. NF-κB activation causes inappropriate inflammatory responses in diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS). Thus, modulation of NF-κB signaling is being widely investigated as an approach to treat chronic inflammatory diseases, autoimmunity and cancer. The emergence of COVID-19 in late 2019, the subsequent pandemic and the huge clinical burden of patients with life-threatening SARS-CoV-2 pneumonia led to a massive scramble to repurpose existing medicines to treat lung inflammation in a wide range of healthcare systems. These efforts continue and have proven to be controversial. Drug repurposing strategies are a promising alternative to de novo drug development, as they minimize drug development timelines and reduce the risk of failure due to unexpected side effects. Different experimental approaches have been applied to identify existing medicines which inhibit NF-κB that could be repurposed as anti-inflammatory drugs.
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Affiliation(s)
| | | | - David R. Greaves
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK; (A.R.); (L.E.C.)
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27
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An P, Zhang LJ, Peng W, Chen YY, Liu QP, Luan X, Zhang H. Natural products are an important source for proteasome regulating agents. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 93:153799. [PMID: 34715511 DOI: 10.1016/j.phymed.2021.153799] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 09/14/2021] [Accepted: 10/07/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Natural medicines have a long history in the prevention and treatment of various diseases in East Asian region, especially in China. Modern research has proved that the pharmacological effects of numerous natural medicines involve the participation of ubiquitin proteasome system (UPS). UPS can degrade the unwanted and damaged proteins widely distributed in the nucleus and cytoplasm of various eukaryotes. PURPOSE The objective of the present study was to review and discuss the regulatory effects of natural products and extracts on proteasome components, which may help to find new proteasome regulators for drug development and clinical applications. METHODS The related information was compiled using the major scientific databases, such as CNKI, Elsevier, ScienceDirect, PubMed, SpringerLink, Wiley Online, and GeenMedical. The keywords "natural product" and "proteasome" were applied to extract the literature. Nature derived extracts, compounds and their derivatives involved in proteasome regulation were included, and the publications related to synthetic proteasome agents were excluded. RESULTS The pharmacological effects of more than 80 natural products and extracts derived from phytomedicines related to the proteasome regulation were reviewed. These natural products were classified according to their chemical properties. We also summarized some laws of action of natural products as proteasome regulators in the treatment of diseases, and listed the action characteristics of the typical natural products. CONCLUSION Natural products derived from nature can induce the degradation of damaged proteins through UPS or act as regulators to directly regulate the activity of proteasome. But few proteasome modulators are applied clinically. Summary of known rules for proteasome modulators will contribute to discover, modify and synthesize more proteasome modulators for clinical applications.
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Affiliation(s)
- Pei An
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No. 1200, Cailun Road, Pudong New Area, Shanghai 201203, China
| | - Li-Jun Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No. 1200, Cailun Road, Pudong New Area, Shanghai 201203, China
| | - Wei Peng
- School of pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yu-Ying Chen
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No. 1200, Cailun Road, Pudong New Area, Shanghai 201203, China
| | - Qiu-Ping Liu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No. 1200, Cailun Road, Pudong New Area, Shanghai 201203, China
| | - Xin Luan
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No. 1200, Cailun Road, Pudong New Area, Shanghai 201203, China.
| | - Hong Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No. 1200, Cailun Road, Pudong New Area, Shanghai 201203, China.
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28
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Wang L, Liu L, Hong X, Liu D, Cheng Z. Delanzomib, a Novel Proteasome Inhibitor, Combined With Adalimumab Drastically Ameliorates Collagen-Induced Arthritis in Rats by Improving and Prolonging the Anti-TNF-α Effect of Adalimumab. Front Pharmacol 2021; 12:782385. [PMID: 34880764 PMCID: PMC8645831 DOI: 10.3389/fphar.2021.782385] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 11/08/2021] [Indexed: 12/16/2022] Open
Abstract
Delanzomib is a novel proteasome inhibitor initially developed for treating multiple myeloma. It was found to inhibit the expression of tumor necrosis factor alpha (TNF-α). This study aimed to investigate the ameliorating effect of delanzomib on collagen-induced arthritis (CIA) and to explore the pharmacodynamics and pharmacokinetics (PK) interactions between delanzomib and adalimumab. Rats with CIA were randomly assigned to receive the treatment with delanzomib, adalimumab, delanzomib combined with adalimumab, or placebo. Visual inspection and biochemical examinations including TNF-α, interleukin 6, and C-reactive protein were performed to assess arthritis severity during the treatment. The adalimumab concentration in rats was determined to evaluate the PK interaction between delanzomib and adalimumab. Also, the levels of neonatal Fc receptor (FcRn) and FcRn mRNA were measured to explore the role of FcRn in the PK interaction between delanzomib and adalimumab. As a result, delanzomib combined with adalimumab exhibited stronger anti-arthritis activity than a single drug because both drugs synergistically reduced TNF-α level in vivo. Delanzomib also decreased adalimumab elimination in rats by increasing the level of FcRn. The slower elimination of adalimumab in rats further prolonged the anti-TNF-α effect of adalimumab. Moreover, FcRn level was increased by delanzomib via suppressing FcRn degradation rather than promoting FcRn production. In conclusion, delanzomib combined with adalimumab may be a potential therapeutic approach for treating rheumatoid arthritis. The initial finding that the PK interaction occurred between delanzomib and adalimumab may have clinical relevance for patients who simultaneously take proteasome inhibitors and anti-TNF-α therapeutic proteins.
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Affiliation(s)
- Lei Wang
- Department of Rheumatology and Immunology, The Second Clinical Medical College, Jinan University (Shenzhen People’s Hospital), Shenzhen, China
- Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, China
| | - Lixiong Liu
- Department of Rheumatology and Immunology, The Second Clinical Medical College, Jinan University (Shenzhen People’s Hospital), Shenzhen, China
| | - Xiaoping Hong
- Department of Rheumatology and Immunology, The Second Clinical Medical College, Jinan University (Shenzhen People’s Hospital), Shenzhen, China
| | - Dongzhou Liu
- Department of Rheumatology and Immunology, The Second Clinical Medical College, Jinan University (Shenzhen People’s Hospital), Shenzhen, China
| | - Zeneng Cheng
- Research Institute of Drug Metabolism and Pharmacokinetics, School of Xiangya Pharmaceutical Sciences, Central South University, Changsha, China
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29
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Klimas R, Sgodzai M, Motte J, Mohamad N, Renk P, Blusch A, Grüter T, Pedreiturria X, Gobrecht P, Fischer D, Schneider-Gold C, Reinacher-Schick A, Tannapfel A, Yoon MS, Gold R, Pitarokoili K. Dose-dependent immunomodulatory effects of bortezomib in experimental autoimmune neuritis. Brain Commun 2021; 3:fcab238. [PMID: 34708206 PMCID: PMC8545613 DOI: 10.1093/braincomms/fcab238] [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] [Received: 01/29/2021] [Revised: 05/02/2021] [Accepted: 06/09/2021] [Indexed: 11/13/2022] Open
Abstract
Proteasome inhibition with bortezomib has been reported to exert an immunomodulatory action in chronic autoimmune neuropathies. However, bortezomib used for the treatment of multiple myeloma induces a painful toxic polyneuropathy at a higher concentration. Therefore, we addressed this controversial effect and evaluated the neurotoxic and immunomodulatory mode of action of bortezomib in experimental autoimmune neuritis. Bortezomib-induced neuropathy was investigated in Lewis rats using the von Frey hair test, electrophysiological, qPCR and histological analyses of the sciatic nerve as well as dorsal root ganglia outgrowth studies. The immunomodulatory potential of bortezomib was characterized in Lewis rats after experimental autoimmune neuritis induction with P253-78 peptide. Clinical, electrophysiological, histological evaluation, von Frey hair test, flow cytometric and mRNA analyses were used to unravel the underlying mechanisms. We defined the toxic concentration of 0.2 mg/kg bortezomib applied intraperitoneally at Days 0, 4, 8 and 12. This dosage induces a painful toxic neuropathy but preserves axonal regeneration in vitro. Bortezomib at a concentration of 0.05 mg/kg significantly ameliorated experimental autoimmune neuritis symptoms, improved experimental autoimmune neuritis-induced hyperalgesia and nerve conduction studies, and reduced immune cell infiltration. Furthermore, proteasome inhibition induced a transcriptional downregulation of Nfkb in the sciatic nerve, while its inhibitor Ikba (also known as Nfkbia) was upregulated. Histological analyses of bone marrow tissue revealed a compensatory increase of CD138+ plasma cells. Our data suggest that low dose bortezomib (0.05 mg/kg intraperitoneally) has an immunomodulatory effect in the context of experimental autoimmune neuritis through proteasome inhibition and downregulation of nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFKB). Higher bortezomib concentrations (0.2 mg/kg intraperitoneally) induce sensory neuropathy; however, the regeneration potential remains unaffected. Our data empathizes that bortezomib may serve as an attractive treatment option for inflammatory neuropathies in lower concentrations.
