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Kong M, Zhai Y, Liu H, Zhang S, Chen S, Li W, Ma X, Ji Y. Insights into the mechanisms of angiogenesis in hepatoblastoma. Front Cell Dev Biol 2025; 13:1535339. [PMID: 40438141 PMCID: PMC12116456 DOI: 10.3389/fcell.2025.1535339] [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: 11/27/2024] [Accepted: 05/02/2025] [Indexed: 06/01/2025] Open
Abstract
Hepatoblastoma (HB), the most common pediatric liver malignancy, is characterized by aggressive growth and metastasis driven by complex angiogenic mechanisms. This review elucidates the pivotal role of angiogenesis in HB progression, emphasizing metabolic reprogramming, tumor microenvironment (TME) dynamics, and oncogenic signalling pathways. The Warburg effect in HB cells fosters a hypoxic microenvironment, stabilizing hypoxia-inducible factor-1α (HIF-1α) and upregulating vascular endothelial growth factor (VEGF), which synergistically enhances angiogenesis. Key pathways such as the Wnt/β-catenin, VEGF, PI3K/AKT, and JAK2/STAT3 pathways are central to endothelial cell proliferation, migration, and vascular maturation, whereas interactions with tumor-associated macrophages (TAMs) and pericytes further remodel the TME to support neovascularization. Long noncoding RNAs and glycolytic enzymes have emerged as critical regulators of angiogenesis, linking metabolic activity with vascular expansion. Anti-angiogenic therapies, including VEGF inhibitors and metabolic pathway-targeting agents, show preclinical promise but face challenges such as resistance and off-target effects. Future directions advocate for dual-target strategies, spatial multiomics technologies to map metabolic-angiogenic crosstalk, and personalized approaches leveraging biomarkers for risk stratification. This synthesis underscores the need for interdisciplinary collaboration to translate mechanistic insights into durable therapies, ultimately improving outcomes for HB patients.
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Affiliation(s)
- Meng Kong
- Department of Pediatric Surgery, Children’s Hospital Affiliated to Shandong University, Jinan, China
- Department of Pediatric Surgery, Jinan Children’s Hospital, Jinan, China
| | - Yunpeng Zhai
- Department of Pediatric Surgery, Children’s Hospital Affiliated to Shandong University, Jinan, China
- Department of Pediatric Surgery, Jinan Children’s Hospital, Jinan, China
| | - Hongzhen Liu
- Department of Pediatric Surgery, Children’s Hospital Affiliated to Shandong University, Jinan, China
- Department of Pediatric Surgery, Jinan Children’s Hospital, Jinan, China
| | - Shisong Zhang
- Department of Pediatric Surgery, Children’s Hospital Affiliated to Shandong University, Jinan, China
- Department of Pediatric Surgery, Jinan Children’s Hospital, Jinan, China
| | - Shuai Chen
- Department of Pediatric Surgery, Children’s Hospital Affiliated to Shandong University, Jinan, China
- Department of Pediatric Surgery, Jinan Children’s Hospital, Jinan, China
| | - Wenfei Li
- School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiang Ma
- Department of Respiratory Disease, Children’s Hospital Affiliated to Shandong University, Jinan, China
- Jinan Key Laboratory of Pediatric Respiratory Diseases, Jinan Children’s Hospital, Jinan, China
| | - Yi Ji
- Division of Oncology, Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, China
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Han C, Zhu X, Sokol CL. Neuroimmune Circuits in Allergic Diseases. Annu Rev Immunol 2025; 43:367-394. [PMID: 39977604 DOI: 10.1146/annurev-immunol-082423-032154] [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: 02/22/2025]
Abstract
Communication between the nervous and immune systems is evolutionarily conserved. From primitive eukaryotes to higher mammals, neuroimmune communication utilizes multiple complex and complementary mechanisms to trigger effective but balanced responses to environmental dangers such as allergens and tissue damage. These responses result from a tight integration of the nervous and immune systems, and accumulating evidence suggests that this bidirectional communication is crucial in modulating the initiation and development of allergic inflammation. In this review, we discuss the basic mechanisms of neuroimmune communication, with a focus on the recent advances underlying the importance of such communication in the allergic immune response. We examine neuronal sensing of allergens, how neuropeptides and neurotransmitters regulate allergic immune cell functions, and how inflammatory factors derived from immune cells coordinate complex peripheral and central nervous system responses. Furthermore, we highlight how fundamental aspects of host biology, from aging to circadian rhythm, might affect these pathways. Appreciating neuroimmune communications as an evolutionarily conserved and functionally integrated system that is fundamentally involved in type 2 immunity will provide new insights into allergic inflammation and reveal exciting opportunities for the management of acute and chronic allergic diseases.
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Affiliation(s)
- Cai Han
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
| | - Xueping Zhu
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
| | - Caroline L Sokol
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
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Muñoz M, Rosso M. Radiotherapy Plus the Neurokinin-1 Receptor Antagonist Aprepitant: A Potent Therapeutic Strategy for the Treatment of Diffuse Intrinsic Pontine Glioma. Cancers (Basel) 2025; 17:520. [PMID: 39941886 PMCID: PMC11816061 DOI: 10.3390/cancers17030520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 01/24/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Background: Diffuse intrinsic pontine glioma (DIPG) is a devastating childhood brainstem tumor. The median survival of DIPG is 16-24 months independent of the treatment received. Therefore, new therapeutic strategies against DIPG are urgently needed. Substance P (SP) peptide, through the neurokinin neurokinin-1 receptor (NK-1R), is involved in glioma progression. It induces glioma cell proliferation by activating MAPKs (p38 MAPK, ERK1/2, and JNK), c-Myc, AP-1, and NF-κB and induces antiapoptotic effects via PI3K/Akt/mTOR in glioma cells. SP favors glycogen breakdown that is essential for glycolysis. The SP/NK-1R system also regulates the migration and invasion of glioma cells, stimulates angiogenesis, and triggers inflammation which contributes to glioma progression. Moreover, all glioma cells express NK-1R, and NK-1R is essential for the viability of glioma cells and not of normal cells. In contrast, in glioma, NK-1R antagonists, such as the drug aprepitant, penetrate the brain and reach therapeutic concentrations, thereby inhibiting mitogenesis, inducing apoptosis, and inhibiting the breakdown of glycogen in glioma cells. In addition, they inhibit angiogenesis and exert antimetastatic and anti-inflammatory effects. The combination of radiotherapy with NK-1R antagonists produces radiosensitization and radioneuroprotection, reduces both peritumoral- and radiation-induced inflammation, and also provides antinausea and antivomiting effects. Objective: This review updates the involvement of the SP/NK-1R system in glioma promotion and progression and the potential clinical application of NK-1R antagonist drugs in DIPG therapy. Conclusions: NK-1R plays a crucial role in glioma progression and NK-1R antagonists such as aprepitant could be used in combination with radiotherapy as a potent therapeutic strategy for the treatment of patients with DIPG.
