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Liu Z, Shang Q, Cheng J, He Q, Liu Y, Li H, Fang D, Li X, Zhu Y, Chen J, Chen J. Mechanistic study of a triterpenoid-enriched fraction derived from Cynomorium songaricum against NAFLD: An integrative elucidation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 142:156782. [PMID: 40318532 DOI: 10.1016/j.phymed.2025.156782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/28/2025] [Accepted: 04/17/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern linked to metabolic dysfunction and inflammation. Traditional Chinese Medicine (TCM), with its emphasis on restoring balance and harmony within the body, is well-suited to address the heterogeneity of NAFLD. Effective strategies to manage NAFLD remain limited, emphasizing the need for novel bioactive compounds with therapeutic potential. PURPOSE This study aimed to investigate the protective effects of a triterpenoid-enriched fraction (CST) derived from Cynomorium songaricum and its active compounds on NAFLD and to elucidate their underlying mechanisms. METHODS CST composition was analyzed using UHPLC/ESI-LTQ-Orbitrap-MS. Anti-inflammatory and lipid-lowering effects were assessed through in vitro and in vivo experiments. Integration of RNA-seq and novel network pharmacology identified key molecular targets, while molecular docking confirmed interactions of oleanolic acid (OLA) and ursolic acid (UA) with IKBKB and TACE, crucial components of the NF-κB pathway. RESULTS CST, OLA and UA significantly reduced lipid accumulation and downregulated inflammatory markers, including TNF-α and lipogenesis-related genes in vitro. In vivo, these compounds reduced lipid accumulation and modulated NF-κB activation, demonstrating robust anti-inflammatory and lipid-regulating effects. CONCLUSION CST exhibits promising bioactive properties in managing NAFLD. IKBKB and TACE mediate CST's protective effects against NAFLD by suppressing NF-κB target genes, reducing TNF-α, and inhibiting lipogenesis. These findings provide a foundation for developing CST and its active components, OLA and UA, as potential therapeutic agents for NAFLD.
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Affiliation(s)
- Zhihao Liu
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Qixiang Shang
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Juanjuan Cheng
- The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China; Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, PR China
| | - Quanrun He
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Yining Liu
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Haimeng Li
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Daozheng Fang
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Xinyue Li
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Yong Zhu
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Jianping Chen
- Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, PR China.
| | - Jihang Chen
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China.
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Jánosi Á, Bódy B, Nagy R, Ocskay K, Kói T, Müller K, Túri I, Garami M, Hegyi P, Párniczky A. Tumour necrosis factor-alpha inhibitors decrease mortality in COVID-19: a systematic review and meta-analysis. Crit Care 2025; 29:232. [PMID: 40481519 PMCID: PMC12144840 DOI: 10.1186/s13054-025-05420-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 04/15/2025] [Indexed: 06/11/2025] Open
Abstract
BACKGROUND Despite widespread vaccination efforts, effective treatment strategies remain critical for severe SARS-CoV-2 infection. Tumour necrosis factor-alpha (TNF-α) plays a central role in the cytokine storm characteristic of severe COVID-19. This systematic review and meta-analysis evaluates the effectiveness, efficacy, and safety of TNF-α inhibitors in the management of COVID-19. PATIENTS AND METHODS A systematic review of PubMed, Embase, and CENTRAL was conducted, focusing on studies involving SARS-CoV-2-infected patients treated with TNF-α inhibitors compared with those receiving standard of care without prior TNF-α inhibitor use. Data from studies published up to August 12, 2024, were analysed. Outcomes assessed included mortality, invasive mechanical ventilation, and C-reactive protein (CRP) levels. Odds ratios (ORs) and mean differences (MD) were calculated with 95% confidence intervals (CI), and subgroup analyses were performed for randomised controlled trials (RCTs) and non-randomised studies. RESULTS Seven studies involving 1393 patients with moderate-to-critical COVID-19 were included. TNF-α inhibitor treatment was associated with a reduced odds of mortality (OR 0.67, 95% CI [0.44-1.00], P = 0.052), which was statistically significant in the RCT subgroup across three studies (OR 0.75, 95% CI [0.58-0.97], P = 0.042, certainty of evidence: very low). The number needed to treat for mortality was calculated to be 16 (95% CI 9.0-inf.), which indicates that one additional death could be avoided for every 16 patients treated with TNF-α inhibitors compared to standard of care. No significant reduction in the need for invasive mechanical ventilation was observed (OR 0.95 [95% CI 0.46-1.94]; P = 0.822). Additionally, TNF-α inhibitors resulted in a significant reduction in CRP levels (MD - 21.9 mg/L [95% CI - 38.46 to - 5.34]; P = 0.024) within three to seven days post-treatment. CONCLUSION Our study indicates a potential role for TNF-α inhibition in the treatment of COVID-19 as their use was associated with reduced mortality, but further studies are needed to provide robust evidence.
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Affiliation(s)
- Ágoston Jánosi
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Heim Pál National Paediatric Institute, Budapest, Hungary
| | - Blanka Bódy
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Heim Pál National Paediatric Institute, Budapest, Hungary
| | - Rita Nagy
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Heim Pál National Paediatric Institute, Budapest, Hungary
| | - Klementina Ocskay
- Heim Pál National Paediatric Institute, Budapest, Hungary
- Pharmaceutical Sciences and Health Technologies Division, Doctoral School, Semmelweis University, Budapest, Hungary
| | - Tamás Kói
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Department of Stochastics, Institute of Mathematics, Budapest University of Technology and Economics, Budapest, Hungary
| | - Katalin Müller
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Heim Pál National Paediatric Institute, Budapest, Hungary
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Department of Family Care Methodology, Faculty of Health Sciences, Semmelweis University, Budapest, Hungary
| | - Ibolya Túri
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- András Pető Faculty, Semmelweis University, Budapest, Hungary
| | - Miklós Garami
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Paediatric Centre, Semmelweis University, Budapest, Hungary
| | - Péter Hegyi
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary
| | - Andrea Párniczky
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary.
- Heim Pál National Paediatric Institute, Budapest, Hungary.
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary.
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Manasyan A, Stanton EW, Moshal T, Daar DA, Carey JN, Koesters E. Flap-Based Reconstruction in Patients with Autoimmune Disease: An Institutional Experience with the Deep Inferior Epigastric Perforator Flap and Review of the Literature. J Reconstr Microsurg 2025; 41:390-397. [PMID: 39134046 DOI: 10.1055/a-2383-4617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/07/2024]
Abstract
BACKGROUND Autoimmune diseases are associated with characteristic chronic inflammation, aberrations in tissue perfusion, and hypercoagulability, and thus have considerable implications for local and free-flap reconstruction. We seek to summarize the current evidence on outcomes of flap-based reconstruction in patients with pre-existing autoimmune disease and present our experience with autologous breast reconstruction in this population. METHODS PubMed, Embase, Scopus, Cochrane, and Web of Science were searched for relevant articles, and pertinent data were presented qualitatively. Institutional data were queried for patients who underwent autologous breast reconstruction with deep inferior epigastric perforator (DIEP) flaps between 2015 and 2024. A retrospective review was conducted to identify DIEP patients with a history of autoimmune disease. Data on patient demographics, medication history, flap outcomes, and perioperative complications were collected. RESULTS The majority of existing studies found no increased independent risk of flap complications. However, other complications, predominantly wound dehiscence, were independently associated with autoimmune disease. Regarding immunosuppressant therapy, the literature demonstrated that perioperative glucocorticoid use was consistently associated with all complications, including seroma, infection, wound disruption, and partial flap loss.Our 13-patient institutional experience identified no cases of total flap loss or microvascular thrombotic complications. There was one case of partial flap necrosis further complicated by abdominal site cellulitis, and one case of recipient-site dehiscence managed with local wound care. No patients required re-operation for flap or donor-site complications. CONCLUSION The literature suggests that flap reconstruction can be performed safely in patients with autoimmune conditions, which was also supported by our institutional experience. While there is likely minimal risk of microsurgical complications in the context of free tissue transfer, donor-site morbidity and wound dehiscence remain major concerns for patients with a history of autoimmune disease. Limiting the use of immunosuppressive agents, especially corticosteroids, may potentially improve outcomes of flap reconstruction.
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Affiliation(s)
- Artur Manasyan
- Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Eloise W Stanton
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine, Los Angeles, California
| | - Tayla Moshal
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine, Los Angeles, California
| | - David A Daar
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine, Los Angeles, California
| | - Joseph N Carey
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine, Los Angeles, California
| | - Emma Koesters
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine, Los Angeles, California
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Shyam M, Sidharth S, Veronica A, Jagannathan L, Srirangan P, Radhakrishnan V, Sabina EP. Diabetic retinopathy: a comprehensive review of pathophysiology and emerging treatments. Mol Biol Rep 2025; 52:380. [PMID: 40205024 DOI: 10.1007/s11033-025-10490-7] [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: 03/05/2025] [Accepted: 04/02/2025] [Indexed: 04/11/2025]
Abstract
Diabetic retinopathy constitutes a major complication associated with diabetes mellitus, resulting in visual impairment and blindness on a global scale. The pathophysiology of DR is characterized by intricate interactions among metabolic, hemodynamic, and inflammatory pathways, which include the activation of the polyol pathway, the accumulation of advanced glycation end products, the overactivation of protein kinase C, dysregulation of the renin-angiotensin-aldosterone system, and retinal neurodegeneration. This review investigates the classification, complex pathophysiology, and therapeutic modalities for DR, encompassing conventional interventions such as anti-VEGF agents, aldose reductase inhibitors, angiotensin receptor blockers, laser photocoagulation, and vitrectomy. Innovative treatments, including advanced anti-VEGF agents, neuroprotective strategies, gene and stem cell therapies, and advancements in drug delivery systems, exhibit considerable transformative potential. Furthermore, integrating artificial intelligence for early detection and modulation of inflammatory pathways signifies cutting-edge progress in the field. By integrating contemporary knowledge and prospective avenues, this review underscores the significance of comprehending the multifaceted nature of DR and the advancements in its therapeutic approaches. The objective is to bridge the gaps between research findings and clinical application, thereby providing a comprehensive resource to enhance outcomes and quality of life for individuals impacted by DR.
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Affiliation(s)
- Mukul Shyam
- Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, India
| | - S Sidharth
- Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, India
| | - Aleen Veronica
- Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, India
| | - Lakshmipriya Jagannathan
- Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, India
| | - Prathap Srirangan
- Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, India
| | - Vidya Radhakrishnan
- VIT School of Agricultural Innovations and Advanced Learning, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Evan Prince Sabina
- Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, India.
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Wang L, Gu T, Yu C, Gao Y, Xuan T, Shen K, Wang G, Wang Z. Kaempferol attenuates experimental autoimmune neuritis through TNFR1/JNK/p38 signaling pathway inhibition. Int Immunopharmacol 2025; 147:113951. [PMID: 39752756 DOI: 10.1016/j.intimp.2024.113951] [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: 11/25/2024] [Revised: 12/14/2024] [Accepted: 12/23/2024] [Indexed: 01/29/2025]
Abstract
Kaempferol (Kae) is a flavonoid that has antioxidant, anti-inflammatory and neuroprotective effects. In recent years, there have been increasing reports on viral infection-induced Guillain-Barré syndrome (GBS) with high rates of disability and fatality. Therefore, in order to search for effective peripheral nerve injury repair drugs, we used rats with experimental autoimmune neuritis (EAN) as the typical animal model for GBS, and implemented Kae treatment intervention on EAN rats. Real-time quantitative polymerase chain reaction (qPCR), western blotting (WB) and immunofluorescence (IF) were utilized to detect the changes of inflammatory factors and signaling pathway proteins in peripheral nerve of rats. The impact of Kae on peripheral nerve damage in EAN rats was evaluated in multiple dimensions by clinical symptom score and neuroelectrophysiology examination, and the protective impact and mechanism of Kae on peripheral nerve injury were revealed. Our results showed that Kae increased the expression of sciatic myelin basic protein (MBP), decreased the expression of peripheral nerve macrophage infiltration and inflammatory cytokines, including TNF-α, IL-1β and IL-6, and down-regulated the expression levels of TNFR1. Additionally, it suppressed the activation of the JNK and p38 pathways. It can alleviate sciatic nerve symptoms and pathological injury in EAN rats. Therefore, we believe that Kae can be used as an adjunct drug in the treatment of GBS.
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Affiliation(s)
- Li Wang
- The First Clinical Medical School, Ningxia Medical University, Yinchuan 750004, China
| | - Tao Gu
- The First Clinical Medical School, Ningxia Medical University, Yinchuan 750004, China
| | - Chunguang Yu
- The First Clinical Medical School, Ningxia Medical University, Yinchuan 750004, China
| | - Yingying Gao
- The First Clinical Medical School, Ningxia Medical University, Yinchuan 750004, China
| | - Tingting Xuan
- The First Clinical Medical School, Ningxia Medical University, Yinchuan 750004, China
| | - Kaichun Shen
- The First Clinical Medical School, Ningxia Medical University, Yinchuan 750004, China
| | - Guowei Wang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, Chongqing 400016, China.
| | - Zhenhai Wang
- Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan 750004, China; Diagnosis and Treatment Engineering Technology Research Center of Nervous System Diseases of Ningxia, Yinchuan 750004, China; Neurology Center, General Hospital of Ningxia Medical University, Yinchuan 750004, China.
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Hosseinpour A, Haj Mohamad Ebrahim Ketabforoush A, Daneshzad E, Babanezhad Gajouti A, Hajimollarabi S. Unexpected multiple sclerosis-like symptoms in a rheumatoid arthritis patient treated with Etanercept: A case report. Clin Case Rep 2024; 12:e9486. [PMID: 39469322 PMCID: PMC11513257 DOI: 10.1002/ccr3.9486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 09/03/2024] [Accepted: 09/16/2024] [Indexed: 10/30/2024] Open
Abstract
Key Clinical Massage Although tumor necrosis factor (TNF) inhibitors are used to prevent autoimmune disease, but they can cause adverse effects. Multiple sclerosis syndrome is one of the rare complications following treatment with TNF inhibitor. We reported a case of rheumatoid arthritis with unfavorable outcome post Etanerecept therapy. Abstract Tumor necrosis factor (TNF) inhibitors are prescribed to treat various autoimmune diseases such as rheumatoid arthritis (RA). Etanercept, a human anti-TNF monoclonal antibody, is a therapeutic option in autoimmune and inflammatory diseases. One of the rare adverse effects of Etanercept is developing central nervous system and peripheral nervous system demyelination however, there is controversy in the cause of it. In this case, we presented a 35-year-old woman with multiple sclerosis (MS)-like symptoms due to taking Etanercept. She had a history of RA since the age of 18 years and was referred to the emergency department with signs and symptoms of para paresthesia, progressive paraparesis of both lower limbs, and urinary retention a year after Etanercept treatment. We discontinued the Etanercept and started Methylprednisolone and Rituximab. Rapid clinical improvement was noted and in the approximately 6-month follow-up, she did not exhibit any neurological worsening. So it is probable that the initiation of Etanercept triggered MS-like syndrome in these patients and healthcare practitioners should take heed of this adverse effect.
