|
1
|
Suryaningtyas IT, Jasmadi, Dayarathne LA, Marasinghe CK, Je JY. Mussels as sustainable marine resources for bioactive peptides for health and the food industry. Food Funct 2025; 16:3255-3272. [PMID: 40261071 DOI: 10.1039/d4fo05397d] [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: 04/24/2025]
Abstract
The growing need for sustainable protein sources has led to increased interest in marine-based alternatives, particularly those with bioactive properties. Mussels, known for their abundance and environmental sustainability, have gained attention as potential sources for bioactive peptides (BAPs). This review focuses on the current research surrounding BAPs derived from marine mussels, exploring their applications in human health and the food industry. Through a comprehensive analysis of the existing literature, the review discusses the ecological significance of mussels, their nutritional value, and the health benefits of mussel-derived peptides, which include antioxidant, anti-inflammatory, anti-osteoporosis, and cardiovascular effects. Additionally, the review examines methods for extracting these peptides, their commercial availability, and the challenges faced in the field, along with future research directions. While mussels have traditionally been consumed for their nutritional benefits, the scientific investigation into their potential for producing BAPs is relatively recent. These peptides, obtained through processes like fermentation and hydrolysis, offer promising applications in functional foods and nutraceuticals. However, further research is necessary to optimize extraction techniques, overcome commercialization hurdles, and fully realize the potential of mussels as sustainable sources of BAPs for enhancing human health.
Collapse
Affiliation(s)
- Indyaswan Tegar Suryaningtyas
- Research Center for Marine-Integrated Bionics Technology, Pukyong National University, Busan 48513, Republic of Korea
- Research Center for Food Technology and Processing, National Research and Innovation Agency, Yogyakarta, 55861, Indonesia
- Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea
| | - Jasmadi
- Research Center for Food Technology and Processing, National Research and Innovation Agency, Yogyakarta, 55861, Indonesia
- Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea
| | - Lakshi Ayoda Dayarathne
- Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea
| | | | - Jae-Young Je
- Major of Human Bioconvergence, Division of Smart Healthcare, Pukyong National University, Busan 48513, Republic of Korea.
| |
Collapse
|
|
2
|
Yin Y, Shuai F, Liu X, Zhao Y, Han X, Zhao H. Biomaterials and therapeutic strategies designed for tooth extraction socket healing. Biomaterials 2025; 316:122975. [PMID: 39626339 DOI: 10.1016/j.biomaterials.2024.122975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/16/2024] [Accepted: 11/28/2024] [Indexed: 12/31/2024]
Abstract
Tooth extraction is the most commonly performed oral surgical procedure, with a wide range of clinical indications. The oral cavity is a complex microenvironment, influenced by oral movements, salivary flow, and bacterial biofilms. These factors can contribute to delayed socket healing and the onset of post-extraction complications, which can burden patients' esthetic and functional rehabilitation. Achieving effective extraction socket healing requires a multidisciplinary approach. Recent advancements in materials science and bioengineering have paved the way for developing novel strategies. This review outlines the fundamental healing processes and cellular-molecular interactions involved in the healing of extraction sockets. It then delves into the current landscape of biomaterials for socket healing, highlighting emerging strategies and potential targets that could transform the treatment paradigm. Building upon this foundation, this review also presents future directions and identifies challenges associated with the clinical application of biomaterials for extraction socket healing.
Collapse
Affiliation(s)
- Yijia Yin
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Orthodontics, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, PR China
| | - Fangyuan Shuai
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Orthodontics, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, PR China
| | - Xian Liu
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Orthodontics, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, PR China
| | - Yuxi Zhao
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Orthodontics, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, PR China
| | - Xianglong Han
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Orthodontics, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, PR China.
| | - Hang Zhao
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Orthodontics, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, PR China.
| |
Collapse
|
|
3
|
Liao M, Zhu Y, Cui Q, Yue M, Li J, Gao L, He Y, Guo Y, Zhang W, Wei Z, Xia Y, Dai Y. Intestinal Butyrate Ameliorates Rheumatoid Arthritis Through Promoting the Expression of Cortistatin in Ileum via HDAC3-Vitamin D Receptor Pathway. Immunology 2025. [PMID: 40304573 DOI: 10.1111/imm.13939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Revised: 04/17/2025] [Accepted: 04/20/2025] [Indexed: 05/02/2025] Open
Abstract
Butyrate, administered orally or via drinking water, can effectively ameliorate experimental rheumatoid arthritis (RA) in mice despite its limited bioavailability. The discrepancy urges us to explore the involvement and role of intestinal anti-RA factors in the action of butyrate. In this study, we found that substituting drinking water with butyrate (75 mM) could promote the expression of cortistatin (CST) in the ileal epithelium of mice with collagen-induced arthritis (CIA), but butyrate did not alter the expression of other anti-RA neuropeptides in the intestine and the expression of CST in the spleen and brain. The anti-RA efficacy of butyrate was remarkably reduced following adeno-associated virus (AAV)-mediated knockdown of CST. Transcription factor screening revealed that butyrate upregulated CST expression via the vitamin D receptor (VDR). Notably, butyrate-induced VDR and CST expression in intestinal epithelial cells was diminished by α-cyano-4-hydroxycinnamic acid (CHC) rather than siRNA targeting G protein-coupled receptors (GPCRs), suggesting that butyrate functions through an intracellular pathway. Furthermore, butyrate significantly reduced HDAC activity in intestinal epithelial cells and HDAC3 plasmid transfection attenuated the upregulation of butyrate against VDR and CST expression. Chromatin immunoprecipitation assay showed that butyrate selectively enhanced histone acetylation in the P3 and P4 regions of the VDR promoter. In summary, intestinal butyrate exerts an anti-RA effect through selectively promoting the expression of CST in ileal epithelial cells via the HDAC3-VDR pathway.
Collapse
Affiliation(s)
- Minghui Liao
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yanrong Zhu
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Qi Cui
- The Second Affiliated Hospital of Inner Mongolia University for the Nationalities, Inner Mongolia General Forestry Hospital, Inner Mongolia Autonomous Region, China
| | - Mengfan Yue
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jialin Li
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Lei Gao
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yue He
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yilei Guo
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Wenjie Zhang
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Zhifeng Wei
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yufeng Xia
- Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yue Dai
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| |
Collapse
|
|
4
|
Xue J, Nian M, Liang Y, Zhu Z, Hu Z, Jia Y, Chi S, Chen J. Neutrophil extracellular traps (NETs) are increased in rheumatoid arthritis-associated interstitial lung disease. Respir Res 2025; 26:33. [PMID: 39844268 PMCID: PMC11756115 DOI: 10.1186/s12931-025-03111-1] [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: 08/30/2024] [Accepted: 01/10/2025] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND Neutrophil extracellular trap (NET) formation has been implicated as a pathogenic mechanism in both rheumatoid arthritis (RA) and interstitial lung disease (ILD). However, the role of NETs in RA-associated ILD (RA-ILD) and the mechanisms driving NET formation remain unclear. This study aimed to assess the involvement of NETs in RA-ILD and elucidate the underlying mechanisms. METHODS Single-cell sequencing was used to identify changes in the quantity and function of neutrophils in the lung tissue of a zymosan A (ZYM)-induced interstitial pneumonia arthritis model. Additionally, nuclear receptor 4A3 (NR4A3) interference was performed in HL-60 cells to assess its impact on NET formation and the transformation of MRC-5 cells into myofibroblasts. The clinical relevance of plasma myeloperoxidase-DNA (MPO-DNA), citrullinated histone 3 (Cit-H3), and cell-free DNA was evaluated in RA-ILD patients with different imaging types via a commercial enzyme-linked immunosorbent assay (ELISA). RESULTS In the ZYM-treated SKG mouse model, which recapitulates key features of RA-ILD, an increased population of neutrophils in the lung tissue was primarily responsible for NET formation. Mechanistically, we found that interference with NR4A3 expression enhanced NET formation in HL-60 cells, which in turn promoted the differentiation of MRC-5 cells into myofibroblasts. Clinically, plasma MPO-DNA levels are elevated in patients with RA-nonspecific interstitial pneumonia (RA-NSIP), whereas Cit-H3 levels are elevated in RA-usual interstitial pneumonia (RA-UIP) patients compared with healthy subjects. ROC curve analysis further revealed that the combination of plasma MPO-DNA, rheumatoid factor (RF), and anti-citrullinated protein (anti-CCP) and the combination of Cit-H3, RF, and anti-CCP were superior diagnostic panels for NSIP and UIP in RA-ILD patients, respectively. Moreover, compared with those from healthy controls, neutrophils from patients with RA-UIP and RA-NSIP demonstrated a significantly increased ability to form NETs and induce the differentiation of MRC-5 cells into myofibroblasts. Specifically, RA-UIP patients exhibited a greater capacity for NET formation and the differentiation of MRC-5 cells into myofibroblasts than did RA-NSIP patients. CONCLUSIONS These findings suggest that targeting NETs may be a novel therapeutic approach for treating ILD in RA patients.
Collapse
Affiliation(s)
- Jing Xue
- Department of Key Laboratory of Ningxia Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Miaomiao Nian
- Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Yangyang Liang
- Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Zeqin Zhu
- Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Zhenyu Hu
- Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Yuanyuan Jia
- Department of Key Laboratory of Ningxia Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Shuhong Chi
- Department of Rheumatology, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
| | - Juan Chen
- Department of Key Laboratory of Ningxia Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
- Department of Pulmonary and Critical Care Medicine, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
| |
Collapse
|
|
5
|
López M, Gualillo O. Rheumatic diseases and metabolism: where centre and periphery meet. Nat Rev Rheumatol 2024; 20:783-794. [PMID: 39478099 DOI: 10.1038/s41584-024-01178-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/30/2024] [Indexed: 11/26/2024]
Abstract
Over the past few decades, the connection between metabolism and various inflammatory and rheumatic diseases has been an area of active investigation. Nonetheless, the precise mechanisms underlying these relationships remain a topic of ongoing debate, owing in part to conflicting data. This discrepancy can be attributed to the predominant focus on peripheral mechanisms in research into the metabolic consequences of rheumatic diseases. However, a wealth of evidence supports the notion that the central nervous system, specifically the hypothalamus, has an important influence on metabolic homeostasis. Notably, links have been established between crucial hypothalamic mechanisms responsible for regulating energy balance (including food intake, thermogenesis, and glucose and lipid metabolism), such as AMP-activated protein kinase, and the pathophysiology of rheumatoid arthritis. This Review aims to comprehensively examine the current understanding of central metabolic control in rheumatic diseases and explore potential therapeutic options that target this pathophysiological mechanism.
Collapse
Affiliation(s)
- Miguel López
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Santiago de Compostela, Spain.
| | - Oreste Gualillo
- Servizo Galego de Saude (SERGAS)-Instituto de Investigación Sanitaria de Santiago (IDIS), the Neuroendocrine Interactions in Rheumatology and Inflammatory Disease (NEIRID) Lab, Santiago University Clinical Hospital, Santiago de Compostela, Spain.
| |
Collapse
|
|
6
|
Straub RH, Cutolo M. A History of Psycho-Neuro-Endocrine Immune Interactions in Rheumatic Diseases. Neuroimmunomodulation 2024; 31:183-210. [PMID: 39168106 DOI: 10.1159/000540959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 08/15/2024] [Indexed: 08/23/2024] Open
Abstract
BACKGROUND All active scientists stand on the shoulders of giants and many other more anonymous scientists, and this is not different in our field of psycho-neuro-endocrine immunology in rheumatic diseases. Too often, the modern world of publishing forgets about the collective enterprise of scientists. Some journals advise the authors to present only literature from the last decade, and it has become a natural attitude of many scientists to present only the latest publications. In order to work against this general unempirical behavior, neuroimmunomodulation devotes the 30th anniversary issue to the history of medical science in psycho-neuro-endocrine immunology. SUMMARY Keywords were derived from the psycho-neuro-endocrine immunology research field very well known to the authors (R.H.S. has collected a list of keywords since 1994). We screened PubMed, the Cochran Library of Medicine, Embase, Scopus database, and the ORCID database to find relevant historical literature. The Snowballing procedure helped find related work. According to the historical appearance of discoveries in the field, the order of presentation follows the subsequent scheme: (1) the sensory nervous system, (2) the sympathetic nervous system, (3) the vagus nerve, (4) steroid hormones (glucocorticoids, androgens, progesterone, estrogens, and the vitamin D hormone), (5) afferent pathways involved in fatigue, anxiety, insomnia, and depression (includes pathophysiology), and (6) evolutionary medicine and energy regulation - an umbrella theory. KEY MESSAGES A brief history on psycho-neuro-endocrine immunology cannot address all relevant aspects of the field. The authors are aware of this shortcoming. The reader must see this review as a viewpoint through the biased eyes of the authors. Nevertheless, the text gives an overview of the history in psycho-neuro-endocrine immunology of rheumatic diseases.
Collapse
Affiliation(s)
- Rainer H Straub
- Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine, University Hospital Regensburg, Regensburg, Germany
| | - Maurizio Cutolo
- Research Laboratories and Academic Division of Clinical Rheumatology, Department of Internal Medicine DIMI, Postgraduate School of Rheumatology, University of Genova, Genoa, Italy
| |
Collapse
|
|
7
|
Xu Y, Zhang S, Zhu F, Liang Y. A deep learning model for anti-inflammatory peptides identification based on deep variational autoencoder and contrastive learning. Sci Rep 2024; 14:18451. [PMID: 39117712 PMCID: PMC11310449 DOI: 10.1038/s41598-024-69419-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 08/05/2024] [Indexed: 08/10/2024] Open
Abstract
As a class of biologically active molecules with significant immunomodulatory and anti-inflammatory effects, anti-inflammatory peptides have important application value in the medical and biotechnology fields due to their unique biological functions. Research on the identification of anti-inflammatory peptides provides important theoretical foundations and practical value for a deeper understanding of the biological mechanisms of inflammation and immune regulation, as well as for the development of new drugs and biotechnological applications. Therefore, it is necessary to develop more advanced computational models for identifying anti-inflammatory peptides. In this study, we propose a deep learning model named DAC-AIPs based on variational autoencoder and contrastive learning for accurate identification of anti-inflammatory peptides. In the sequence encoding part, the incorporation of multi-hot encoding helps capture richer sequence information. The autoencoder, composed of convolutional layers and linear layers, can learn latent features and reconstruct features, with variational inference enhancing the representation capability of latent features. Additionally, the introduction of contrastive learning aims to improve the model's classification ability. Through cross-validation and independent dataset testing experiments, DAC-AIPs achieves superior performance compared to existing state-of-the-art models. In cross-validation, the classification accuracy of DAC-AIPs reached around 88%, which is 7% higher than previous models. Furthermore, various ablation experiments and interpretability experiments validate the effectiveness of DAC-AIPs. Finally, a user-friendly online predictor is designed to enhance the practicality of the model, and the server is freely accessible at http://dac-aips.online .