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Affiliation(s)
- Rafael Klimas
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Melissa Sgodzai
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Jeremias Motte
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Nuwin Mohamad
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Pia Renk
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Alina Blusch
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Thomas Grüter
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Xiomara Pedreiturria
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Philipp Gobrecht
- Department of Cell Physiology, Faculty of Biology and Biotechnology, Ruhr-University Bochum, 44801 Bochum, Germany
| | - Dietmar Fischer
- Department of Cell Physiology, Faculty of Biology and Biotechnology, Ruhr-University Bochum, 44801 Bochum, Germany
| | | | - Anke Reinacher-Schick
- Department of Oncology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Andrea Tannapfel
- Institute of Pathology, Ruhr-University Bochum, 44801 Bochum, Germany
| | - Min-Suk Yoon
- Department of Neurology, Evangelisches Krankenhaus Hattingen, 45525 Hattingen, Germany
| | - Ralf Gold
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Kalliopi Pitarokoili
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
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30
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Feng Q, Xia W, Wang S, Dai G, Jiao W, Guo N, Li H, Zhang G. Etodolac improves collagen induced rheumatoid arthritis in rats by inhibiting synovial inflammation, fibrosis and hyperplasia. MOLECULAR BIOMEDICINE 2021; 2:33. [PMID: 35006449 PMCID: PMC8607370 DOI: 10.1186/s43556-021-00052-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 08/04/2021] [Indexed: 12/14/2022] Open
Abstract
Synovial hyperplasia is the main cause of chronic rheumatoid arthritis (RA), but the mechanism of synovial hyperplasia is still unclear. Etodolac (ETD) is a selective COX-2 inhibitor for relieving pain and stiffness in RA, but the disease modifying effect is still lack of evidence. Proteomics method was used to study the differential proteome of synovial tissue in collagen induced arthritis (CIA) in rats. With the help of STRING analysis, the upregulated proteins enriched in the cluster of complement and coagulation cascades and platelet degranulation were highlighted, these proteins with fibrogenic factors Lum, CIV, CXI and Tgfbi participated in the synovial inflammation, fibrosis and hyperplasia in CIA. Based on KOG function class analysis, the proteins involved in the events of the central dogma was explored. They might be hyperplasia related proteins for most of them are related to the proliferation of cancer. ETD significantly attenuated synovial inflammation, fibrosis and hyperplasia in CIA rats by downregulating these proteins. Several proteins have not been observed in RA so far, such as Tmsb4x, Pura, Nfic, Ruvbl1, Snrpd3, U2af2, Srrm2, Srsf7, Elavl1, Hnrnph1, Wars, Yars, Bzw2, Mcts1, Eif4b, Ctsh, Lamp1, Dpp7, Ptges3, Cdc37 and Septin9, they might be potentials targets for RA. Blood biochemistry tests showed the safety of 7 months use of ETD on rats. In conclusion, present study displayed a comprehensive mechanism of synovial hyperplasia in CIA rats, on this basis, the clinical value of ETD in the treatment of RA was well confirmed.
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Affiliation(s)
- Qin Feng
- Lunan Pharmaceutical Group Co., Ltd., Linyi, China.,Center for New Drug Safety Evaluation of Lunan Pharmaceutical, Lunan Pharmaceutical Group Co. Ltd., Linyi, China.,National Engineering and Technology Research Center of Chirality Pharmaceutical, Lunan Pharmaceutical Group Co. Ltd., Linyi, China
| | - Wenkai Xia
- Lunan Pharmaceutical Group Co., Ltd., Linyi, China.,Center for New Drug Safety Evaluation of Lunan Pharmaceutical, Lunan Pharmaceutical Group Co. Ltd., Linyi, China
| | - Shenglan Wang
- Lunan Pharmaceutical Group Co., Ltd., Linyi, China.,Center for New Drug Safety Evaluation of Lunan Pharmaceutical, Lunan Pharmaceutical Group Co. Ltd., Linyi, China
| | - Guoxin Dai
- Lunan Pharmaceutical Group Co., Ltd., Linyi, China.,Center for New Drug Safety Evaluation of Lunan Pharmaceutical, Lunan Pharmaceutical Group Co. Ltd., Linyi, China
| | - Weimei Jiao
- Lunan Pharmaceutical Group Co., Ltd., Linyi, China.,Center for New Drug Safety Evaluation of Lunan Pharmaceutical, Lunan Pharmaceutical Group Co. Ltd., Linyi, China
| | - Na Guo
- Lunan Pharmaceutical Group Co., Ltd., Linyi, China.,Center for New Drug Safety Evaluation of Lunan Pharmaceutical, Lunan Pharmaceutical Group Co. Ltd., Linyi, China
| | - Honghua Li
- Lunan Pharmaceutical Group Co., Ltd., Linyi, China.,Center for New Drug Safety Evaluation of Lunan Pharmaceutical, Lunan Pharmaceutical Group Co. Ltd., Linyi, China
| | - Guimin Zhang
- Lunan Pharmaceutical Group Co., Ltd., Linyi, China. .,Center for New Drug Safety Evaluation of Lunan Pharmaceutical, Lunan Pharmaceutical Group Co. Ltd., Linyi, China. .,National Engineering and Technology Research Center of Chirality Pharmaceutical, Lunan Pharmaceutical Group Co. Ltd., Linyi, China.