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Affiliation(s)
- Ali Hosseinpour
- Clinical Research Development Unit (CRDU) of Shahid Rajaei HospitalAlborz University of Medical SciencesKarajIran
- Non‐Communicable Diseases Research CenterAlborz University of Medical SciencesKarajIran
| | | | - Elnaz Daneshzad
- Non‐Communicable Diseases Research CenterAlborz University of Medical SciencesKarajIran
| | | | - Samaneh Hajimollarabi
- Clinical Research Development Unit (CRDU) of Shahid Rajaei HospitalAlborz University of Medical SciencesKarajIran
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Maniaci A, Briglia M, Allia F, Montalbano G, Romano GL, Zaouali MA, H’mida D, Gagliano C, Malaguarnera R, Lentini M, Graziano ACE, Giurdanella G. The Role of Pericytes in Inner Ear Disorders: A Comprehensive Review. BIOLOGY 2024; 13:802. [PMID: 39452111 PMCID: PMC11504721 DOI: 10.3390/biology13100802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 10/02/2024] [Accepted: 10/06/2024] [Indexed: 10/26/2024]
Abstract
Inner ear disorders, including sensorineural hearing loss, Meniere's disease, and vestibular neuritis, are prevalent conditions that significantly impact the quality of life. Despite their high incidence, the underlying pathophysiology of these disorders remains elusive, and current treatment options are often inadequate. Emerging evidence suggests that pericytes, a type of vascular mural cell specialized to maintain the integrity and function of the microvasculature, may play a crucial role in the development and progression of inner ear disorders. The pericytes are present in the microvasculature of both the cochlea and the vestibular system, where they regulate blood flow, maintain the blood-labyrinth barrier, facilitate angiogenesis, and provide trophic support to neurons. Understanding their role in inner ear disorders may provide valuable insights into the pathophysiology of these conditions and lead to the development of novel diagnostic and therapeutic strategies, improving the standard of living. This comprehensive review aims to provide a detailed overview of the role of pericytes in inner ear disorders, highlighting the anatomy and physiology in the microvasculature, and analyzing the mechanisms that contribute to the development of the disorders. Furthermore, we explore the potential pericyte-targeted therapies, including antioxidant, anti-inflammatory, and angiogenic approaches, as well as gene therapy strategies.
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Affiliation(s)
- Antonino Maniaci
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
- Department of Surgery, ENT Unit, Asp 7 Ragusa, 97100 Ragusa, Italy
| | - Marilena Briglia
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Fabio Allia
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Giuseppe Montalbano
- Zebrafish Neuromorphology Laboratory, Department of Veterinary Sciences, University of Messina, 98168 Messina, Italy;
| | - Giovanni Luca Romano
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Mohamed Amine Zaouali
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy, University of Monastir, Avicenne Street, 5019 Monastir, Tunisia;
| | - Dorra H’mida
- Department of Cytogenetics and Reproductive Biology, Farhat Hached Hospital, 4021 Sousse, Tunisia;
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Roberta Malaguarnera
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Mario Lentini
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
- Department of Surgery, ENT Unit, Asp 7 Ragusa, 97100 Ragusa, Italy
| | - Adriana Carol Eleonora Graziano
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Giovanni Giurdanella
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
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Bonazzi E, Maniero D, Lorenzon G, Bertin L, Bray K, Bahur B, Barberio B, Zingone F, Savarino EV. Comparing Point-of-Care Technology to ELISA Testing for Infliximab and Adalimumab Levels in Adult Inflammatory Bowel Disease Patients: A Prospective Pilot Study. Diagnostics (Basel) 2024; 14:2140. [PMID: 39410544 PMCID: PMC11482612 DOI: 10.3390/diagnostics14192140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/19/2024] [Accepted: 09/24/2024] [Indexed: 10/19/2024] Open
Abstract
Introduction: Therapeutic drug monitoring (TDM) has proven to be a valuable strategy for optimizing biologic therapies, among which are anti-tumor necrosis factor (anti-TNF) treatments in inflammatory bowel disease (IBD). In particular, reactive TDM has been shown to manage treatment failures more cost-effectively than empirical dose adjustments for anti-TNF drugs. However, several challenges currently impede the widespread adoption of TDM in clinical practice, particularly addressing the delay between sample collection and result availability. To overcome this limitation, the use of point-of-care technology tests (POCTs) is a potential solution. Point-of-care technology tests are medical diagnostic tests performed at the site of patient care to provide immediate results, allowing for quicker decision-making and treatment. The current standard of care (SOC) for drug level measurement relies on the enzyme-linked immunosorbent assay (ELISA), a method that is time-consuming and requires specialized personnel. This study aims to evaluate a novel, user-friendly, and efficient POCT method (ProciseDx Inc.) and compare its performance with the SOC ELISA in assessing infliximab and adalimumab levels in blood samples from IBD patients. Methods: In this prospective, single-center study, we collected blood samples from IBD patients, both CD and UC, receiving infliximab (87 IBD patients; 50% UC and 50% CD) or adalimumab (60 patients; 14% UC and 48% CD) and we analyzed the blood's drugs levels using both the ProciseDx Analyzer POC and the SOC ELISA. We examined the correlation between the two methods using statistical analyses, including the Deming regression test. Additionally, we assessed the ease of use, turnaround time, and overall practicality of the POCT in a clinical setting. Results: The ProciseDx test demonstrated a strong correlation with the SOC ELISA for measuring both infliximab and adalimumab levels. In particular, the overall correlation between the ProciseDx POCT and the ELISA assessments showed an r coefficient of 0.83 with an R squared value of 0.691 (95% CI 0.717-0.902) for IFX measurements, and an r coefficient of 0.85 with an R squared value of 0.739 (95% CI 0.720-0.930). Conclusions: the ProciseDx POC test offers significantly faster turnaround times and is more straightforward to use, making it a viable alternative for routine clinical monitoring. Despite its promising potential, further refinement and validation of the ProciseDx test are necessary to ensure its effectiveness across diverse patient populations and clinical settings. Future research should focus on optimizing the POC tests' performance and evaluating its long-term impact on IBD management.
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Affiliation(s)
- Erica Bonazzi
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (E.B.); (D.M.); (G.L.); (L.B.); (F.Z.)
| | - Daria Maniero
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (E.B.); (D.M.); (G.L.); (L.B.); (F.Z.)
| | - Greta Lorenzon
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (E.B.); (D.M.); (G.L.); (L.B.); (F.Z.)
| | - Luisa Bertin
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (E.B.); (D.M.); (G.L.); (L.B.); (F.Z.)
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy;
| | - Kurtis Bray
- ProciseDx Inc., 9449 Carroll Park Drive, San Diego, CA 92121, USA; (K.B.); (B.B.)
| | - Bayda Bahur
- ProciseDx Inc., 9449 Carroll Park Drive, San Diego, CA 92121, USA; (K.B.); (B.B.)
| | - Brigida Barberio
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy;
| | - Fabiana Zingone
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (E.B.); (D.M.); (G.L.); (L.B.); (F.Z.)
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy;
| | - Edoardo Vincenzo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (E.B.); (D.M.); (G.L.); (L.B.); (F.Z.)
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy;
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9
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Guo P, Gao X, Nelson AL, Huard M, Lu A, Hambright WS, Huard J. TIPE2 gene transfer ameliorates aging-associated osteoarthritis in a progeria mouse model by reducing inflammation and cellular senescence. Mol Ther 2024; 32:3101-3113. [PMID: 39095992 PMCID: PMC11403236 DOI: 10.1016/j.ymthe.2024.07.027] [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: 01/12/2024] [Revised: 07/13/2024] [Accepted: 07/30/2024] [Indexed: 08/04/2024] Open
Abstract
Osteoarthritis (OA) pain is often associated with the expression of tumor necrosis factor alpha (TNF-α), suggesting that TNF-α is one of the main contributing factors that cause inflammation, pain, and OA pathology. Thus, inhibition of TNF-α could potentially improve OA symptoms and slow disease progression. Anti-TNF-α treatments with antibodies, however, require multiple treatments and cannot entirely block TNF-α. TNF-α-induced protein 8-like 2 (TIPE2) was found to regulate the immune system's homeostasis and inflammation through different mechanisms from anti-TNF-α therapies. With a single treatment of adeno-associated virus (AAV)-TIPE2 gene delivery in the accelerated aging Zmpste24-/- (Z24-/-) mouse model, we found differences in Safranin O staining intensity within the articular cartilage (AC) region of the knee between TIPE2-treated mice and control mice. The glycosaminoglycan content (orange-red) was degraded in the Z24-/- cartilage while shown to be restored in the TIPE2-treated Z24-/- cartilage. We also observed that chondrocytes in Z24-/- mice exhibited a variety of senescent-associated phenotypes. Treatment with TIPE2 decreased TNF-α-positive cells, β-galactosidase (β-gal) activity, and p16 expression seen in Z24-/- mice. Our study demonstrated that AAV-TIPE2 gene delivery effectively blocked TNF-α-induced inflammation and senescence, resulting in the prevention or delay of knee OA in our accelerated aging Z24-/- mouse model.
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Affiliation(s)
- Ping Guo
- Center for Regenerative & Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA.
| | - Xueqin Gao
- Center for Regenerative & Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA
| | - Anna-Laura Nelson
- Center for Regenerative & Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA
| | - Matthieu Huard
- Center for Regenerative & Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA
| | - Aiping Lu
- Center for Regenerative & Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA
| | - William Sealy Hambright
- Center for Regenerative & Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA
| | - Johnny Huard
- Center for Regenerative & Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA.
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10
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Watson S, Cabrera-Silva RI, Parkos CA, Nusrat A, Quiros M. Interferon-gamma signaling drives epithelial TNF-alpha receptor-2 expression during colonic tissue repair. FASEB J 2024; 38:e70001. [PMID: 39139033 PMCID: PMC11878270 DOI: 10.1096/fj.202401695] [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: 07/23/2024] [Accepted: 08/06/2024] [Indexed: 08/15/2024]
Abstract
Interferon-gamma (IFNγ) is traditionally recognized for its pro-inflammatory role during intestinal inflammation. Here, we demonstrate that IFNγ also functions as a pro-repair molecule by increasing TNFα receptor 2 (TNFR2 protein/TNFRSF1B gene) expression on intestinal epithelial cells (IEC) following injury in vitro and in vivo. In silico analyses identified binding sites for the IFNγ signaling transcription factor STAT1 in the promoter region of TNFRSF1B. Scratch-wounded IEC exposed to IFNγ exhibited a STAT1-dependent increase in TNFR2 expression. In situ hybridization revealed elevated Tnfrsf1b mRNA levels in biopsy-induced colonic mucosal wounds, while intraperitoneal administration of IFNγ neutralizing antibodies following mucosal injury resulted in impaired IEC Tnfrsf1b mRNA and inhibited colonic mucosal repair. These findings challenge conventional notions that "pro-inflammatory" mediators solely exacerbate damage by highlighting latent pro-repair functions. Moreover, these results emphasize the critical importance of timing and amount in the synthesis and release of IFNγ and TNFα during the inflammatory process, as they are pivotal in restoring tissue homeostasis.
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Grants
- R01 DK079392 NIDDK NIH HHS
- DK129214 HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM)
- R01 DK072564 NIDDK NIH HHS
- DK72564 HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM)
- R01 DK055679 NIDDK NIH HHS
- DK79392 HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM)
- R01 DK059888 NIDDK NIH HHS
- DK055679 HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM)
- R01 DK129214 NIDDK NIH HHS
- DK059888 HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM)
- DK61739 HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM)
- R01 DK061379 NIDDK NIH HHS
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Affiliation(s)
- Sean Watson
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Charles A. Parkos
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Asma Nusrat
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Miguel Quiros
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
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11
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Babaei M, Heidari B, Sadeghi Haddad Zavareh M, Ahmadnia Z, Ghorbani H, Rouhi S. Serum tumor necrosis factor-alpha status in hospitalized patients with coronavirus disease-2019 (COVID-19). CASPIAN JOURNAL OF INTERNAL MEDICINE 2024; 15:601-605. [PMID: 39359436 PMCID: PMC11444111 DOI: 10.22088/cjim.15.4.601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 10/08/2022] [Indexed: 10/04/2024]
Abstract
Background Tumor necrosis factor alpha (TNF-α) produces an inflammatory process and plays a critical role against infection and in the control of viral infection. The present study was conducted to determine the status of serum TNF-α in hospitalized patients with coronavirus disease-2019 (COVID-19). Methods In this cross-sectional study the serum TNF-α level, sex, and age, were determined in patients with COVID-19. The association between variables was determined using the student t-test, analysis of variance (ANOVA) test, multiple logistic regression analysis, and the statistical package for the Social Sciences (SPSS)-18 (p < 0.05). Results A total of 91 (women 41.75%, and men 58.24%) patients with a mean serum TNF-α level of 9.9 picograms per milliliter (pg/mL) were considered. In all (100%) patients, the TNF-α serum level was more than the normal limit (P=0.95). 95.60% of patients suffered severe COVID-19, with a TNF-a serum level of 10.20 pg/mL (P=0.87). Mean TNF-α serum levels in women and men were 11.37 pg/mL and 8.8 pg/mL, respectively (P= 0.17). In the age group of > 70 years (11.30 pg/mL), serum TNF-α concentration was higher than the other age groups (p>0.05). Conclusion A significant proportion of women and men patients with COVID-19 in the middle and old age had a high concentration of serum TNF-α which may indicate the severity of the disease. Serum TNF-α level is different in women and men of different ages, so it can contribute to treatment strategies.
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Affiliation(s)
- Mansour Babaei
- Mobility Impairment Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
- Clinical Research Development Unit of Ayatollah Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran
| | - Behzad Heidari
- Mobility Impairment Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
- Clinical Research Development Unit of Ayatollah Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran
| | | | - Zahra Ahmadnia
- Clinical Research Development Unit of Ayatollah Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran
| | - Hossein Ghorbani
- Clinical Research Development Unit of Ayatollah Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran
| | - Samaneh Rouhi
- Clinical Research Development Unit of Ayatollah Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran
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12
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Huang ZM, Kang JQ, Chen PZ, Deng LF, Li JX, He YX, Liang J, Huang N, Luo TY, Lan QW, Chen HK, Guo XG. Identifying the Interaction Between Tuberculosis and SARS-CoV-2 Infections via Bioinformatics Analysis and Machine Learning. Biochem Genet 2024; 62:2606-2630. [PMID: 37991568 DOI: 10.1007/s10528-023-10563-x] [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: 08/08/2023] [Accepted: 10/25/2023] [Indexed: 11/23/2023]
Abstract
The number of patients with COVID-19 caused by severe acute respiratory syndrome coronavirus 2 is still increasing. In the case of COVID-19 and tuberculosis (TB), the presence of one disease affects the infectious status of the other. Meanwhile, coinfection may result in complications that make treatment more difficult. However, the molecular mechanisms underpinning the interaction between TB and COVID-19 are unclear. Accordingly, transcriptome analysis was used to detect the shared pathways and molecular biomarkers in TB and COVID-19, allowing us to determine the complex relationship between COVID-19 and TB. Two RNA-seq datasets (GSE114192 and GSE163151) from the Gene Expression Omnibus were used to find concerted differentially expressed genes (DEGs) between TB and COVID-19 to identify the common pathogenic mechanisms. A total of 124 common DEGs were detected and used to find shared pathways and drug targets. Several enterprising bioinformatics tools were applied to perform pathway analysis, enrichment analysis and networks analysis. Protein-protein interaction analysis and machine learning was used to identify hub genes (GAS6, OAS3 and PDCD1LG2) and datasets GSE171110, GSE54992 and GSE79362 were used for verification. The mechanism of protein-drug interactions may have reference value in the treatment of coinfection of COVID-19 and TB.