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Affiliation(s)
- Miguel Muñoz
- Research Laboratory on Neuropeptides, Institute of Biomedicine of Seville (IBIS), 41013 Seville, Spain;
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Liu L, Chen H, Zhao X, Han Q, Xu Y, Liu Y, Zhang A, Li Y, Zhang W, Chen B, Wang J. Advances in the application and research of biomaterials in promoting bone repair and regeneration through immune modulation. Mater Today Bio 2025; 30:101410. [PMID: 39811613 PMCID: PMC11731593 DOI: 10.1016/j.mtbio.2024.101410] [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: 07/06/2024] [Revised: 12/02/2024] [Accepted: 12/15/2024] [Indexed: 01/16/2025] Open
Abstract
With the ongoing development of osteoimmunology, increasing evidence indicates that the local immune microenvironment plays a critical role in various stages of bone formation. Consequently, modulating the immune inflammatory response triggered by biomaterials to foster a more favorable immune microenvironment for bone regeneration has emerged as a novel strategy in bone tissue engineering. This review first examines the roles of various immune cells in bone tissue injury and repair. Then, the contributions of different biomaterials, including metals, bioceramics, and polymers, in promoting osteogenesis through immune regulation, as well as their future development directions, are discussed. Finally, various design strategies, such as modifying the physicochemical properties of biomaterials and integrating bioactive substances, to optimize material design and create an immune environment conducive to bone formation, are explored. In summary, this review comprehensively covers strategies and approaches for promoting bone tissue regeneration through immune modulation. It offers a thorough understanding of current research trends in biomaterial-based immune regulation, serving as a theoretical reference for the further development and clinical application of biomaterials in bone tissue engineering.
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Affiliation(s)
- Li Liu
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Hao Chen
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Xue Zhao
- Department of Endocrinology, The First Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Qing Han
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Yongjun Xu
- Department of Orthopedics Surgery, Wangqing County People's Hospital, Yanbian, 133000, Jilin, China
| | - Yang Liu
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Aobo Zhang
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Yongyue Li
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Weilong Zhang
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Bingpeng Chen
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Jincheng Wang
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
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Alcaide C, Perez F, Esteban F, Muñoz M. Substance P and Neurokinin-1 receptor are overexpressed in adamantinomatous craniopharyngioma than in the pituitary gland. Pituitary 2024; 28:5. [PMID: 39724307 DOI: 10.1007/s11102-024-01490-0] [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] [Accepted: 12/17/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND Human adamantinomatous craniopharyngioma (ACP) is a brain tumor that originates at the base of the skull and shows aggressive local behavior, invading sensitive structures such as the optic pathways and hypothalamus. The conventional treatment of the tumor has been surgery and radiotherapy with the consequent development of serious sequelae. It is well known that Substance P (SP) peptide and Neurokinin-1 receptor (NK-1R) are involved in inflammation and cancer progression and its blockage with NK-1R antagonists has been shown to effectively counteract tumor development in preclinical trials. The oncogenic mechanism underlying ACP is based on a secretory phenotype associated with the production of paracrine biomarkers that establish an inflammatory and angiogenic microenvironment for the progression of ACP. METHODS With the aim of describing the existence and distribution of SP/NK-1R in the ACP, we studied by immunohistochemistry the expression of SP and NK-1R in 43 human ACP and compared with healthy pituitary gland samples. RESULTS SP and the NK-1R were overexpressed in all ACP more than in pituitary glands samples. SP expression is found widespread the ACP and is preferentially localized in the nucleus than in cytoplasm of tumor cells. Likewise, areas of glial reaction and endothelial cells also express SP preferentially in the cell nuclei. NK-1R is expressed mainly in the glial reaction, especially in the nuclei and membranes of its inflammatory cells and less prominently in the cytoplasm. In ACP neovessels, NK-1R is expressed in endothelial cells and fibroblasts that constitute their basement membranes. Tumor cells did not show significant NK-1R expression. CONCLUSIONS These findings, reported here for the first time, suggest a role for SP and NK-1R in pituitary gland and ACP and opens the door to future clinical trials on treatment with NK-1R antagonist drugs in ACP patients.
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Affiliation(s)
- Carlos Alcaide
- Department of Pediatric Oncology, Hospital Regional Universitario de Málaga, Malaga, Spain.
| | - Francisco Perez
- Department of Pathology, Facultad de Medicina, Universidad Camilo José Cela / HM Hospitales, Madrid, Spain
| | - Francisco Esteban
- Department of Otorinolaringology, Facultad de Medicina, Universidad de Sevilla / Hospital Universitario Virgen Del Rocío, Seville, Spain
| | - Miguel Muñoz
- Research Laboratory on Neuropeptides, Institute of Biomedicine of Seville (IBIS), Seville, Spain
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Dang C, Liu M, Liu P, Liu J, Yu X, Dong Y, Zhao J. Causal relationship between inflammatory factors and gynecological cancer: a Bayesian Mendelian randomization study. Sci Rep 2024; 14:29868. [PMID: 39622847 PMCID: PMC11612437 DOI: 10.1038/s41598-024-80747-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 11/21/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Cervical cancer, ovarian cancer, and endometrial cancer are the three most common cancers in gynecology. Understanding their respective pathology is currently incomplete. Inflammatory factors play an important role in the pathophysiology of these three cancers, but the causal relationship between inflammatory factors and these three cancers is unclear. METHODS Based on publicly available genetic databases, relevant instrumental variables were extracted according to predefined thresholds, and causal analyses of CRP, 41 circulating inflammatory factors, and three gynecological cancers were performed, mainly using the inverse variance weighted method, while bayesian analysis was performed to improve the accuracy of the results. Finally, heterogeneity, horizontal pleiotropy test, and MR Steiger test were carried out to evaluate the reliability of the findings and the causal inference strength. RESULTS One inflammatory factor (PDGF-BB) and four inflammatory factors (CXCL9, IL-6, CXCL1, and G-CSF) were identified as significantly associated with the risk of ovarian and endometrial cancers, respectively. In comparison, cervical cancer was found to have a negative causal association with one inflammatory factor (G-CSF) and endometrial cancer with two inflammatory factors (CXCL10 and CCL11). CONCLUSIONS Our MR study suggests potential causal relationships between circulating inflammatory regulators and three gynecological cancers from a genetic perspective, which contributes to further understanding of the pathomechanisms of cervical, ovarian and endometrial cancers and highlights the potential of targeting inflammatory factors as therapeutic interventions and predictors.
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Affiliation(s)
- Chunxiao Dang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Mengmeng Liu
- Dongying People's Hospital (Dongying Hospital of Shandong Provincial Hospital Group), Dongying, 257000, China
| | - Pengfei Liu
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Jinxing Liu
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Xiao Yu
- Department of Gynecology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Yan Dong
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jingba Road No. 1, Jinan, 250014, China.
| | - Junde Zhao
- Shandong University of Traditional Chinese Medicine, Jingshi Road No. 16369, Jinan, 250014, China.