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31
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Zhong B, Wang Y, Zou Q, Xuemeng C, Qian C, Chen C, Xiong J, Zheng Z, Zou L, Li J. Trajectory mapping of primary Sjögren's syndrome via transcriptome learning demonstrates limitations of peripheral blood sequencing. Int J Rheum Dis 2021; 24:1491-1499. [PMID: 34668328 DOI: 10.1111/1756-185x.14229] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 08/30/2021] [Accepted: 09/27/2021] [Indexed: 12/17/2022]
Abstract
Primary Sjögren's syndrome (pSS) is a complex autoimmune disease characterized by aberrant immune cell action against secretory glands throughout the body. A number of studies have previously identified unique characteristics in the circulating expression profile of white blood cells of pSS patients. However, the molecular progression pattern of pSS is unclear. Through a systematic analysis of pSS transcriptome information, we found that pSS transcriptomes display broad heterogeneity, but cannot be distinguished from the broad range of possible profiles of healthy controls. Instead, only sample learning using a subset of pre-identified signature genes could achieve partial separation through a trajectory governed by interferon activity. Interestingly, this trajectory is correlated with a decrease in dendritic cell counts. Our study thus highlights a major limitation to the utility of broad blood transcriptome analysis in the context of pSS, while also identifying several factors that influence the divergence between patient samples.
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Affiliation(s)
- Bing Zhong
- Department of Rheumatology, Southwest Hospital, Army Medical University, Chongqing, China
| | - Yaqiong Wang
- Department of Stomatology, Southwest Hospital, Army Medical University, Chongqing, China
| | - Qinghua Zou
- Department of Rheumatology, Southwest Hospital, Army Medical University, Chongqing, China
| | - Chen Xuemeng
- Department of Rheumatology, Southwest Hospital, Army Medical University, Chongqing, China
| | - Can Qian
- Department of Rheumatology, Southwest Hospital, Army Medical University, Chongqing, China
| | - Chengshun Chen
- Department of Rheumatology, Southwest Hospital, Army Medical University, Chongqing, China
| | - Jie Xiong
- Department of Ophthalmology, Southwest Hospital, Army Medical University, Chongqing, China
| | - Zihan Zheng
- Chongqing International Institute for Immunology, Chongqing, China
| | - Liyun Zou
- Department of Rheumatology, Southwest Hospital, Army Medical University, Chongqing, China.,Department of Immunology, Army Medical University, Chongqing, China
| | - Jingyi Li
- Department of Rheumatology, Southwest Hospital, Army Medical University, Chongqing, China.,Chongqing International Institute for Immunology, Chongqing, China
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32
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Fidor A, Cekała K, Wieczerzak E, Cegłowska M, Kasprzykowski F, Edwards C, Mazur-Marzec H. Nostocyclopeptides as New Inhibitors of 20S Proteasome. Biomolecules 2021; 11:biom11101483. [PMID: 34680116 PMCID: PMC8533403 DOI: 10.3390/biom11101483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/29/2021] [Accepted: 10/05/2021] [Indexed: 11/16/2022] Open
Abstract
Nostocyclopeptides (Ncps) are a small class of bioactive nonribosomal peptides produced solely by cyanobacteria of the genus Nostoc. In the current work, six Ncps were isolated from Nostoc edaphicum strain CCNP1411. The bioactivity of these compounds was tested in vitro against 20S proteasome, a proteolytic complex that plays an important role in maintaining cellular proteostasis. Dysfunction of the complex leads to many pathological disorders. The assays indicated selective activity of specific Ncp variants. For two linear peptide aldehydes, Ncp-A2-L and Ncp-E2-L, the inhibitory effects on chymotrypsin-like activity were revealed, while the cyclic variant, Ncp-A2, inactivated the trypsin-like site of this enzymatic complex. The aldehyde group was confirmed to be an important element of the chymotrypsin-like activity inhibitors. The nostocyclopeptides, as novel inhibitors of 20S proteasome, increased the number of natural products that can be considered potential regulators of cellular processes.
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Affiliation(s)
- Anna Fidor
- Division of Marine Biotechnology, Institute of Oceanography, University of Gdańsk, Marszałka Józefa Piłsudskiego 46, PL-81378 Gdynia, Poland;
| | - Katarzyna Cekała
- Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, PL-80308 Gdańsk, Poland; (K.C.); (E.W.); (F.K.)
| | - Ewa Wieczerzak
- Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, PL-80308 Gdańsk, Poland; (K.C.); (E.W.); (F.K.)
| | - Marta Cegłowska
- Institute of Oceanology, Polish Academy of Sciences, Powstańców Warszawy 55, PL-81712 Sopot, Poland;
| | - Franciszek Kasprzykowski
- Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, PL-80308 Gdańsk, Poland; (K.C.); (E.W.); (F.K.)
| | - Christine Edwards
- School of Pharmacy and Life Sciences, Robert Gordon University, Aberdeen AB10 7GJ, UK;
| | - Hanna Mazur-Marzec
- Division of Marine Biotechnology, Institute of Oceanography, University of Gdańsk, Marszałka Józefa Piłsudskiego 46, PL-81378 Gdynia, Poland;
- Correspondence:
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33
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Adams CD, Boutwell BB. Using multiple Mendelian randomization approaches and genetic correlations to understand obesity, urate, and gout. Sci Rep 2021; 11:17799. [PMID: 34493793 PMCID: PMC8423843 DOI: 10.1038/s41598-021-97410-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 08/18/2021] [Indexed: 11/09/2022] Open
Abstract
Observational studies suggest relationships between obesity, urate, and gout but are possibly confounded. We assessed whether genetically determined obesity, higher urate (and related traits), and gout were causal using multiple Mendelian randomization (MR) approaches and linkage disequilibrium score regression for genetic correlations (rg). For data, we used genome-wide association study summary statistics available through MR-Base. We observed that obesity increased urate (beta = 0.127; 95% CI = 0.098, 0.157; P-value = 1.2E-17; rg = 0.25 [P-value = 0.001]) and triglycerides (beta = 0.082; 95% CI = 0.065, 0.099; P-value = 1.2E-21; rg = 0.23 [P-value = 8.8E-12]) and decreased high-density lipoprotein cholesterol (HDL) (beta = - 0.083; 95% CI = - 0.101, - 0.065; P-value = 2.5E-19; rg = - 0.28; [P-value = 5.2E-24]). Higher triglycerides increased urate (beta = 0.198; 95% CI = 0.146, 0.251; P-value = 8.9E-14; rg = 0.29 [P-value = 0.001]) and higher HDL decreased urate (beta = - 0.109; 95% CI = - 0.148, - 0.071; P-value = 2.7E- 08; rg = - 0.21 [P-value = 9.8E-05]). Higher urate (OR = 1.030; 95% CI = 1.028, 1.032; P-value = 1.1E-130; rg = 0.89 [P-value = 1.7E-55]) and obesity caused gout (OR = 1.003; 95% CI = 1.001, 1.004; P-value = 1.3E-04; rg = 0.23 [P-value = 2.7E-05]). Obesity on gout with urate as a mediator revealed all the effect of obesity on gout occurred through urate. Obesity on low-density lipoprotein cholesterol (LDL) was null (beta = -0.011; 95% CI = -0.030, 0.008; P-value = 2.6E-01; rg = 0.03 [P-value = 0.369]). A multivariable MR of obesity, HDL, and triglycerides on urate showed obesity influenced urate when accounting for HDL and triglycerides. Obesity's impact on urate was exacerbated by it decreasing HDL.