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Affiliation(s)
- Ze-Min Huang
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, 511436, China
| | - Jia-Qi Kang
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- Department of Clinical Medicine, The First Clinical School of Guangzhou Medical University, Guangzhou, 511436, China
| | - Pei-Zhen Chen
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, 511436, China
| | - Lin-Fen Deng
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, 511436, China
| | - Jia-Xin Li
- Department of Clinical Medicine, The First Clinical School of Guangzhou Medical University, Guangzhou, 511436, China
| | - Ying-Xin He
- Clinical Laboratory Medicine, Guangzhou Medical University, Guangzhou, 510006, China
| | - Jie Liang
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, 511436, China
| | - Nan Huang
- Clinical Laboratory Medicine, Guangzhou Medical University, Guangzhou, 510006, China
| | - Tian-Ye Luo
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, 511436, China
| | - Qi-Wen Lan
- Department of Clinical Medicine, The Second Clinical School of Guangzhou Medical University, Guangzhou, 511436, China
| | - Hao-Kai Chen
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, 511436, China
| | - Xu-Guang Guo
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
- Department of Clinical Laboratory Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, King Med School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 510000, China.
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13
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Alkheraiji A, Alotaibi H, Irfan Thalib H. Lichenoid Drug Eruption Secondary to Adalimumab: A Case Report. Cureus 2024; 16:e64013. [PMID: 39114193 PMCID: PMC11304408 DOI: 10.7759/cureus.64013] [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] [Accepted: 07/06/2024] [Indexed: 08/10/2024] Open
Abstract
Adalimumab, an anti-tumor necrosis factor-α (TNF-α), is widely prescribed for many autoimmune diseases and chronic inflammatory skin diseases such as hidradenitis suppurative, psoriasis, etc. We report a case of lichenoid drug eruption secondary to adalimumab, a rare side effect, in a 62-year-old female with ulcerative colitis. The skin eruption appeared two weeks after initiating adalimumab. A skin biopsy was taken, and the histopathological findings correlated with a lichenoid drug eruption. Although rare, drug-induced lichen planus has been associated with adalimumab. Early recognition and a high index of suspicion are key in the prompt management of these cases. The discontinuation of adalimumab must be carefully weighed against its therapeutic benefits, as the discontinuation might trigger a severe form of inflammation in the primary autoimmune disease being treated. Extreme caution, early intervention, and a multidisciplinary approach are best for the overall well-being and optimal care of the individual.
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Affiliation(s)
- Asma Alkheraiji
- College of Medicine: Dermatology, Majmaah University, Riyadh, SAU
| | | | - Husna Irfan Thalib
- College of Medicine: General Medicine and Surgery, Batterjee Medical College, Jeddah, SAU
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14
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Sen’kova AV, Savin IA, Chernolovskaya EL, Davydova AS, Meschaninova MI, Bishani A, Vorobyeva MA, Zenkova MA. LPS-Induced Acute Lung Injury: Analysis of the Development and Suppression by the TNF-α-Targeting Aptamer. Acta Naturae 2024; 16:61-71. [PMID: 39188267 PMCID: PMC11345095 DOI: 10.32607/actanaturae.27393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 04/15/2024] [Indexed: 08/28/2024] Open
Abstract
Acute lung injury (ALI) is a specific form of lung inflammation characterized by diffuse alveolar damage, noncardiogenic pulmonary edema, as well as a pulmonary and systemic inflammation. The pathogenesis of ALI involves a cascade inflammatory response accompanied by an increase in the local and systemic levels of proinflammatory cytokines and chemokines. The development of molecular tools targeting key components of cytokine signaling appears to be a promising approach in ALI treatment. The development of lipopolysaccharide (LPS)-induced ALI, as well as the feasibility of suppressing it by an aptamer targeting the proinflammatory cytokine TNF-α, was studied in a mouse model. The TNF-α level was shown to increase significantly and remain steadily high during the development of ALI. LPS-induced morphological signs of inflammation in the respiratory system become most pronounced 24 h after induction. Intranasal administration of TNF-α-targeting aptamers conjugated with polyethylene glycol (PEG-aptTNF-α) to mice with ALI reduced the intensity of inflammatory changes in lung tissue. Assessment of the levels of potential TNF-α target genes (Usp18, Traf1, and Tnfaip3) showed that their expression levels in the lungs increase during ALI development, while declining after the application of PEG-aptTNF-α. Therefore, topical use of TNF-α- targeting aptamers may be an efficient tool for treating ALI and other inflammatory lung diseases.
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Affiliation(s)
- A. V. Sen’kova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090 Russian Federation
| | - I. A. Savin
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090 Russian Federation
| | - E. L. Chernolovskaya
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090 Russian Federation
| | - A. S. Davydova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090 Russian Federation
| | - M. I. Meschaninova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090 Russian Federation
| | - A. Bishani
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090 Russian Federation
| | - M. A. Vorobyeva
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090 Russian Federation
| | - M. A. Zenkova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090 Russian Federation
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15
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Tajdari M, Peyrovinasab A, Bayanati M, Ismail Mahboubi Rabbani M, Abdolghaffari AH, Zarghi A. Dual COX-2/TNF-α Inhibitors as Promising Anti-inflammatory and Cancer Chemopreventive Agents: A Review. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2024; 23:e151312. [PMID: 39830670 PMCID: PMC11742592 DOI: 10.5812/ijpr-151312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 09/28/2024] [Accepted: 09/29/2024] [Indexed: 01/22/2025]
Abstract
Cyclooxygenases (COX) play a pivotal role in inflammation and are responsible for the production of prostaglandins (PGs). Two types of COXs have been identified as key biological targets for drug design: Constitutive COX-1 and inducible COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs) target COX-1, while selective COX-2 inhibitors are designed for COX-2. These COX isoforms are involved in multiple physiological and pathological pathways throughout the body. Overproduction of tumor necrosis factor-alpha (TNF-α) plays a role in COX-2's inflammatory activity. Tumor necrosis factor-alpha can contribute to cardiac fibrosis, heart failure, and various cancers by upregulating the COX-2/PGE2 axis. Therefore, suppressing COX activity has emerged as a potentially effective treatment for chronic inflammatory disorders and cancer. This review explores the mechanisms of TNF-α-induced COX-2/PGE2 expression, a significant pathophysiological feature of cancer development. Furthermore, we summarize chemical compounds with dual COX-2/TNF-α inhibitory actions, providing an overview of their structure-activity relationship. These insights may contribute to the development of new generations of dual-acting COX-2/TNF-α inhibitors with enhanced efficacy.
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Affiliation(s)
- Mobina Tajdari
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Amirreza Peyrovinasab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Maryam Bayanati
- Department of Food Technology Research, National Nutrition, and Food Technology Research Institute, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Amir Hossein Abdolghaffari
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Afshin Zarghi
- Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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16
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Sharma A, Goel A, Lin Z. Analysis of anti-rheumatic activity of Nyctanthes arbor-tristis via in vivo and pharmacovigilance approaches. Front Pharmacol 2023; 14:1307799. [PMID: 38116080 PMCID: PMC10728290 DOI: 10.3389/fphar.2023.1307799] [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: 10/05/2023] [Accepted: 11/20/2023] [Indexed: 12/21/2023] Open
Abstract
Introduction: Rheumatoid arthritis (RA) is an immune-mediated disease associated with chronic inflammation of numerous joints. Nyctanthes arbor-tristis (NAT) is a traditional remedy for RA, a chronic inflammatory disorder. Aim: The current project aims to demonstrate the role of the NAT extracts in sub-acute toxicity, pharmacovigilance, and anti-rheumatic biomarkers. Method: Hydroethanolic extract (1:1) of plant leaves was prepared by using the reflux method. The safety of the dose was evaluated in Sprague-Dawley rats, and the anti-inflammatory effects of NAT on RA symptoms, including paw volumes, body weight, arthritic index, withdrawal latency, hematology and serological test, radiology, and histopathology, were evaluated in Freund's complete adjuvant (FCA)-induced arthritis Sprague-Dawley rat models. The inflammatory (TNF-α and COX-2) and anti-inflammatory markers (IL-10) were analyzed in control and experimental groups. Result: The study showed that 500 mg/kg BW NAT leaf extract was found to be least toxic without showing any subacute toxicity symptoms. The pharmacovigilance study highlighted the potential side effects of NAT, such as drowsiness, sedation, and lethargy, at high dosages. Treatment with the plant extract mitigated paw edema, restored the immune organ and body weights, and ameliorated the level of blood parameters such as hemoglobin, red blood cells, platelets, white blood cells, aspartate aminotransferase (AST), alanine transaminase (ALT), C-reactive proteins, and rheumatoid factor. Treatment with the plant extracts also reduced the level of cyclooxygenase 2 and TNF-α and increased the level of IL-10 in the serum of arthritic rats dose-dependently. Radiographic analysis of the ankle joint showed an improvement in the hind legs. Histological examination of the ankle joints revealed that the plant extract treatment decreased pannus formation, inflammation, and synovial hyperplasia in arthritic animals. Conclusion: NAT 500 mg/kg could serve as a promising therapeutic option for the treatment of inflammatory arthritis.
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Affiliation(s)
- Ayushi Sharma
- Department of Biotechnology, Institute of Applied Sciences and Humanities, GLA University, Mathura, Uttar Pradesh, India
| | - Anjana Goel
- Department of Biotechnology, Institute of Applied Sciences and Humanities, GLA University, Mathura, Uttar Pradesh, India
| | - Zhijian Lin
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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17
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Ben-Khemis M, Liu D, Pintard C, Song Z, Hurtado-Nedelec M, Marie JC, El-Benna J, Dang PMC. TNFα counteracts interleukin-10 anti-inflammatory pathway through the NOX2-Lyn-SHP-1 axis in human monocytes. Redox Biol 2023; 67:102898. [PMID: 37757542 PMCID: PMC10539668 DOI: 10.1016/j.redox.2023.102898] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/30/2023] [Accepted: 09/19/2023] [Indexed: 09/29/2023] Open
Abstract
TNFα-mediated signaling pathways play a pivotal role in the pathogenesis of inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) by promoting phagocyte inflammatory functions, notably cytokine release and reactive oxygen species (ROS) production by NOX2. In contrast, interleukin-10 (IL-10), a powerful anti-inflammatory cytokine, potently shuts down phagocyte activation, making IL-10 an attractive therapeutic candidate. However, IL-10 therapy has shown limited efficacy in patients with inflammatory diseases. Here, we report that TNFα blocks IL-10 anti-inflammatory pathways in human monocytes, thereby prolonging inflammation. TNFα decreased IL-10-induced phosphorylation of STAT3 and consequently IL-10-induced expression of the major anti-inflammatory factor, SOCS3. Decreased STAT3 phosphorylation was due to a SHP1/2 phosphatase, as NSC-87877, a SHP1/2 inhibitor, restored STAT3 phosphorylation and prevented the TNFα-induced inhibition of IL-10 signaling. TNFα activated only SHP1 in human monocytes and this activation was NOX2-dependent, as diphenyleneiodonium, a NOX2 inhibitor, suppressed SHP1 activation and STAT3 dephosphorylation triggered by TNFα. ROS-induced activation of SHP1 was mediated by the redox-sensitive kinase, Lyn, as its inhibition impeded TNFα-induced SHP1 activation and STAT3 dephosphorylation. Furthermore, H2O2 recapitulated TNFα-inhibitory activity on IL-10 signaling. Finally, NSC-87877 dampened collagen antibody-induced arthritis (CAIA) in mice. These results reveal that TNFα disrupts IL-10 signaling by inducing STAT3 dephosphorylation through a NOX2-ROS-Lyn-SHP1 axis in human monocytes and that inhibition of SHP1/2 in vivo protects against CAIA. These new findings might explain the poor efficacy of IL-10 therapy in patients with inflammatory diseases and suggest that anti-TNFα agents and SHP1/2 inhibitors could improve the therapeutic use of IL-10.
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Affiliation(s)
- Marwa Ben-Khemis
- INSERM U1149, CNRS ERL8252, Centre de Recherche sur l'Inflammation, Université Paris-Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, F-75018, France
| | - Dan Liu
- INSERM U1149, CNRS ERL8252, Centre de Recherche sur l'Inflammation, Université Paris-Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, F-75018, France
| | - Coralie Pintard
- INSERM U1149, CNRS ERL8252, Centre de Recherche sur l'Inflammation, Université Paris-Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, F-75018, France
| | - Zhuoyao Song
- INSERM U1149, CNRS ERL8252, Centre de Recherche sur l'Inflammation, Université Paris-Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, F-75018, France
| | - Margarita Hurtado-Nedelec
- INSERM U1149, CNRS ERL8252, Centre de Recherche sur l'Inflammation, Université Paris-Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, F-75018, France; Département d'Immunologie et d'Hématologie, UF Dysfonctionnements Immunitaires, HUPNVS, Hôpital Bichat, Paris, France
| | - Jean-Claude Marie
- INSERM U1149, CNRS ERL8252, Centre de Recherche sur l'Inflammation, Université Paris-Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, F-75018, France
| | - Jamel El-Benna
- INSERM U1149, CNRS ERL8252, Centre de Recherche sur l'Inflammation, Université Paris-Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, F-75018, France
| | - Pham My-Chan Dang
- INSERM U1149, CNRS ERL8252, Centre de Recherche sur l'Inflammation, Université Paris-Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, F-75018, France.
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18
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Parisi GF, Papale M, Pecora G, Rotolo N, Manti S, Russo G, Leonardi S. Cystic Fibrosis and Cancer: Unraveling the Complex Role of CFTR Gene in Cancer Susceptibility. Cancers (Basel) 2023; 15:4244. [PMID: 37686519 PMCID: PMC10486401 DOI: 10.3390/cancers15174244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/06/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
Cystic fibrosis (CF) is a genetic disorder affecting multiple organs, primarily the lungs and digestive system. Over the years, advancements in medical care and treatments have significantly increased the life expectancy of individuals with CF. However, with this improved longevity, concerns about the potential risk of developing certain types of cancers have arisen. This narrative review aims to explore the relationship between CF, increased life expectancy, and the associated risk for cancers. We discuss the potential mechanisms underlying this risk, including chronic inflammation, immune system dysregulation, and genetic factors. Additionally, we review studies that have examined the incidence and types of cancers seen in CF patients, with a focus on gastrointestinal, breast, and respiratory malignancies. We also explore the impact of CFTR modulator therapies on cancer risk. In the gastrointestinal tract, CF patients have an elevated risk of developing colorectal cancer, pancreatic cancer, and possibly esophageal cancer. The underlying mechanisms contributing to these increased risks are not fully understood, but chronic inflammation, altered gut microbiota, and genetic factors are believed to play a role. Regular surveillance and colonoscopies are recommended for early detection and management of colorectal cancer in CF patients. Understanding the factors contributing to cancer development in CF patients is crucial for implementing appropriate surveillance strategies and improving long-term outcomes. Further research is needed to elucidate the molecular mechanisms involved and develop targeted interventions to mitigate cancer risk in individuals with CF.