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Wang S, Naderi A, Kahale F, Ortiz G, Forouzanfar K, Chen Y, Dana R. Substance P regulates memory Th17 cell generation and maintenance in chronic dry eye disease. J Leukoc Biol 2024; 116:1446-1453. [PMID: 38916986 PMCID: PMC11599119 DOI: 10.1093/jleuko/qiae142] [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: 01/03/2024] [Revised: 05/13/2024] [Accepted: 05/24/2024] [Indexed: 06/27/2024] Open
Abstract
Substance P is a neuropeptide expressed by nerves and an array of cells that serves as a critical mediator of neuroinflammation. Our recent work has demonstrated that blocking the preferred receptor for substance P, neurokinin 1 receptor, effectively suppresses the induction of acute dry eye disease by preserving regulatory T-cell function, while inhibiting antigen-presenting cell maturation and subsequent generation of effector Th17 cells. Clinically, dry eye disease is a chronic disorder characterized by sustained ocular surface inflammation, which is mediated by long-lived memory Th17 cells demonstrated in our well-established chronic dry eye disease model. The present study aimed to further understand the function of substance P in the chronic phase of dry eye disease and its role in regulating the underlying pathogenic memory Th17. In vitro culture of effector T cells isolated from acute dry eye disease with substance P led to an enhanced conversion of effector Th17 to memory Th17, while culturing memory T cells isolated from chronic dry eye disease with substance P effectively preserved the memory Th17 cells. In contrast, the addition of a neurokinin 1 receptor antagonist in the cultures abolished the substance P-mediated effects. Furthermore, in vivo treatment with the neurokinin 1 receptor antagonist during the resolution phase of acute dry eye disease significantly suppressed memory Th17 generation, and treatment in the chronic phase of dry eye disease disrupted the maintenance of memory Th17. Taken together, our results demonstrate that increased expression of substance P promotes memory Th17 generation and maintenance in chronic dry eye disease, and thus blockade of substance P represents a novel promising memory Th17-targeting strategy in treating chronic ocular surface inflammation.
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Affiliation(s)
- Shudan Wang
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, United States
- Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University, 143 Yiman Street, Harbin, Heilongjiang Province, 150001, P.R. China
| | - Amirreza Naderi
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, United States
| | - Francesca Kahale
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, United States
| | - Gustavo Ortiz
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, United States
| | - Katayoon Forouzanfar
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, United States
| | - Yihe Chen
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, United States
| | - Reza Dana
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, United States
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Kim M, Shin M, Zhao Y, Ghosh M, Son Y. Transformative Impact of Nanocarrier‐Mediated Drug Delivery: Overcoming Biological Barriers and Expanding Therapeutic Horizons. SMALL SCIENCE 2024; 4. [DOI: 10.1002/smsc.202400280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025] Open
Abstract
Advancing therapeutic progress is centered on developing drug delivery systems (DDS) that control therapeutic molecule release, ensuring precise targeting and optimal concentrations. Targeted DDS enhances treatment efficacy and minimizes off‐target effects, but struggles with drug degradation. Over the last three decades, nanopharmaceuticals have evolved from laboratory concepts into clinical products, highlighting the profound impact of nanotechnology in medicine. Despite advancements, the effective delivery of therapeutics remains challenging because of biological barriers. Nanocarriers offer a solution with a small size, high surface‐to‐volume ratios, and customizable properties. These systems address physiological and biological challenges, such as shear stress, protein adsorption, and quick clearance. They allow targeted delivery to specific tissues, improve treatment outcomes, and reduce adverse effects. Nanocarriers exhibit controlled release, decreased degradation, and enhanced efficacy. Their size facilitates cell membrane penetration and intracellular delivery. Surface modifications increase affinity for specific cell types, allowing precise treatment delivery. This study also elucidates the potential integration of artificial intelligence with nanoscience to innovate future nanocarrier systems.
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Affiliation(s)
- Minhye Kim
- Interdisciplinary Graduate Program in Advanced Convergence Technology and Science Jeju National University Jeju‐si Jeju Special Self‐Governing Province 63243 Republic of Korea
| | - Myeongyeon Shin
- Department of Animal Biotechnology Faculty of Biotechnology College of Applied Life Sciences Jeju National University Jeju‐si Jeju Special Self‐Governing Province 63243 Republic of Korea
| | - Yaping Zhao
- School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Jiao Tong University Shanghai 200240 P. R. China
| | - Mrinmoy Ghosh
- Department of Animal Biotechnology Faculty of Biotechnology College of Applied Life Sciences Jeju National University Jeju‐si Jeju Special Self‐Governing Province 63243 Republic of Korea
| | - Young‐Ok Son
- Interdisciplinary Graduate Program in Advanced Convergence Technology and Science Jeju National University Jeju‐si Jeju Special Self‐Governing Province 63243 Republic of Korea
- Department of Animal Biotechnology Faculty of Biotechnology College of Applied Life Sciences Jeju National University Jeju‐si Jeju Special Self‐Governing Province 63243 Republic of Korea
- Bio‐Health Materials Core‐Facility Center Jeju National University Jeju‐si 63243 Republic of Korea
- Practical Translational Research Center Jeju National University Jeju‐si 63243 Republic of Korea
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Xing L, Chen B, Qin Y, Li X, Zhou S, Yuan K, Zhao R, Qin D. The role of neuropeptides in cutaneous wound healing: a focus on mechanisms and neuropeptide-derived treatments. Front Bioeng Biotechnol 2024; 12:1494865. [PMID: 39539691 PMCID: PMC11557334 DOI: 10.3389/fbioe.2024.1494865] [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: 09/17/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
An extensive network of cutaneous nerves, neuropeptides, and specific receptors richly innervates the skin and influences a variety of physiological and pathological processes. The sensory and autonomic nerve fibers secrete a variety of neuropeptides that are essential to the different phases of wound healing. In addition to initiating a neurogenic inflammatory response in the early stages of healing, neuropeptides also control wound healing by influencing immune cells, repair cells, and the growth factor network. However, the precise mechanism by which they accomplish these roles in the context of cutaneous wound healing is still unknown. Investigating the mechanisms of action of neuropeptides in wound healing and potential therapeutic applications is therefore urgently necessary. The present review discusses the process of wound healing, types of neuropeptides, potential mechanisms underlying the role of neuropeptides in cutaneous wound healing, as well as some neuropeptide-derived treatment strategies, such as hydrogels, new dressings, electro stimulation, and skin-derived precursors. Future in-depth mechanistic studies of neuropeptides in cutaneous wound healing may provide opportunities to develop therapeutic technologies that harness the roles of neuropeptides in the wound healing process.
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Affiliation(s)
- Liwei Xing
- First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Bing Chen
- School of Medicine, Kunming University, Kunming, China
| | - Yuliang Qin
- Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming, China
| | - Xinyao Li
- Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming, China
| | - Sitong Zhou
- Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming, China
| | - Kai Yuan
- Second Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Rong Zhao
- First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Dongdong Qin
- Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming, China
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Zou Y, Liu C, Wang Z, Li G, Xiao J. Neural and immune roles in osteoarthritis pain: Mechanisms and intervention strategies. J Orthop Translat 2024; 48:123-132. [PMID: 39220678 PMCID: PMC11363721 DOI: 10.1016/j.jot.2024.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 07/18/2024] [Accepted: 07/24/2024] [Indexed: 09/04/2024] Open
Abstract
Pain is the leading symptom for most individuals with osteoarthritis (OA), a complex condition marked by joint discomfort. Recently, the dynamic interplay between the nervous and immune systems has become a focal point for understanding pain regulation. Despite this, there is still a substantial gap in our comprehensive understanding of the neuroimmune interactions and their effects on pain in OA. This review examines the bidirectional influences between immune cells and nerves in OA progression. It explores current approaches that target neuroimmune pathways, including promoting M2 macrophage polarization and specific neuronal receptor targeting, for effective pain reduction. Translational potential statement This review provides a comprehensive overview of the mechanisms underlying the interplay between the immune system and nervous system during the progression of OA, as well as their contributions to pain. Additionally, it compiles existing intervention strategies targeting neuroimmunity for the treatment of OA pain. This information offers valuable insights for researchers seeking to address the challenge of OA pain.