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Affiliation(s)
- Charleen D Adams
- Department of Environmental Health, Program in Molecular and Integrative Physiological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
| | - Brian B Boutwell
- School of Applied Science, The University of Mississippi, P.O. Box 1848, University, MS, 38677, USA
- John D. Bower School of Population Health, University of Mississippi Medical Center, Jackson, MS, 39216, USA
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34
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Bortezomib: a proteasome inhibitor for the treatment of autoimmune diseases. Inflammopharmacology 2021; 29:1291-1306. [PMID: 34424482 DOI: 10.1007/s10787-021-00863-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 08/02/2021] [Indexed: 12/19/2022]
Abstract
Autoimmune diseases (ADs) are conditions in which the immune system cannot distinguish self from non-self and, as a result, tissue injury occurs primarily due to the action of various inflammatory mediators. Different immunosuppressive agents are used for the treatment of patients with ADs, but some clinical cases develop resistance to currently available therapies. The proteasome inhibitor bortezomib (BTZ) is an approved agent for first-line therapy of people with multiple myeloma. BTZ has been shown to improve the symptoms of different ADs in animal models and ameliorated symptoms in patients with systemic lupus erythematous, rheumatoid arthritis, myasthenia gravis, neuromyelitis optica spectrum disorder, Chronic inflammatory demyelinating polyneuropathy, and autoimmune hematologic diseases that were nonresponsive to conventional therapies. Proteasome inhibition provides a potent strategy for treating ADs. BTZ represents a proteasome inhibitor that can potentially be used to treat AD patients resistant to conventional therapies.
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35
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Kollár L, Gobec M, Szilágyi B, Proj M, Knez D, Ábrányi-Balogh P, Petri L, Imre T, Bajusz D, Ferenczy GG, Gobec S, Keserű GM, Sosič I. Discovery of selective fragment-sized immunoproteasome inhibitors. Eur J Med Chem 2021; 219:113455. [PMID: 33894528 DOI: 10.1016/j.ejmech.2021.113455] [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: 12/14/2020] [Revised: 03/14/2021] [Accepted: 04/05/2021] [Indexed: 11/26/2022]
Abstract
Proteasomes contribute to maintaining protein homeostasis and their inhibition is beneficial in certain types of cancer and in autoimmune diseases. However, the inhibition of the proteasomes in healthy cells leads to unwanted side-effects and significant effort has been made to identify inhibitors specific for the immunoproteasome, especially to treat diseases which manifest increased levels and activity of this proteasome isoform. Here, we report our efforts to discover fragment-sized inhibitors of the human immunoproteasome. The screening of an in-house library of structurally diverse fragments resulted in the identification of benzo[d]oxazole-2(3H)-thiones, benzo[d]thiazole-2(3H)-thiones, benzo[d]imidazole-2(3H)-thiones, and 1-methylbenzo[d]imidazole-2(3H)-thiones (with a general term benzoXazole-2(3H)-thiones) as inhibitors of the chymotrypsin-like (β5i) subunit of the immunoproteasome. A subsequent structure-activity relationship study provided us with an insight regarding growing vectors. Binding to the β5i subunit was shown and selectivity against the β5 subunit of the constitutive proteasome was determined. Thorough characterization of these compounds suggested that they inhibit the immunoproteasome by forming a disulfide bond with the Cys48 available specifically in the β5i active site. To obtain fragments with biologically more tractable covalent interactions, we performed a warhead scan, which yielded benzoXazole-2-carbonitriles as promising starting points for the development of selective immunoproteasome inhibitors with non-peptidic scaffolds.
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Affiliation(s)
- Levente Kollár
- Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, H-1117, Budapest, Hungary
| | - Martina Gobec
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, SI-1000, Ljubljana, Slovenia
| | - Bence Szilágyi
- Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, H-1117, Budapest, Hungary
| | - Matic Proj
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, SI-1000, Ljubljana, Slovenia
| | - Damijan Knez
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, SI-1000, Ljubljana, Slovenia
| | - Péter Ábrányi-Balogh
- Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, H-1117, Budapest, Hungary
| | - László Petri
- Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, H-1117, Budapest, Hungary
| | - Tímea Imre
- MS Metabolomics Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, H-1117, Budapest, Hungary
| | - Dávid Bajusz
- Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, H-1117, Budapest, Hungary
| | - György G Ferenczy
- Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, H-1117, Budapest, Hungary
| | - Stanislav Gobec
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, SI-1000, Ljubljana, Slovenia
| | - György M Keserű
- Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, H-1117, Budapest, Hungary.
| | - Izidor Sosič
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, SI-1000, Ljubljana, Slovenia.
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36
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Zian Z, Berry SPDG, Bahmaie N, Ghotbi D, Kashif A, Madkaikar M, Bargir UA, Abdullahi H, Khan H, Azizi G. The clinical efficacy of Rituximab administration in autoimmunity disorders, primary immunodeficiency diseases and malignancies. Int Immunopharmacol 2021; 95:107565. [PMID: 33773205 DOI: 10.1016/j.intimp.2021.107565] [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: 10/23/2020] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 02/06/2023]
Abstract
Rituximab (RTX), as a monoclonal antibody-based immunotherapeutic intervention targeting CD20 on B cells, has proven efficacy in the treatment of patients with some immune-mediated diseases. In the present review, we provided information on the immunobiological mechanisms of signaling for RTX and its clinical applications, according to the immune-pathophysiology involved in the microenvironment of multiple diseases. We highlighted combination therapy, dose schedules, and laboratory monitoring, as well as the associated common and rare side effects to avoid. We also discussed the efficacy and safety of RTX-based therapeutic strategies and whether RTX therapy can be used as a promising treatment regimen for autoimmune diseases, primary immunodeficiency diseases, and malignancies. Our review highlights and supports the importance of collaboration between basic medical researchers and clinical specialists when considering the use of RTX in the treatment of various immune-mediated disorders.
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Affiliation(s)
- Zeineb Zian
- Biomedical Genomics and Oncogenetics Research Laboratory, Faculty of Sciences and Techniques of Tangier, P.B. 416, Abdelmalek Essaadi University, Tetouan, Morocco
| | - S P Déo-Gracias Berry
- Centre de Recherches Médicales (CERMEL) de Lambaréné, B.P: 242, Gabon; Technical University of Munich, 80333, Germany
| | - Nazila Bahmaie
- Department of Allergy and Immunology, Faculty of Medicine, Graduate School of Health Science, Near East University (NEU), Nicosia, 99138, Northern Cyprus, Cyprus
| | - Dana Ghotbi
- Faculty of Biological Sciences, University of Kharazmi, Tehran 14911-15719, Iran
| | - Ali Kashif
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
| | - Manisha Madkaikar
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohaematology, Mumbai 400070, India
| | - Umair Ahmed Bargir
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohaematology, Mumbai 400070, India
| | - Hamisu Abdullahi
- Department of Immunology, School of Medical Laboratory Sciences, Usmanu Danfodiyo University Sokoto, 840232, Nigeria
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
| | - Gholamreza Azizi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj 3149779453, Iran.