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Affiliation(s)
- Giuseppe Fabio Parisi
- Pediatric Respiratory Unit, Department of Clinical and Experimental Medicine, San Marco Hospital, University of Catania, Viale Carlo Azeglio Ciampi sn, 95121 Catania, Italy; (M.P.); (G.P.); (N.R.); (S.L.)
| | - Maria Papale
- Pediatric Respiratory Unit, Department of Clinical and Experimental Medicine, San Marco Hospital, University of Catania, Viale Carlo Azeglio Ciampi sn, 95121 Catania, Italy; (M.P.); (G.P.); (N.R.); (S.L.)
| | - Giulia Pecora
- Pediatric Respiratory Unit, Department of Clinical and Experimental Medicine, San Marco Hospital, University of Catania, Viale Carlo Azeglio Ciampi sn, 95121 Catania, Italy; (M.P.); (G.P.); (N.R.); (S.L.)
| | - Novella Rotolo
- Pediatric Respiratory Unit, Department of Clinical and Experimental Medicine, San Marco Hospital, University of Catania, Viale Carlo Azeglio Ciampi sn, 95121 Catania, Italy; (M.P.); (G.P.); (N.R.); (S.L.)
| | - Sara Manti
- Pediatric Unit, Department of Human and Pediatric Pathology “Gaetano Barresi”, AOUP G. Martino, University of Messina, Via Consolare Valeria, 1, 98124 Messina, Italy;
| | - Giovanna Russo
- Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy;
| | - Salvatore Leonardi
- Pediatric Respiratory Unit, Department of Clinical and Experimental Medicine, San Marco Hospital, University of Catania, Viale Carlo Azeglio Ciampi sn, 95121 Catania, Italy; (M.P.); (G.P.); (N.R.); (S.L.)
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19
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Hey GE, Vedam-Mai V, Beke M, Amaris M, Ramirez-Zamora A. The Interface between Inflammatory Bowel Disease, Neuroinflammation, and Neurological Disorders. Semin Neurol 2023; 43:572-582. [PMID: 37562450 DOI: 10.1055/s-0043-1771467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/12/2023]
Abstract
Inflammatory Bowel Disease (IBD) is a complex, chronic inflammatory condition affecting the gastrointestinal tract. IBD has been associated with a variety of neurologic manifestations including peripheral nerve involvement, increased risk of thrombotic, demyelinating and events. Furthermore, an evolving association between IBD and neurodegenerative disorders has been recognized, and early data suggests an increased risk of these disorders in patients diagnosed with IBD. The relationship between intestinal inflammatory disease and neuroinflammation is complex, but the bidirectional interaction between the brain-gut-microbiome axis is likely to play an important role in the pathogenesis of these disorders. Identification of common mechanisms and pathways will be key to developing potential therapies. In this review, we discuss the evolving interface between IBD and neurological conditions, with a focus on clinical, mechanistic, and potentially therapeutic implications.
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Affiliation(s)
- Grace E Hey
- Department of Neurology, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida
| | - Vinata Vedam-Mai
- Department of Neurology, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida
| | - Matthew Beke
- Department of Neurology, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida
- Department of Food Science and Human Nutrition, University of Florida, Gainesville, Florida
| | - Manuel Amaris
- Department of Gastroenterology, University of Florida, Gainesville, Florida
| | - Adolfo Ramirez-Zamora
- Department of Neurology, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida
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20
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Maity S, Santra A, Vardhan Hebbani A, Pulakuntla S, Chatterjee A, Rao Badri K, Damodara Reddy V. Targeting cytokine storm as the potential anti-viral therapy: Implications in regulating SARS-CoV-2 pathogenicity. Gene 2023:147612. [PMID: 37423400 DOI: 10.1016/j.gene.2023.147612] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 06/18/2023] [Accepted: 07/03/2023] [Indexed: 07/11/2023]
Abstract
The latest global pandemic corona virus disease - 2019 (COVID-19) caused by the virus SARS-CoV-2 is still a matter of worrying concern both for the scientific communities and health care organizations. COVID-19 disease is proved to be a highly contagious disease transmitted through respiratory droplets and even close contact with affected individuals. COVID-19 disease is also understood to exhibit diverse symptoms of ranging severities i.e., from mild fatigue to death. Affected individuals' susceptibility to induce immunologic dysregulation phenomena termed 'cytokine storm' seems to be playing the damaging role of escalating the disease manifestation from mild to severe. Cytokine storm in patients with severe symptoms is understood to be characterized by enhanced serum levels of many cytokines including interleukin-1β, interleukin-6, IL-10, TNF, interferon-γ, MIP-1α, MIP-1β and VEGF. Since cytokine production in general is the most important antiviral defense response, understanding the COVID-19 associated cytokine storm in particular and differentiating it from the regular cytokine production response becomes crucial in developing an effective therapeutic strategy.This review focuses on the potential targeting of COVID-19 associated cytokine storm and its challenges.
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Affiliation(s)
- Subashish Maity
- Department of Biotechnology, REVA University, Bengaluru-560064, Karnataka, India
| | - Ayantika Santra
- Department of Biochemistry, Indian Academy Degree College, Bengaluru, 560 043, India
| | | | - Swetha Pulakuntla
- Department of Biotechnology, REVA University, Bengaluru-560064, Karnataka, India
| | - Ankita Chatterjee
- Department of Biotechnology, REVA University, Bengaluru-560064, Karnataka, India
| | - Kameswara Rao Badri
- Department of Pharmacology and Toxicology, Cardiovascular Research Institute, Morehouse School of Medicine, GA, Atlanta-30310, USA; Clinical Analytical Chemistry Laboratory, COVID-19 Testing Laboratory, Morehouse School of Medicine, GA, Atlanta-30310, USA.
| | - Vaddi Damodara Reddy
- Department of Biotechnology, REVA University, Bengaluru-560064, Karnataka, India.
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21
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Gong T, Zhang P, Ruan SF, Xiao Z, Chen W, Lin M, Zhong Q, Luo R, Xu Q, Peng J, Cheng B, Chen F, Chen L, Chung WH, Ji C. APOA4 as a novel predictor of prognosis in Stevens-Johnson syndrome/toxic epidermal necrolysis: A proteomics analysis from two prospective cohorts. J Am Acad Dermatol 2023; 89:45-52. [PMID: 36963506 DOI: 10.1016/j.jaad.2023.02.058] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/25/2023] [Accepted: 02/27/2023] [Indexed: 03/26/2023]
Abstract
BACKGROUND Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening adverse drug reactions. Conventional systemic therapies are of limited efficacy and often exhibit strong side effects. OBJECTIVE To assess the efficacy and safety of the combination treatment with a tumor necrosis factor-α antagonist adalimumab and delineate the underlying mechanisms. METHODS We evaluated the efficacy and safety of the combination therapy with adalimumab by comparing 2 treatment cohorts of SJS/TEN patients. Patient plasma samples were collected for proteomics analysis. RESULTS The combination therapy with adalimumab significantly shortened the time to mucocutaneous re-epithelization and healing, with reduced side effects caused by corticosteroids. Plasma proteomic profiling showed that apolipoprotein A-IV (APOA4) was one of the most significant differentially expressed proteins. Multivariate regression analysis revealed that APOA4 level was significantly associated with prognosis parameter of SJS/TEN (P = .004), but not with disease severity score (severity-of-illness score for toxic epidermal necrolysis [SCORTEN]) (P = .118). Thus further research will be helpful to effectively incorporate APOA4 into current SCORTEN-driven protocols. LIMITATIONS The cohort size is relatively small. Both cohorts had low overall SCORTEN scores. CONCLUSION Adalimumab in combination with corticosteroids demonstrates significant clinical benefits over corticosteroids alone in SJS/TEN patients. Moreover, APOA4 may serve as a novel prognostic marker of SJS/TEN.
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Affiliation(s)
- Ting Gong
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China; Central Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Peng Zhang
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Shi-Fan Ruan
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Zhixun Xiao
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Wen Chen
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Min Lin
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Qingmei Zhong
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Renwei Luo
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Qiuyun Xu
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Jiamei Peng
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Bo Cheng
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Fa Chen
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China
| | - Lihong Chen
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Wen-Hung Chung
- Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan.
| | - Chao Ji
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China; Key Laboratory of Skin Cancer of Fujian Higher Education Institutions, Fujian Medical University, Fuzhou, Fujian, China.
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22
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Ortí-Casañ N, Boerema AS, Köpke K, Ebskamp A, Keijser J, Zhang Y, Chen T, Dolga AM, Broersen K, Fischer R, Pfizenmaier K, Kontermann RE, Eisel ULM. The TNFR1 antagonist Atrosimab reduces neuronal loss, glial activation and memory deficits in an acute mouse model of neurodegeneration. Sci Rep 2023; 13:10622. [PMID: 37391534 PMCID: PMC10313728 DOI: 10.1038/s41598-023-36846-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 06/11/2023] [Indexed: 07/02/2023] Open
Abstract
Tumor necrosis factor alpha (TNF-α) and its key role in modulating immune responses has been widely recognized as a therapeutic target for inflammatory and neurodegenerative diseases. Even though inhibition of TNF-α is beneficial for the treatment of certain inflammatory diseases, total neutralization of TNF-α largely failed in the treatment of neurodegenerative diseases. TNF-α exerts distinct functions depending on interaction with its two TNF receptors, whereby TNF receptor 1 (TNFR1) is associated with neuroinflammation and apoptosis and TNF receptor 2 (TNFR2) with neuroprotection and immune regulation. Here, we investigated the effect of administering the TNFR1-specific antagonist Atrosimab, as strategy to block TNFR1 signaling while maintaining TNFR2 signaling unaltered, in an acute mouse model for neurodegeneration. In this model, a NMDA-induced lesion that mimics various hallmarks of neurodegenerative diseases, such as memory loss and cell death, was created in the nucleus basalis magnocellularis and Atrosimab or control protein was administered centrally. We showed that Atrosimab attenuated cognitive impairments and reduced neuroinflammation and neuronal cell death. Our results demonstrate that Atrosimab is effective in ameliorating disease symptoms in an acute neurodegenerative mouse model. Altogether, our study indicates that Atrosimab may be a promising candidate for the development of a therapeutic strategy for the treatment of neurodegenerative diseases.
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Affiliation(s)
- Natalia Ortí-Casañ
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands.
| | - Ate S Boerema
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands
- Applied Research Center, Van Hall Larenstein University of Applied Science, Leeuwarden, The Netherlands
| | - Karina Köpke
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands
| | - Amber Ebskamp
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands
| | - Jan Keijser
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands
| | - Yuequ Zhang
- Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Tingting Chen
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands
- Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Amalia M Dolga
- Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Kerensa Broersen
- Applied Stem Cell Technology, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
| | - Roman Fischer
- Stuttgart Research Center Systems Biology, University of Stuttgart, Stuttgart, Germany
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
| | - Klaus Pfizenmaier
- Stuttgart Research Center Systems Biology, University of Stuttgart, Stuttgart, Germany
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
| | - Roland E Kontermann
- Stuttgart Research Center Systems Biology, University of Stuttgart, Stuttgart, Germany
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
| | - Ulrich L M Eisel
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands.
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23
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Fiedler T, Fairless R, Pichi K, Fischer R, Richter F, Kontermann RE, Pfizenmaier K, Diem R, Williams SK. Co-modulation of TNFR1 and TNFR2 in an animal model of multiple sclerosis. J Neuroinflammation 2023; 20:100. [PMID: 37122019 PMCID: PMC10149004 DOI: 10.1186/s12974-023-02784-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 04/20/2023] [Indexed: 05/02/2023] Open
Abstract
BACKGROUND Tumour necrosis factor (TNF) is a pleiotropic cytokine and master regulator of the immune system. It acts through two receptors resulting in often opposing biological effects, which may explain the lack of therapeutic potential obtained so far in multiple sclerosis (MS) with non-receptor-specific anti-TNF therapeutics. Under neuroinflammatory conditions, such as MS, TNF receptor-1 (TNFR1) is believed to mediate the pro-inflammatory activities associated with TNF, whereas TNF receptor-2 (TNFR2) may instead induce anti-inflammatory effects as well as promote remyelination and neuroprotection. In this study, we have investigated the therapeutic potential of blocking TNFR1 whilst simultaneously stimulating TNFR2 in a mouse model of MS. METHODS Experimental autoimmune encephalomyelitis (EAE) was induced with myelin oligodendrocyte glycoprotein (MOG35-55) in humanized TNFR1 knock-in mice. These were treated with a human-specific TNFR1-selective antagonistic antibody (H398) and a mouse-specific TNFR2 agonist (EHD2-sc-mTNFR2), both in combination and individually. Histopathological analysis of spinal cords was performed to investigate demyelination and inflammatory infiltration, as well as axonal and neuronal degeneration. Retinas were examined for any protective effects on retinal ganglion cell (RGC) degeneration and neuroprotective signalling pathways analysed by Western blotting. RESULTS TNFR modulation successfully ameliorated symptoms of EAE and reduced demyelination, inflammatory infiltration and axonal degeneration. Furthermore, the combinatorial approach of blocking TNFR1 and stimulating TNFR2 signalling increased RGC survival and promoted the phosphorylation of Akt and NF-κB, both known to mediate neuroprotection. CONCLUSION These results further support the potential of regulating the balance of TNFR signalling, through the co-modulation of TNFR1 and TNFR2 activity, as a novel therapeutic approach in treating inflammatory demyelinating disease.
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Affiliation(s)
- Timon Fiedler
- Department of Neurology, University Clinic Heidelberg, University of Heidelberg, Otto-Mayerhof-Zentrum (OMZ), Im Neuenheimer Feld 350, 69120, Heidelberg, Germany
- Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Richard Fairless
- Department of Neurology, University Clinic Heidelberg, University of Heidelberg, Otto-Mayerhof-Zentrum (OMZ), Im Neuenheimer Feld 350, 69120, Heidelberg, Germany
- Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Kira Pichi
- Department of Neurology, University Clinic Heidelberg, University of Heidelberg, Otto-Mayerhof-Zentrum (OMZ), Im Neuenheimer Feld 350, 69120, Heidelberg, Germany
- Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Roman Fischer
- Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
- BioNtech SE, An der Goldgrube 12, 55131, Mainz, Germany
| | - Fabian Richter
- Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
- Immatics Biotechnologies GmbH, Paul-Ehrlich-Str. 15, 72076, Tübingen, Germany
| | - Roland E Kontermann
- Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Klaus Pfizenmaier
- Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Ricarda Diem
- Department of Neurology, University Clinic Heidelberg, University of Heidelberg, Otto-Mayerhof-Zentrum (OMZ), Im Neuenheimer Feld 350, 69120, Heidelberg, Germany
- Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Sarah K Williams
- Department of Neurology, University Clinic Heidelberg, University of Heidelberg, Otto-Mayerhof-Zentrum (OMZ), Im Neuenheimer Feld 350, 69120, Heidelberg, Germany.
- Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
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24
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Shnayder NA, Ashkhotov AV, Trefilova VV, Nurgaliev ZA, Novitsky MA, Petrova MM, Narodova EA, Al-Zamil M, Chumakova GA, Garganeeva NP, Nasyrova RF. Molecular Basic of Pharmacotherapy of Cytokine Imbalance as a Component of Intervertebral Disc Degeneration Treatment. Int J Mol Sci 2023; 24:ijms24097692. [PMID: 37175399 PMCID: PMC10178334 DOI: 10.3390/ijms24097692] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/15/2023] Open
Abstract
Intervertebral disc degeneration (IDD) and associated conditions are an important problem in modern medicine. The onset of IDD may be in childhood and adolescence in patients with a genetic predisposition. With age, IDD progresses, leading to spondylosis, spondylarthrosis, herniated disc, spinal canal stenosis. One of the leading mechanisms in the development of IDD and chronic back pain is an imbalance between pro-inflammatory and anti-inflammatory cytokines. However, classical therapeutic strategies for correcting cytokine imbalance in IDD do not give the expected response in more than half of the cases. The purpose of this review is to update knowledge about new and promising therapeutic strategies based on the correction of the molecular mechanisms of cytokine imbalance in patients with IDD. This review demonstrates that knowledge of the molecular mechanisms of the imbalance between pro-inflammatory and anti-inflammatory cytokines may be a new key to finding more effective drugs for the treatment of IDD in the setting of acute and chronic inflammation.