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Affiliation(s)
- Yi Zou
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei, 430030, China
| | - Changyu Liu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei, 430030, China
| | - Zhenggang Wang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei, 430030, China
| | - Guanghui Li
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei, 430030, China
| | - Jun Xiao
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei, 430030, China
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Zhu X, Chen S, Xie Y, Cheng Z, Zhu X, Guo Q. Role of M1/M2 macrophages in pain modulation. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2024; 49:1155-1163. [PMID: 39788503 PMCID: PMC11495980 DOI: 10.11817/j.issn.1672-7347.2024.240017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Indexed: 01/12/2025]
Abstract
Pain is a signal of inflammation that can have both protective and pathogenic effects. Macrophages, significant components of the immune system, play crucial roles in the occurrence and development of pain, particularly in neuroimmune communication. Macrophages exhibit plasticity and heterogeneity, adopting either pro-inflammatory M1 or anti-inflammatory M2 phenotypes depending on their functional orientation. Recent research highlights the contribution of macrophages to pain dynamics by undergoing changes in their functional polarity, leading to macrophage activation, tissue infiltration, and cytokine secretion. M1 macrophages release pro-inflammatory mediators that are not only essential in defending against infections, but also contributing to tissue damage and the elicitation of pain. However, this process can be counteracted by M2 macrophages, facilitating pain relief through producing anti-inflammatory cytokines and opioid peptides or enhancing efferocytosis. M1 and M2 macrophages play important roles in both the initiation and mitigation of pain.
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Affiliation(s)
- Xiaoye Zhu
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410008.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
| | - Saige Chen
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410008
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yongqiu Xie
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410008
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Zhigang Cheng
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410008
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xiaoyan Zhu
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410008.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
| | - Qulian Guo
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410008
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
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Gardashli M, Baron M, Huang C, Kaplan LD, Meng Z, Kouroupis D, Best TM. Mechanical loading and orthobiologic therapies in the treatment of post-traumatic osteoarthritis (PTOA): a comprehensive review. Front Bioeng Biotechnol 2024; 12:1401207. [PMID: 38978717 PMCID: PMC11228341 DOI: 10.3389/fbioe.2024.1401207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 06/03/2024] [Indexed: 07/10/2024] Open
Abstract
The importance of mechanical loading and its relationship to orthobiologic therapies in the treatment of post-traumatic osteoarthritis (PTOA) is beginning to receive attention. This review explores the current efficacy of orthobiologic interventions, notably platelet-rich plasma (PRP), bone marrow aspirate (BMA), and mesenchymal stem/stromal cells (MSCs), in combating PTOA drawing from a comprehensive review of both preclinical animal models and human clinical studies. This review suggests why mechanical joint loading, such as running, might improve outcomes in PTOA management in conjunction with orthiobiologic administration. Accumulating evidence underscores the influence of mechanical loading on chondrocyte behavior and its pivotal role in PTOA pathogenesis. Dynamic loading has been identified as a key factor for optimal articular cartilage (AC) health and function, offering the potential to slow down or even reverse PTOA progression. We hypothesize that integrating the activation of mechanotransduction pathways with orthobiologic treatment strategies may hold a key to mitigating or even preventing PTOA development. Specific loading patterns incorporating exercise and physical activity for optimal joint health remain to be defined, particularly in the clinical setting following joint trauma.
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Affiliation(s)
- Mahammad Gardashli
- Department of Education, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Max Baron
- Department of Education, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Charles Huang
- Department of Biomedical Engineering, University of Miami, Miami, FL, United States
| | - Lee D Kaplan
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
- Department of Biomedical Engineering, University of Miami, Miami, FL, United States
| | - Zhipeng Meng
- Department of Molecular and Cellular Pharmacology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Dimitrios Kouroupis
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
- Diabetes Research Institute and Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Thomas M Best
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
- Department of Biomedical Engineering, University of Miami, Miami, FL, United States
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Lee JK, Kim DS, Park SY, Jung JW, Baek SW, Lee S, Kim JH, Ahn TK, Han DK. Osteoporotic Bone Regeneration via Plenished Biomimetic PLGA Scaffold with Sequential Release System. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2310734. [PMID: 38143290 DOI: 10.1002/smll.202310734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/21/2023] [Indexed: 12/26/2023]
Abstract
Achieving satisfactory bone tissue regeneration in osteoporotic patients with ordinary biomaterials is challenging because of the decreased bone mineral density and aberrant bone microenvironment. In addressing this issue, a biomimetic scaffold (PMEH/SP), incorporating 4-hexylresorcinol (4HR), and substance P (SP) into the poly(lactic-go-glycolic acid) (PLGA) scaffold with magnesium hydroxide (M) and extracellular matrix (E) is introduced, enabling the consecutive release of bioactive agents. 4HR and SP induced the phosphorylation of p38 MAPK and ERK in human umbilical vein endothelial cells (HUVECs), thereby upregulating VEGF expression level. The migration and tube-forming ability of endothelial cells can be promoted by the scaffold, which accelerates the formation and maturation of the bone. Moreover, 4HR played a crucial role in the inhibition of osteoclastogenesis by interrupting the IκB/NF-κB signaling pathway and exhibiting SP, thereby enhancing the migration and angiogenesis of HUVECs. Based on such a synergistic effect, osteoporosis can be suppressed, and bone regeneration can be achieved by inhibiting the RANKL pathway in vitro and in vivo, which is a commonly known mechanism of bone physiology. Therefore, the study presents a promising approach for developing a multifunctional regenerative material for sophisticated osteoporotic bone regeneration.
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Affiliation(s)
- Jun-Kyu Lee
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Da-Seul Kim
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
- Division of Engineering in Medicine, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Cambridge, MA, 02139, USA
| | - So-Yeon Park
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Ji-Won Jung
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Seung-Woon Baek
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Semi Lee
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Jun Hyuk Kim
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
| | - Tae-Keun Ahn
- Department of Orthopedic Surgery, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea
| | - Dong Keun Han
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea
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Ye Y, Cheng H, Wang Y, Sun Y, Zhang LD, Tang J. Macrophage: A key player in neuropathic pain. Int Rev Immunol 2024; 43:326-339. [PMID: 38661566 DOI: 10.1080/08830185.2024.2344170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/22/2024] [Accepted: 04/13/2024] [Indexed: 04/26/2024]
Abstract
Research on the relationship between macrophages and neuropathic pain has flourished in the past two decades. It has long been believed that macrophages are strong immune effector cells that play well-established roles in tissue homeostasis and lesions, such as promoting the initiation and progression of tissue injury and improving wound healing and tissue remodeling in a variety of pathogenesis-related diseases. They are also heterogeneous and versatile cells that can switch phenotypically/functionally in response to the micro-environment signals. Apart from microglia (resident macrophages of both the spinal cord and brain), which are required for the neuropathic pain processing of the CNS, neuropathic pain signals in PNS are influenced by the interaction of tissue-resident macrophages and BM infiltrating macrophages with primary afferent neurons. And the current review looks at new evidence that suggests sexual dimorphism in neuropathic pain are caused by variations in the immune system, notably macrophages, rather than the neurological system.