Collapse
Affiliation(s)
- Yujie Xu
- School of Mathematics and Statistics, Xidian University, Xi'an, 710071, People's Republic of China
| | - Shengli Zhang
- School of Mathematics and Statistics, Xidian University, Xi'an, 710071, People's Republic of China.
| | - Feng Zhu
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China
| | - Yunyun Liang
- School of Science, Xi'an Polytechnic University, Xi'an, 710048, People's Republic of China
| |
Collapse
|
|
8
|
Sun K, Sun J, Yan C, Sun J, Xu X, Shi J. Sympathetic Neurotransmitter, VIP, Delays Intervertebral Disc Degeneration via FGF18/FGFR2-Mediated Activation of Akt Signaling Pathway. Adv Biol (Weinh) 2024; 8:e2300250. [PMID: 38047500 DOI: 10.1002/adbi.202300250] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 09/28/2023] [Indexed: 12/05/2023]
Abstract
Neuromodulation-related intervertebral disc degeneration (IVDD) is a novel IVDD pattern and are proposed recently. However, the mechanistic basis of neuromodulation and intervertebral disc (IVD) homeostasis remains unclear. Here, this study aimed to investigate the expression of postganglionic sympathetic nerve fiber-derived vasoactive intestinal peptide (VIP) system in human IVD tissue, and to assess the role of VIP-related neuromodulation in IVDD. Patient samples and in vitro cell experiments showed that the expression of receptors for VIP is negatively correlated with the severity of IVDD, and the administration of exogenous VIP can ameliorate interleukin 1β-induced nucleus pulposus (NP) cell apoptosis and inflammation. Further mRNA-seq analysis revealed that fibroblast growth factor 18- (FGF18)-mediated activation of V-akt murine thymoma viral oncogene homolog signaling pathway is involved in the protective effects of VIP on inflammation-induced NP cell degeneration. Further analysis identified VIP via its receptor vasoactive intestinal peptide receptor 2 can directly result in decreased expression of miR-15a-5p, which targeted FGF18. Finally, in vivo mice lumbar IVDD model confirmed that focally exogenous administration of VIP can effectively ameliorated the progression of IVDD, as shown by the radiological and histological analysis. In conclusion, these results indicated that sympathetic neurotransmitter, VIP, delayed IVDD via FGF18/FGFR2-mediated activation of V-akt murine thymoma viral oncogene homolog signaling pathway, which will broaden the horizon concerning how the neuromodulation correlates with IVDD and shed new light on novel therapeutical alternatives to IVDD.
Collapse
Affiliation(s)
- Kaiqiang Sun
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai, 200003, China
- Department of Orthopedics, Naval Medical Center of PLA, Navy Medical University, No.338 Western HuaiHai Road, Shanghai, 200003, China
| | - Jiuyi Sun
- Department of Orthopedics, Naval Medical Center of PLA, Navy Medical University, No.338 Western HuaiHai Road, Shanghai, 200003, China
| | - Chen Yan
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai, 200003, China
| | - Jingchuan Sun
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai, 200003, China
| | - Ximing Xu
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai, 200003, China
| | - Jiangang Shi
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai, 200003, China
| |
Collapse
|
|
9
|
Wei Z, Kawashima H. Prevention of Collagen-Induced Arthritis by an Anti-Glycan Monoclonal Antibody Reactive with 6-Sulfo Sialyl Lewis x in DBA/1 Mice. Monoclon Antib Immunodiagn Immunother 2024; 43:3-9. [PMID: 38064497 DOI: 10.1089/mab.2023.0019] [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] [Indexed: 02/28/2024] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial tissue inflammation, substantially impacting the quality of life of patients. The interaction between L-selectin and its glycoprotein ligands modified with 6-sulfo sialyl Lewis x (6-sulfo sLex) is known to mediate lymphocyte homing to initiate immune responses. Thus, this process could be a potential therapeutic target for RA. Herein, we explored the preventive effects of an anti-6-sulfo sLex monoclonal antibody (mAb), SF1, on collagen-induced arthritis (CIA) in DBA/1 mice. Mice were administered SF1 from day 21 postfirst immunization with type II collagen (CII), and the effects of SF1 on both clinical and histopathological disease progression evoked by the second immunization were examined. SF1 significantly suppressed clinical features and histological levels associated with arthritis severity. Enzyme-linked immunosorbent assay consistently indicated that SF1 inhibited the production of CII-specific IgG2a. Based on the reverse transcription-quantitative PCR analysis, SF1 suppressed the expression of interferon-γ, a T helper 1 cytokine, as well as that of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, in draining lymph nodes. Collectively, these results indicate that SF1, an anti-sulfated glycan mAb, could be beneficial in preventing CIA in mice and may afford as a novel agent to treat RA.
Collapse
Affiliation(s)
- Zihong Wei
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Hiroto Kawashima
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| |
Collapse
|
|
10
|
Zhao Y, Peng X, Wang Q, Zhang Z, Wang L, Xu Y, Yang H, Bai J, Geng D. Crosstalk Between the Neuroendocrine System and Bone Homeostasis. Endocr Rev 2024; 45:95-124. [PMID: 37459436 DOI: 10.1210/endrev/bnad025] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Indexed: 01/05/2024]
Abstract
The homeostasis of bone microenvironment is the foundation of bone health and comprises 2 concerted events: bone formation by osteoblasts and bone resorption by osteoclasts. In the early 21st century, leptin, an adipocytes-derived hormone, was found to affect bone homeostasis through hypothalamic relay and the sympathetic nervous system, involving neurotransmitters like serotonin and norepinephrine. This discovery has provided a new perspective regarding the synergistic effects of endocrine and nervous systems on skeletal homeostasis. Since then, more studies have been conducted, gradually uncovering the complex neuroendocrine regulation underlying bone homeostasis. Intriguingly, bone is also considered as an endocrine organ that can produce regulatory factors that in turn exert effects on neuroendocrine activities. After decades of exploration into bone regulation mechanisms, separate bioactive factors have been extensively investigated, whereas few studies have systematically shown a global view of bone homeostasis regulation. Therefore, we summarized the previously studied regulatory patterns from the nervous system and endocrine system to bone. This review will provide readers with a panoramic view of the intimate relationship between the neuroendocrine system and bone, compensating for the current understanding of the regulation patterns of bone homeostasis, and probably developing new therapeutic strategies for its related disorders.
Collapse
Affiliation(s)
- Yuhu Zhao
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Xiaole Peng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Qing Wang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Zhiyu Zhang
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
| | - Liangliang Wang
- Department of Orthopedics, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, China
| | - Yaozeng Xu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Huilin Yang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| | - Jiaxiang Bai
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
- Department of Orthopedics, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230022, China
| | - Dechun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University; Orthopedics Institute, Medical College, Soochow University, Suzhou, Jiangsu 215006, China
| |
Collapse
|
|
11
|
Zhu L, Qiao L, Dou X, Song X, Chang J, Zeng X, Xu C. Lactobacillus casei ATCC 393 combined with vasoactive intestinal peptide alleviates dextran sodium sulfate-induced ulcerative colitis in C57BL/6 mice via NF-κB and Nrf2 signaling pathways. Biomed Pharmacother 2023; 165:115033. [PMID: 37379640 DOI: 10.1016/j.biopha.2023.115033] [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: 02/23/2023] [Revised: 06/08/2023] [Accepted: 06/19/2023] [Indexed: 06/30/2023] Open
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) which is related to an immunological imbalance of the intestinal mucosa. Many clinical evidences indicate probiotics supplementation appears to be effective and safe in patients with UC. Vasoactive intestinal peptide (VIP) is an endogenous neuropeptide with multiple physiological and pathological effects. In this study, we investigated the protective effect of the combination of Lactobacillus casei ATCC 393 (L. casei ATCC 393) with VIP on dextran sodium sulfate (DSS)-induced UC in mice and the potential mechanism. The results showed that, compared with the control group, DSS treatment significantly shortened the colon length, caused inflammation and oxidative stress, and further resulted in the intestinal barrier dysfunction and gut microbiota dysbiosis. In addition, intervention with L. casei ATCC 393, VIP or L. casei ATCC 393 combined with VIP significantly reduced UC disease activity index. However, compared with L. casei ATCC 393 or VIP, L. casei ATCC 393 combined with VIP effectively relieved symptoms of UC by regulating immune response, enhancing antioxidant capacity, and regulating nuclear factor kappa-B (NF-κB) and nuclear factor erythroid-derived-2-like 2 (Nrf2) signaling pathways. In conclusion, this study suggests that L. casei ATCC 393 combined with VIP can effectively relieve DSS-induced UC, which is a promising treatment strategy for UC.
Collapse
Affiliation(s)
- Lixu Zhu
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Lei Qiao
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Xina Dou
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Xiaofan Song
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Jiajing Chang
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Xiaonan Zeng
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Chunlan Xu
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China.
| |
Collapse
|
|
12
|
Lee JM, Choi YJ, Yoo MC, Yeo SG. Central Facial Nervous System Biomolecules Involved in Peripheral Facial Nerve Injury Responses and Potential Therapeutic Strategies. Antioxidants (Basel) 2023; 12:antiox12051036. [PMID: 37237902 DOI: 10.3390/antiox12051036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/20/2023] [Accepted: 04/29/2023] [Indexed: 05/28/2023] Open
Abstract
Peripheral facial nerve injury leads to changes in the expression of various neuroactive substances that affect nerve cell damage, survival, growth, and regeneration. In the case of peripheral facial nerve damage, the injury directly affects the peripheral nerves and induces changes in the central nervous system (CNS) through various factors, but the substances involved in these changes in the CNS are not well understood. The objective of this review is to investigate the biomolecules involved in peripheral facial nerve damage so as to gain insight into the mechanisms and limitations of targeting the CNS after such damage and identify potential facial nerve treatment strategies. To this end, we searched PubMed using keywords and exclusion criteria and selected 29 eligible experimental studies. Our analysis summarizes basic experimental studies on changes in the CNS following peripheral facial nerve damage, focusing on biomolecules that increase or decrease in the CNS and/or those involved in the damage, and reviews various approaches for treating facial nerve injury. By establishing the biomolecules in the CNS that change after peripheral nerve damage, we can expect to identify factors that play an important role in functional recovery from facial nerve damage. Accordingly, this review could represent a significant step toward developing treatment strategies for peripheral facial palsy.
Collapse
Affiliation(s)
- Jae-Min Lee
- Department of Otorhinolaryngology, Head & Neck Surgery, College of Medicine, Kyung Hee University Medical Center, Seoul 02447, Republic of Korea
| | - You Jung Choi
- Department of Otorhinolaryngology, Head & Neck Surgery, College of Medicine, Kyung Hee University Medical Center, Seoul 02447, Republic of Korea
| | - Myung Chul Yoo
- Department of Physical Medicine & Rehabilitation, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Seung Geun Yeo
- Department of Otorhinolaryngology, Head & Neck Surgery, College of Medicine, Kyung Hee University Medical Center, Seoul 02447, Republic of Korea
| |
Collapse
|
|
13
|
Figueiredo CA, Düsedau HP, Steffen J, Ehrentraut S, Dunay MP, Toth G, Reglödi D, Heimesaat MM, Dunay IR. The neuropeptide PACAP alleviates T. gondii infection-induced neuroinflammation and neuronal impairment. J Neuroinflammation 2022; 19:274. [PMCID: PMC9675261 DOI: 10.1186/s12974-022-02639-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 10/23/2022] [Indexed: 11/21/2022] Open
Abstract
Background Cerebral infection with the protozoan Toxoplasma gondii (T. gondii) is responsible for inflammation of the central nervous system (CNS) contributing to subtle neuronal alterations. Albeit essential for brain parasite control, continuous microglia activation and recruitment of peripheral immune cells entail distinct neuronal impairment upon infection-induced neuroinflammation. PACAP is an endogenous neuropeptide known to inhibit inflammation and promote neuronal survival. Since PACAP is actively transported into the CNS, we aimed to assess the impact of PACAP on the T. gondii-induced neuroinflammation and subsequent effects on neuronal homeostasis. Methods Exogenous PACAP was administered intraperitoneally in the chronic stage of T. gondii infection, and brains were isolated for histopathological analysis and determination of pathogen levels. Immune cells from the brain, blood, and spleen were analyzed by flow cytometry, and the further production of inflammatory mediators was investigated by intracellular protein staining as well as expression levels by RT-qPCR. Neuronal and synaptic alterations were assessed on the transcriptional and protein level, focusing on neurotrophins, neurotrophin-receptors and signature synaptic markers. Results Here, we reveal that PACAP administration reduced the inflammatory foci and the number of apoptotic cells in the brain parenchyma and restrained the activation of microglia and recruitment of monocytes. The neuropeptide reduced the expression of inflammatory mediators such as IFN-γ, IL-6, iNOS, and IL-1β. Moreover, PACAP diminished IFN-γ production by recruited CD4+ T cells in the CNS. Importantly, PACAP promoted neuronal health via increased expression of the neurotrophin BDNF and reduction of p75NTR, a receptor related to neuronal cell death. In addition, PACAP administration was associated with increased expression of transporters involved in glutamatergic and GABAergic signaling that are particularly affected during cerebral toxoplasmosis. Conclusions Together, our findings unravel the beneficial effects of exogenous PACAP treatment upon infection-induced neuroinflammation, highlighting the potential implication of neuropeptides to promote neuronal survival and minimize synaptic prejudice. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02639-z.