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37
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Schiffrer ES, Proj M, Gobec M, Rejc L, Šterman A, Mravljak J, Gobec S, Sosič I. Synthesis and Biochemical Evaluation of Warhead-Decorated Psoralens as (Immuno)Proteasome Inhibitors. Molecules 2021; 26:molecules26020356. [PMID: 33445542 PMCID: PMC7826781 DOI: 10.3390/molecules26020356] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 01/03/2021] [Accepted: 01/09/2021] [Indexed: 02/07/2023] Open
Abstract
The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. Selective inhibition of its catalytic activities is therefore a viable approach for the treatment of these diseases. However, the development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. We previously reported 7H-furo[3,2-g]chromen-7-one (psoralen)-based compounds with an oxathiazolone warhead as selective inhibitors of the chymotrypsin-like (β5i) subunit of immunoproteasome. Here, we describe the influence of the electrophilic warhead variations at position 3 of the psoralen core on the inhibitory potencies. Despite mapping the chemical space with different warheads, all compounds showed decreased inhibition of the β5i subunit of immunoproteasome in comparison to the parent oxathiazolone-based compound. Although suboptimal, these results provide crucial information about structure–activity relationships that will serve as guidance for the further design of (immuno)proteasome inhibitors.
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Affiliation(s)
- Eva Shannon Schiffrer
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia; (E.S.S.); (M.P.); (M.G.); (A.Š.); (J.M.); (S.G.)
| | - Matic Proj
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia; (E.S.S.); (M.P.); (M.G.); (A.Š.); (J.M.); (S.G.)
| | - Martina Gobec
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia; (E.S.S.); (M.P.); (M.G.); (A.Š.); (J.M.); (S.G.)
| | - Luka Rejc
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia;
| | - Andrej Šterman
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia; (E.S.S.); (M.P.); (M.G.); (A.Š.); (J.M.); (S.G.)
| | - Janez Mravljak
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia; (E.S.S.); (M.P.); (M.G.); (A.Š.); (J.M.); (S.G.)
| | - Stanislav Gobec
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia; (E.S.S.); (M.P.); (M.G.); (A.Š.); (J.M.); (S.G.)
| | - Izidor Sosič
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia; (E.S.S.); (M.P.); (M.G.); (A.Š.); (J.M.); (S.G.)
- Correspondence: ; Tel.: +386-1-4769-569
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Fernández-Simón E, Lleixà C, Suarez-Calvet X, Diaz-Manera J, Illa I, Gallardo E, de Luna N. Proteasome inhibitors reduce thrombospondin-1 release in human dysferlin-deficient myotubes. BMC Musculoskelet Disord 2020; 21:784. [PMID: 33246442 PMCID: PMC7697384 DOI: 10.1186/s12891-020-03756-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 10/30/2020] [Indexed: 11/16/2022] Open
Abstract
Background Dysferlinopathies are a group of muscle disorders causing muscle weakness and absence or low levels of dysferlin, a type-II transmembrane protein and the causative gene of these dystrophies. Dysferlin is implicated in vesicle fusion, trafficking, and membrane repair. Muscle biopsy of patients with dysferlinopathy is characterized by the presence of inflammatory infiltrates. Studies in the muscle of both human and mouse models of dysferlinopathy suggest dysferlin deficient muscle plays a role in this inflammation by releasing thrombospondin-1. It has also been reported that vitamin D3 treatment enhances dysferlin expression. The ubiquitin-proteasome system recognizes and removes proteins that fail to fold or assemble properly and previous studies suggest that its inhibition could have a therapeutic effect in muscle dystrophies. Here we assessed whether inhibition of the ubiquitin proteasome system prevented degradation of dysferlin in immortalized myoblasts from a patients with two missense mutations in exon 44. Methods To assess proteasome inhibition we treated dysferlin deficient myotubes with EB1089, a vitamin D3 analog, oprozomib and ixazomib. Western blot was performed to analyze the effect of these treatments on the recovery of dysferlin and myogenin expression. TSP-1 was quantified using the enzyme-linked immunosorbent assay to analyze the effect of these drugs on its release. A membrane repair assay was designed to assess the ability of treated myotubes to recover after membrane injury and fusion index was also measured with the different treatments. Data were analyzed using a one-way ANOVA test followed by Tukey post hoc test and analysis of variance. A p ≤ 0.05 was considered statistically significant. Results Treatment with proteasome inhibitors and EB1089 resulted in a trend towards an increase in dysferlin and myogenin expression. Furthermore, EB1089 and proteasome inhibitors reduced the release of TSP-1 in myotubes. However, no effect was observed on the repair of muscle membrane after injury. Conclusions Our findings indicate that the ubiquitin-proteasome system might not be the main mechanism of mutant dysferlin degradation. However, its inhibition could help to improve muscle inflammation by reducing TSP-1 release. Supplementary Information The online version contains supplementary material available at 10.1186/s12891-020-03756-7.
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Affiliation(s)
- Esther Fernández-Simón
- Neuromuscular Diseases group. Institut de Recerca Hospital de Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autónoma de Barcelona, c/Sant Antoni Mª Claret 167, 08025, Barcelona, Spain
| | - Cinta Lleixà
- Neuromuscular Diseases group. Institut de Recerca Hospital de Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autónoma de Barcelona, c/Sant Antoni Mª Claret 167, 08025, Barcelona, Spain
| | - Xavier Suarez-Calvet
- Neuromuscular Diseases group. Institut de Recerca Hospital de Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autónoma de Barcelona, c/Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain
| | - Jordi Diaz-Manera
- Neuromuscular Diseases group. Institut de Recerca Hospital de Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autónoma de Barcelona, c/Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain.,Department of Neurology, Neuromuscular Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Isabel Illa
- Neuromuscular Diseases group. Institut de Recerca Hospital de Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autónoma de Barcelona, c/Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain.,Department of Neurology, Neuromuscular Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Eduard Gallardo
- Neuromuscular Diseases group. Institut de Recerca Hospital de Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autónoma de Barcelona, c/Sant Antoni Mª Claret 167, 08025, Barcelona, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
| | - Noemí de Luna
- Neuromuscular Diseases group. Institut de Recerca Hospital de Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autónoma de Barcelona, c/Sant Antoni Mª Claret 167, 08025, Barcelona, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
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Sprague DJ, Johnston JN. Substituted Imidazoline Synthesis: A Diastereo- and Enantioselective aza-Henry Route to a Human Proteasome Modulator. Org Lett 2020; 22:8496-8499. [PMID: 33054232 DOI: 10.1021/acs.orglett.0c03096] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The first enantio- and diastereoselective synthesis of Tepe's human proteasome modulator is described. Routes to this and other highly substituted chiral imidazolines generally produce racemic material. Key to the route disclosed here is a gram-scale anti-selective aza-Henry reaction of an α-alkyl α-nitro ester nucleophile, catalyzed by a Bis(Amidine) [BAM] chiral proton complex, delivering the key intermediate in high yield as a single stereoisomer. The adduct is reduced to the amino ester and converted to an imidazoline.