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Affiliation(s)
- Natalia A Shnayder
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
- Shared Core Facilities "Molecular and Cell Technologies", V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia
| | - Azamat V Ashkhotov
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
| | - Vera V Trefilova
- Department of Neurology, Hospital for War Veterans, 193079 Saint Petersburg, Russia
| | - Zaitun A Nurgaliev
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
- Department of Neurology, Hospital for War Veterans, 193079 Saint Petersburg, Russia
| | - Maxim A Novitsky
- Department of Neurology, Hospital for War Veterans, 193079 Saint Petersburg, Russia
| | - Marina M Petrova
- Shared Core Facilities "Molecular and Cell Technologies", V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia
| | - Ekaterina A Narodova
- Shared Core Facilities "Molecular and Cell Technologies", V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia
| | - Mustafa Al-Zamil
- Department of Physiotherapy, Faculty of Continuing Medical Education, Peoples' Friendship University of Russia, 117198 Moscow, Russia
| | - Galina A Chumakova
- Department of Therapy and General Medical Practice with a Course of Postgraduate Professional Education, Altai State Medical University, 656038 Barnaul, Russia
| | - Natalia P Garganeeva
- Department of General Medical Practice and Outpatient Therapy, Siberian State Medical University, 634050 Tomsk, Russia
| | - Regina F Nasyrova
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
- International Centre for Education and Research in Neuropsychiatry, Samara State Medical University, 443016 Samara, Russia
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25
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Ma J, Kitaura H, Ogawa S, Ohori F, Noguchi T, Marahleh A, Nara Y, Pramusita A, Kinjo R, Kanou K, Kishikawa A, Ichimura A, Mizoguchi I. Docosahexaenoic acid inhibits TNF-α-induced osteoclast formation and orthodontic tooth movement through GPR120. Front Immunol 2023; 13:929690. [PMID: 36741381 PMCID: PMC9889988 DOI: 10.3389/fimmu.2022.929690] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 12/30/2022] [Indexed: 01/19/2023] Open
Abstract
Docosahexaenoic acid (DHA) is an omega-3 fatty acid that has a range of positive impacts on human health, including anti-inflammatory effects and inhibition of osteoclast formation via G-protein-coupled receptor 120 (GPR120). Orthodontic force was reported to induce tumor necrosis factor-α (TNF-α) expression, which activates osteoclast differentiation during orthodontic tooth movement (OTM). The aim of this study was to investigate the influence of DHA on TNF-α-induced osteoclast formation and OTM in vivo. We examined osteoclast formation and bone resorption within the calvaria of both wild-type (WT) and GPR120-deficient (GPR120-KO) mice injected with phosphate-buffered saline (PBS), TNF-α, TNF-α and DHA, or DHA. DHA inhibited TNF-α-induced osteoclast formation and bone resorption in WT mice but had no effect in GPR120-KO mice. OTM experiments were performed in mouse strains with or without regular injection of DHA, and the effects of DHA on osteoclast formation in the alveolar bones during OTM were examined. DHA also suppressed OTM in WT but not GPR120-KO mice. Our data showed that DHA suppresses TNF-α-induced osteoclastogenesis and bone resorption via GPR120. TNF-α has considerable significance in OTM, and therefore, DHA may also inhibit TNF-α-induced osteoclast formation and bone resorption in OTM.
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Affiliation(s)
- Jinghan Ma
- Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan
| | - Hideki Kitaura
- Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan,*Correspondence: Hideki Kitaura,
| | - Saika Ogawa
- Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan
| | - Fumitoshi Ohori
- Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan
| | - Takahiro Noguchi
- Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan
| | - Aseel Marahleh
- Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Miyagi, Japan
| | - Yasuhiko Nara
- Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan
| | - Adya Pramusita
- Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan
| | - Ria Kinjo
- Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan
| | - Kayoko Kanou
- Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan
| | - Akiko Kishikawa
- Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan
| | - Atsuhiko Ichimura
- Department of Biological Chemistry Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Itaru Mizoguchi
- Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan
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Stratos I, Behrendt AK, Anselm C, Gonzalez A, Mittlmeier T, Vollmar B. Inhibition of TNF-α Restores Muscle Force, Inhibits Inflammation, and Reduces Apoptosis of Traumatized Skeletal Muscles. Cells 2022; 11:2397. [PMID: 35954240 PMCID: PMC9367740 DOI: 10.3390/cells11152397] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 07/31/2022] [Accepted: 08/02/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Muscle injuries are common in humans and are often associated with irrecoverable damage and disability. Upon muscle injury, TNF-α signaling pathways modulate the healing process and are predominantly associated with tissue degradation. In this study we assumed that TNF-α inhibition could reduce the TNF-α-associated tissue degradation after muscle injury. MATERIALS AND METHODS Therefore, the left soleus muscle of 42 male Wistar rats was injured using a standardized open muscle injury model. All rats were treated immediately after injury either with infliximab (single i.p. injection; 10 mg/kg b.w.) or saline solution i.p. Final measurements were conducted at day one, four, and 14 post injury. The muscle force, the muscle cell proliferation, the muscle cell coverage as well as the myofiber diameter served as read out parameters of our experiment. RESULTS Systemic application of infliximab could significantly reduce the TNF-α levels in the injured muscle at day four upon trauma compared to saline treated animals. The ratio of muscle weight to body weight was increased and the twitch muscle force showed a significant rise 14 days after trauma and TNF-α inhibition. Quantification of myofiber diameter in the penumbra zone showed a significant difference between both groups at day one and four after injury, indicated by muscle hypertrophy in the infliximab group. Planimetric analysis of the injured muscle at day 14 revealed increased muscle tissue fraction in the infliximab group compared to the control animals. Muscle cell proliferation did not differ between both groups. CONCLUSIONS These data provide evidence that the TNF-α blockade positively regulates the restauration of skeletal muscles upon injury.
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Affiliation(s)
- Ioannis Stratos
- Department of Orthopaedic Surgery, Julius-Maximilians University Wuerzburg, 97074 Wuerzburg, Germany
- Department of Trauma, Hand and Reconstructive Surgery, University of Rostock, 18057 Rostock, Germany; (A.-K.B.); (A.G.); (T.M.)
| | - Ann-Kathrin Behrendt
- Department of Trauma, Hand and Reconstructive Surgery, University of Rostock, 18057 Rostock, Germany; (A.-K.B.); (A.G.); (T.M.)
- Institute for Experimental Surgery, University of Rostock, 18057 Rostock, Germany; (C.A.); (B.V.)
| | - Christian Anselm
- Institute for Experimental Surgery, University of Rostock, 18057 Rostock, Germany; (C.A.); (B.V.)
| | - Aldebarani Gonzalez
- Department of Trauma, Hand and Reconstructive Surgery, University of Rostock, 18057 Rostock, Germany; (A.-K.B.); (A.G.); (T.M.)
- Institute for Experimental Surgery, University of Rostock, 18057 Rostock, Germany; (C.A.); (B.V.)
| | - Thomas Mittlmeier
- Department of Trauma, Hand and Reconstructive Surgery, University of Rostock, 18057 Rostock, Germany; (A.-K.B.); (A.G.); (T.M.)
| | - Brigitte Vollmar
- Institute for Experimental Surgery, University of Rostock, 18057 Rostock, Germany; (C.A.); (B.V.)
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27
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Li Y, Mai Y, Cao P, Wen X, Fan T, Wang X, Ruan G, Tang S, Ding C, Zhu Z. Relative Efficacy and Safety of Anti-Inflammatory Biologic Agents for Osteoarthritis: A Conventional and Network Meta-Analysis. J Clin Med 2022; 11:3958. [PMID: 35887724 PMCID: PMC9317938 DOI: 10.3390/jcm11143958] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/01/2022] [Accepted: 07/04/2022] [Indexed: 12/18/2022] Open
Abstract
Previous studies have consistently revealed that both local and systemic inflammations are the key to the onset and progression of osteoarthritis (OA). Thus, anti-inflammatory biologic agents could potentially attenuate the progression of OA. We conducted this meta-analysis to examine the efficacy and safety of ant-inflammatory biologic agents among OA patients. METHODS Five databases were searched for randomized controlled trials (RCTs) comparing biologics with placebo or each other in OA patients. Data of pain, physical function, stiffness, and adverse events (AEs) were extracted for a conventional and a Bayesian network meta-analysis. RESULTS 15 studies with data for 1566 patients were analyzed. In the conventional meta-analysis, etanercept (SMD -0.47; 95% CI -0.89, -0.05) and infliximab (SMD -2.04; CI -2.56, -1.52) were superior to placebo for knee pain. In the network meta-analysis, infliximab was superior to all the other biologic agents in improving pain (vs. hyaluronic acid (SMD -22.95; CI -34.21, -10.43), vs. adalimumab (SMD -21.71; CI -32.65, -11.00), vs. anakinra (SMD -24.63; CI -38.79, -10.05), vs. canakinumab (SMD -32.83; CI -44.45, -20.68), vs. etanercept (SMD -18.40; CI -29.93, -5.73), vs. lutikizumab (SMD -25.11; CI -36.47, -14.78), vs. naproxen (SMD -30.16; CI -41.78, -17.38), vs. tocilizumab (SMD -24.02; CI -35.63, -11.86) and vs. placebo (SMD -25.88; CI -34.87, -16.60)). No significant differences were observed between biologics and placebo regarding physical function, stiffness, and risk of AEs. CONCLUSIONS The findings suggest that infliximab may relieve pain more than other biological agents in OA patients. No significant differences were observed between biologics and placebo regarding physical function, stiffness, and risk of AEs. The results must be interpreted cautiously; therefore, further randomized controlled trials are warranted.
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Affiliation(s)
- Yang Li
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; (Y.L.); (Y.M.); (P.C.); (X.W.); (T.F.); (X.W.); (G.R.); (S.T.); (C.D.)
| | - Yiying Mai
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; (Y.L.); (Y.M.); (P.C.); (X.W.); (T.F.); (X.W.); (G.R.); (S.T.); (C.D.)
| | - Peihua Cao
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; (Y.L.); (Y.M.); (P.C.); (X.W.); (T.F.); (X.W.); (G.R.); (S.T.); (C.D.)
| | - Xin Wen
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; (Y.L.); (Y.M.); (P.C.); (X.W.); (T.F.); (X.W.); (G.R.); (S.T.); (C.D.)
| | - Tianxiang Fan
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; (Y.L.); (Y.M.); (P.C.); (X.W.); (T.F.); (X.W.); (G.R.); (S.T.); (C.D.)
| | - Xiaoshuai Wang
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; (Y.L.); (Y.M.); (P.C.); (X.W.); (T.F.); (X.W.); (G.R.); (S.T.); (C.D.)
| | - Guangfeng Ruan
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; (Y.L.); (Y.M.); (P.C.); (X.W.); (T.F.); (X.W.); (G.R.); (S.T.); (C.D.)
| | - Su’an Tang
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; (Y.L.); (Y.M.); (P.C.); (X.W.); (T.F.); (X.W.); (G.R.); (S.T.); (C.D.)
| | - Changhai Ding
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; (Y.L.); (Y.M.); (P.C.); (X.W.); (T.F.); (X.W.); (G.R.); (S.T.); (C.D.)
- Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Zhaohua Zhu
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; (Y.L.); (Y.M.); (P.C.); (X.W.); (T.F.); (X.W.); (G.R.); (S.T.); (C.D.)
- Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
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Neuenfeldt F, Schumacher JC, Grieshaber-Bouyer R, Habicht J, Schröder-Braunstein J, Gauss A, Merle U, Niesler B, Heineken N, Dalpke A, Gaida MM, Giese T, Meuer S, Samstag Y, Wabnitz G. Inflammation induces pro-NETotic neutrophils via TNFR2 signaling. Cell Rep 2022; 39:110710. [PMID: 35443164 DOI: 10.1016/j.celrep.2022.110710] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 02/24/2022] [Accepted: 03/29/2022] [Indexed: 11/19/2022] Open
Abstract
Cytokines released during chronic inflammatory diseases induce pro-inflammatory properties in polymorphonuclear neutrophils (PMNs). Here, we describe the development of a subgroup of human PMNs expressing CCR5, termed CCR5+ PMNs. Auto- and paracrine tumor necrosis factor (TNF) signaling increases intracellular neutrophil elastase (ELANE) abundance and induces neutrophil extracellular traps formation (NETosis) in CCR5+ PMNs, and triggering of CCR5 amplifies NETosis. Membranous TNF (mTNF) outside-in signaling induces the formation of reactive oxygen species, known activators of NETosis. In vivo, we find an increased number of CCR5+ PMNs in the peripheral blood and inflamed lamina propria of patients with ulcerative colitis (UC). Notably, failure of anti-TNF therapy is associated with higher frequencies of CCR5+ PMNs. In conclusion, we identify a phenotype of pro-NETotic, CCR5+ PMNs present in inflamed tissue in vivo and inducible in vitro. These cells may reflect an important component of tissue damage during chronic inflammation and could be of diagnostic value.
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Affiliation(s)
- Friederike Neuenfeldt
- Institute of Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany
| | - Jan Christoph Schumacher
- Institute of Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany
| | - Ricardo Grieshaber-Bouyer
- Department of Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Jüri Habicht
- Institute of Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany
| | | | - Annika Gauss
- Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Uta Merle
- Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Beate Niesler
- Department of Human Molecular Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany; nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | - Niko Heineken
- Institute of Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany
| | - Alexander Dalpke
- Institute of Medical Microbiology and Virology, University Hospital Carl Gustav Carus, TU Dresden, 01069 Dresden, Germany
| | - Matthias M Gaida
- Institute of Pathology, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany
| | - Thomas Giese
- Institute of Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany
| | - Stefan Meuer
- Institute of Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany
| | - Yvonne Samstag
- Institute of Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany
| | - Guido Wabnitz
- Institute of Immunology, Heidelberg University, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
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Bhat S, Patel M, Duly K, Choi D. Adalimumab-Adbm: The First Interchangeable Biosimilar for the Treatment of Inflammatory Diseases. Ann Pharmacother 2022; 56:1356-1364. [PMID: 35392668 DOI: 10.1177/10600280221082196] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE The objective of the study was to review the pharmacologic and clinical profile of adalimumab-adbm (BI 695501), the first interchangeable biosimilar for treatment of inflammatory diseases. DATA SOURCES A PubMed search was conducted from inception to December 2021 using the keywords BI 695501 and adalimumab-adbm. Information was also obtained from published abstracts and package inserts. STUDY SELECTION AND DATA EXTRACTION Phase 1, 2 and 3 studies plus relevant literature on adalimumab-adbm pharmacologic and clinical profile were reviewed. DATA SYNTHESIS Adalimumab-adbm approval was based on a series of phase 3 VOLTAIRE trials, which evaluated the biosimilar's efficacy and safety in the treatment of moderate to severe Crohn's disease, rheumatoid arthritis, and psoriasis. Interchangeability status was granted based on data from the VOLTAIRE-X trial. The VOLTAIRE and VOLTAIRE-X studies demonstrated comparable efficacy and safety between adalimumab-adbm and reference adalimumab. Common adverse events included infections and injection site reactions. Similar to reference adalimumab, adalimumab-adbm contains black box warnings related to serious infections and malignancy. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE Adalimumab-adbm is the first interchangeable biosimilar to be approved for inflammatory diseases and has the potential to improve patient access to treatment while decreasing medication-related costs. However, it will not be commercially available for patient use until 2023 and its adoption into clinical practice may face potential barriers seen with other biosimilars. CONCLUSION As an interchangeable biosimilar with comparable efficacy and safety to reference adalimumab, adalimumab-adbm is an important advance toward cost-effective management of inflammatory diseases.