Collapse
Affiliation(s)
- Caio Andreeta Figueiredo
- grid.5807.a0000 0001 1018 4307Institute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke University, Magdeburg, Germany
| | - Henning Peter Düsedau
- grid.5807.a0000 0001 1018 4307Institute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke University, Magdeburg, Germany
| | - Johannes Steffen
- grid.5807.a0000 0001 1018 4307Institute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke University, Magdeburg, Germany
| | - Stefanie Ehrentraut
- grid.5807.a0000 0001 1018 4307Institute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke University, Magdeburg, Germany
| | - Miklos P. Dunay
- grid.483037.b0000 0001 2226 5083Department and Clinic of Surgery and Ophthalmology, University of Veterinary Medicine, Budapest, Hungary
| | - Gabor Toth
- grid.9008.10000 0001 1016 9625Department of Medical Chemistry, University of Szeged, Budapest, Hungary
| | - Dora Reglödi
- grid.9679.10000 0001 0663 9479Department of Anatomy, MTA-PTE PACAP Research Team and Szentagothai Research Center, University of Pecs Medical School, Pecs, Hungary
| | - Markus M. Heimesaat
- grid.6363.00000 0001 2218 4662Institute of Microbiology, Infectious Diseases and Immunology, Charité - University Medicine Berlin, Berlin, Germany
| | - Ildiko Rita Dunay
- grid.5807.a0000 0001 1018 4307Institute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-Von-Guericke University, Magdeburg, Germany ,grid.418723.b0000 0001 2109 6265Center for Behavioral Brain Sciences – CBBS, Magdeburg, Germany
| |
Collapse
|
|
14
|
Sequí-Sabater JM, Beretta L. Defining the Role of Monocytes in Sjögren's Syndrome. Int J Mol Sci 2022; 23:ijms232112765. [PMID: 36361554 PMCID: PMC9654893 DOI: 10.3390/ijms232112765] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/20/2022] [Accepted: 10/20/2022] [Indexed: 01/24/2023] Open
Abstract
Sjögren's syndrome is one of the most prevalent autoimmune diseases after rheumatoid arthritis, with a preference for middle age, and is characterised by exocrine glandular involvement leading to xerostomia and xerophthalmia. It can have systemic implications with vascular, neurological, renal, and pulmonary involvement, and in some cases, it may evolve to non-Hodgkin's lymphoma. For a long time, B- and T-lymphocytes have been the focus of research and have been considered key players in Sjögren's syndrome pathogenesis and evolution. With the development of new technologies, including omics, more insights have been found on the different signalling pathways that lead to inflammation and activation of the immune system. New evidence indicates that a third actor linking innate and adaptive immunity plays a leading role in the Sjögren's syndrome play: the monocyte. This review summarises the recent insights from transcriptomic, proteomic, and epigenetic studies that help us to understand more about the Sjögren's syndrome pathophysiology and redefine the involvement of monocytes in this disease.
Collapse
Affiliation(s)
- Jose Miguel Sequí-Sabater
- Rheumatology Department, Reina Sofía University Hospital, Menéndez Pidal Ave., 14005 Córdoba, Spain
- Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), University of Córdoba, Menéndez Pidal Ave., 14005 Córdoba, Spain
| | - Lorenzo Beretta
- Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico di Milano, Francesco Sforza St. 35, 20122 Milan, Italy
- Correspondence:
| |
Collapse
|
|
15
|
Fu Y, Li J, Zhang Z, Ren F, Wang Y, Jia H, Liu J, Chang Z. Umbilical cord mesenchymal stem cell-derived exosomes alleviate collagen-induced arthritis by balancing the population of Th17 and regulatory T cells. FEBS Lett 2022; 596:2668-2677. [PMID: 35918178 DOI: 10.1002/1873-3468.14460] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/20/2022] [Accepted: 07/13/2022] [Indexed: 11/07/2022]
Abstract
Exosomes released by mesenchymal stem cells (MSCs) are thought to function as extensions of the MSCs. However, it remains unclear whether exosomes derived from human umbilical cord MSCs (HUMSCs) possess immunoregulatory functions in rheumatoid arthritis. We report that when mice with collagen-induced arthritis were injected with exosomes derived from HUMSC (HUMSC-Exo), their paws became less swollen, and they had lower serum pro-inflammatory cytokine and anti-collagen IgG levels, and decreased synovial hyperplasia. The HUMSC-Exo appeared to restore the balance between Th17 and Treg cells, and this effect was accompanied by reduced IL-17 and enhanced TGF-β and IL-10 levels. These findings suggest that HUMSC-Exo function as important regulator of the balance between Th1/Th17 and Treg cells during immune and inflammatory responses.
Collapse
Affiliation(s)
- Yanxia Fu
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, China
- State Key Laboratory of Membrane Biology, School of Medicine, Institute of Precision Medicine, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, China
| | - Jun Li
- TsCell Biotech Inc., Beijing, China
| | - Ziyu Zhang
- State Key Laboratory of Membrane Biology, School of Medicine, Institute of Precision Medicine, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, China
| | - Fangli Ren
- State Key Laboratory of Membrane Biology, School of Medicine, Institute of Precision Medicine, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, China
| | - Yinyin Wang
- State Key Laboratory of Membrane Biology, School of Medicine, Institute of Precision Medicine, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, China
| | - Huihui Jia
- State Key Laboratory of Membrane Biology, School of Medicine, Institute of Precision Medicine, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, China
| | - Jihe Liu
- Beijing No. 2 Middle School, China
| | - Zhijie Chang
- State Key Laboratory of Membrane Biology, School of Medicine, Institute of Precision Medicine, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, China
| |
Collapse
|
|
16
|
Dhanda SK, Malviya J, Gupta S. Not all T cell epitopes are equally desired: a review of in silico tools for the prediction of cytokine-inducing potential of T-cell epitopes. Brief Bioinform 2022; 23:6692551. [PMID: 36070623 DOI: 10.1093/bib/bbac382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 08/01/2022] [Accepted: 08/09/2022] [Indexed: 11/13/2022] Open
Abstract
Assessment of protective or harmful T cell response induced by any antigenic epitope is important in designing any immunotherapeutic molecule. The understanding of cytokine induction potential also helps us to monitor antigen-specific cellular immune responses and rational vaccine design. The classical immunoinformatics tools served well for prediction of B cell and T cell epitopes. However, in the last decade, the prediction algorithms for T cell epitope inducing specific cytokines have also been developed and appreciated in the scientific community. This review summarizes the current status of such tools, their applications, background algorithms, their use in experimental setup and functionalities available in the tools/web servers.
Collapse
Affiliation(s)
- Sandeep Kumar Dhanda
- Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, USA-38015.,Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Chennai, India
| | - Jitendra Malviya
- Department of Life Sciences and Biological Science, IES University Bhopal, India
| | - Sudheer Gupta
- NGS & Bioinformatics Division, 3B BlackBio Biotech India Ltd., 7-C, Industrial Area, Govindpura, Bhopal, India
| |
Collapse
|
|
17
|
Lu J, Piper SJ, Zhao P, Miller LJ, Wootten D, Sexton PM. Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors. Int J Mol Sci 2022; 23:8069. [PMID: 35897648 PMCID: PMC9331257 DOI: 10.3390/ijms23158069] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/18/2022] [Accepted: 07/20/2022] [Indexed: 12/16/2022] Open
Abstract
Pituitary Adenylate Cyclase-Activating Peptide (PACAP) and Vasoactive Intestinal Peptide (VIP) are neuropeptides involved in a diverse array of physiological and pathological processes through activating the PACAP subfamily of class B1 G protein-coupled receptors (GPCRs): VIP receptor 1 (VPAC1R), VIP receptor 2 (VPAC2R), and PACAP type I receptor (PAC1R). VIP and PACAP share nearly 70% amino acid sequence identity, while their receptors PAC1R, VPAC1R, and VPAC2R share 60% homology in the transmembrane regions of the receptor. PACAP binds with high affinity to all three receptors, while VIP binds with high affinity to VPAC1R and VPAC2R, and has a thousand-fold lower affinity for PAC1R compared to PACAP. Due to the wide distribution of VIP and PACAP receptors in the body, potential therapeutic applications of drugs targeting these receptors, as well as expected undesired side effects, are numerous. Designing selective therapeutics targeting these receptors remains challenging due to their structural similarities. This review discusses recent discoveries on the molecular mechanisms involved in the selectivity and signaling of the PACAP subfamily of receptors, and future considerations for therapeutic targeting.
Collapse
Affiliation(s)
- Jessica Lu
- Drug Discovery Biology, Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; (J.L.); (S.J.P.); (P.Z.)
| | - Sarah J. Piper
- Drug Discovery Biology, Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; (J.L.); (S.J.P.); (P.Z.)
| | - Peishen Zhao
- Drug Discovery Biology, Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; (J.L.); (S.J.P.); (P.Z.)
| | - Laurence J. Miller
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ 85259, USA;
| | - Denise Wootten
- Drug Discovery Biology, Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; (J.L.); (S.J.P.); (P.Z.)
| | - Patrick M. Sexton
- Drug Discovery Biology, Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; (J.L.); (S.J.P.); (P.Z.)
| |
Collapse
|
|
18
|
Chae DS, Park YJ, Kim SW. Anti-Arthritogenic Property of Interleukin 10-Expressing Human Amniotic MSCs Generated by Gene Editing in Collagen-Induced Arthritis. Int J Mol Sci 2022; 23:ijms23147913. [PMID: 35887258 PMCID: PMC9320257 DOI: 10.3390/ijms23147913] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/29/2022] [Accepted: 07/12/2022] [Indexed: 11/16/2022] Open
Abstract
Although stem cells are promising tools for the treatment of arthritis, their therapeutic effects remain controversial. In this study, we investigated the therapeutic properties of interleukin (IL)-10-overexpressing human amniotic mesenchymal stem cells (AMMs) generated via gene editing in a collagen-induced mouse model. IL-10 was inserted into the genomic loci of AMMs via transcription activator-like effector nucleases. In vitro immunomodulatory effects of IL-10-overexpressing AMMs (AMM/I) were evaluated and their anti-arthritogenic properties were determined in collagen-induced arthritis (CIA) mice. Transplantation of AMM/I attenuates CIA progression. In addition, the regulatory T cell population was increased, while T helper-17 cell activation was suppressed by AMM/I administration in CIA mice. Consistently, AMM/I injection increased proteoglycan expression, while reducing inflammation and the expression levels of the pro-inflammatory factors, IL-1 β, IL-6, monocyte chemoattractant protein-1, and tumor necrosis factor- α, in joint tissues. In conclusion, use of IL-10-edited human AMM/I may be a novel therapeutic strategy for the treatment of arthritis.
Collapse
Affiliation(s)
- Dong-Sik Chae
- Department of Orthopedic Surgery, International St. Mary’s Hospital, College of Medicine, Catholic Kwandong University, Incheon 22711, Korea;
| | - Young-Jin Park
- Department of Family Medicine, College of Medicine, Dong-A University, Dong-A University Medical Center, Busan 49201, Korea;
| | - Sung-Whan Kim
- Department Medicine, College of Medicine, Catholic Kwandong University, Gangneung 25601, Korea
- Correspondence: ; Tel.: +82-(32)-290-2616; Fax: +82-(32)-290-2620
| |
Collapse
|
|
19
|
Sun Q, Li G, Liu D, Xie W, Xiao W, Li Y, Cai M. Peripheral nerves in the tibial subchondral bone : the role of pain and homeostasis in osteoarthritis. Bone Joint Res 2022; 11:439-452. [PMID: 35775136 PMCID: PMC9350689 DOI: 10.1302/2046-3758.117.bjr-2021-0355.r1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Osteoarthritis (OA) is a highly prevalent degenerative joint disorder characterized by joint pain and physical disability. Aberrant subchondral bone induces pathological changes and is a major source of pain in OA. In the subchondral bone, which is highly innervated, nerves have dual roles in pain sensation and bone homeostasis regulation. The interaction between peripheral nerves and target cells in the subchondral bone, and the interplay between the sensory and sympathetic nervous systems, allow peripheral nerves to regulate subchondral bone homeostasis. Alterations in peripheral innervation and local transmitters are closely related to changes in nociception and subchondral bone homeostasis, and affect the progression of OA. Recent literature has substantially expanded our understanding of the physiological and pathological distribution and function of specific subtypes of neurones in bone. This review summarizes the types and distribution of nerves detected in the tibial subchondral bone, their cellular and molecular interactions with bone cells that regulate subchondral bone homeostasis, and their role in OA pain. A comprehensive understanding and further investigation of the functions of peripheral innervation in the subchondral bone will help to develop novel therapeutic approaches to effectively prevent OA, and alleviate OA pain. Cite this article: Bone Joint Res 2022;11(7):439–452.