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Affiliation(s)
- Daniel J Sprague
- Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United States
| | - Jeffrey N Johnston
- Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United States
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Lee HS, Jeong GS. Salinosporamide A, a Marine-Derived Proteasome Inhibitor, Inhibits T Cell Activation through Regulating Proliferation and the Cell Cycle. Molecules 2020; 25:molecules25215031. [PMID: 33138297 PMCID: PMC7663257 DOI: 10.3390/molecules25215031] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/26/2020] [Accepted: 10/28/2020] [Indexed: 12/31/2022] Open
Abstract
The appropriate regulation of T cell activity under inflammatory conditions is crucial for maintaining immune homeostasis. Salinosporamide A discovered as a self-resistance product from the marine bacterium Salinospora tropica, has been used as a potent proteasome inhibitor (PI). Although PIs have been developed as novel therapeutics for autoimmune diseases, due to their immunosuppressive effect, whether salinosporamide A inhibits T cell activation remains unknown. The current study finds that salinosporamide A is not cytotoxic, but controls T cell proliferation. Results from our cell cycle arrest analysis revealed that salinosporamide A leads to cell cycle arrest and regulates the expression of cyclin-dependent kinases. Under activated conditions, salinosporamide A abrogated T cell activation by T cell receptor-mediated stimulation, in which the production of cytokines was inhibited by pretreatment with salinosporamide A. Furthermore, we demonstrated that the regulation of T cell activation by salinosporamide A is mediated by suppressing the MAPK pathway. Therefore, our results suggest that salinosporamide A effectively suppresses T cell activation through regulating T cell proliferation and the cell cycle and provides great insight into the development of novel therapeutics for autoimmune diseases or graft-versus-host disease.
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Affiliation(s)
| | - Gil-Saeng Jeong
- Correspondence: ; Tel.: +82-53-580-6649; Fax: +82-53-580-6645
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41
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Klöß S, Dehmel S, Braun A, Parnham MJ, Köhl U, Schiffmann S. From Cancer to Immune-Mediated Diseases and Tolerance Induction: Lessons Learned From Immune Oncology and Classical Anti-cancer Treatment. Front Immunol 2020; 11:1423. [PMID: 32733473 PMCID: PMC7360838 DOI: 10.3389/fimmu.2020.01423] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 06/02/2020] [Indexed: 12/27/2022] Open
Abstract
Success in cancer treatment over the last four decades has ranged from improvements in classical drug therapy to immune oncology. Anti-cancer drugs have also often proven beneficial for the treatment of inflammatory and autoimmune diseases. In this review, we report on challenging examples that bridge between treatment of cancer and immune-mediated diseases, addressing mechanisms and experimental models as well as clinical investigations. Patient-derived tumor xenograft (PDX) (humanized) mouse models represent useful tools for preclinical evaluation of new therapies and biomarker identification. However, new developments using human ex vivo approaches modeling cancer, for example in microfluidic human organs-on-chips, promise to identify key molecular, cellular and immunological features of human cancer progression in a fully human setting. Classical drugs which bridge the gap, for instance, include cytotoxic drugs, proteasome inhibitors, PI3K/mTOR inhibitors and metabolic inhibitors. Biologicals developed for cancer therapy have also shown efficacy in the treatment of autoimmune diseases. In immune oncology, redirected chimeric antigen receptor (CAR) T cells have achieved spectacular remissions in refractory B cell leukemia and lymphoma and are currently under development for tolerance induction using cell-based therapies such as CAR Tregs or NK cells. Finally, a brief outline will be given of the lessons learned from bridging cancer and autoimmune diseases as well as tolerance induction.
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Affiliation(s)
- Stephan Klöß
- Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany.,Institute of Cellular Therapeutics, Hannover Medical School (MHH), Hanover, Germany
| | - Susann Dehmel
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hanover, Germany
| | - Armin Braun
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hanover, Germany
| | - Michael J Parnham
- Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Frankfurt, Germany.,Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), Frankfurt, Germany
| | - Ulrike Köhl
- Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany.,Institute of Cellular Therapeutics, Hannover Medical School (MHH), Hanover, Germany.,Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), Frankfurt, Germany.,Institute of Clinical Immunology, University of Leipzig, Leipzig, Germany
| | - Susanne Schiffmann
- Institute of Clinical Pharmacology, University Hospital Frankfurt, Frankfurt, Germany.,Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Branch for Translational Medicine and Pharmacology (TMP), Frankfurt, Germany
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Hu J, Lu J, Zhang X, Wang C, Ren K, Chang Q, Ji M, Pan W, Ma B, Fan W. Peptidomic analysis on synovial tissue reveals galectin-1 derived peptide as a potential bioactive molecule against rheumatoid arthritis. Cytokine 2020; 131:155020. [DOI: 10.1016/j.cyto.2020.155020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 01/26/2020] [Accepted: 01/27/2020] [Indexed: 12/11/2022]
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43
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Autoimmune encephalitis and immune therapy: lessons from Argentina. Acta Neurol Belg 2020; 120:565-572. [PMID: 30182259 DOI: 10.1007/s13760-018-1013-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 08/30/2018] [Indexed: 10/28/2022]
Abstract
Autoimmune encephalitis (AE) is a common cause of noninfectious acute encephalitis. We aimed to provide the first review of immune therapy regimens used for patients with AE in Latin America, as well as the safety and efficacy associated with them, by reviewing the medical records of Argentine patients with AE treated between 2013 and 2018. Data included clinical symptoms, laboratory tests, electroencephalography, magnetic resonance imaging, cerebral spinal fluid, and neoplasm screenings. We examined ten AE patients who received first-line immunotherapy at a median of 2.5 months following symptom onset. Among these patients, five required second-line treatment: three received therapy at a median of 4 months (2-112) after symptom onset and were treated with rituximab, while two received therapy at a median of 4.5 (4-5) months after onset and received methylprednisolone for 6 months and initiated chronic treatment with azathioprine. By the last follow-up, their respective outcomes improved significantly. On the modified Rankin Scale, the median score decreased from 5 to 1 (p ≤ 0.05). Only two of the ten patients in our series experienced relapses; both had been treated with a combination of methylprednisolone and IVIG. The regimen after recurrence included rituximab and corticoids plus azathioprine. Neither patient had experienced another relapse by their last follow-up. Our findings demonstrate the importance of early and aggressive immunosuppressive therapy to achieve a good clinical outcome and a fast recovery without relapses.
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Turnbull MT, Siegel JL, Becker TL, Stephens AJ, Lopez-Chiriboga AS, Freeman WD. Early Bortezomib Therapy for Refractory Anti-NMDA Receptor Encephalitis. Front Neurol 2020; 11:188. [PMID: 32292386 PMCID: PMC7118211 DOI: 10.3389/fneur.2020.00188] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 02/27/2020] [Indexed: 11/26/2022] Open
Abstract
Introduction: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an increasingly recognized form of immune-mediated encephalitis. Here we present a case that represents the shortest hospitalization-to-bortezomib treatment timeline (42 days), and we believe that this is reflected in the patient's outcome with complete independence within a short timeframe. Case Report: We describe a case of anti-NMDA receptor encephalitis in an 18-year-old African American female presenting with progressive, medically refractory disease. Despite two rounds of high-dose intravenous steroids, plasma exchange, immunoglobulin administration, and rituximab for B-cell depletion, the patient failed to respond by hospital day 42 and received off-label use of the proteasome inhibitor bortezomib. During the 15 days after the bortezomib administration, the patient showed dramatic neurologic recovery that allowed her transfer out of the intensive care unit. At follow-up after 1-month, the patient reported feeling normal cognitively and showed dramatic improvement in cognitive scores. Conclusion: This case and literature review provide preliminary evidence that early treatment of anti-NMDA receptor encephalitis with the proteasome inhibitor bortezomib appears safe and tolerable. However, randomized trials are needed to show the efficacy and the long-term benefit.