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Affiliation(s)
- Ying Ye
- Department of Anesthesiology, Jinling Hospital, Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
| | - Hao Cheng
- Department of Anesthesiology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, PR China
| | - Yan Wang
- Department of Anesthesiology, Jinling Hospital, Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
| | - Yan Sun
- Department of Anesthesiology, Jinling Hospital, Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
| | - Li-Dong Zhang
- Department of Anesthesiology, Jinling Hospital, Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
| | - Jun Tang
- Department of Anesthesiology, Jinling Hospital, Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
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Liebmann K, Castillo MA, Jergova S, Best TM, Sagen J, Kouroupis D. Modification of Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles by Calcitonin Gene Related Peptide (CGRP) Antagonist: Potential Implications for Inflammation and Pain Reversal. Cells 2024; 13:484. [PMID: 38534328 PMCID: PMC10969778 DOI: 10.3390/cells13060484] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/07/2024] [Accepted: 03/08/2024] [Indexed: 03/28/2024] Open
Abstract
During the progression of knee osteoarthritis (OA), the synovium and infrapatellar fat pad (IFP) can serve as source for Substance P (SP) and calcitonin gene-related peptide (CGRP), two important pain-transmitting, immune, and inflammation modulating neuropeptides. Our previous studies showed that infrapatellar fat pad-derived mesenchymal stem/stromal cells (MSC) acquire a potent immunomodulatory phenotype and actively degrade Substance P via CD10 both in vitro and in vivo. On this basis, our hypothesis is that CD10-bound IFP-MSC sEVs can be engineered to target CGRP while retaining their anti-inflammatory phenotype. Herein, human IFP-MSC cultures were transduced with an adeno-associated virus (AAV) vector carrying a GFP-labelled gene for a CGRP antagonist peptide (aCGRP). The GFP positive aCGRP IFP-MSC were isolated and their sEVs' miRNA and protein cargos were assessed using multiplex methods. Our results showed that purified aCGRP IFP-MSC cultures yielded sEVs with cargo of 147 distinct MSC-related miRNAs. Reactome analysis of miRNAs detected in these sEVs revealed strong involvement in the regulation of target genes involved in pathways that control pain, inflammation and cartilage homeostasis. Protein array of the sEVs cargo demonstrated high presence of key immunomodulatory and reparative proteins. Stimulated macrophages exposed to aCGRP IFP-MSC sEVs demonstrated a switch towards an alternate M2 status. Also, stimulated cortical neurons exposed to aCGRP IFP-MSC sEVs modulate their molecular pain signaling profile. Collectively, our data suggest that yielded sEVs can putatively target CGRP in vivo, while containing potent anti-inflammatory and analgesic cargo, suggesting the promise for novel sEVs-based therapeutic approaches to diseases such as OA.
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Affiliation(s)
- Kevin Liebmann
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (K.L.); (M.A.C.); (T.M.B.)
- Diabetes Research Institute & Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (S.J.); (J.S.)
| | - Mario A. Castillo
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (K.L.); (M.A.C.); (T.M.B.)
- Diabetes Research Institute & Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Stanislava Jergova
- Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (S.J.); (J.S.)
| | - Thomas M. Best
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (K.L.); (M.A.C.); (T.M.B.)
| | - Jacqueline Sagen
- Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (S.J.); (J.S.)
| | - Dimitrios Kouroupis
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of Medicine, University of Miami, Miami, FL 33146, USA; (K.L.); (M.A.C.); (T.M.B.)
- Diabetes Research Institute & Cell Transplant Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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Li M, Zhong X, Xu W. Substance P Increases STAT6-Mediated Transcription Activation of Lymphocyte Cytosolic Protein 2 to Sustain M2 Macrophage Predominance in Pediatric Asthma. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:238-252. [PMID: 37995836 DOI: 10.1016/j.ajpath.2023.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 10/13/2023] [Accepted: 11/06/2023] [Indexed: 11/25/2023]
Abstract
Substance P (SP) is a neuropeptide released by neurons and participates in various biological processes, including inflammation. M2 macrophages are major immune cells associated with type 2 inflammation in asthma. This study investigated the effect of SP on macrophage phenotype in pediatric asthma and the underpinning factors. Asthmatic children exhibited an increased level of SP, along with a higher proportion of M2 macrophages in their bronchoalveolar lavage fluid. Flow cytometry revealed that SP treatment enhanced the M2 polarization of 12-O-tetradecanoylphorbol 13-acetate-treated THP-1 cells (macrophages) in vitro. By contrast, the administration of a neutralizing antibody of SP reduced the M2 macrophage population, mitigated inflammatory cell infiltration in mouse lung tissues, and decreased the population of immune cells in the mouse bronchoalveolar lavage fluid. SP up-regulated the expression of STAT6, which, in turn, activated the transcription of lymphocyte cytosolic protein 2 (LCP2). The population of macrophages and allergic inflammatory responses in mice were reduced by STAT6 inhibition but restored by LCP2 overexpression. Collectively, the present study demonstrated that SP sustains M2 macrophage predominance and allergic inflammation in pediatric asthma by enhancing STAT6-dependent transcription activation of LCP2.
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Affiliation(s)
- Miao Li
- Department of Pediatrics, Shengjing Hospital of China Medical University, Liaoning, China.
| | - Xiao Zhong
- Department of Pediatrics, Shengjing Hospital of China Medical University, Liaoning, China
| | - Wenting Xu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Liaoning, China
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Rodriguez FD, Covenas R. Association of Neurokinin-1 Receptor Signaling Pathways with Cancer. Curr Med Chem 2024; 31:6460-6486. [PMID: 37594106 DOI: 10.2174/0929867331666230818110812] [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: 02/03/2023] [Revised: 06/14/2023] [Accepted: 07/01/2023] [Indexed: 08/19/2023]
Abstract
BACKGROUND Numerous biochemical reactions leading to altered cell proliferation cause tumorigenesis and cancer treatment resistance. The mechanisms implicated include genetic and epigenetic changes, modified intracellular signaling, and failure of control mechanisms caused by intrinsic and extrinsic factors alone or combined. No unique biochemical events are responsible; entangled molecular reactions conduct the resident cells in a tissue to display uncontrolled growth and abnormal migration. Copious experimental research supports the etiological responsibility of NK-1R (neurokinin-1 receptor) activation, alone or cooperating with other mechanisms, in cancer appearance in different tissues. Consequently, a profound study of this receptor system in the context of malignant processes is essential to design new treatments targeting NK-1R-deviated activity. METHODS This study reviews and discusses recent literature that analyzes the main signaling pathways influenced by the activation of neurokinin 1 full and truncated receptor variants. Also, the involvement of NK-1R in cancer development is discussed. CONCLUSION NK-1R can signal through numerous pathways and cross-talk with other receptor systems. The participation of override or malfunctioning NK-1R in malignant processes needs a more precise definition in different types of cancers to apply satisfactory and effective treatments. A long way has already been traveled: the current disposal of selective and effective NK-1R antagonists and the capacity to develop new drugs with biased agonistic properties based on the receptor's structural states with functional significance opens immediate research action and clinical application.