Collapse
Affiliation(s)
- Qi Sun
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Gen Li
- Department of Orthopedics, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
| | - Di Liu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
| | - Wenqing Xie
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
| | - Wenfeng Xiao
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Ming Cai
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China
| |
Collapse
|
|
20
|
Bai Y, Pei Y, Xia L, Ma L, Deng S. A Novel Immune-Prognosis Index Predicts the Benefit of Lung Adenocarcinoma Patients. Front Pharmacol 2022; 13:818170. [PMID: 35614936 PMCID: PMC9124834 DOI: 10.3389/fphar.2022.818170] [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: 11/22/2021] [Accepted: 04/08/2022] [Indexed: 12/12/2022] Open
Abstract
Background: Constructed an immune-prognosis index (IPI) and divided lung adenocarcinoma (LUAD) patients into different subgroups according to IPI score, describe the molecular and immune characteristics of patients between different IPI subgroups, and explore their response to immune checkpoint blockade (ICB) treatment. Methods: Based on the transcriptome profile of LUAD patients in TCGA and immune gene sets from ImmPort and InnateDB, 15 hub immune genes were identified through correlation and Bayesian causal network analysis. Then, IPI was constructed with 5 immune genes by using COX regression analysis and verified with external datasets (GSE30219, GSE37745, GSE68465, GSE126044 and GSE135222). Finally, the characteristics and the response to ICB treatment of LUAD patients between two different IPI subgroups were analyzed. Results: IPI was constructed based on the expression of 5 genes, including A2M, ADRB1, ADRB2, VIPR1 and PTH1R. IPI-high LUAD patients have a better overall survival than IPI-low LUAD patients, consistent with the results in the GEO cohorts. The comprehensive results showed that patients in the IPI-high subgroup were exhibited characters as metabolism-related signaling pathways activation, lower TP53 and TTN mutation rate, more infiltrations of CD8 T cells, dendritic cells and macrophages M1, especially earned more benefit from ICB treatment. In contrast, patients in the IPI-low subgroup were exhibited characters as p53 signaling pathways activation, higher TP53 and TTN mutation rate, more infiltrations of resting memory CD4 T cells, macrophages M2, immune-suppressive response and less benefit from ICB treatment. Conclusion: IPI is a potentially valuable prognostic evaluation method for LUAD, which works well in the benefit predicting of LUAD patients within ICB treatment.
Collapse
Affiliation(s)
- Yuquan Bai
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Yun Pei
- Department of Interventional Radiology and Vascular Surgery, Peking University Third Hospital, Beijing, China
| | - Liang Xia
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Lin Ma
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Senyi Deng
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Senyi Deng,
| |
Collapse
|
|
21
|
Xie X, Geng C, Li X, Liao J, Li Y, Guo Y, Wang C. Roles of gastrointestinal polypeptides in intestinal barrier regulation. Peptides 2022; 151:170753. [PMID: 35114316 DOI: 10.1016/j.peptides.2022.170753] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/29/2022] [Accepted: 01/30/2022] [Indexed: 12/17/2022]
Abstract
The intestinal barrier is a dynamic entity that is organized as a multilayer system and includes various intracellular and extracellular elements. The gut barrier functions in a coordinated manner to impede the passage of antigens, toxins, and microbiome components and simultaneously preserves the balanced development of the epithelial barrier and the immune system and the acquisition of tolerance to dietary antigens and intestinal pathogens.Numerous scientific studies have shown a significant association between gut barrier damage and gastrointestinal and extraintestinal diseases such as inflammatory bowel disease, celiac disease and hepatic fibrosis. Various internal and external factors regulate the intestinal barrier. Gastrointestinal peptides originate from enteroendocrine cells in the luminal digestive tract and are critical gut barrier regulators. Recent studies have demonstrated that gastrointestinal peptides have a therapeutic effect on digestive tract diseases, enhancing epithelial barrier activity and restoring the gut barrier. This review demonstrates the roles and mechanisms of gastrointestinal polypeptides, especially somatostatin (SST) and vasoactive intestinal peptide (VIP), in intestinal barrier regulation.
Collapse
Affiliation(s)
- Xiaoxi Xie
- Department of Gastroenterology, West China Hospital of Sichuan University, Chengdu, China
| | - Chong Geng
- Department of Gastroenterology, West China Hospital of Sichuan University, Chengdu, China
| | - Xiao Li
- Department of Gastroenterology, West China Hospital of Sichuan University, Chengdu, China; Division of Digestive Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Juan Liao
- Non-communicable Diseases Research Center, West China-PUMC C.C. Chen Institute of Health, Sichuan University, Chengdu, China
| | - Yanni Li
- Department of Gastroenterology, West China Hospital of Sichuan University, Chengdu, China
| | - Yaoyu Guo
- Department of Gastroenterology, West China Hospital of Sichuan University, Chengdu, China
| | - Chunhui Wang
- Department of Gastroenterology, West China Hospital of Sichuan University, Chengdu, China.
| |
Collapse
|
|
22
|
Wang X, Zhang R, Lindaman BD, Leeper CN, Schrum AG, Ulery BD. Vasoactive Intestinal Peptide Amphiphile Micelle Chemical Structure and Hydrophobic Domain Influence Immunomodulatory Potentiation. ACS APPLIED BIO MATERIALS 2022; 5:1464-1475. [PMID: 35302343 DOI: 10.1021/acsabm.1c00981] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Vasoactive intestinal peptide (VIP) is a neuropeptide capable of downregulating innate immune responses in antigen presenting cells (APCs) by suppressing their pro-inflammatory cytokine secretion and cell surface marker expression. Though VIP's bioactivity could possibly be leveraged as a treatment for transplant tolerance, drug delivery innovation is required to overcome its intrinsically limited cellular delivery capacity. One option is to employ peptide amphiphiles (PAs) which are lipidated peptides capable of self-assembling into micelles in water that can enhance cellular association. With this approach in mind, a series of triblock VIP amphiphiles (VIPAs) has been synthesized to explore the influence of block arrangement and hydrophobicity on micelle biocompatibility and bioactivity. VIPA formulation has been found to influence the shape, size, and surface charge of VIPA micelles (VIPAMs) as well as their cytotoxicity and immunomodulatory effects. Specifically, the enclosed work provides strong evidence that cylindrical VIPAMs with aspect ratios of 1.5-150 and moderate positive surface charge are able to potentiate the bioactivity of VIP limiting TNF-α secretion and MHC II and CD86 surface expression on APCs. With these criteria, we have identified PalmK-(EK)4-VIP as our lead formulation, which showed comparable or enhanced anti-inflammatory effects relative to the unmodified VIP at all dosages evaluated. Additionally, the relationships between peptide block location and lipid block size provide further information on the chemical structure-function relationships of PA micelles for the delivery of VIP as well as potentially for other peptides more broadly.
Collapse
Affiliation(s)
- Xiaofei Wang
- Department of Biomedical, Biological, and Chemical Engineering, University of Missouri, Columbia, Missouri 65211, United States
| | - Rui Zhang
- Department of Biomedical, Biological, and Chemical Engineering, University of Missouri, Columbia, Missouri 65211, United States
| | - Bryce D Lindaman
- Department of Biomedical, Biological, and Chemical Engineering, University of Missouri, Columbia, Missouri 65211, United States
| | - Caitlin N Leeper
- Department of Biomedical, Biological, and Chemical Engineering, University of Missouri, Columbia, Missouri 65211, United States
| | - Adam G Schrum
- Departments of Molecular Microbiology & Immunology, Surgery, and Biomedical, Biological & Chemical Engineering, University of Missouri, Columbia, Missouri 65211, United States
| | - Bret D Ulery
- Department of Biomedical, Biological, and Chemical Engineering, University of Missouri, Columbia, Missouri 65211, United States
| |
Collapse
|
|
23
|
Azevedo MDCS, Fonseca AC, Colavite PM, Melchiades JL, Tabanez AP, Codo AC, de Medeiros AI, Trombone APF, Garlet GP. Macrophage Polarization and Alveolar Bone Healing Outcome: Despite a Significant M2 Polarizing Effect, VIP and PACAP Treatments Present a Minor Impact in Alveolar Bone Healing in Homeostatic Conditions. Front Immunol 2021; 12:782566. [PMID: 34992601 PMCID: PMC8724033 DOI: 10.3389/fimmu.2021.782566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 11/29/2021] [Indexed: 12/20/2022] Open
Abstract
Host inflammatory immune response comprises an essential element of the bone healing process, where M2 polarization allegedly contributes to a favorable healing outcome. In this context, immunoregulatory molecules that modulate host response, including macrophage polarization, are considered potential targets for improving bone healing. This study aims to evaluate the role of the immunoregulatory molecules VIP (Vasoactive intestinal peptide) and PACAP (Pituitary adenylate cyclase activating polypeptide), which was previously described to favor the development of the M2 phenotype, in the process of alveolar bone healing in C57Bl/6 (WT) mice. Experimental groups were submitted to tooth extraction and maintained under control conditions or treated with VIP or PACAP were evaluated by microtomographic (µCT), histomorphometric, immunohistochemical, and molecular analysis at 0, 3, 7, and 14 days to quantify tissue healing and host response indicators at the healing site. Gene expression analysis demonstrates the effectiveness of VIP or PACAP in modulating host response, evidenced by the early dominance of an M2-type response, which was paralleled by a significant increase in M2 (CD206+) in treated groups. However, despite the marked effect of M1/M2 balance in the healing sites, the histomorphometric analysis does not reveal an equivalent/corresponding modulation of the healing process. µCT reveals a slight increase in bone matrix volume and the trabecular thickness number in the PACAP group, while histomorphometric analyzes reveal a slight increase in the VIP group, both at a 14-d time-point; despite the increased expression of osteogenic factors, osteoblastic differentiation, activity, and maturation markers in both VIP and PACAP groups. Interestingly, a lower number of VIP and PACAP immunolabeled cells were observed in the treated groups, suggesting a reduction in endogenous production. In conclusion, while both VIP and PACAP treatments presented a significant immunomodulatory effect with potential for increased healing, no major changes were observed in bone healing outcome, suggesting that the signals required for bone healing under homeostatic conditions are already optimal, and additional signals do not improve an already optimal process. Further studies are required to elucidate the role of macrophage polarization in the bone healing process.
Collapse
Affiliation(s)
| | - Angélica Cristina Fonseca
- Bauru School of Dentistry, Department of Biological Sciences, University of São Paulo, Bauru, Brazil
| | - Priscila Maria Colavite
- Bauru School of Dentistry, Department of Biological Sciences, University of São Paulo, Bauru, Brazil
| | - Jéssica Lima Melchiades
- Bauru School of Dentistry, Department of Biological Sciences, University of São Paulo, Bauru, Brazil
| | - André Petenuci Tabanez
- Bauru School of Dentistry, Department of Biological Sciences, University of São Paulo, Bauru, Brazil
| | - Ana Campos Codo
- School of Pharmaceutical Sciences, Department of Immunology, São Paulo State University, Araraquara, Brazil
| | - Alexandra Ivo de Medeiros
- School of Pharmaceutical Sciences, Department of Immunology, São Paulo State University, Araraquara, Brazil
| | | | | |
Collapse
|
|
24
|
The Neuropeptide VIP Limits Human Osteoclastogenesis: Clinical Associations with Bone Metabolism Markers in Patients with Early Arthritis. Biomedicines 2021; 9:biomedicines9121880. [PMID: 34944693 PMCID: PMC8698638 DOI: 10.3390/biomedicines9121880] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/09/2021] [Accepted: 12/09/2021] [Indexed: 12/19/2022] Open
Abstract
We aimed to evaluate the direct action of VIP on crucial molecules involved in human osteoclast differentiation and function. We also investigated the relationship between VIP serum levels and bone remodeling mediators in early arthritis patients. The expression of VIP receptors and osteoclast gene markers in monocytes and in vitro differentiated osteoclasts was studied by real-time PCR. NFATc1 activity was measured using a TransAM® kit. Osteoclastogenesis was confirmed by quantification of tartrate-resistant acid phosphatase positive multinucleated cells. OsteoAssay® Surface Multiple Well Plate was used to evaluate bone-resorbing activity. The ring-shaped actin cytoskeleton and the VPAC1 and VPAC2 expression were analyzed by immunofluorescence. We described the presence of VIP receptors in monocytes and mature osteoclasts. Osteoclasts that formed in the presence of VIP showed a decreased expression of osteoclast differentiation gene markers and proteolytic enzymes involved in bone resorption. VIP reduced the resorption activity and decreased both β3 integrin expression and actin ring formation. Elevated serum VIP levels in early arthritis patients were associated with lower BMD loss and higher serum OPG concentration. These results demonstrate that VIP exerts an anti-osteoclastogenic action impairing both differentiation and resorption activity mainly through the negative regulation of NFATc1, evidencing its bone-protective effects in humans.
Collapse
|
|
25
|
Li X, Xu Y, Li H, Jia L, Wang J, Liang S, Cai A, Tan X, Wang L, Wang X, Huang Y, Tao E, Ye H, Asakawa T. Verification of pain-related neuromodulation mechanisms of icariin in knee osteoarthritis. Biomed Pharmacother 2021; 144:112259. [PMID: 34607107 DOI: 10.1016/j.biopha.2021.112259] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 09/21/2021] [Accepted: 09/26/2021] [Indexed: 12/19/2022] Open
Abstract
Knee osteoarthritis (KOA) is a common disease with no specific treatment. Icariin (ICA) is considered an agent for KOA. This study aimed to confirm the pain-related neuromodulation mechanisms of ICA on KOA. Three experiments were designed: (1) verifying the therapeutic effects of ICA in vivo and in vitro, (2) exploring the potential pain-related neuromodulation pathways involved in ICA treatment by functional magnetic resonance imaging (fMRI) and virus retrograde tracing (VRT) and (3) confirming the pain-related targets by tandem mass tag (TMT)-based quantitative proteomics and bioinformatic analyses. Experiment 1 verified the efficacy of ICA in OA animal and cell models. Experiment 2 found a series of brain regions associated with KOA reversed by ICA treatment, indicating that a pain-related hypothalamic-mediated neuromodulation pathway and an endocannabinoid (EC)-related pathway contribute to ICA mechanisms. Experiment 3 explored and confirmed four pain-related genes involved in KOA and ICA treatment. We confirmed the key role of pain-related neuromodulation mechanisms in ICA treatment associated with its analgesic effect. Our findings contribute to considering ICA as a novel therapy for KOA.