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Affiliation(s)
- Shubha Bhat
- Department of Pharmacy and Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Maitri Patel
- Department of Pharmacy and Dermatology, University of Chicago Medicine, Chicago, IL, USA
| | - Kristine Duly
- Department of Pharmacy and Orthopedic and Rheumatologic Institute, Cleveland Clinic, Cleveland, OH, USA
| | - David Choi
- Department of Pharmacy and Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
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Oliver CE, Patel H, Hong J, Carter J, Kraus WE, Huffman KM, Truskey GA. Tissue engineered skeletal muscle model of rheumatoid arthritis using human primary skeletal muscle cells. J Tissue Eng Regen Med 2022; 16:128-139. [PMID: 34781416 PMCID: PMC9487182 DOI: 10.1002/term.3266] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 10/15/2021] [Accepted: 11/05/2021] [Indexed: 02/03/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily targeting the joints. Autoreactive immune cells involved in RA affect other tissues, including skeletal muscle. Patients with RA experience diminished physical function, limited mobility, reduced muscle function, chronic pain, and increased mortality. To explore the impact of RA on skeletal muscle, we engineered electrically responsive, contractile human skeletal muscle constructs (myobundles) using primary skeletal muscle cells isolated from the vastus lateralis muscle of 11 RA patients (aged 57-74) and 10 aged healthy donors (aged 55-76), as well as from the hamstring muscle of six young healthy donors (less than 18 years of age) as a benchmark. Since all patients were receiving treatment for the disease, RA disease activity was mild. In 2D culture, RA myoblast purity, growth rate, and senescence were not statistically different than aged controls; however, RA myoblast purity showed greater variance compared to controls. Surprisingly, in 3D culture, contractile force production by RA myobundles was greater compared to aged controls. In support of this finding, assessment of RA myofiber maturation showed increased area of sarcomeric α-actinin (SAA) expression over time compared to aged controls. Furthermore, a linear regression test indicated a positive correlation between SAA protein levels and tetanus force production in RA and controls. Our findings suggest that medications prescribed to RA patients may maintain-or even enhance-muscle function, and this effect is retained and observed in in vitro culture. Future studies regarding the effects of RA therapeutics on RA skeletal muscle, in vivo and in vitro, are warranted.
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Affiliation(s)
| | - Hailee Patel
- Department of Biomedical Engineering, Duke University
| | - James Hong
- Department of Biomedical Engineering, Duke University
| | | | | | - Kim M. Huffman
- Department of Medicine, Duke University School of Medicine
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31
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Arbo BD, Schimith LE, Goulart dos Santos M, Hort MA. Repositioning and development of new treatments for neurodegenerative diseases: Focus on neuroinflammation. Eur J Pharmacol 2022; 919:174800. [DOI: 10.1016/j.ejphar.2022.174800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 01/18/2022] [Accepted: 02/02/2022] [Indexed: 11/03/2022]
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Kitaura H, Marahleh A, Ohori F, Noguchi T, Nara Y, Pramusita A, Kinjo R, Ma J, Kanou K, Mizoguchi I. Role of the Interaction of Tumor Necrosis Factor-α and Tumor Necrosis Factor Receptors 1 and 2 in Bone-Related Cells. Int J Mol Sci 2022; 23:ijms23031481. [PMID: 35163403 PMCID: PMC8835906 DOI: 10.3390/ijms23031481] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 02/04/2023] Open
Abstract
Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine expressed by macrophages, monocytes, and T cells, and its expression is triggered by the immune system in response to pathogens and their products, such as endotoxins. TNF-α plays an important role in host defense by inducing inflammatory reactions such as phagocytes and cytocidal systems activation. TNF-α also plays an important role in bone metabolism and is associated with inflammatory bone diseases. TNF-α binds to two cell surface receptors, the 55kDa TNF receptor-1 (TNFR1) and the 75kDa TNF receptor-2 (TNFR2). Bone is in a constant state of turnover; it is continuously degraded and built via the process of bone remodeling, which results from the regulated balance between bone-resorbing osteoclasts, bone-forming osteoblasts, and the mechanosensory cell type osteocytes. Precise interactions between these cells maintain skeletal homeostasis. Studies have shown that TNF-α affects bone-related cells via TNFRs. Signaling through either receptor results in different outcomes in different cell types as well as in the same cell type. This review summarizes and discusses current research on the TNF-α and TNFR interaction and its role in bone-related cells.
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33
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Zhou L, He Q, Yang X, Zheng S, Ou X. Research on Mechanism of Superparamagnetic Iron Oxide Nanoparticles in Activating Endoplasmic Reticulum and Prompting Apoptosis of Liver Cells Through Mediation of Tumor Necrosis Factor- α/Tumor Necrosis Factor Receptor 1 (TNF- α/TNFR1) Pathway. J Biomed Nanotechnol 2021; 17:2413-2419. [PMID: 34974864 DOI: 10.1166/jbn.2021.3199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The aim of this study was to assess mechanism of superparamagnetic iron oxide nanoparticles (SPIO-NPs) in activating endoplasmic reticulum (ER) and prompting apoptosis of liver cells through mediating the TNF-α/TNFR1 pathway. The SPIO-NPs were prepared and identified, and HegG2 cells were cultivated in vitro, and their apoptosis was detected. The specific pathogen-free (SPF)-grade rats were divided into several groups; which included blank group, low concentration group, high concentration group and control group. The enzymatic activity of Caspase-3 in liver tissue was tested, and expressions of Caspase-3, Bax, Bcl-2, TNF-α, p-TNFR1, IRE1α, and eIF2α were tested. The size of prepared SPIO-NPs was 7.5 nm and there was no coagulation. There was good dispersity and electric potential, and appearance was stable. The apoptotic rate in the high concentration group was notably higher than in the other groups. There was notable inflammatory cell infiltration in the high concentration group, where quantity of apoptosis was highest. The quantity of apoptosis and fluorocyte in the high concentration group were notably higher than in the other groups. Moreover, there were over expressions of Caspase-3, Bax, Caspase-3, p-TNFR1, IRE1α, and eIF2α in the high concentration group while the expression of TNF-α was lowest. The apoptosis of HegG2 cells was prompted by SPIO-NPs, and quantity of apoptosis was increased with increased adopted concentration. The active expression of p-TNFR1, IRE1α, and eIF2α could be prompted to reduce the expression of TNF-α and increase the expression of Caspase-3 and Bax for prompting the apoptosis.
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Affiliation(s)
- Liyang Zhou
- Department of Infectious Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China
| | - Qin He
- Department of Infectious Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China
| | - Xiaoàn Yang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, China
| | - Shuo Zheng
- Department of Infectious Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China
| | - Xueting Ou
- Department of Infectious Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China
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Kaminsky LW, Al-Sadi R, Ma TY. IL-1β and the Intestinal Epithelial Tight Junction Barrier. Front Immunol 2021; 12:767456. [PMID: 34759934 PMCID: PMC8574155 DOI: 10.3389/fimmu.2021.767456] [Citation(s) in RCA: 223] [Impact Index Per Article: 55.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 10/11/2021] [Indexed: 02/06/2023] Open
Abstract
The intestinal epithelial tight junction (TJ) barrier controls the paracellular permeation of contents from the intestinal lumen into the intestinal tissue and systemic circulation. A defective intestinal TJ barrier has been implicated as an important pathogenic factor in inflammatory diseases of the gut including Crohn's disease, ulcerative colitis, necrotizing enterocolitis, and celiac disease. Previous studies have shown that pro-inflammatory cytokines, which are produced during intestinal inflammation, including interleukin-1β (IL-1β), tumor necrosis factor-α, and interferon-γ, have important intestinal TJ barrier-modulating actions. Recent studies have shown that the IL-1β-induced increase in intestinal TJ permeability is an important contributing factor of intestinal inflammation. The IL-1β-induced increase in intestinal TJ permeability is mediated by regulatory signaling pathways and activation of nuclear transcription factor nuclear factor-κB, myosin light chain kinase gene activation, and post-transcriptional occludin gene modulation by microRNA and contributes to the intestinal inflammatory process. In this review, the regulatory role of IL-1β on intestinal TJ barrier, the intracellular mechanisms that mediate the IL-1β modulation of intestinal TJ permeability, and the potential therapeutic targeting of the TJ barrier are discussed.
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Affiliation(s)
- Lauren W Kaminsky
- Section of Allergy, Asthma, and Immunology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Rana Al-Sadi
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Thomas Y Ma
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, United States
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35
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Smyth DJ, Ren B, White MPJ, McManus C, Webster H, Shek V, Evans C, Pandhal J, Fields F, Maizels RM, Mayfield S. Oral delivery of a functional algal-expressed TGF-β mimic halts colitis in a murine DSS model. J Biotechnol 2021; 340:1-12. [PMID: 34390759 PMCID: PMC8516079 DOI: 10.1016/j.jbiotec.2021.08.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/04/2021] [Accepted: 08/06/2021] [Indexed: 12/14/2022]
Abstract
Inflammatory bowel disease (IBD) is a set of immunological disorders which can generate chronic pain and fatigue associated with the inflammatory symptoms. The treatment of IBD remains a significant hurdle with current therapies being only partially effective or having significant side effects, suggesting that new therapies that elicit different modes of action and delivery strategies are required. TGM1 is a TGF-β mimic that was discovered from the intestinal helminth parasite Heligmosomoides polygyrus and is thought to be produced by the parasite to suppress the intestinal inflammation response to help evade host immunity, making it an ideal candidate to be developed as a novel anti-inflammatory bio-therapeutic. Here we utilized the expression system of the edible green algae Chlamydomonas reinhardtii in order to recombinantly produce active TGM1 in a form that could be ingested. C. reinhardtii robustly expressed TGM1, and the resultant recombinant protein is biologically active as measured by regulatory T cell induction. When delivered orally to mice, the algal expressed TGM1 is able to ameliorate weight loss, lymphadenopathy, and disease symptoms in a mouse model of DSS-induced colitis, demonstrating the potential of this biologic as a novel treatment of IBD.
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Affiliation(s)
- Danielle J Smyth
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK
| | - Bijie Ren
- California Center for Algae Biotechnology, Division of Biological Sciences, University of California, San Diego, USA
| | - Madeleine P J White
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK
| | - Caitlin McManus
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK
| | - Holly Webster
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK
| | - Vivien Shek
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK
| | - Caroline Evans
- Bioanalytical Facility, Dept Chemical and Biological Engineering, University of Sheffield, UK
| | - Jagroop Pandhal
- Bioanalytical Facility, Dept Chemical and Biological Engineering, University of Sheffield, UK
| | - Francis Fields
- California Center for Algae Biotechnology, Division of Biological Sciences, University of California, San Diego, USA
| | - Rick M Maizels
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK.
| | - Stephen Mayfield
- California Center for Algae Biotechnology, Division of Biological Sciences, University of California, San Diego, USA.
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Alvarez-de Miranda FJ, Alonso-Sánchez I, Alcamí A, Hernaez B. TNF Decoy Receptors Encoded by Poxviruses. Pathogens 2021; 10:pathogens10081065. [PMID: 34451529 PMCID: PMC8401223 DOI: 10.3390/pathogens10081065] [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: 06/22/2021] [Revised: 07/29/2021] [Accepted: 08/18/2021] [Indexed: 12/16/2022] Open
Abstract
Tumour necrosis factor (TNF) is an inflammatory cytokine produced in response to viral infections that promotes the recruitment and activation of leukocytes to sites of infection. This TNF-based host response is essential to limit virus spreading, thus poxviruses have evolutionarily adopted diverse molecular mechanisms to counteract TNF antiviral action. These include the expression of poxvirus-encoded soluble receptors or proteins able to bind and neutralize TNF and other members of the TNF ligand superfamily, acting as decoy receptors. This article reviews in detail the various TNF decoy receptors identified to date in the genomes from different poxvirus species, with a special focus on their impact on poxvirus pathogenesis and their potential use as therapeutic molecules.
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Nagarajan UM, Cho C, Gyorke CE, Nagarajan S, Ezzell JA, Brochu H, Huntress I, Harrell E, Peng X. Tumor Necrosis Factor Alpha-Induced Interleukin-1 Alpha Synthesis and Cell Death Is Increased in Mouse Epithelial Cells Infected With Chlamydia muridarum. J Infect Dis 2021; 224:S47-S55. [PMID: 34396406 DOI: 10.1093/infdis/jiab168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Chlamydia trachomatis-genital infection in women can be modeled in mice using Chlamydia muridarum. Using this model, it has been shown that the cytokines tumor necrosis factor (TNF)α and interleukin (IL)-1α lead to irreversible tissue damage in the oviducts. In this study, we investigated the contribution of TNFα on IL-1α synthesis in infected epithelial cells. We show that C muridarum infection enhanced TNFα-induced IL-1α expression and release in a mouse epithelial cell line. In addition to IL-1α, several TNFα-induced inflammatory genes were also highly induced, and infection enhanced TNF-induced cell death. In the mouse model of genital infection, oviducts from mice lacking the TNFα receptor displayed minimal staining for IL-1α compared with wild-type oviducts. Our results suggest TNFα and IL-1α enhance each other's downstream effects resulting in a hyperinflammatory response to chlamydial infection. We propose that biologics targeting TNF-induced IL-1α synthesis could be used to mitigate tissue damage during chlamydial infection.
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Affiliation(s)
- Uma M Nagarajan
- Department of Pediatrics, University of North Carolina, University of North Carolina, Chapel Hill, North Carolina, USA.,Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Crescentia Cho
- Department of Pediatrics, University of North Carolina, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Clare E Gyorke
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Shanmugam Nagarajan
- Department of Pathology and Labortaory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - J Ashley Ezzell
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Hayden Brochu
- Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina, USA
| | - Ian Huntress
- Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina, USA
| | - Erin Harrell
- Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina, USA
| | - Xinxia Peng
- Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina, USA.,Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA
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Bower JAJ, O'Flynn L, Kakad R, Aldulaimi D. Effect of inflammatory bowel disease treatments on patients with diabetes mellitus. World J Diabetes 2021; 12:1248-1254. [PMID: 34512890 PMCID: PMC8394226 DOI: 10.4239/wjd.v12.i8.1248] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/13/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023] Open
Abstract
As medical care progresses and the number of patients with chronic conditions increases there is the inevitable challenge of managing patients with multiple co-morbidities. Inflammatory bowel disease (IBD) is an umbrella term for are inflammatory conditions affecting the gastrointestinal tract, the two most common forms being Ulcerative Colitis and Crohn’s disease. These diseases, usually diagnosed in young adults, exhibit a relapsing and remitting course and usually require long-term treatment. IBD can be treated with a number of topical and systemic treatments. We conducted a review of the current published evidence for the effects these medications can have on diabetes mellitus (DM) and glycaemic control. Searches were conducted on medline and embase with a timeframe from 1947 (the date from which studies on embase are recorded) to November 2020. Suitable publications were selected and reviewed. Current evidence of the impact of aminosalicylates, corticosteroids, thiopurines, and biologic agents was reviewed. Though there was limited evidence for certain agents, IBD medications have been shown to have an effect of DM and these effects should be considered in managing patients with dual pathologies. The effects of steroids on blood sugar control is well documented, but consideration of other agents is also important. In patients requiring steroids for Ulcerative Colitis, locally acting steroid agents delivered rectally may be preferred to minimise side effects in those with distal bowel Ulcerative Colitis. A switch to other agents should be considered as soon as possible in people with diabetes to limit the impact on glycaemic control. 5-aminosalicylates appear to play a role in the reduction of hemoglobin A1c (HbA1c), although the literature suggests these may be falsely low readings. Consequently, monitoring of people with diabetes on these agents may require daily monitoring of capillary blood sugars rather than relying simply on HbA1c; for example fructosamine performed 3-6 monthly, although this risks missing the rise in readings. There is only limited evidence of the effects of thiopurines on diabetes and further investigation is needed into the possible relationship between them. However, given the current available evidence it may be preferable to commence patients with diabetes on thiopurines as soon as possible, whilst also monitoring for side effects such as pancreatitis. There appears to be more evidence supporting a link between tumor necrosis factor-α inhibitors and DM. Both infliximab and adalimumab have evidence suggesting that both can cause reduced blood sugar levels. Further studies on the effects of the various biological agents mentioned are required alongside any novel biologic therapy and the impact of dual biologic therapy in the future.