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Affiliation(s)
- Francisco David Rodriguez
- Department of Biochemistry and Molecular Biology, Faculty of Chemical Sciences, University of Salamanca, 37007 Salamanca, Spain
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), University of Salamanca, Salamanca, Spain
| | - Rafael Covenas
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), University of Salamanca, Salamanca, Spain
- Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neurosciences of Castilla y León (INCYL), University of Salamanca, 37007 Salamanca, Spain
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Hanif MA, Hossen S, Cho DH, Kho KH. The Neuropeptide HGAP Regulates Growth, Reproduction, Metamorphosis, Tissue Damage Repair, and Response against Starvation in Pacific Abalone. Neuroendocrinology 2023; 114:453-467. [PMID: 38142675 PMCID: PMC11108583 DOI: 10.1159/000535945] [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: 07/25/2023] [Accepted: 12/18/2023] [Indexed: 12/26/2023]
Abstract
INTRODUCTION Neuropeptides regulate vital physiological processes in multicellular organisms, including growth, reproduction, metamorphosis, and feeding. Recent transcriptome analyses have revealed neuropeptide genes with potential roles in vertebrate and invertebrate growth and reproduction. Among these genes, haliotid growth-associated peptide (HGAP) was identified as a novel gene in abalone. METHODS This study focused on HGAP in Pacific abalone (Haliotis discus hannai), where the complete cDNA sequence named Hdh-HGAP was identified and characterized. Samples from different experiments, such as metamorphosis, juvenile abalone growth, gonad development stages, muscle remodeling, and starvation, were collected for mRNA expression analysis. RESULTS The sequence spans 552 bp, encoding 96 amino acids with a molecular weight of 10.96 kDa. Expression analysis revealed that Hdh-HGAP exhibited higher levels in muscle tissue. Notably, during metamorphosis, Hdh-HGAP exhibited greater expression in the trochophore, veliger, and juvenile stages than in the cell division stages. Regarding growth patterns, Hdh-HGAP was highly expressed during rapid growth compared to stunted, minimal, and normal growth. In gonadal development, Hdh-HGAP mRNA reached its highest expression level during the ripening stage, indicating a potential role in gonadal cell proliferation and maturation. The in vivo effects of GnRH on gonad development and the expression of the Hdh-HGAP neuropeptide indicate its involvement in regulating reproduction in Pacific abalone. While tissue remodeling is primarily governed by immune genes, Hdh-HGAP was also upregulated during muscle tissue remodeling. Conversely, Hdh-HGAP was downregulated during prolonged starvation. CONCLUSION This study marks the first comprehensive exploration of the Hdh-HGAP neuropeptide gene in Pacific abalone, shedding light on its involvement in growth, reproduction, metamorphosis, tissue remodeling, and response to starvation, although regulatory mechanisms are mostly unknown.
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Affiliation(s)
- Md Abu Hanif
- Department of Fisheries Science, Chonnam National University, Yeosu, Republic of Korea
| | - Shaharior Hossen
- Department of Fisheries Science, Chonnam National University, Yeosu, Republic of Korea
| | - Doo Hyun Cho
- Department of Fisheries Science, Chonnam National University, Yeosu, Republic of Korea
| | - Kang Hee Kho
- Department of Fisheries Science, Chonnam National University, Yeosu, Republic of Korea
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Sun W, Ye B, Chen S, Zeng L, Lu H, Wan Y, Gao Q, Chen K, Qu Y, Wu B, Lv X, Guo X. Neuro-bone tissue engineering: emerging mechanisms, potential strategies, and current challenges. Bone Res 2023; 11:65. [PMID: 38123549 PMCID: PMC10733346 DOI: 10.1038/s41413-023-00302-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 10/08/2023] [Accepted: 10/31/2023] [Indexed: 12/23/2023] Open
Abstract
The skeleton is a highly innervated organ in which nerve fibers interact with various skeletal cells. Peripheral nerve endings release neurogenic factors and sense skeletal signals, which mediate bone metabolism and skeletal pain. In recent years, bone tissue engineering has increasingly focused on the effects of the nervous system on bone regeneration. Simultaneous regeneration of bone and nerves through the use of materials or by the enhancement of endogenous neurogenic repair signals has been proven to promote functional bone regeneration. Additionally, emerging information on the mechanisms of skeletal interoception and the central nervous system regulation of bone homeostasis provide an opportunity for advancing biomaterials. However, comprehensive reviews of this topic are lacking. Therefore, this review provides an overview of the relationship between nerves and bone regeneration, focusing on tissue engineering applications. We discuss novel regulatory mechanisms and explore innovative approaches based on nerve-bone interactions for bone regeneration. Finally, the challenges and future prospects of this field are briefly discussed.
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Affiliation(s)
- Wenzhe Sun
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Bing Ye
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Siyue Chen
- School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Lian Zeng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Hongwei Lu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yizhou Wan
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Qing Gao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Kaifang Chen
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yanzhen Qu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Bin Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiao Lv
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
| | - Xiaodong Guo
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
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Wu J, Xiong W, Li J, Liao H, Chai J, Huang X, Lai S, Kozlov S, Chu X, Xu X. Peptide TK-HR from the Skin of Chinese Folk Medicine Frog Hoplobatrachus Rugulosus Accelerates Wound Healing via the Activation of the Neurokinin-1 Receptor. J Med Chem 2023; 66:16002-16017. [PMID: 38015459 DOI: 10.1021/acs.jmedchem.3c01434] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Wound healing is a complex process and remains a considerable challenge in clinical trials due to the lack of ideal therapeutic drugs. Here, a new peptide TK-HR identified from the skin of the frog Hoplobatrachus rugulosus was tested for its ability to heal cutaneous wounds in mice. Topical application of TK-HR at doses of 50-200 μg/mL significantly accelerated wound closure without causing any adverse effects in the animals. In vitro and in vivo investigations proved the regulatory role of the peptide on neutrophils, macrophages, keratinocytes, and vein endothelial cells involved in the inflammatory, proliferative, and remodeling phases of wound healing. Notably, TK-HR activated the MAPK and TGF-β-Smad signaling pathways by acting on NK1R in RAW264.7 cells and mice. The current work has identified that TK-HR is a potent wound healing regulator that can be applied for the treatment of wounds, including diabetic foot ulcers and infected wounds, in the future.