Collapse
MESH Headings
- Analgesics/pharmacology
- Animals
- Antirheumatic Agents/pharmacology
- Arthritis, Experimental/diagnostic imaging
- Arthritis, Experimental/drug therapy
- Arthritis, Experimental/metabolism
- Arthritis, Experimental/physiopathology
- Behavior, Animal/drug effects
- Brain/diagnostic imaging
- Brain/drug effects
- Brain/metabolism
- Brain/physiopathology
- Cells, Cultured
- Chondrocytes/drug effects
- Chondrocytes/metabolism
- Flavonoids/pharmacology
- Gene Expression Regulation
- Inflammation Mediators/metabolism
- Joints/drug effects
- Joints/innervation
- Joints/metabolism
- Magnetic Resonance Imaging
- Male
- Mice, Inbred C57BL
- Neuroanatomical Tract-Tracing Techniques
- Neuropeptides/genetics
- Neuropeptides/metabolism
- Osteoarthritis, Knee/diagnostic imaging
- Osteoarthritis, Knee/drug therapy
- Osteoarthritis, Knee/metabolism
- Osteoarthritis, Knee/physiopathology
- Pain Threshold/drug effects
- Proteomics
- Rats, Sprague-Dawley
- Signal Transduction
- Tandem Mass Spectrometry
- Mice
- Rats
Collapse
Affiliation(s)
- Xihai Li
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China
| | - Yunteng Xu
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Hui Li
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Liangliang Jia
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Jie Wang
- State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan 430071, China; Innovation Academy for Precision Measurement Science, Wuhan 430071, China
| | - Shengxiang Liang
- National-Local Joint Engineering Research Center of Rehabilitation Medicine Technology, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; Rehabilitation Industry Institute, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Aoling Cai
- State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan 430071, China; Innovation Academy for Precision Measurement Science, Wuhan 430071, China
| | - Xue Tan
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Lili Wang
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Xiaoning Wang
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China
| | - Yanfeng Huang
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Enxiang Tao
- Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China
| | - Hongzhi Ye
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fuzhou 350122, China; Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
| | - Tetsuya Asakawa
- Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China; Research Base of Traditional Chinese Medicine Syndrome, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
| |
Collapse
|
|
26
|
Levescot A, Chang MH, Schnell J, Nelson-Maney N, Yan J, Martínez-Bonet M, Grieshaber-Bouyer R, Lee PY, Wei K, Blaustein RB, Morris A, Wactor A, Iwakura Y, Lederer JA, Rao DA, Charles JF, Nigrovic PA. IL-1β-driven osteoclastogenic Tregs accelerate bone erosion in arthritis. J Clin Invest 2021; 131:141008. [PMID: 34343136 PMCID: PMC8439607 DOI: 10.1172/jci141008] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 07/22/2021] [Indexed: 11/17/2022] Open
Abstract
IL-1β is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1β contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn-/-), we observed that IL-1β blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn-/- Tregs and wild-type Tregs differentiated with IL-1β accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1β-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.
Collapse
MESH Headings
- Adoptive Transfer
- Animals
- Arthritis, Experimental/etiology
- Arthritis, Experimental/immunology
- Arthritis, Experimental/pathology
- Arthritis, Rheumatoid/etiology
- Arthritis, Rheumatoid/immunology
- Arthritis, Rheumatoid/pathology
- Cell Differentiation/immunology
- Female
- Humans
- Interleukin 1 Receptor Antagonist Protein/deficiency
- Interleukin 1 Receptor Antagonist Protein/genetics
- Interleukin 1 Receptor Antagonist Protein/immunology
- Interleukin-1beta/immunology
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Knockout
- Osteoclasts/immunology
- Osteoclasts/pathology
- Osteogenesis/immunology
- RANK Ligand/immunology
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
Collapse
Affiliation(s)
- Anaïs Levescot
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Margaret H. Chang
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Julia Schnell
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Department of Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Nathan Nelson-Maney
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Jing Yan
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Department of Orthopaedic Surgery, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Marta Martínez-Bonet
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Ricardo Grieshaber-Bouyer
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Pui Y. Lee
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Kevin Wei
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Rachel B. Blaustein
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Allyn Morris
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Alexandra Wactor
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Yoichiro Iwakura
- Center for Experimental Animal Models, Research Institute for Science & Technology, Tokyo University of Science, Tokyo, Japan
| | - James A. Lederer
- Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Deepak A. Rao
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Julia F. Charles
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Department of Orthopaedic Surgery, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Peter A. Nigrovic
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
| |
Collapse
|
|
27
|
Zhang J, Zhang Z, Pu L, Tang J, Guo F. AIEpred: An Ensemble Predictive Model of Classifier Chain to Identify Anti-Inflammatory Peptides. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2021; 18:1831-1840. [PMID: 31985437 DOI: 10.1109/tcbb.2020.2968419] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Anti-inflammatory peptides (AIEs) have recently emerged as promising therapeutic agent for treatment of various inflammatory diseases, such as rheumatoid arthritis and Alzheimer's disease. Therefore, detecting the correlation between amino acid sequence and its anti-inflammatory property is of great importance for the discovery of new AIEs. To address this issue, we propose a novel prediction tool for accurate identification of peptides as anti-inflammatory epitopes or non anti-inflammatory epitopes. Most of all, we encode the original peptide sequence for better mining and exploring the information and patterns, based on the three feature representations as amino acid contact, position specific scoring matrix, physicochemical property. At the same time, we exploit several feature extraction models and utilize one feature selection model, in order to construct many base classifiers from various feature representations. More specifically, we develop an effective classification model, with which we can extract and learn a set of informative features from the ensemble classifier chain model with different group of base classifiers. Furthermore, in order to test the predictive power of our model, we conduct the comparative experiments on the leave-one-out cross-validation and the independent test. It shows that our novel predictor performs great accurate for identification of AIEs as well as existing outstanding prediction tools. Source codes are available at https://github.com/guofei-tju/Ensemble-classifier-chain-model.
Collapse
|
|
28
|
Liu S, Fu Y, Mei K, Jiang Y, Sun X, Wang Y, Ren F, Jiang C, Meng L, Lu S, Qin Z, Dong C, Wang X, Chang Z, Yang S. A shedding soluble form of interleukin-17 receptor D exacerbates collagen-induced arthritis through facilitating TNF-α-dependent receptor clustering. Cell Mol Immunol 2021; 18:1883-1895. [PMID: 32963355 PMCID: PMC8322419 DOI: 10.1038/s41423-020-00548-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 08/27/2020] [Indexed: 02/05/2023] Open
Abstract
Rheumatoid arthritis (RA) is exacerbated by TNF-alpha signaling. However, it remains unclear whether TNF-α-activated TNFR1 and TNFR2 are regulated by extracellular factors. Here, we showed that soluble glycosylated interleukin-17 receptor D (sIL-17RD), which was produced by proteolytic cleavage, enhanced TNF-α-induced RA. We revealed that IL-17RD shedding was induced by the proteolytic enzyme TACE and enhanced by TNF-α expression in macrophages. Intriguingly, sIL-17RD was elevated in the sera of arthritic mice and rats. Recombinant sIL-17RD significantly enhanced the TNF-α-induced proinflammatory response by promoting TNF-α-TNFR-sIL-17RD complex formation and receptor clustering, leading to the accelerated development of collagen-induced arthritis. Our observations revealed that ectodomain shedding of IL-17RD occurred in RA to boost the TNF-α-induced inflammatory response. Targeting sIL-17RD may provide a new strategy for the therapy of RA.
Collapse
Affiliation(s)
- Sihan Liu
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, 100084, Beijing, China
| | - Yanxia Fu
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, 100084, Beijing, China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, 515041, Guangdong, China
- Department of Biochemistry and Molecular Biology, Capital Medical University, 100069, Beijing, China
| | - Kunrong Mei
- Center for Structural Biology, School of Life Sciences, Ministry of Education Key Laboratory of Protein Science, Tsinghua University, 100084, Beijing, China
| | - Yinan Jiang
- Center for Structural Biology, School of Life Sciences, Ministry of Education Key Laboratory of Protein Science, Tsinghua University, 100084, Beijing, China
| | - Xiaojun Sun
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, 100084, Beijing, China
| | - Yinyin Wang
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, 100084, Beijing, China
| | - Fangli Ren
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, 100084, Beijing, China
| | - Congshan Jiang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University Health Science Center, Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, Shanxi, China
| | - Liesu Meng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University Health Science Center, Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, Shanxi, China
| | - Shemin Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University Health Science Center, Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, Shanxi, China
| | - Zhihai Qin
- Key Laboratory of Protein and Peptide Pharmaceuticals, CAS-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Chen Dong
- Institute for Immunology and School of Medicine, Tsinghua University, 100084, Beijing, China
| | - Xinquan Wang
- Center for Structural Biology, School of Life Sciences, Ministry of Education Key Laboratory of Protein Science, Tsinghua University, 100084, Beijing, China
| | - Zhijie Chang
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, 100084, Beijing, China.
| | - Shigao Yang
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, 100084, Beijing, China.
- School of Life Sciences, Anhui Medical University, Hefei, 230032, China.
| |
Collapse
|
|
29
|
Leceta J, Garin MI, Conde C. Mechanism of Immunoregulatory Properties of Vasoactive Intestinal Peptide in the K/BxN Mice Model of Autoimmune Arthritis. Front Immunol 2021; 12:701862. [PMID: 34335612 PMCID: PMC8322839 DOI: 10.3389/fimmu.2021.701862] [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: 04/28/2021] [Accepted: 06/25/2021] [Indexed: 11/13/2022] Open
Abstract
The K/BxN mouse model of rheumatoid arthritis (RA) closely resembles the human disease. In this model, arthritis results from activation of autoreactive KRN T cells recognizing the glycolytic enzyme glucose-6-phosphate isomerase (GPI) autoantigen, which provides help to GPI-specific B cells, resulting in the production of pathogenic anti-GPI antibodies that ultimately leads to arthritis symptoms from 4 weeks of age. Vasoactive intestinal peptide (VIP) is a neuropeptide broadly distributed in the central and peripheral nervous system that is also expressed in lymphocytes and other immune cell types. VIP is a modulator of innate and adaptive immunity, showing anti-inflammatory and immunoregulatory properties. Basically, this neuropeptide promotes a shift in the Th1/Th2 balance and enhances dedifferentiation of T regulatory cells (Treg). It has demonstrated its therapeutic effects on the collagen-induced arthritis (CIA) mouse model of RA. In the present hypothesis and theory article, we propose that the immunoregulatory properties of VIP may be due likely to the inhibition of T cell plasticity toward non-classic Th1 cells and an enhanced follicular regulatory T cells (Tfr) activity. The consequences of these regulatory properties are the reduction of systemic pathogenic antibody titers.
Collapse
Affiliation(s)
- Javier Leceta
- Department of Cell Biology, Faculty of Biology, Complutense University of Madrid, Madrid, Spain
| | - Marina I Garin
- Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid, Spain.,Advanced Therapy Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD/UAM), Madrid, Spain
| | - Carmen Conde
- Laboratorio de Reumatología Experimental y Observacional, Instituto de Investigación Sanitaria de Santiago (IDIS), Hospital Clínico Universitario de Santiago de Compostela (CHUS), SERGAS, Santiago de Compostela, Spain
| |
Collapse
|
|
30
|
Proteomic Analysis of Synovial Fibroblasts and Articular Chondrocytes Co-Cultures Reveals Valuable VIP-Modulated Inflammatory and Degradative Proteins in Osteoarthritis. Int J Mol Sci 2021; 22:ijms22126441. [PMID: 34208590 PMCID: PMC8235106 DOI: 10.3390/ijms22126441] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/09/2021] [Accepted: 06/11/2021] [Indexed: 12/20/2022] Open
Abstract
Osteoarthritis (OA) is the most common musculoskeletal disorder causing a great disability and a reduction in the quality of life. In OA, articular chondrocytes (AC) and synovial fibroblasts (SF) release innate-derived immune mediators that initiate and perpetuate inflammation, inducing cartilage extracellular matrix (ECM) degradation. Given the lack of therapies for the treatment of OA, in this study, we explore biomarkers that enable the development of new therapeutical approaches. We analyze the set of secreted proteins in AC and SF co-cultures by stable isotope labeling with amino acids (SILAC). We describe, for the first time, 115 proteins detected in SF-AC co-cultures stimulated by fibronectin fragments (Fn-fs). We also study the role of the vasoactive intestinal peptide (VIP) in this secretome, providing new proteins involved in the main events of OA, confirmed by ELISA and multiplex analyses. VIP decreases proteins involved in the inflammatory process (CHI3L1, PTX3), complement activation (C1r, C3), and cartilage ECM degradation (DCN, CTSB and MMP2), key events in the initiation and progression of OA. Our results support the anti-inflammatory and anti-catabolic properties of VIP in rheumatic diseases and provide potential new targets for OA treatment.
Collapse
|
|
31
|
Chae DS, Han S, Lee MK, Kim SW. Genome Edited Sirt1-Overexpressing Human Mesenchymal Stem Cells Exhibit Therapeutic Effects in Treating Collagen-Induced Arthritis. Mol Cells 2021; 44:245-253. [PMID: 33935044 PMCID: PMC8112166 DOI: 10.14348/molcells.2021.0037] [Citation(s) in RCA: 8] [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: 02/16/2021] [Revised: 03/18/2021] [Accepted: 04/01/2021] [Indexed: 12/15/2022] Open
Abstract
Even though mesenchymal stem cells (MSCs) are known for cartilage regeneration, their therapeutic efficacy needs to be enhanced. In the present study, we produced genome-edited silent information regulator 2 type 1 (Sirt1)-overexpressing MSCs, and evaluated their therapeutic potential in a damaged cartilage mouse liver fibrosis model. The Sirt1 gene was successfully inserted into a 'safe harbor' genomic locus in amniotic mesenchymal stem cells (AMMs), and the chondrogenic properties of the Sirt1 gene overexpressing AMMs (AMM/S) were characterized using quantitative PCR and histology. Therapeutic potentials were investigated in a collagen-induced arthritis (CIA) mouse model. Chondrocyte-differentiated AMM/S expressed cartilage-specific genes and were positive for Safranin O staining. Transplantation of AMM/S attenuated CIA progression and suppressed T helper (Th)-17 cell activation while increasing the Treg cell population in CIA mice. Pro-inflammatory factors, such as interleukin (IL)-1β, IL-6, monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF)-α were significantly decreased in AMM/S-injected joint tissues. In conclusion, genome-edited AMM/S may represent a safe and alternative therapeutic option for the treatment and repair of damaged cartilage, or in inflammatory joint arthritis.