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Affiliation(s)
- Joshua Ashley Jack Bower
- Department of Gastroenterology, South Warwickshire Foundation Trust, Warwick CV34 5BW, United Kingdom
| | - Lauren O'Flynn
- Department of Gastroenterology, South Warwickshire Foundation Trust, Warwick CV34 5BW, United Kingdom
| | - Rakhi Kakad
- Department of Endocrinology, South Warwickshire Foundation Trust, Warwick CV34 5BW, United Kingdom
| | - David Aldulaimi
- Department of Gastroenterology, South Warwickshire Foundation Trust, Warwick CV34 5BW, United Kingdom
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Piszko P, Włodarczyk M, Zielińska S, Gazińska M, Płociński P, Rudnicka K, Szwed A, Krupa A, Grzymajło M, Sobczak-Kupiec A, Słota D, Kobielarz M, Wojtków M, Szustakiewicz K. PGS/HAp Microporous Composite Scaffold Obtained in the TIPS-TCL-SL Method: An Innovation for Bone Tissue Engineering. Int J Mol Sci 2021; 22:8587. [PMID: 34445293 PMCID: PMC8395318 DOI: 10.3390/ijms22168587] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/06/2021] [Accepted: 08/08/2021] [Indexed: 12/16/2022] Open
Abstract
In this research, we synthesize and characterize poly(glycerol sebacate) pre-polymer (pPGS) (1H NMR, FTiR, GPC, and TGA). Nano-hydroxyapatite (HAp) is synthesized using the wet precipitation method. Next, the materials are used to prepare a PGS-based composite with a 25 wt.% addition of HAp. Microporous composites are formed by means of thermally induced phase separation (TIPS) followed by thermal cross-linking (TCL) and salt leaching (SL). The manufactured microporous materials (PGS and PGS/HAp) are then subjected to imaging by means of SEM and µCT for the porous structure characterization. DSC, TGA, and water contact angle measurements are used for further evaluation of the materials. To assess the cytocompatibility and biological potential of PGS-based composites, preosteoblasts and differentiated hFOB 1.19 osteoblasts are employed as in vitro models. Apart from the cytocompatibility, the scaffolds supported cell adhesion and were readily populated by the hFOB1.19 preosteoblasts. HAp-facilitated scaffolds displayed osteoconductive properties, supporting the terminal differentiation of osteoblasts as indicated by the production of alkaline phosphatase, osteocalcin and osteopontin. Notably, the PGS/HAp scaffolds induced the production of significant amounts of osteoclastogenic cytokines: IL-1β, IL-6 and TNF-α, which induced scaffold remodeling and promoted the reconstruction of bone tissue. Initial biocompatibility tests showed no signs of adverse effects of PGS-based scaffolds toward adult BALB/c mice.
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Affiliation(s)
- Paweł Piszko
- Department of Polymer Engineering and Technology, Faculty of Chemistry, Wrocław University of Science and Technology (WUST), Wyb. Wyspiańskiego 27, 50-370 Wrocław, Poland; (S.Z.); (M.G.); (M.G.)
| | - Marcin Włodarczyk
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Łódź, Banacha 12-16, 90-237 Łódź, Poland; (M.W.); (P.P.); (K.R.); (A.S.); (A.K.)
| | - Sonia Zielińska
- Department of Polymer Engineering and Technology, Faculty of Chemistry, Wrocław University of Science and Technology (WUST), Wyb. Wyspiańskiego 27, 50-370 Wrocław, Poland; (S.Z.); (M.G.); (M.G.)
| | - Małgorzata Gazińska
- Department of Polymer Engineering and Technology, Faculty of Chemistry, Wrocław University of Science and Technology (WUST), Wyb. Wyspiańskiego 27, 50-370 Wrocław, Poland; (S.Z.); (M.G.); (M.G.)
| | - Przemysław Płociński
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Łódź, Banacha 12-16, 90-237 Łódź, Poland; (M.W.); (P.P.); (K.R.); (A.S.); (A.K.)
| | - Karolina Rudnicka
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Łódź, Banacha 12-16, 90-237 Łódź, Poland; (M.W.); (P.P.); (K.R.); (A.S.); (A.K.)
| | - Aleksandra Szwed
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Łódź, Banacha 12-16, 90-237 Łódź, Poland; (M.W.); (P.P.); (K.R.); (A.S.); (A.K.)
| | - Agnieszka Krupa
- Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Łódź, Banacha 12-16, 90-237 Łódź, Poland; (M.W.); (P.P.); (K.R.); (A.S.); (A.K.)
| | - Michał Grzymajło
- Department of Polymer Engineering and Technology, Faculty of Chemistry, Wrocław University of Science and Technology (WUST), Wyb. Wyspiańskiego 27, 50-370 Wrocław, Poland; (S.Z.); (M.G.); (M.G.)
| | - Agnieszka Sobczak-Kupiec
- Institute of Materials Science, Faculty of Materials Science and Physics, Cracow University of Technology, 37 Jana Pawła II Av., 31-864 Krakow, Poland; (A.S.-K.); (D.S.)
| | - Dagmara Słota
- Institute of Materials Science, Faculty of Materials Science and Physics, Cracow University of Technology, 37 Jana Pawła II Av., 31-864 Krakow, Poland; (A.S.-K.); (D.S.)
| | - Magdalena Kobielarz
- Department of Mechanics, Materials and Biomedical Engineering, Faculty of Mechanical Engineering, Wroclaw University of Science and Technology (WUST), Wyb. Wyspiańskiego 27, 50-370 Wrocław, Poland; (M.K.); (M.W.)
| | - Magdalena Wojtków
- Department of Mechanics, Materials and Biomedical Engineering, Faculty of Mechanical Engineering, Wroclaw University of Science and Technology (WUST), Wyb. Wyspiańskiego 27, 50-370 Wrocław, Poland; (M.K.); (M.W.)
| | - Konrad Szustakiewicz
- Department of Polymer Engineering and Technology, Faculty of Chemistry, Wrocław University of Science and Technology (WUST), Wyb. Wyspiańskiego 27, 50-370 Wrocław, Poland; (S.Z.); (M.G.); (M.G.)
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Bioengineered Nanoparticles Loaded-Hydrogels to Target TNF Alpha in Inflammatory Diseases. Pharmaceutics 2021; 13:pharmaceutics13081111. [PMID: 34452074 PMCID: PMC8400713 DOI: 10.3390/pharmaceutics13081111] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/13/2021] [Accepted: 07/18/2021] [Indexed: 12/13/2022] Open
Abstract
Rheumatoid Arthritis (RA) is an incurable autoimmune disease that promotes the chronic impairment of patients’ mobility. For this reason, it is vital to develop therapies that target early inflammatory symptoms and act before permanent articular damage. The present study offers two novel therapies based in advanced drug delivery systems for RA treatment: encapsulated chondroitin sulfate modified poly(amidoamine) dendrimer nanoparticles (NPs) covalently bonded to monoclonal anti-TNF α antibody in both Tyramine-Gellan Gum and Tyramine-Gellan Gum/Silk Fibroin hydrogels. Using pro-inflammatory THP-1 (i.e., human monocytic cell line), the therapy was tested in an inflammation in vitro model under both static and dynamic conditions. Firstly, we demonstrated effective NP-antibody functionalization and TNF-α capture. Upon encapsulation, the NPs were released steadily over 21 days. Moreover, in static conditions, the approaches presented good anti-inflammatory activity over time, enabling the retainment of a high percentage of TNF α. To mimic the physiological conditions of the human body, the hydrogels were evaluated in a dual-chamber bioreactor. Dynamic in vitro studies showed absent cytotoxicity in THP-1 cells and a significant reduction of TNF-α in suspension over 14 days for both hydrogels. Thus, the developed approach showed potential for use as personalized medicine to obtain better therapeutic outcomes and decreased adverse effects.
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Maleki Dizaji N, Garjani A, Mousavi S, Mohammadi M, Vaez H. Time-dependent influence of infliximab on hemodynamic responses and cardiac injuries of isoproterenol-induced myocardial infarction in rats. Eur J Pharmacol 2021; 903:174122. [PMID: 33932452 DOI: 10.1016/j.ejphar.2021.174122] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 04/04/2021] [Accepted: 04/21/2021] [Indexed: 10/21/2022]
Abstract
Immune-induced inflammation plays an important role both in aggravating and healing of post myocardial infarction (MI) injuries. Potent anti-inflammatory and local immunomodulatory activity of infliximab has been suggested to have modulating effects on immune responses after MI. The aim of the present study was to evaluate the efficacy of infliximab on hemodynamic responses and myocardial injuries following isoproterenol-induced myocardial infarction. Male Wistar rats, weighting 260 ± 20 g were assigned into ten groups (n = 6) of saline (normal saline), infliximab (7 mg/kg), isoproterenol (100 mg/kg for two consecutive days), and isoproterenol plus infliximab (30 min after the second injection of isoproterenol). The heart tissues and serums were analyzed 24, 48, 72, and 96 h post-MI and hemodynamic parameters, histopathological changes, malondialdehyde (MDA), Total antioxidant capacity (TAC), lactate dehydrogenase (LDH), and lactate levels were assessed in the respective groups. Infliximab partially improved hemodynamic depression in the first days after MI, but the heart became more suppressed later. A similar result also obtained at the MDA tissue levels but not serum levels. Anti-inflammatory effects of Infliximab may improve cardiac function and prevent heart tissue injury early after MI; however, it can worsen the condition later by inhibiting compensatory reactions such as cardiac remodeling and tissue repair.
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Affiliation(s)
- Nasrin Maleki Dizaji
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Garjani
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samin Mousavi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdieh Mohammadi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Haleh Vaez
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
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The Migration of Human Follicular Dendritic Cell-Like Cell Is Facilitated by Matrix Metalloproteinase 3 Expression That Is Mediated through TNF α-ERK1/2-AP1 Signaling. J Immunol Res 2021; 2021:8483938. [PMID: 34222497 PMCID: PMC8225449 DOI: 10.1155/2021/8483938] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/31/2021] [Accepted: 06/04/2021] [Indexed: 11/17/2022] Open
Abstract
Follicular dendritic cells are important stromal components of the germinal center (GC) and have pivotal roles in maintaining the GC microenvironment for high-affinity antibody production. Tumor necrosis factor-α (TNFα) is essential for the development and functions of follicular dendritic cells. Despite the importance of follicular dendritic cells in humoral immunity, their molecular control mechanisms have yet to be fully elucidated due to the lack of an adequate investigation system. Here, we have used a unique human primary follicular dendritic cell-like cell (FDCLC) to demonstrate that the migration of these cells is enhanced by TNFα-mediated metalloproteinase 3 (MMP3) expression. MMP3 was found to be highly expressed in normal human GCs and markedly upregulated in human primary FDCLCs by TNFα. TNFα induced ERK1/2 phosphorylation and the transcription of MMP3 through AP1. TNFα treatment increased FDCLC migration, and a knockdown of MMP3 significantly reduced the TNFα-induced migration of FDCLCs. Overall, we have newly identified a control mechanism for the expression of MMP3 in FDCLCs that modulates their migration and may indicate an important role in GC biology. Since GCs are observed in the lesions of autoimmune diseases and lymphomas, targeting the MMP3/TNFα-mediated migration of stromal cells in the B cell follicle may have great potential as a future therapeutic modality against aberrant GC-associated disorders.
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Mohammadi MR, Rodriguez SM, Luong JC, Li S, Cao R, Alshetaiwi H, Lau H, Davtyan H, Jones MB, Jafari M, Kessenbrock K, Villalta SA, de Vos P, Zhao W, Lakey JRT. Exosome loaded immunomodulatory biomaterials alleviate local immune response in immunocompetent diabetic mice post islet xenotransplantation. Commun Biol 2021; 4:685. [PMID: 34083739 PMCID: PMC8175379 DOI: 10.1038/s42003-021-02229-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 05/07/2021] [Indexed: 12/16/2022] Open
Abstract
Foreign body response (FBR) to biomaterials compromises the function of implants and leads to medical complications. Here, we report a hybrid alginate microcapsule (AlgXO) that attenuated the immune response after implantation, through releasing exosomes derived from human Umbilical Cord Mesenchymal Stem Cells (XOs). Upon release, XOs suppress the local immune microenvironment, where xenotransplantation of rat islets encapsulated in AlgXO led to >170 days euglycemia in immunocompetent mouse model of Type 1 Diabetes. In vitro analyses revealed that XOs suppressed the proliferation of CD3/CD28 activated splenocytes and CD3+ T cells. Comparing suppressive potency of XOs in purified CD3+ T cells versus splenocytes, we found XOs more profoundly suppressed T cells in the splenocytes co-culture, where a heterogenous cell population is present. XOs also suppressed CD3/CD28 activated human peripheral blood mononuclear cells (PBMCs) and reduced their cytokine secretion including IL-2, IL-6, IL-12p70, IL-22, and TNFα. We further demonstrate that XOs mechanism of action is likely mediated via myeloid cells and XOs suppress both murine and human macrophages partly by interfering with NFκB pathway. We propose that through controlled release of XOs, AlgXO provide a promising new platform that could alleviate the local immune response to implantable biomaterials.