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Affiliation(s)
- Marion T Turnbull
- Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
| | - Jason L Siegel
- Department of Neurology, Mayo Clinic, Jacksonville, FL, United States.,Department of Critical Care Medicine, Mayo Clinic, Jacksonville, FL, United States
| | - Tara L Becker
- Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
| | - Alana J Stephens
- Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
| | | | - William D Freeman
- Department of Neurology, Mayo Clinic, Jacksonville, FL, United States.,Department of Critical Care Medicine, Mayo Clinic, Jacksonville, FL, United States.,Department of Neurologic Surgery, Mayo Clinic, Jacksonville, FL, United States
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Abstract
Antibody-secreting plasma cells are the central pillars of humoral immunity. They are generated in a fundamental cellular restructuring process from naive B cells upon contact with antigen. This outstanding process is guided and controlled by a complex transcriptional network accompanied by a fascinating morphological metamorphosis, governed by the combined action of Blimp-1, Xbp-1 and IRF-4. The survival of plasma cells requires the intimate interaction with a specific microenvironment, consisting of stromal cells and cells of hematopoietic origin. Cell-cell contacts, cytokines and availability of metabolites such as glucose and amino acids modulate the survival abilities of plasma cells in their niches. Moreover, plasma cells have been shown to regulate immune responses by releasing cytokines. Furthermore, plasma cells are central players in autoimmune diseases and malignant transformation of plasma cells can result in the generation of multiple myeloma. Hence, the development of sophisticated strategies to deplete autoreactive plasma cells and myeloma cells represents a challenge for current and future research.
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Affiliation(s)
- Wolfgang Schuh
- Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger Center, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.
| | - Dirk Mielenz
- Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger Center, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Hans-Martin Jäck
- Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger Center, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
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Cordani R, Micalizzi C, Giacomini T, Gastaldi M, Franciotta D, Fioredda F, Buratti S, Morana G, Pirlo D, Renna S, Castagnola E, Risso M, Lanteri P, Vari MS, Mancardi MM. Bortezomib-Responsive Refractory Anti-N-Methyl-d-Aspartate Receptor Encephalitis. Pediatr Neurol 2020; 103:61-64. [PMID: 31759783 DOI: 10.1016/j.pediatrneurol.2019.09.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 08/23/2019] [Accepted: 09/09/2019] [Indexed: 11/24/2022]
Abstract
BACKGROUND Anti-N-methyl-d-aspartate receptor encephalitis is a central nervous system inflammatory autoimmune disease affecting adults and children. The use of first- and second-line immunotherapies is supported. Recent reports suggest the efficacy of bortezomib in severe anti-N-methyl-d-aspartate encephalitis in adult patients not responsive to second-line treatment; there are no data about pediatric patients. PATIENT DESCRIPTION We describe an eight-year-old child with anti-N-methyl-d-aspartate encephalitis not responsive to first- and second-line treatments who experienced marked clinical improvement after bortezomib administration. DISCUSSION Bortezomib is a selective and reversible inhibitor of the 26S proteasome, which is used to treat oncologic and rare autoimmune disorders in pediatric patients. As observed in adult patients, bortezomib administration induced anti-N-methyl-d-aspartate antibody titer decline and clinical improvement with an acceptable risk profile. CONCLUSION This is the first report of the use of bortezomib in children with anti-N-methyl-d-aspartate encephalitis; it could be a useful therapeutic option in children with refractory anti-N-methyl-d-aspartate encephalitis.
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Affiliation(s)
- Ramona Cordani
- Unit of Child Neuropsichiatry, Department of Neuroscience, Ophthalmology Genetics and Maternal Infantile Sciences (DINOGMI), University of Genoa, IRCCS Giannina Gaslini, Genova, Italy
| | | | - Thea Giacomini
- Unit of Child Neuropsichiatry, Department of Neuroscience, Ophthalmology Genetics and Maternal Infantile Sciences (DINOGMI), University of Genoa, IRCCS Giannina Gaslini, Genova, Italy
| | - Matteo Gastaldi
- Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy
| | - Diego Franciotta
- Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy
| | | | - Silvia Buratti
- Neonatal and Pediatric Intensive Care Unit, IRCCS Giannina Gaslini, Genova, Italy
| | - Giovanni Morana
- Unit of Neuroradiology, IRCCS Giannina Gaslini, Genova, Italy
| | - Daniela Pirlo
- Department of Emergency, IRCCS Giannina Gaslini, Genova, Italy
| | - Salvatore Renna
- Department of Emergency, IRCCS Giannina Gaslini, Genova, Italy
| | - Elio Castagnola
- Unit of Infectious Diseases, IRCCS Giannina Gaslini, Genova, Italy
| | - Marco Risso
- Unit of Immunology and Transfusional Medicine, IRCCS Giannina Gaslini, Genova, Italy
| | - Paola Lanteri
- Unit of Neurophysiology, IRCCS Giannina Gaslini, Genova, Italy
| | - Maria Stella Vari
- Unit of Pediatric Neurology and Neurogenerative Diseases, IRCCS Giannina Gaslini, Genova, Italy
| | - Maria Margherita Mancardi
- Unit of Child Neuropsichiatry, Department of Clinical and Surgical Neurosciences and Rehabilitation, IRCCS Giannina Gaslini, Genova, Italy.
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Is There a Future for Anti-CD38 Antibody Therapy in Systemic Autoimmune Diseases? Cells 2019; 9:cells9010077. [PMID: 31892266 PMCID: PMC7016693 DOI: 10.3390/cells9010077] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 12/17/2019] [Accepted: 12/23/2019] [Indexed: 12/14/2022] Open
Abstract
CD38 is a type II glycoprotein highly expressed on plasmablasts, short-lived and long-lived plasma cells, but weakly expressed on other lymphoid cells, myeloid cells and non-hematopoietic cells. This expression pattern makes CD38 an interesting target for a targeted therapy aiming to deplete antibody-producing plasma cells. We present data suggesting that anti-CD38 therapy may be effective for the prevention at the preclinical stage and for the treatment of established autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, Sjögren’s syndrome and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Given the high unmet need for efficacious disease-modifying treatment in these diseases, studies are warranted to determine if anti-CD38 antibody-based therapies may delay or prevent the disease progression of systemic autoimmune diseases.
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KONG L, LU J, ZHU H, ZHANG J. [Research progress on selective immunoproteasome inhibitors]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2019; 48:688-694. [PMID: 31955545 PMCID: PMC8800774 DOI: 10.3785/j.issn.1008-9292.2019.12.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 03/26/2019] [Indexed: 06/10/2023]
Abstract
Immunoproteasome is associated with various diseases such as hematologic malignancies, inflammatory, autoimmune and central nervous system diseases, and over expression of immunoproteasome is observed in all of these diseases. Immunoproteasome inhibitors can reduce the expression of immunoproteasome by inhibiting the production of related cell-inducing factors and the activity of T lymphocyte for treating related diseases. In order to achieve good efficacy and reduce the toxic effects, key for development of selective immunoproteasome inhibitors is the high selectivity and potent activity of the three active subunits of the proteasome. This review summarizes the structure and functions of immunoproteasome and the associated diseases. Besides, structure, activity and status of selective immunoproteasome inhibitors are also been highlighted.