Collapse
Affiliation(s)
- Dong-Sik Chae
- Department of Orthopedic Surgery, International St. Mary’s Hospital, Catholic Kwandong University College of Medicine, Incheon 22711, Korea
| | - Seongho Han
- Department of Family Medicine, Dong-A University Medical Center, Dong-A University College of Medicine, Busan 49201, Korea
| | - Min-Kyung Lee
- Department of Dental Hygine, Dong-Eui Universtigy, Busan 47340, Korea
| | - Sung-Whan Kim
- Department Medicine, Catholic Kwandong University College of Medicine, Gangneung 25601, Korea
| |
Collapse
|
|
32
|
Chae DS, Han JH, Park YJ, Kim SW. TGF-β1 overexpressing human MSCs generated using gene editing show robust therapeutic potential for treating collagen-induced arthritis. J Tissue Eng Regen Med 2021; 15:513-523. [PMID: 33749143 DOI: 10.1002/term.3191] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 11/29/2020] [Accepted: 03/12/2021] [Indexed: 12/14/2022]
Abstract
Transforming growth factor β (TGF-β) plays a pivotal role in cartilage differentiation and other functions of mesenchymal stem cells (MSCs). In this study, we investigated the therapeutic potential of TGF-β1 overexpressing amniotic MSCs (AMMs) generated using gene editing in a mouse model of damaged cartilage. The TGF-β1 gene was inserted into a safe harbor genomic locus in AMMs using transcription activator-like effector nucleases. The chondrogenic properties of TGF-β1-overexpressing AMMs (AMM/T) were characterized using reverse transcription polymerase chain reaction (RT-PCR), quantitative RT-PCR, and histological analysis, and their therapeutic effects were evaluated in mouse model of collagen-induced arthritis (CIA). AMM/T expressed cartilage-specific genes and showed intense Safranin O and Alcian blue staining. Furthermore, injecting AMM/T attenuated CIA progression compared with AMM injection, and increased the regulatory T (Treg) cell population, while suppressing T helper (Th)17 cell activation in CIA mice. Proinflammatory factors, such as interleukin-1β (IL-1β), IL-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α were significantly decreased in AMM/T injected CIA mice compared with their AMM injected counterparts. In conclusion, genome-edited AMMs overexpressing TGF-β1 may be a novel and alternative therapeutic option for protecting cartilage and treating inflammatory joint arthritis.
Collapse
Affiliation(s)
- Dong-Sik Chae
- Department of Orthopedic Surgery, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon, Republic of Korea
| | - Ju Hye Han
- Department Medicine, Catholic Kwandong University College of Medicine, Gangneung, Republic of Korea
| | - Young-Jin Park
- Department of Family Medicine, Dong-A University College of Medicine, Dong-A University Medical Center, Busan, Republic of Korea
| | - Sung-Whan Kim
- Department Medicine, Catholic Kwandong University College of Medicine, Gangneung, Republic of Korea
| |
Collapse
|
|
33
|
Moody TW, Jensen RT. Pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal peptide (Part 2): biology and clinical importance in central nervous system and inflammatory disorders. Curr Opin Endocrinol Diabetes Obes 2021; 28:206-213. [PMID: 33481421 PMCID: PMC7961158 DOI: 10.1097/med.0000000000000621] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
PURPOSE OF REVIEW To discuss recent advances of vasoactive intestinal peptide/pituitary adenylate cyclase-activating polypeptide (VIP/PACAP) receptors in the selected central nervous system (CNS) and inflammatory disorders. RECENT FINDINGS Recent studies provide evidence that PACAP plays an important role in a number of CNS disorders, particularly the pathogenesis of headaches (migraine, etc.) as well as posttraumatic stress disorder and drug/alcohol/smoking addiction. VIP has important therapeutic effects in a number of autoimmune/inflammatory disorder such as rheumatoid arthritis. In some cases, these insights have advanced to therapeutic trials. SUMMARY Recent insights from studies of VIP/PACAP and their receptors in both CNS disorders (migraine, posttraumatic stress disorder, addiction [drugs, alcohol, smoking]) and inflammatory disorders [such as rheumatoid arthritis] are suggesting new treatment approaches. The elucidation of the importance of VIP/PACAP system in these disorders combined recent development of specific drugs acting on this system (i.e., monoclonal VIP/PACAP antibodies) will likely lead to importance novel treatment approaches in these diseases.
Collapse
Affiliation(s)
- Terry W Moody
- Department of Health and Human services, National Cancer Institute, Center for Cancer Training. Bethesda, Maryland, USA
| | - Robert T Jensen
- National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Diseases, Digestive Diseases Branch, Bethesda, Maryland, USA
| |
Collapse
|
|
34
|
Lu K, Iwenofu OH, Mitra R, Mo X, Dasgupta PS, Basu S. Chebulinic acid is a safe and effective antiangiogenic agent in collagen-induced arthritis in mice. Arthritis Res Ther 2020; 22:273. [PMID: 33225986 PMCID: PMC7682078 DOI: 10.1186/s13075-020-02370-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 11/05/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Although vascular endothelial growth factor-A (VEGF)-induced angiogenesis has been reported to play an important role in the pathogenesis of rheumatoid arthritis (RA), serious side effects, mainly grade 2-3 hypertension, which is commonly observed with currently available anti-VEGF agents, can be detrimental for RA patients due to hypertension and associated cardiovascular complications seen in these patients. Thus, identification of anti-VEGF molecules that do not increase blood pressure could be useful for the treatment of RA. Chebulinic acid (CI), a water-soluble small-molecule tannin, can inhibit the actions of VEGF, and a report suggested that CI might not increase blood pressure due to its compensatory effects on the cardiovascular system. Therefore, the effects of CI on blood pressure in mice and the progression of the disease in a murine collagen-induced arthritis (CIA) model were investigated. METHODS CIA was induced in DBA/1J mice with type II collagen. The effects of CI in these animals were then evaluated by determination of clinical, histopathological, and immunohistochemical parameters. The effects of CI on VEGF-induced proangiogenic genes and signaling pathways were examined in vitro and in vivo. RESULTS Significant CD31 and VEGF expressions were detected in the synovial tissues of mice with CIA, similar to their expressions observed in human RA patients. However, treatment with CI significantly inhibited paw swelling, decreased the mean articular index and joint pathology scores in these animals through inhibition of VEGF-induced proangiogenic gene expressions and signaling pathways that regulate angiogenesis. Unlike currently used antiangiogenic agents, CI at a dose that inhibits VEGF actions did not increase blood pressure in mice. CONCLUSION CI can act as a safe and potent anti-VEGF antiangiogenic agent for the treatment of types of inflammatory arthritis, such as RA.
Collapse
Affiliation(s)
- Kai Lu
- Department of Pathology, Ohio State University, Hamilton Hall (H166), 1645 Neil Avenue, Columbus, OH 43210 USA
| | - O. Hans Iwenofu
- Department of Pathology, Ohio State University, Hamilton Hall (H166), 1645 Neil Avenue, Columbus, OH 43210 USA
| | - Rita Mitra
- KPC Medical College, Kolkata, 700032 India
| | - Xiaokui Mo
- Center for Biostatistics, Department of Biomedical Informatics, Ohio State University, Columbus, OH 43210 USA
| | | | - Sujit Basu
- Department of Pathology, Ohio State University, Hamilton Hall (H166), 1645 Neil Avenue, Columbus, OH 43210 USA
- Division of Medical Oncology, Department of Internal Medicine, Ohio State University, Columbus, OH 43210 USA
| |
Collapse
|
|
35
|
Mishra R, Krishnamoorthy P, Gangamma S, Raut AA, Kumar H. Particulate matter (PM 10) enhances RNA virus infection through modulation of innate immune responses. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2020; 266:115148. [PMID: 32771845 PMCID: PMC7357538 DOI: 10.1016/j.envpol.2020.115148] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 06/28/2020] [Accepted: 06/28/2020] [Indexed: 05/07/2023]
Abstract
Sensing of pathogens by specialized receptors is the hallmark of the innate immunity. Innate immune response also mounts a defense response against various allergens and pollutants including particulate matter present in the atmosphere. Air pollution has been included as the top threat to global health declared by WHO which aims to cover more than three billion people against health emergencies from 2019 to 2023. Particulate matter (PM), one of the major components of air pollution, is a significant risk factor for many human diseases and its adverse effects include morbidity and premature deaths throughout the world. Several clinical and epidemiological studies have identified a key link between the PM existence and the prevalence of respiratory and inflammatory disorders. However, the underlying molecular mechanism is not well understood. Here, we investigated the influence of air pollutant, PM10 (particles with aerodynamic diameter less than 10 μm) during RNA virus infections using Highly Pathogenic Avian Influenza (HPAI) - H5N1 virus. We thus characterized the transcriptomic profile of lung epithelial cell line, A549 treated with PM10 prior to H5N1infection, which is known to cause severe lung damage and respiratory disease. We found that PM10 enhances vulnerability (by cellular damage) and regulates virus infectivity to enhance overall pathogenic burden in the lung cells. Additionally, the transcriptomic profile highlights the connection of host factors related to various metabolic pathways and immune responses which were dysregulated during virus infection. Collectively, our findings suggest a strong link between the prevalence of respiratory illness and its association with the air quality.
Collapse
Affiliation(s)
- Richa Mishra
- Laboratory of Immunology and Infectious Disease Biology, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, 462066, MP, India
| | - Pandikannan Krishnamoorthy
- Laboratory of Immunology and Infectious Disease Biology, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, 462066, MP, India
| | - S Gangamma
- National Institute of Technology Karnataka (NITK), Surathkal, Mangaluru, 575025, Karnataka, India; Centre for Water Food and Environment, IIT Ropar, Rupnagar, 140001, Punjab, India
| | - Ashwin Ashok Raut
- Pathogenomics Laboratory, ICAR - National Institute of High Security Animal Diseases (NIHSAD), OIE Reference Laboratory for Avian Influenza, Bhopal, 462021, MP, India
| | - Himanshu Kumar
- Laboratory of Immunology and Infectious Disease Biology, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, 462066, MP, India; WPI Immunology, Frontier Research Centre, Osaka University, Osaka, 5650871, Japan.
| |
Collapse
|
|
36
|
Barloese M, Chitgar M, Hannibal J, Møller S. Pituitary adenylate cyclase-activating peptide: Potential roles in the pathophysiology and complications of cirrhosis. Liver Int 2020; 40:2578-2589. [PMID: 32654367 DOI: 10.1111/liv.14602] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 06/29/2020] [Accepted: 07/05/2020] [Indexed: 12/20/2022]
Abstract
Pituitary adenylate cyclase-activating peptide (PACAP) is a ubiquitous neuropeptide with diverse functions throughout the organism. Most abundantly investigated for its role in several neurological disorders as well as in circadian rhythms, other fields of medicine, including cardiology, have recently shown interest in the role of PACAP and its potential as a biomarker. Timely diagnosis and treatment of cirrhosis and its complications is a considerable challenge for health services world-wide and development of new areas of research is warranted. Direct and indirect evidence exists of PACAP involvement in the cascade of pathological events and processes ultimately leading to cirrhosis and its complications, but its exact role remains to be determined. Studies have documented PACAP involvement in immune function, metabolism, local vasoconstriction and dilatation and systemic vascular decompensation and there is ongoing research of a possible role in liver reperfusion injury. Considering these reports, PACAP could theoretically exude influence on the disease course of cirrhosis through the hypothalamus-pituitary-adrenal axis, chronic inflammation, fibrogenesis, vasodilation and reduced vascular resistance. The paucity of literature on the specific topic of PACAP and cirrhosis reflects complex mechanisms and difficulty in accurate measurements and sample taking. This does not detract from the need to further characterize and elucidate the role PACAP plays in the underdiagnosed and undertreated condition of cirrhosis.
Collapse
Affiliation(s)
- Mads Barloese
- Department of Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Faculty of Health Sciences Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | - Mohammadnavid Chitgar
- Department of Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Faculty of Health Sciences Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | - Jens Hannibal
- Department of Clinical Biochemistry, Bispebjerg Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Søren Møller
- Department of Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Faculty of Health Sciences Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| |
Collapse
|
|
37
|
Musson R, Szukała W, Jura J. MCPIP1 RNase and Its Multifaceted Role. Int J Mol Sci 2020; 21:ijms21197183. [PMID: 33003343 PMCID: PMC7582464 DOI: 10.3390/ijms21197183] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 09/27/2020] [Accepted: 09/28/2020] [Indexed: 12/11/2022] Open
Abstract
Inflammation is an organism’s physiological response to harmful septic and aseptic stimuli. This process begins locally through the influx of immune system cells to the damaged tissue and the subsequent activation and secretion of inflammatory mediators to restore homeostasis in the organism. Inflammation is regulated at many levels, and one of these levels is post-transcriptional regulation, which controls the half-life of transcripts that encode inflammatory mediators. One of the proteins responsible for controlling the amount of mRNA in a cell is the RNase monocyte chemoattractant protein-induced protein 1 (MCPIP1). The studies conducted so far have shown that MCPIP1 is involved not only in the regulation of inflammation but also in many other physiological and pathological processes. This paper provides a summary of the information on the role of MCPIP1 in adipogenesis, angiogenesis, cell differentiation, cancer, and skin inflammation obtained to date.