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Affiliation(s)
- Jiena Wu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, P. R. China
| | - Weichen Xiong
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, P. R. China
| | - Jinqiao Li
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, P. R. China
| | - Hang Liao
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, P. R. China
| | - Jinwei Chai
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, P. R. China
| | - Xiaowen Huang
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Shian Lai
- Department of Molecular Chemistry and Biochemistry, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan
| | - Sergey Kozlov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya 16/10, Moscow 117997, Russia
| | - Xinwei Chu
- Department of Nutrition and Food Hygiene, School of Public Health, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Xueqing Xu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, P. R. China
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Cui Y, Wang X, Xu Y, Cao Y, Luo G, Zhao Z, Zhang J. Ropivacaine Promotes Axon Regeneration by Regulating Nav1.8-mediated Macrophage Signaling after Sciatic Nerve Injury in Rats. Anesthesiology 2023; 139:782-800. [PMID: 37669448 PMCID: PMC10723771 DOI: 10.1097/aln.0000000000004761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 02/08/2023] [Accepted: 08/31/2023] [Indexed: 09/07/2023]
Abstract
BACKGROUND Continuous nerve block with ropivacaine is commonly performed after repair surgery for traumatic peripheral nerve injuries. After peripheral nerve injury, tetrodotoxin-resistant voltage-gated sodium channel Nav1.8 is upregulated and contributes to macrophage inflammation. This study investigated whether ropivacaine promotes peripheral nerve regeneration through Nav1.8-mediated macrophage signaling. METHODS A sciatic nerve transection-repair (SNT) model was established in adult Sprague-Dawley rats of both sexes. The rats received 0.2% ropivacaine or 10 μM Nav1.8-selective inhibitor A-803467 around the injured site or near the sacrum for 3 days. Nerve regeneration was evaluated using behavioral, electrophysiologic, and morphological examinations. Moreover, myelin debris removal, macrophage phenotype, Nav1.8 expression, and neuropeptide expression were assessed using immunostaining, enzyme-linked immunosorbent assay, and Western blotting. RESULTS Compared to the SNT-plus-vehicle group, the sensory, motor, and sensory-motor coordination functions of the two ropivacaine groups were significantly improved. Electrophysiologic (mean ± SD: recovery index of amplitude, vehicle 0.43 ± 0.17 vs. ropivacaine 0.83 ± 0.25, n = 11, P < 0.001) and histological analysis collectively indicated that ropivacaine significantly promoted axonal regrowth (percentage of neurofilament 200 [NF-200]-positive area: vehicle 19.88 ± 2.81 vs. ropivacaine 31.07 ± 2.62, n = 6, P < 0.001). The authors also found that, compared to the SNT-plus-vehicle group, the SNT-plus-ropivacaine group showed faster clearance of myelin debris, accompanied by significantly increased macrophage infiltration and transition from the M1 to M2 phenotype. Moreover, ropivacaine significantly attenuated Nav1.8 upregulation at 9 days after sciatic nerve transection (vehicle 4.12 ± 0.30-fold vs. ropivacaine 2.75 ± 0.36-fold, n = 5, P < 0.001), which coincided with the increased expression of chemokine ligand 2 and substance P. Similar changes were observed when using the selective Nav1.8 channel inhibitor A-803467. CONCLUSIONS Continuous nerve block with ropivacaine promotes the structural and functional recovery of injured sciatic nerves, possibly by regulating Nav1.8-mediated macrophage signaling. EDITOR’S PERSPECTIVE
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Affiliation(s)
- Yongchen Cui
- Department of Anesthesiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiaofeng Wang
- Department of Anesthesiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yang Xu
- Department of Anesthesiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yue Cao
- Department of Anesthesiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Gang Luo
- Department of Anesthesiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhe Zhao
- Department of Geriatrics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Junfeng Zhang
- Department of Anesthesiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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22
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Piao J, Cho H, Park JH, Yoo KH, Jeong I, Hong HS. Preconditioning with Substance P Restores Therapeutic Efficacy of Aged ADSC by Elevating TNFR2 and Paracrine Potential. BIOLOGY 2023; 12:1458. [PMID: 38132284 PMCID: PMC10740808 DOI: 10.3390/biology12121458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/16/2023] [Accepted: 11/21/2023] [Indexed: 12/23/2023]
Abstract
Aging leads to a decline in stem cell activity by reducing the repopulation rate and paracrine potential, ultimately diminishing efficacy in vivo. TNF-α can exert inflammatory and cell death actions via Erk by binding to TNFR-1, and survival and tissue repair actions via Akt by binding to TNFR-2. Aged cells are reported to have insufficient expression of TNFR-2, indicating that aged adipose-derived stem cells (ADSCs-E) lack the ability for cell survival and immune control compared to young ADSCs (ADSCs-Y). This study aims to assess the preconditioning effect of SP on the response of ADSCs-E to inflammation. ADSCs-E were treated with SP and then exposed to a high dose of TNF-α for 24 h. Consequently, ADSC-E exhibited weaker viability and lower TNFR2 levels compared to ADSC-Y. In response to TNF-α, the difference in TNFR2 expression became more pronounced in ADSC-E and ADSC-Y. Moreover, ADSC-E showed a severe deficiency in proliferation and paracrine activity. However, preconditioning with SP significantly enhanced the viability of ADSCs-E and also restored TNFR2 expression and paracrine potential, similar to ADSC-Y under inflammatory conditions. Our findings support the idea that preconditioning with SP has the potential to restore the cellular function of senescent stem cells before transplantation.
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Affiliation(s)
- Jiyuan Piao
- Department of Genetic Engineering, Graduate School of Biotechnology, Kyung Hee University, Yongin-si 17104, Republic of Korea; (J.P.)
| | - Hyunchan Cho
- Department of Genetic Engineering, Graduate School of Biotechnology, Kyung Hee University, Yongin-si 17104, Republic of Korea; (J.P.)
| | - Jong Hyun Park
- Department of Dance, College of Performing Arts & Sport, Han Yang University, Seoul 04763, Republic of Korea
| | - Ki Hyun Yoo
- SIMPLE Planet Inc., Seoul 04790, Republic of Korea
| | - Ildoo Jeong
- SIMPLE Planet Inc., Seoul 04790, Republic of Korea
| | - Hyun Sook Hong
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- East-West Medical Research Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Kyung Hee Institute of Regenerative Medicine (KIRM), Medical Science Research Institute, Kyung Hee University Medical Center, Seoul 02447, Republic of Korea
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23
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Zhou Z, Sui X, Cao Z, Li X, Qing L, Tang J. Substance P promote macrophage M2 polarization to attenuate secondary lymphedema by regulating NF-kB/NLRP3 signaling pathway. Peptides 2023; 168:171045. [PMID: 37507091 DOI: 10.1016/j.peptides.2023.171045] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/25/2023] [Accepted: 06/09/2023] [Indexed: 07/30/2023]
Abstract
Secondary lymphedema often occurs after filariasis, trauma, lymph node dissection and radiation therapy, which is manifested by infiltration of inflammatory cells and fibrosis formation in pathologically. Substance P is a widely used neuropeptide in the field of tissue repair, while the regenerative potential of the substance P has not been proven in the secondary lymphedema. In this study, animal model of secondary lymphedema was constructed by excising the skin and subcutaneous lymphatic network in the tail of mice, and the degree of swelling in the tail of mice was evaluated after 6 weeks under the treatment with substance P. Immunofluorescence staining was also performed to assess immune cell infiltration, subcutaneous fibrosis and lymphangiogenesis. The results revealed that substance P significantly alleviated post-surgical lymphedema in mice. Furthermore, we found that substance P promoted macrophages M2 polarization, a process associated with downregulation of the NF-kB/NLRP3 pathway. After application of disodium clodronate (macrophage scavenger, CLO), the positive effect of substance P in lymphedema is significantly inhibited. In vitro experiments, we further demonstrated the polarizing effect of substance P on bone marrow-derived macrophages (BMDMs), while substance P inhibited the activation of the NF-kB/NLRP3 pathway in BMDMs after the treatment of lipopolysaccharide (LPS). In addition, polarized macrophages were demonstrated to promote the proliferation, tube-forming and migratory functions of human lymphatic endothelial cells (hLEC). In conclusion, our study provides preliminary evidence that substance P alleviates secondary lymphedema by promoting macrophage M2 polarization, and this therapeutic effect may be associated with downregulation of the NF-kB/NLRP3 pathway.
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Affiliation(s)
- Zekun Zhou
- Xiangya hospital of central south university, Changsha, China
| | - Xinlei Sui
- Xiangya hospital of central south university, Changsha, China
| | - Zheming Cao
- Xiangya hospital of central south university, Changsha, China
| | - Xiaoxiao Li
- Changsha Medical University, Changsha, China
| | - Liming Qing
- Xiangya hospital of central south university, Changsha, China.
| | - Juyu Tang
- Xiangya hospital of central south university, Changsha, China.