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Affiliation(s)
- M Rezaa Mohammadi
- Department of Materials Science and Engineering, University of California Irvine, Irvine, CA, USA
- Sue and Bill Stem Cell Center, University of California Irvine, Irvine, CA, USA
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA
- Department of Surgery, University of California Irvine, Irvine, CA, USA
| | | | - Jennifer Cam Luong
- Sue and Bill Stem Cell Center, University of California Irvine, Irvine, CA, USA
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA
- Department of Surgery, University of California Irvine, Irvine, CA, USA
| | - Shiri Li
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA
- Department of Surgery, University of California Irvine, Irvine, CA, USA
| | - Rui Cao
- Sue and Bill Stem Cell Center, University of California Irvine, Irvine, CA, USA
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA
- Department of Surgery, University of California Irvine, Irvine, CA, USA
| | - Hamad Alshetaiwi
- Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA
| | - Hien Lau
- Sue and Bill Stem Cell Center, University of California Irvine, Irvine, CA, USA
| | - Hayk Davtyan
- Sue and Bill Stem Cell Center, University of California Irvine, Irvine, CA, USA
- Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA
| | - Mathew Blurton Jones
- Sue and Bill Stem Cell Center, University of California Irvine, Irvine, CA, USA
- Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA
- Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA
- Institute for Immunology, University of California Irvine, Irvine, CA, USA
| | - Mahtab Jafari
- Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA
| | - Kai Kessenbrock
- Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA
| | - S Armando Villalta
- Institute for Immunology, University of California Irvine, Irvine, CA, USA
| | - Paul de Vos
- Department of Pathology and Medical Biology, Section Immunoendocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Weian Zhao
- Sue and Bill Stem Cell Center, University of California Irvine, Irvine, CA, USA
- Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center; Edwards Life Sciences Center for Advanced Cardiovascular Technology; Department of Biomedical Engineering, Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA
| | - Jonathan R T Lakey
- Sue and Bill Stem Cell Center, University of California Irvine, Irvine, CA, USA.
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA.
- Department of Surgery, University of California Irvine, Irvine, CA, USA.
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Melo AT, Campanilho-Marques R, Fonseca JE. Golimumab (anti-TNF monoclonal antibody): where we stand today. Hum Vaccin Immunother 2021; 17:1586-1598. [PMID: 33369527 PMCID: PMC8115761 DOI: 10.1080/21645515.2020.1836919] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/17/2020] [Accepted: 10/09/2020] [Indexed: 01/07/2023] Open
Abstract
Tumor necrosis factor (TNF) is a pro-inflammatory cytokine and its overexpression has been implicated in the pathophysiology of several chronic immune-mediated inflammatory diseases. Biological therapies, like TNF inhibitors, have been revolutionizing the course of these disorders. Golimumab is a transgenic anti-TNF monoclonal antibody that acts primarily by targeting and neutralizing TNF, thus preventing inflammation. It is approved for the treatment of Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Nonradiographic axial Spondyloarthritis, Juvenile Idiopathic Arthritis, and Ulcerative Colitis. Clinical trials are also being conducted in other conditions. This review charts the clinical development of golimumab and outlines the data that support its potential use across several Immune-mediated inflammatory diseases.
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Affiliation(s)
- Ana Teresa Melo
- Rheumatology Department, Hospital De Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon Academic Medical Centre, Lisbon, Portugal
- Rheumatology Research Unit, Instituto De Medicina Molecular João Lobo Antunes, Faculdade De Medicina, Universidade De Lisboa, Lisbon, Portugal
| | - Raquel Campanilho-Marques
- Rheumatology Department, Hospital De Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon Academic Medical Centre, Lisbon, Portugal
- Rheumatology Research Unit, Instituto De Medicina Molecular João Lobo Antunes, Faculdade De Medicina, Universidade De Lisboa, Lisbon, Portugal
| | - João Eurico Fonseca
- Rheumatology Department, Hospital De Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon Academic Medical Centre, Lisbon, Portugal
- Rheumatology Research Unit, Instituto De Medicina Molecular João Lobo Antunes, Faculdade De Medicina, Universidade De Lisboa, Lisbon, Portugal
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AlQranei MS, Senbanjo LT, Aljohani H, Hamza T, Chellaiah MA. Lipopolysaccharide- TLR-4 Axis regulates Osteoclastogenesis independent of RANKL/RANK signaling. BMC Immunol 2021; 22:23. [PMID: 33765924 PMCID: PMC7995782 DOI: 10.1186/s12865-021-00409-9] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 03/01/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Lipopolysaccharide (LPS) is an endotoxin and a vital component of gram-negative bacteria's outer membrane. During gram-negative bacterial sepsis, LPS regulates osteoclast differentiation and activity, in addition to increasing inflammation. This study aimed to investigate how LPS regulates osteoclast differentiation of RAW 264.7 cells in vitro. RESULTS Herein, we revealed that RAW cells failed to differentiate into mature osteoclasts in vitro in the presence of LPS. However, differentiation occurred in cells primed with receptor activator of nuclear factor-kappa-Β ligand (RANKL) for 24 h and then treated with LPS for 48 h (henceforth, denoted as LPS-treated cells). In cells treated with either RANKL or LPS, an increase in membrane levels of toll-like receptor 4 (TLR4) receptor was observed. Mechanistically, an inhibitor of TLR4 (TAK-242) reduced the number of osteoclasts as well as the secretion of tumor necrosis factor (TNF)-α in LPS-treated cells. RANKL-induced RAW cells secreted a very basal level TNF-α. TAK-242 did not affect RANKL-induced osteoclastogenesis. Increased osteoclast differentiation in LPS-treated osteoclasts was not associated with the RANKL/RANK/OPG axis but connected with the LPS/TLR4/TNF-α tumor necrosis factor receptor (TNFR)-2 axis. We postulate that this is because TAK-242 and a TNF-α antibody suppress osteoclast differentiation. Furthermore, an antibody against TNF-α reduced membrane levels of TNFR-2. Secreted TNF-α appears to function as an autocrine/ paracrine factor in the induction of osteoclastogenesis independent of RANKL. CONCLUSION TNF-α secreted via LPS/TLR4 signaling regulates osteoclastogenesis in macrophages primed with RANKL and then treated with LPS. Our findings suggest that TLR4/TNF-α might be a potential target to suppress bone loss associated with inflammatory bone diseases, including periodontitis, rheumatoid arthritis, and osteoporosis.
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Affiliation(s)
- Mohammed S AlQranei
- Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, 650 W Baltimore Street, Baltimore, MD, 21201, USA
- Preventive Dental Sciences Department, School of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Linda T Senbanjo
- Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, 650 W Baltimore Street, Baltimore, MD, 21201, USA
| | - Hanan Aljohani
- Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, 650 W Baltimore Street, Baltimore, MD, 21201, USA
- Department of Oral Medicine and Diagnostics Sciences, King Saud University, School of Dentistry, Riyadh, Kingdom of Saudi Arabia
| | - Therwa Hamza
- Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, 650 W Baltimore Street, Baltimore, MD, 21201, USA
| | - Meenakshi A Chellaiah
- Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, 650 W Baltimore Street, Baltimore, MD, 21201, USA.
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An immune therapy model for effective treatment on inflammatory bowel disease. PLoS One 2020; 15:e0238918. [PMID: 32970698 PMCID: PMC7514012 DOI: 10.1371/journal.pone.0238918] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 08/26/2020] [Indexed: 01/12/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a disease that causes inflammation throughout the digestive tract. Repeated inflammation and frequent relapses cause intestinal damage and expose the patient to a higher risk. In this work, we proposed an immune therapy model for effective treatment strategy through mathematical modeling for patients with IBD. We evaluated the ability of the patient's immune system to recover during treatment. For this, we defined the interval of healthy individual, and examined the frequency of compartments such as T cells and cytokines considered in the model maintain the normal state. Based on the fact that each patient has a unique immune system, we have shown at the same drug works differently, depending on the individual immune system characteristics for every patient. It is known that IBD is related to an imbalance between pro- and anti- inflammatory cytokines as the cause of the disease. So the ratios of pro- to anti- inflammatory cytokines are used as an indicator of patient's condition and inflammation status in various diseases. We compared the ratios of pro- to anti- inflammatory cytokine according to patient's individual immune system and drugs. Since the effects of biological drugs are highly dependent on the patient's own immune system, it is essential to define the immune system status before selecting and using a biological drug.
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Wojtulewicz K, Krawczyńska A, Tomaszewska-Zaremba D, Wójcik M, Herman AP. Effect of Acute and Prolonged Inflammation on the Gene Expression of Proinflammatory Cytokines and Their Receptors in the Anterior Pituitary Gland of Ewes. Int J Mol Sci 2020; 21:E6939. [PMID: 32967383 PMCID: PMC7554822 DOI: 10.3390/ijms21186939] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/19/2020] [Accepted: 09/20/2020] [Indexed: 01/01/2023] Open
Abstract
An acute and prolonged inflammation inhibits the reproduction process by the disruption of the neurohormonal activity of the hypothalamic-pituitary-gonadal axis. It is thought that these changes may be caused by proinflammatory cytokines, i.e., interleukin (IL) -1β, IL-6 and tumor necrosis factor (TNF) α. The aim of this study was to determine the effect of an acute and prolonged inflammation on the expression of genes encoding cytokine and their receptors, gonadotropin releasing hormone receptor (GnRHR), beta subunits of luteinizing hormone (LHβ) and follicle-stimulating (FSHβ) in the anterior pituitary (AP). Moreover, the circulating concentration of LH and FSH was also assayed. Two experiments were carried out on adult ewes which were divided into two control groups and treated with lipopolysaccharide (LPS; 400 ng / kg). Acute inflammation was caused by a single injection of LPS into the external jugular vein, while the chronic inflammation was induced by seven times LPS injection (one a day). In both experiments, animals were euthanized 3h after the last LPS / NaCl injection and the blood samples collected 15 min before euthanasia. An acute inflammation stimulates the expression of the IL-1β, IL-6 and TNFα genes and their receptors in the AP of sheep. Prolonged inflammation increased TNFα gene expression and both types of TNFα and IL-6 receptors. Both an acute and prolonged inflammation inhibited LHβ gene expression in the AP and reduced LH level in blood. A sevenfold LPS injection raises FSH concentration. The gene expression of GnRHR was reduced in the ovine AP only after a single injection of endotoxin. Our results suggest that there are important differences in the way how an acute and prolonged inflammation influence proinflammatory cytokines and their receptors gene expression in the AP of anestrous ewes, which could be reflected by differences in the AP secretory activity during these states.
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Affiliation(s)
- Karolina Wojtulewicz
- The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 03-105 Jabłonna, Poland; (A.K.); (D.T.-Z.); (M.W.); (A.P.H.)
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Hirukawa M, Zhang M, Echenique–Diaz LM, Mizota K, Ohdachi SD, Begué–Quiala G, Delgado–Labañino JL, Gámez–Díez J, Alvarez–Lemus J, Machado LG, Núñez MS, Shibata T, Kigoshi H, Kita M. Isolation and structure–activity relationship studies of jacaranones: Anti-inflammatory quinoids from the Cuban endemic plant Jacaranda arborea (Bignoniaceae). Tetrahedron Lett 2020. [DOI: 10.1016/j.tetlet.2020.152005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Correger E, Marcos J, Laguens G, Stringa P, Cardinal-Fernández P, Blanch L. Pretreatment with adalimumab reduces ventilator-induced lung injury in an experimental model. Rev Bras Ter Intensiva 2020; 32:58-65. [PMID: 32401991 PMCID: PMC7206963 DOI: 10.5935/0103-507x.20200010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 09/29/2019] [Indexed: 02/05/2023] Open
Abstract
Objective To determine whether adalimumab administration before mechanical ventilation reduces ventilator-induced lung injury (VILI). Methods Eighteen rats randomized into 3 groups underwent mechanical ventilation for 3 hours with a fraction of inspired oxygen = 0.40% including a low tidal volume group (n = 6), where tidal volume = 8mL/kg and positive end-expiratory pressure = 5cmH2O; a high tidal volume group (n = 6), where tidal volume = 35mL/kg and positive end-expiratory pressure = 0; and a pretreated + high tidal volume group (n = 6) where adalimumab (100ug/kg) was administered intraperitoneally 24 hours before mechanical ventilation + tidal volume = 35mL/kg and positive end-expiratory pressure = 0. ANOVA was used to compare histological damage (ATS 2010 Lung Injury Scoring System), pulmonary edema, lung compliance, arterial partial pressure of oxygen, and mean arterial pressure among the groups. Results After 3 hours of ventilation, the mean histological lung injury score was higher in the high tidal volume group than in the low tidal volume group (0.030 versus 0.0051, respectively, p = 0.003). The high tidal volume group showed diminished lung compliance at 3 hours (p = 0.04) and hypoxemia (p = 0,018 versus control). Pretreated HVt group had an improved histological score, mainly due to a significant reduction in leukocyte infiltration (p = 0.003). Conclusion Histological examination after 3 hours of injurious ventilation revealed ventilator-induced lung injury in the absence of measurable changes in lung mechanics or oxygenation; administering adalimumab before mechanical ventilation reduced lung edema and histological damage.
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Affiliation(s)
- Enrique Correger
- Grupo de Trabalho em Fisiopatologia Pulmonar Experimental, Faculdade de Medicina, Universidad Nacional de La Plata, La Plata, Argentina
| | - Josefina Marcos
- Grupo de Trabalho em Fisiopatologia Pulmonar Experimental, Faculdade de Medicina, Universidad Nacional de La Plata, La Plata, Argentina
| | - Graciela Laguens
- Cadeira de Patologia, Faculdade de Medicina, Universidad Nacional de La Plata, La Plata, Argentina
| | - Pablo Stringa
- Grupo de Trabalho em Fisiopatologia Pulmonar Experimental, Faculdade de Medicina, Universidad Nacional de La Plata, La Plata, Argentina
| | | | - Lluis Blanch
- Centro de Cuidados Intensivos, Corporació Sanitària Parc Taulí, Sabadell, Barcelona, Spain
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Martin-Higueras C, Ludwig-Portugall I, Hoppe B, Kurts C. Targeting kidney inflammation as a new therapy for primary hyperoxaluria? Nephrol Dial Transplant 2020; 34:908-914. [PMID: 30169827 DOI: 10.1093/ndt/gfy239] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Indexed: 12/27/2022] Open
Abstract
The primary hyperoxalurias (PHs) are inborn errors of glyoxylate metabolism characterized by endogenous oxalate overproduction in the liver, and thus elevated urinary oxalate excretion. The urinary calcium-oxalate (CaOx) supersaturation and the continuous renal accumulation of insoluble CaOx crystals yield a progressive decline in renal function that often ends with renal failure. In PH Type 1 (AGXT mutated), the most frequent and severe condition, patients typically progress to end-stage renal disease (ESRD); in PH Type 2 (GRHPR mutated), 20% of patients develop ESRD, while only one patient with PH Type 3 (HOGA1 mutated) has been reported with ESRD so far. Patients with ESRD undergo frequent maintenance (haemo)dialysis treatment, and finally must receive a combined liver-kidney transplantation as the only curative treatment option available in PH Type 1. In experimental models using oxalate-enriched chow, CaOx crystals were bound to renal tubular cells, promoting a pro-inflammatory environment that led to fibrogenesis in the renal parenchyma by activation of a NACHT, LRR and PYD domains-containing protein 3 (NALP3)-dependent inflammasome in renal dendritic cells and macrophages. Chronic fibrogenesis progressively impaired renal function. Targeting the inflammatory response has recently been suggested as a therapeutic strategy to treat not only oxalate-induced crystalline nephropathies, but also those characterized by accumulation of cystine and urate in other organs. Herein, we summarize the pathogenesis of PH, revising the current knowledge of the CaOx-mediated inflammatory response in animal models of endogenous oxalate overproduction. Furthermore, we highlight the possibility of modifying the NLRP3-dependent inflammasome as a new and complementary therapeutic strategy to treat this severe and devastating kidney disease.
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Affiliation(s)
- Cristina Martin-Higueras
- Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany.,Department of Pediatrics, Division of Pediatric Nephrology, University Children's Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Isis Ludwig-Portugall
- Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Bernd Hoppe
- Department of Pediatrics, Division of Pediatric Nephrology, University Children's Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Christian Kurts
- Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
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