Collapse
|
|
38
|
Fan NW, Dohlman TH, Foulsham W, McSoley M, Singh RB, Chen Y, Dana R. The role of Th17 immunity in chronic ocular surface disorders. Ocul Surf 2020; 19:157-168. [PMID: 32470612 DOI: 10.1016/j.jtos.2020.05.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/06/2020] [Accepted: 05/14/2020] [Indexed: 12/23/2022]
Abstract
Th17 cells have been implicated in the pathogenesis of numerous inflammatory and autoimmune conditions. At the ocular surface, Th17 cells have been identified as key effector cells in chronic ocular surface disease. Evidence from murine studies indicates that following differentiation and expansion, Th17 cells migrate from the lymphoid tissues to the eye, where they release inflammatory cytokines including, but not limited to, their hallmark cytokine IL-17A. As the acute phase subsides, a population of long-lived memory Th17 cells persist, which predispose hosts both to chronic inflammation and severe exacerbations of disease; of great interest is the small subset of Th17/1 cells that secrete both IL-17A and IFN-γ in acute-on-chronic disease exacerbation. Over the past decade, substantial progress has been made in deciphering how Th17 cells interact with the immune and neuroimmune pathways that mediate chronic ocular surface disease. Here, we review (i) the evidence for Th17 immunity in chronic ocular surface disease, (ii) regulatory mechanisms that constrain the Th17 immune response, and (iii) novel therapeutic strategies targeting Th17 cells.
Collapse
Affiliation(s)
- Nai-Wen Fan
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA; Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Thomas H Dohlman
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA
| | - William Foulsham
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA
| | - Matthew McSoley
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA; University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Rohan Bir Singh
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA
| | - Yihe Chen
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA
| | - Reza Dana
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA.
| |
Collapse
|
|
39
|
Wei K, Korsunsky I, Marshall JL, Gao A, Watts GFM, Major T, Croft AP, Watts J, Blazar PE, Lange JK, Thornhill TS, Filer A, Raza K, Donlin LT, Siebel CW, Buckley CD, Raychaudhuri S, Brenner MB. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature 2020; 582:259-264. [PMID: 32499639 PMCID: PMC7841716 DOI: 10.1038/s41586-020-2222-z] [Citation(s) in RCA: 306] [Impact Index Per Article: 61.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 02/26/2020] [Indexed: 12/26/2022]
Abstract
The synovium is a mesenchymal tissue composed mainly of fibroblasts with a lining and sublining that surrounds the joints. In rheumatoid arthritis (RA), the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive and destroys the joint1,2. Recently, we and others found that a subset of fibroblasts located in the sublining undergoes major expansion in RA and is linked to disease activity3,4,5. However, the molecular mechanism by which these fibroblasts differentiate and expand in RA remains unknown. Here, we identified a critical role for NOTCH3 signaling in the differentiation of perivascular and sublining CD90(THY1)+ fibroblasts. Using single cell RNA-sequencing and synovial tissue organoids, we found that NOTCH3 signaling drives both transcriptional and spatial gradients in fibroblasts emanating from vascular endothelial cells outward. In active RA, NOTCH3 and NOTCH target genes are markedly upregulated in synovial fibroblasts. Importantly, genetic deletion of Notch3 or monoclonal antibody-blockade of NOTCH3 signaling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit positional identity regulated by endothelium-derived Notch signaling and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis.
Collapse
Affiliation(s)
- Kevin Wei
- Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Ilya Korsunsky
- Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.,Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.,Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.,Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Jennifer L Marshall
- Rheumatology Research Group, Institute for Inflammation and Ageing, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK
| | - Anqi Gao
- Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Gerald F M Watts
- Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Triin Major
- Rheumatology Research Group, Institute for Inflammation and Ageing, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK
| | - Adam P Croft
- Rheumatology Research Group, Institute for Inflammation and Ageing, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK
| | - Jordan Watts
- Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Philip E Blazar
- Department of Orthopedic Surgery, Brigham and Women's Hospital, Boston, MA, USA
| | - Jeffrey K Lange
- Department of Orthopedic Surgery, Brigham and Women's Hospital, Boston, MA, USA
| | - Thomas S Thornhill
- Department of Orthopedic Surgery, Brigham and Women's Hospital, Boston, MA, USA
| | - Andrew Filer
- Rheumatology Research Group, Institute for Inflammation and Ageing, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK
| | - Karim Raza
- Rheumatology Research Group, Institute for Inflammation and Ageing, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK
| | - Laura T Donlin
- Arthritis and Tissue Degeneration, Hospital for Special Surgery, New York, NY, USA
| | | | - Christian W Siebel
- Department of Discovery Oncology, Genentech, South San Francisco, CA, USA
| | - Christopher D Buckley
- Rheumatology Research Group, Institute for Inflammation and Ageing, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.,The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Soumya Raychaudhuri
- Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. .,Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA. .,Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. .,Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. .,Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. .,Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
| | - Michael B Brenner
- Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
40
|
Harada A, Tsutsuki H, Zhang T, Lee R, Yahiro K, Sawa T, Niidome T. Preparation of Biodegradable PLGA-Nanoparticles Used for pH-Sensitive Intracellular Delivery of an Anti-inflammatory Bacterial Toxin to Macrophages. Chem Pharm Bull (Tokyo) 2020; 68:363-368. [PMID: 32238653 DOI: 10.1248/cpb.c19-00917] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Poly(D,L-lactide-co-glycolic) acid (PLGA) is a synthetic copolymer that has been used to design micro/nanoparticles as a carrier for macromolecules, such as protein and nucleic acids, that can be internalized by the endocytosis pathway. However, it is difficult to control the intracellular delivery to target organelles. Here we report an intracellular delivery system of nanoparticles modified with bacterial cytotoxins to the endoplasmic reticulum (ER) and anti-inflammatory activity of the nanoparticles. Subtilase cytotoxin (SubAB) is a bacterial toxin in certain enterohemorrhagic Escherichia coli (EHEC) strains that cleaves the host ER chaperone BiP and suppresses nuclear factor-kappaB (NF-κB) activation and nitric oxide (NO) generation in macrophages at sub-lethal concentration. PLGA-nanoparticles were modified with oligo histidine-tagged (6 × His-tagged) recombinant SubAB (SubAB-PLGA) through a pH-sensitive linkage, and their translocation to the ER in macrophage cell line J774.1 cells, effects on inducible NO synthase (iNOS), and levels of tumor necrosis factor (TNF)-α cytokine induced by lipopolysaccharide (LPS) were examined. Compared with free SubAB, SubAB-PLGA was significantly effective in BiP cleavage and the induction of the ER stress marker C/EBP homologous protein (CHOP) in J774.1 cells. Furthermore, SubAB-PLGA attenuated LPS-stimulated induction of iNOS and TNF-α. Our findings provide useful information for protein delivery to macrophages and may encourage therapeutic applications of nanoparticles to the treatment of inflammatory diseases.
Collapse
Affiliation(s)
- Ayaka Harada
- Faculty of Advanced Science and Technology, Kumamoto University
| | - Hiroyasu Tsutsuki
- Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University
| | - Tianli Zhang
- Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University
| | - Ruda Lee
- International Research Organization for Advanced Science and Technology, Kumamoto University
| | - Kinnosuke Yahiro
- Department of Molecular Infectiology, Graduate School of Medicine, Chiba University
| | - Tomohiro Sawa
- Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University
| | - Takuro Niidome
- Faculty of Advanced Science and Technology, Kumamoto University
| |
Collapse
|
|
41
|
Yang Y, Wei Z, Teichmann AT, Wieland FH, Wang A, Lei X, Zhu Y, Yin J, Fan T, Zhou L, Wang C, Chen L. Development of a novel nitric oxide (NO) production inhibitor with potential therapeutic effect on chronic inflammation. Eur J Med Chem 2020; 193:112216. [PMID: 32208222 DOI: 10.1016/j.ejmech.2020.112216] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 03/07/2020] [Accepted: 03/07/2020] [Indexed: 02/08/2023]
Abstract
Inflammation is a complex biological response to stimuli. Activated macrophages induced excessively release of pro-inflammatory cytokines and mediators such as endogenous radical nitric oxide (NO) play a significant role in the progression of multiple inflammatory diseases. Both natural and synthetic chalcones possess a wide range of bioactivities. In this work, thirty-nine chalcones and three related compounds, including several novel ones, based on bioactive kava chalcones were designed, synthesized and their inhibitory effects on NO production in RAW 264.7 cells were evaluated. The novel compound (E)-1-(2'-hydroxy-4',6'-dimethoxyphenyl)-3-(3-methoxy-4-(3-morpholinopropoxy)phenyl)prop-2-en-1-one (53) exhibited a better inhibitory activity (84.0%) on NO production at 10 μM (IC50 = 6.4 μM) with the lowest cytotoxicity (IC50 > 80 μM) among the tested compounds. Besides, western blot analysis indicated that compound 53 was a potent down-regulator of inducible nitric oxide synthase (iNOS) protein. Docking study revealed that compound 53 also can dock into the active site of iNOS. Furthermore, at the dose of 10 mg/kg/day, compound 53 could both significantly suppress the progression of inflammation on collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models. In addition, the structure-activity relationship (SAR) of the kava chalcones based analogs was also depicted.
Collapse
Affiliation(s)
- Youzhe Yang
- Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, PR China; Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, PR China.
| | - Zhe Wei
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, PR China
| | - Alexander Tobias Teichmann
- Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, PR China
| | - Frank Heinrich Wieland
- Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, PR China
| | - Amu Wang
- School of Science, Xihua University, Chengdu, 610039, PR China
| | - Xiangui Lei
- School of Science, Xihua University, Chengdu, 610039, PR China
| | - Yue Zhu
- School of Science, Xihua University, Chengdu, 610039, PR China
| | - Jinxiang Yin
- School of Science, Xihua University, Chengdu, 610039, PR China
| | - Tiantian Fan
- Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, PR China
| | - Li Zhou
- Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, PR China
| | - Chao Wang
- Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, PR China
| | - Lijuan Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, PR China.
| |
Collapse
|
|
42
|
Tian J, Shi R, Xiao P, Liu T, She R, Wu Q, An J, Hao W, Soomro M. Hepatitis E Virus Induces Brain Injury Probably Associated With Mitochondrial Apoptosis. Front Cell Infect Microbiol 2019; 9:433. [PMID: 31921708 PMCID: PMC6932957 DOI: 10.3389/fcimb.2019.00433] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Accepted: 12/04/2019] [Indexed: 01/01/2023] Open
Abstract
Hepatitis E virus (HEV) infection has been associated with extrahepatic manifestations, particularly neurological disorders. Although it has been reported that HEV infection induced hepatocyte apoptosis associated with mitochondria injury, activation of mitochondrial apoptotic pathway in the central nervous system during HEV infection was not clearly understood. In this study, the induction of mitochondrial apoptosis-associated proteins and pro-inflammatory cytokines were detected in HEV infected Mongolian gerbil model and primary human brain microvascular endothelial cells (HBMVECs). Mitochondrial exhibited fragments with loss of cristae and matrix in HEV infected brain tissue by transmission electron microscope (TEM). In vitro studies showed that expression of NADPH oxidase 4 (NOX4) was significantly increased in HEV infected HBMVECs (p < 0.05), while ATP5A1 was significantly decreased (p < 0.01). Expressions of pro-apoptotic proteins were further evaluated. Bax was significantly increased in both HEV infected brain tissues and HBMVECs (p < 0.01). In vivo studies showed that caspase-9 and caspase-3 were activated after HEV inoculation (p < 0.01), associated with PCNA overexpression as response to apoptosis. Cytokines were measured to evaluate tissue inflammatory levels. Results showed that the release of TNFα and IL-1β were significantly increased after HEV infection (p < 0.01), which might be attributed to microglia activation characterized by high level of IBA1 expression (p < 0.01). Taken together, these data support that HEV infection induces high levels of pro-inflammatory cytokines, associated with mitochondria-mediated apoptosis. The results provide new insight into mechanisms of extra-hepatic injury of HEV infection, especially in the central nervous system.
Collapse
Affiliation(s)
- Jijing Tian
- Laboratory of Animal Pathology and Public Health, Key Laboratory of Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Ruihan Shi
- Laboratory of Animal Pathology and Public Health, Key Laboratory of Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China.,Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing, China
| | - Peng Xiao
- Laboratory of Animal Pathology and Public Health, Key Laboratory of Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Tianlong Liu
- Laboratory of Animal Pathology and Public Health, Key Laboratory of Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Ruiping She
- Laboratory of Animal Pathology and Public Health, Key Laboratory of Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Qiaoxing Wu
- Laboratory of Animal Pathology and Public Health, Key Laboratory of Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Junqing An
- Laboratory of Animal Pathology and Public Health, Key Laboratory of Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Wenzhuo Hao
- Laboratory of Animal Pathology and Public Health, Key Laboratory of Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - MajidHussain Soomro
- Laboratory of Animal Pathology and Public Health, Key Laboratory of Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China
| |
Collapse
|
|
43
|
Martínez C, Juarranz Y, Gutiérrez-Cañas I, Carrión M, Pérez-García S, Villanueva-Romero R, Castro D, Lamana A, Mellado M, González-Álvaro I, Gomariz RP. A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases. Int J Mol Sci 2019; 21:E65. [PMID: 31861827 PMCID: PMC6982157 DOI: 10.3390/ijms21010065] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 12/16/2019] [Accepted: 12/18/2019] [Indexed: 12/11/2022] Open
Abstract
The neuroendocrine and immune systems are coordinated to maintain the homeostasis of the organism, generating bidirectional communication through shared mediators and receptors. Vasoactive intestinal peptide (VIP) is the paradigm of an endogenous neuropeptide produced by neurons and endocrine and immune cells, involved in the control of both innate and adaptive immune responses. Exogenous administration of VIP exerts therapeutic effects in models of autoimmune/inflammatory diseases mediated by G-protein-coupled receptors (VPAC1 and VPAC2). Currently, there are no curative therapies for inflammatory and autoimmune diseases, and patients present complex diagnostic, therapeutic, and prognostic problems in daily clinical practice due to their heterogeneous nature. This review focuses on the biology of VIP and VIP receptor signaling, as well as its protective effects as an immunomodulatory factor. Recent progress in improving the stability, selectivity, and effectiveness of VIP/receptors analogues and new routes of administration are highlighted, as well as important advances in their use as biomarkers, contributing to their potential application in precision medicine. On the 50th anniversary of VIP's discovery, this review presents a spectrum of potential clinical benefits applied to inflammatory and autoimmune diseases.