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Affiliation(s)
| | | | | | - Jiankang ZHANG
- 张建康(1987-), 男, 博士, 讲师, 硕士生导师, 主要从事抗肿瘤药物研发工作, E-mail:
;
https://orcid.org/0000-0003-0365-7238
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Hirsch L, Bellesoeur A, Boudou-Rouquette P, Arrondeau J, Thomas-Schoemann A, Kirchgesner J, Gervais C, Jouinot A, Chapron J, Giraud F, Wislez M, Alexandre J, Blanchet B, Goldwasser F. The impact of body composition parameters on severe toxicity of nivolumab. Eur J Cancer 2019; 124:170-177. [PMID: 31794927 DOI: 10.1016/j.ejca.2019.11.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 10/25/2019] [Accepted: 11/04/2019] [Indexed: 12/29/2022]
Abstract
BACKGROUND The occurrence of severe, acute limiting toxicity in patients receiving anti-programmed cell death receptor-1 monoclonal antibodies, such as nivolumab, is largely unpredictable. Sarcopenia was found to be associated with anti-cytotoxic T-lymphocyte-associated protein 4 acute toxicity. We explore the clinical and pharmacological parameters influencing nivolumab toxicity, including body composition. METHODS From June 2015 to January 2017, all consecutive patients treated with nivolumab in our institution were prospectively included. We studied the relationship between muscle mass assessed by computed tomography, nivolumab trough level (Cmin) at day 14 assessed using the enzyme-linked immunosorbent assay method, and the occurrence of immune grade III or IV toxicity or any toxicity leading to treatment discontinuation (immune-related acute limiting toxicity [irALT]). RESULTS In our population (n = 92) with a majority of lung cancer (72%), forty-five (51.7%) patients were sarcopenic. The median plasma nivolumab Cmin at day 14 was 15.4 μg/mL (interquartile range = 11.8-21.0). In multivariate analysis, hypoalbuminaemia (<35 g/L) was independently associated with low nivolumab Cmin on day 14 (odds ratio [OR] = 0.09; 95% confidence interval [CI] = 0.01-0.59, p = 0.01) and overweight/obesity with high nivolumab Cmin on day 14 (OR = 5.94; 95% CI = 1.25-28.29, p = 0.03). We observed 22 irALTs in 19 patients (21%). The most frequent irALT was respiratory (6.5%) disorders and gastrointestinal (4.3%) disorders. Patients with sarcopenia were at significantly increased risk of experiencing an irALT (OR = 3.84; 95% CI = 1.02-14.46, p = 0.047). No association was found between toxicity and nivolumab plasma Cmin at day 14. CONCLUSIONS Our results highlight the importance of assessing body composition and suggest that sarcopenia could predict severe immune-related toxicity of nivolumab in real life.
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Affiliation(s)
- Laure Hirsch
- Department of Medical Oncology, Cochin Hospital, AP-HP 5, CARPEM, CERTIM, Paris, France.
| | - Audrey Bellesoeur
- Department of Medical Oncology, Cochin Hospital, AP-HP 5, CARPEM, CERTIM, Paris, France
| | | | - Jennifer Arrondeau
- Department of Medical Oncology, Cochin Hospital, AP-HP 5, CARPEM, CERTIM, Paris, France
| | - Audrey Thomas-Schoemann
- Department of Clinical Pharmacy, Cochin Hospital, AP-HP 5, CERTIM, Paris, France; UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, Université Paris Descartes, PRES Sorbonne Paris Cité, 75006, Paris, France
| | - Julien Kirchgesner
- Department of Gastroenterology, Saint-Antoine Hospital, AP-HP 6, Paris, France; Sorbonne Université, INSERM, Institut Pierre Louis D'Épidémiologie et de Santé Publique, Paris, France
| | - Claire Gervais
- Department of Medical Oncology, Cochin Hospital, AP-HP 5, CARPEM, CERTIM, Paris, France
| | - Anne Jouinot
- Department of Medical Oncology, Cochin Hospital, AP-HP 5, CARPEM, CERTIM, Paris, France; Cochin Institute, Inserm U1016, Université Paris Descartes, Paris, France
| | - Jeanne Chapron
- Department of Pneumology, Cochin Hospital, AP-HP 5, Paris, France
| | | | - Marie Wislez
- Department of Pneumology, Cochin Hospital, AP-HP 5, Paris, France; Cordeliers Research Center, Université Paris Descartes, Université de Paris, UMRS1138 "Inflammation, Complement and Cancer" Team, F-75006, Paris, France
| | - Jérôme Alexandre
- Department of Medical Oncology, Cochin Hospital, AP-HP 5, CARPEM, CERTIM, Paris, France; Cochin Institute, Inserm U1016, Université Paris Descartes, Paris, France
| | - Benoit Blanchet
- UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, Université Paris Descartes, PRES Sorbonne Paris Cité, 75006, Paris, France; Department of Pharmacokinetics and Pharmacochemisty, Cochin Hospital, AP-HP 5, CARPEM, Paris, France
| | - François Goldwasser
- Department of Medical Oncology, Cochin Hospital, AP-HP 5, CARPEM, CERTIM, Paris, France; Laboratory of Biological Nutrition EA, Pharmacy University, Université Paris Descartes, 4466, Paris, France
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Barnas JL, Looney RJ, Anolik JH. B cell targeted therapies in autoimmune disease. Curr Opin Immunol 2019; 61:92-99. [PMID: 31733607 DOI: 10.1016/j.coi.2019.09.004] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 09/17/2019] [Accepted: 09/22/2019] [Indexed: 12/26/2022]
Abstract
PURPOSE OF REVIEW FDA-approved B cell-targeted therapy has expanded to a multitude of autoimmune diseases ranging from organ specific diseases, like pemphigus and multiple sclerosis, to systemic diseases such as ANCA-associated vasculitis, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In this review, we discuss the variability in response to B cell-targeted therapies with a focus on the diversity of human B cells and plasma cells, and will discuss several of the promising new B cell-targeted therapies. RECENT FINDING The pathogenic roles for B cells include autoantibody-dependent and autoantibody-independent functions whose importance may vary across diseases or even in subsets of patients with the same disease. Recent data have further demonstrated the diversity of human B cell subsets that contribute to disease as well as novel pathways of B cell activation in autoimmune disease. The importance of eliminating autoreactive B cells and plasma cells will be discussed, as well as new approaches to do so. SUMMARY The past several years has witnessed significant advances in our knowledge of human B cell subsets and function. This has created a nuanced picture of the diverse ways B cells contribute to autoimmunity and an ever-expanding armamentarium of B cell-targeted therapies.
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Affiliation(s)
- Jennifer L Barnas
- Department of Medicine, Division of Allergy Immunology and Rheumatology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, United States
| | - Richard John Looney
- Department of Medicine, Division of Allergy Immunology and Rheumatology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, United States
| | - Jennifer H Anolik
- Department of Medicine, Division of Allergy Immunology and Rheumatology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, United States.
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