Collapse
Affiliation(s)
- Carmen Martínez
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Yasmina Juarranz
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Irene Gutiérrez-Cañas
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Mar Carrión
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Selene Pérez-García
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Raúl Villanueva-Romero
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - David Castro
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Amalia Lamana
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Mario Mellado
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología (CNB)/CSIC, 28049 Madrid, Spain;
| | - Isidoro González-Álvaro
- Servicio de Reumatología, Instituto de Investigación Médica, Hospital Universitario La Princesa, 28006 Madrid, Spain;
| | - Rosa P. Gomariz
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| |
Collapse
|
|
44
|
Xiao S, Tang Y, Lv Z, Lin Y, Chen L. Nanomedicine - advantages for their use in rheumatoid arthritis theranostics. J Control Release 2019; 316:302-316. [PMID: 31715278 DOI: 10.1016/j.jconrel.2019.11.008] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 11/07/2019] [Accepted: 11/08/2019] [Indexed: 02/08/2023]
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease accompanies with synovial inflammation and progressive bone destruction. Currently, anti-rheumatic drugs need high dose and frequent use for a long-term, which lead to serious side effect and low patient compliance. To overcome above problems and improve clinical efficacy, nano-technology with targeting ability, sustained release and so forth, has been proposed on RA treatment and already achieved success in RA animal models. In this review, authors summarize and illustrate representative nanomedicine targeting to RA states, which is achieved either through passive or active targeting with high affinity to the receptors that are over-expressed in macrophages or angiogenesis. In particular, authors highlight the new strategies to promote the efficacy of nanoscale treatments through phototherapy and the addition of contrast elements for theranostic application. The described advances may pave the way to better understanding and designing the novel nanomedicine and multifunctional nano-system on efficient RA treatment.
Collapse
Affiliation(s)
- Shuyi Xiao
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, PR China; Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, PR China
| | - Yufu Tang
- Key Laboratory of Flexible Electronics (KLOFE), Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing Tech University (NanjingTech), Nanjing 211816, PR China
| | - Zhuang Lv
- Key Laboratory for Organic Electronics and Information Displays, Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts and Telecommunications (NUPT), Nanjing 210023, PR China
| | - Yimu Lin
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, PR China
| | - Liang Chen
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, PR China.
| |
Collapse
|
|
45
|
Mosley RL, Lu Y, Olson KE, Machhi J, Yan W, Namminga KL, Smith JR, Shandler SJ, Gendelman HE. A Synthetic Agonist to Vasoactive Intestinal Peptide Receptor-2 Induces Regulatory T Cell Neuroprotective Activities in Models of Parkinson's Disease. Front Cell Neurosci 2019; 13:421. [PMID: 31619964 PMCID: PMC6759633 DOI: 10.3389/fncel.2019.00421] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 09/02/2019] [Indexed: 12/12/2022] Open
Abstract
A paradigm shift has emerged in Parkinson’s disease (PD) highlighting the prominent role of CD4+ Tregs in pathogenesis and treatment. Bench to bedside research, conducted by others and our own laboratories, advanced a neuroprotective role for Tregs making pharmacologic transformation of immediate need. Herein, a vasoactive intestinal peptide receptor-2 (VIPR2) peptide agonist, LBT-3627, was developed as a neuroprotectant for PD-associated dopaminergic neurodegeneration. Employing both 6-hydroxydopamine (6-OHDA) and α-synuclein (α-Syn) overexpression models in rats, the sequential administration of LBT-3627 increased Treg activity without altering cell numbers both in naïve animals and during progressive nigrostriatal degeneration. LBT-3627 administration was linked to reductions of inflammatory microglia, increased survival of dopaminergic neurons, and improved striatal densities. While α-Syn overexpression resulted in reduced Treg activity, LBT-3627 rescued these functional deficits. This occurred in a dose-dependent manner closely mimicking neuroprotection. Taken together, these data provide the basis for the use of VIPR2 agonists as potent therapeutic immune modulating agents to restore Treg activity, attenuate neuroinflammation, and interdict dopaminergic neurodegeneration in PD. The data underscore an important role of immunity in PD pathogenesis.
Collapse
Affiliation(s)
- R Lee Mosley
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, United States
| | - Yaman Lu
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, United States
| | - Katherine E Olson
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, United States
| | - Jatin Machhi
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, United States
| | - Wenhui Yan
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, United States
| | - Krista L Namminga
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, United States
| | - Jenell R Smith
- Longevity Biotech, Inc., Philadelphia, PA, United States
| | | | - Howard E Gendelman
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, United States
| |
Collapse
|
|
46
|
de Campos Soriani Azevedo M, Garlet TP, Francisconi CF, Colavite PM, Tabanez AP, Melchiades JL, Favaro Trombone AP, Sfeir C, Little S, Silva RM, Garlet GP. Vasoactive Intestinal Peptide Immunoregulatory Role at the Periapex: Associative and Mechanistic Evidences from Human and Experimental Periapical Lesions. J Endod 2019; 45:1228-1236. [PMID: 31402064 DOI: 10.1016/j.joen.2019.06.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 05/09/2019] [Accepted: 06/30/2019] [Indexed: 11/26/2022]
Abstract
INTRODUCTION The balance between the host proinflammatory immune response and the counteracting anti-inflammatory and reparative responses supposedly determine the outcome of periapical lesions. In this scenario, the vasoactive intestinal peptide (VIP) may exert a protective role because of its prominent immunoregulatory capacity. In this study, we investigated (in a cause-and-effect manner) the potential involvement of VIP in the development of human and experimental periapical lesions. METHODS Periapical granulomas (n = 124) and control samples (n = 48) were comparatively assessed for VIP and multiple immunologic/activity marker expression through real-time polymerase chain reaction. Experimental periapical lesions (C57Bl/6 wild-type mice) were evaluated regarding endogenous VIP expression correlation with lesion development and the effect of recombinant VIP therapy in lesion outcome. CCR4KO and IL4KO strains and anti-glucocorticoid-induced TNFR-related protein inhibition were used to test the involvement of Treg and Th2 cells in VIP-mediated effects. RESULTS VIP expression was more prevalent in periapical granulomas than in controls, presenting a positive association with immunoregulatory factors and an inverse association/correlation with proinflammatory mediators and the receptor activator of nuclear factor kappa B ligand/osteoprotegerin ratio. Endogenous VIP expression up-regulation was temporally associated with lesion immunoregulation and a decline of bone loss. VIP therapy in mice prompted the arrest of lesion development, being associated with an anti-inflammatory and proreparative response that limits the proinflammatory, Th1, Th17, and osteoclastogenic response in the periapex. The VIP protective effect was dependent of Treg migration and activity and independent of interleukin 4. CONCLUSIONS Our results show that VIP overexpression in human and experimental periapical lesions is associated with lesion inactivity and that VIP therapy results in the attenuation of experimental lesion progression associated with the immunosuppressive response involving Treg cells.
Collapse
Affiliation(s)
| | - Thiago Pompermaier Garlet
- Department of Structural and Molecular Biology and Genetics, State University of Ponta Grossa, Ponta Grossa, Parana, Brazil
| | - Carolina Favaro Francisconi
- Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil
| | - Priscila Maria Colavite
- Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil
| | - André Petenuci Tabanez
- Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil
| | - Jessica Lima Melchiades
- Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil
| | | | - Charles Sfeir
- Center for Craniofacial Regeneration, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Periodontics and Preventive Dentistry, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Steven Little
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Renato Menezes Silva
- Department of Endodontics, School of Dentistry, University of Texas Health Science Center at Houston, Houston, Texas
| | - Gustavo Pompermaier Garlet
- Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil.
| |
Collapse
|
|
47
|
Fang G, Zhang Q, Pang Y, Thu HE, Hussain Z. Nanomedicines for improved targetability to inflamed synovium for treatment of rheumatoid arthritis: Multi-functionalization as an emerging strategy to optimize therapeutic efficacy. J Control Release 2019; 303:181-208. [DOI: 10.1016/j.jconrel.2019.04.027] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 04/18/2019] [Accepted: 04/19/2019] [Indexed: 12/18/2022]
|
|
48
|
Yu Y, Yoon K, Kang T, Jeon H, Sim Y, Choe SH, Baek SY, Lee S, Seo K, Kang K. Therapeutic effect of long‐interval repeated intravenous administration of human umbilical cord blood‐derived mesenchymal stem cells in
DBA
/1 mice with collagen‐induced arthritis. J Tissue Eng Regen Med 2019; 13:1134-1142. [DOI: 10.1002/term.2861] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 12/20/2018] [Accepted: 02/13/2019] [Indexed: 12/20/2022]
Affiliation(s)
- Yeonsil Yu
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology CenterSeoul National University Seoul South Korea
| | - Kyung‐Ae Yoon
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology CenterSeoul National University Seoul South Korea
| | - Tae‐Wook Kang
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology CenterSeoul National University Seoul South Korea
| | - Hyo‐Jin Jeon
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology CenterSeoul National University Seoul South Korea
| | - Yun‐Beom Sim
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology CenterSeoul National University Seoul South Korea
| | - Seung Hoon Choe
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology CenterSeoul National University Seoul South Korea
| | - Song Yi Baek
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology CenterSeoul National University Seoul South Korea
| | - Seunghee Lee
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology CenterSeoul National University Seoul South Korea
| | - Kwang‐Won Seo
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology CenterSeoul National University Seoul South Korea
| | - Kyung‐Sun Kang
- Stem Cell and Regenerative Bioengineering Institute, Kangstem Biotech Co., Ltd., Biotechnology CenterSeoul National University Seoul South Korea
- Adult Stem Cell Research Center, College of Veterinary MedicineSeoul National University Seoul South Korea
- Research Institute for Veterinary Science, College of Veterinary MedicineSeoul National University Seoul South Korea
| |
Collapse
|
|
49
|
Ganguly A, Sharma K, Majumder K. Food-derived bioactive peptides and their role in ameliorating hypertension and associated cardiovascular diseases. ADVANCES IN FOOD AND NUTRITION RESEARCH 2019; 89:165-207. [PMID: 31351525 DOI: 10.1016/bs.afnr.2019.04.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Non-communicable diseases including cardiovascular diseases (CVDs) and associated metabolic disorders are responsible for nearly 40 million deaths globally per year. Hypertension or high blood pressure (BP) is one of the primary reasons for the development of CVDs. A healthy nutritional strategy complementing with physical activity can substantially reduce high BP and prevent the occurrence of CVD-associated morbidity and mortality. Bioactive peptides currently are the next wave of the promising bench to clinic options for potential targeting chronic and acute health issues including hypertension. Peptides demonstrating anti-inflammatory, anti-oxidant, and angiotensin-converting enzyme-I inhibitory activity are widely studied for the amelioration of hypertension and associated CVDs. Isolating these potent bioactive peptides from different food sources is a promising endeavor toward nutraceutical based dietary management and prevention of hypertension. Understanding the pathophysiology of hypertension and the action mechanisms of the bioactive peptides would complement in designing and characterizing more potent peptides and suitable comprehensive dietary plans for the prevention of hypertension and associated CVDs.
Collapse
Affiliation(s)
- Advaita Ganguly
- Comprehensive Tissue Centre, UAH Transplant Services, Alberta Health Services, Edmonton, AB, Canada
| | - Kumakshi Sharma
- Health, Safety and Environment Branch, National Research Council Canada, Edmonton, AB, Canada
| | - Kaustav Majumder
- Department of Food Science and Technology, University of Nebraska-Lincoln, Lincoln, NE, United States.
| |
Collapse
|
|
50
|
Villanueva-Romero R, Gutiérrez-Cañas I, Carrión M, González-Álvaro I, Rodríguez-Frade JM, Mellado M, Martínez C, Gomariz RP, Juarranz Y. Activation of Th lymphocytes alters pattern expression and cellular location of VIP receptors in healthy donors and early arthritis patients. Sci Rep 2019; 9:7383. [PMID: 31089161 PMCID: PMC6517580 DOI: 10.1038/s41598-019-43717-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 04/29/2019] [Indexed: 12/15/2022] Open
Abstract
Vasoactive Intestinal Peptide (VIP) is an important immunomodulator of CD4+ cells in normal and pathological conditions, which exerts its anti-inflammatory and immunomodulatory actions through VPAC receptors, VPAC1 and VPAC2. Only a decrease in the expression of VPAC1 mRNA on Th cells upon activation has been reported. Thus, the deepening in the knowledge of the behavior of these receptors may contribute to the design of new therapies based on their activation and/or blockade. In this study, we describe the expression pattern, cellular location and functional role of VIP receptors during the activation of human Th cells in healthy conditions and in early arthritis (EA). The protein expression pattern of VPAC1 did not change with the activation of Th lymphocytes, whereas VPAC2 was up-regulated. In resting cells, VPAC1 was located on the plasma membrane and nucleus, whereas it only appeared in the nucleus in activated cells. VPAC2 was always found in plasma membrane location. VIP receptors signaled through a PKA-dependent pathway in both conditions, and also by a PKA-independent pathway in activated cells. Both receptors exhibit a potent immunomodulatory capacity by controlling the pathogenic profile and the activation markers of Th cells. These results highlight a novel translational view in inflammatory/autoimmune diseases.
Collapse
Affiliation(s)
- R Villanueva-Romero
- Departamento de Biología Celular, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - I Gutiérrez-Cañas
- Departamento de Biología Celular, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - M Carrión
- Departamento de Biología Celular, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - I González-Álvaro
- Servicio de Reumatología, Instituto de Investigación Sanitaria Hospital La Princesa (IIS-IP), Madrid, Spain
| | - J M Rodríguez-Frade
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - M Mellado
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - C Martínez
- Departamento de Biología Celular, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - R P Gomariz
- Departamento de Biología Celular, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Y Juarranz
- Departamento de Biología Celular, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.
| |
Collapse
|