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24
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Chen J, Ye P, Gu R, Zhu H, He W, Mu X, Wu X, Pang H, Han F, Nie X. Neuropeptide substance P: A promising regulator of wound healing in diabetic foot ulcers. Biochem Pharmacol 2023; 215:115736. [PMID: 37549795 DOI: 10.1016/j.bcp.2023.115736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/09/2023]
Abstract
In the past, neuropeptide substance P (SP) was predominantly recognized as a neuroinflammatory factor, while its potent healing activity was overlooked. This paper aims to review the regulatory characteristics of neuropeptide SP in both normal and diabetic wound healing. SP actively in the regulation of wound healing-related cells directly and indirectly, exhibiting robust inflammatory properties, promoting cell proliferation and migration and restoring the activity and paracrine ability of skin cells under diabetic conditions. Furthermore, SP not only regulates healing-related cells but also orchestrates the immune environment, thereby presenting unique and promising application prospects in wound intervention. As new SP-based preparations are being explored, SP-related drugs are poised to become an effective therapeutic intervention for diabetic foot ulcers (DFU).
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Affiliation(s)
- Jitao Chen
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China; Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Penghui Ye
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China; Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Rifang Gu
- University Medical Office, Zunyi Medical University, Zunyi 563000, China
| | - Huan Zhu
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China; Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Wenjie He
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China; Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Xingrui Mu
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China; Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Xingqian Wu
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China; Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Huiwen Pang
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Felicity Han
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Xuqiang Nie
- College of Pharmacy, Zunyi Medical University, Zunyi 563000, China; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia; Key Lab of the Basic Pharmacology of the Ministry of Education & Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi 563000, China.
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25
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Menon N, Kishen A. Nociceptor-Macrophage Interactions in Apical Periodontitis: How Biomolecules Link Inflammation with Pain. Biomolecules 2023; 13:1193. [PMID: 37627258 PMCID: PMC10452348 DOI: 10.3390/biom13081193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
Periradicular tissues have a rich supply of peripheral afferent neurons, also known as nociceptive neurons, originating from the trigeminal nerve. While their primary function is to relay pain signals to the brain, these are known to be involved in modulating innate and adaptive immunity by initiating neurogenic inflammation (NI). Studies have investigated neuroanatomy and measured the levels of biomolecules such as cytokines and neuropeptides in human saliva, gingival crevicular fluid, or blood/serum samples in apical periodontitis (AP) to validate the possible role of trigeminal nociceptors in inflammation and tissue regeneration. However, the contributions of nociceptors and the mechanisms involved in the neuro-immune interactions in AP are not fully understood. This narrative review addresses the complex biomolecular interactions of trigeminal nociceptors with macrophages, the effector cells of the innate immune system, in the clinical manifestations of AP.
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Affiliation(s)
| | - Anil Kishen
- Dental Research Institute, Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada;
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26
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Ahn W, Chi G, Kim S, Son Y, Zhang M. Substance P Reduces Infarct Size and Mortality After Ischemic Stroke, Possibly Through the M2 Polarization of Microglia/Macrophages and Neuroprotection in the Ischemic Rat Brain. Cell Mol Neurobiol 2023; 43:2035-2052. [PMID: 36112332 PMCID: PMC11412183 DOI: 10.1007/s10571-022-01284-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 09/08/2022] [Indexed: 12/12/2022]
Abstract
Substance-P (SP) is an 11 amino acid neuropeptide that is known to stimulate the peripheral mobilization of bone marrow mesenchymal stem cells and M2 polarization in monocytes/macrophages in a variety of acute and chronic tissue injuries. To examine the role of SP in protection and recovery from acute ischemic brain injury, experimental ischemic stroke was induced by transient middle cerebral artery occlusion (tMCAo) in rats for 1 h with subsequent reperfusion. Two injections of SP, immediately and one day post-tMCAo, resulted in approximately threefold lower mortality and 40% less infarct volume than those of saline-treated rats at seven days post-tMCAo. At 4.5 h, SP markedly increased CD11b/c+CD163+/CD 206+ cells in the blood, which were concomitantly decreased in the bone marrow, suggesting that SP preferentially mobilized M2-polarized monocytes. After two days, SP increased the expression of neuroprotective and anti-inflammatory genes in the ischemic brain and induced neuronal survival in the brain penumbra. Additionally, SP markedly increased CD68+CD163+ and CD68+CD206+ M2 microglia/macrophages in the ischemic brain during seven days post-tMCAo. Furthermore, SP preserved the blood‒brain barrier in the ischemic brain, which was confirmed by the abundant levels of SMI71+ brain endothelial cells that colocalized with α-SMA+ pericytes. The beneficial effects of SP on functional recovery and tissue preservation were maintained for six weeks. Collectively, SP treatment in the early phase of ischemic stroke markedly suppressed the destructive inflammatory response and improved the microenvironment for tissue protection and repair.
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Affiliation(s)
- Woosung Ahn
- Department of Genetics and Biotechnology, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Seocheon-dong, Kiheung-gu 446-701, Yongin-Si, Republic of Korea
| | - Guangfan Chi
- Department of Genetics and Biotechnology, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Seocheon-dong, Kiheung-gu 446-701, Yongin-Si, Republic of Korea
| | - Sumin Kim
- Department of Genetics and Biotechnology, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Seocheon-dong, Kiheung-gu 446-701, Yongin-Si, Republic of Korea
| | - Youngsook Son
- Department of Genetics and Biotechnology, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Seocheon-dong, Kiheung-gu 446-701, Yongin-Si, Republic of Korea.
| | - Mingzi Zhang
- Department of Genetics and Biotechnology, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Seocheon-dong, Kiheung-gu 446-701, Yongin-Si, Republic of Korea
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27
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Garcia Garcia JM, Vannuzzi V, Donati C, Bernacchioni C, Bruni P, Petraglia F. Endometriosis: Cellular and Molecular Mechanisms Leading to Fibrosis. Reprod Sci 2023; 30:1453-1461. [PMID: 36289173 PMCID: PMC10160154 DOI: 10.1007/s43032-022-01083-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 09/09/2022] [Indexed: 10/31/2022]
Abstract
Endometriosis is a chronic inflammatory condition affecting women of reproductive age. A relevant feature of endometriosis is the presence of fibrotic tissue inside and around the lesions, thus contributing to the classic endometriosis-related symptoms, pain, and infertility. The molecular mechanisms responsible for the development of fibrosis in endometriosis are not yet defined. The present review aimed to examine the biological mechanisms and signalling pathways involved in fibrogenesis of endometriotic lesions, highlighting the difference between deep infiltrating and ovarian endometriosis. The main cell types involved in the development of fibrosis are platelets, myofibroblasts, macrophages, and sensory nerve fibers. Members of the transforming growth factor (TGF) -β family, as well as the receptor Notch, or the bioactive sphingolipid sphingosine 1-phosphate (S1P), play a role in the development of tissue fibrosis, resulting in their metabolism and/or their signalling pathways altered in endometriotic lesions. It is relevant the knowledge of the molecular mechanisms that guide and support fibrosis in endometriosis, to identify new drug targets and provide new therapeutic approaches to patients.
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Affiliation(s)
- Jose Manuel Garcia Garcia
- Obstetrics and Gynecology and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences "M. Serio, " University of Florence, Florence, Italy
| | - Valentina Vannuzzi
- Obstetrics and Gynecology and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences "M. Serio, " University of Florence, Florence, Italy
| | - Chiara Donati
- Obstetrics and Gynecology and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences "M. Serio, " University of Florence, Florence, Italy
| | - Caterina Bernacchioni
- Obstetrics and Gynecology and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences "M. Serio, " University of Florence, Florence, Italy
| | - Paola Bruni
- Obstetrics and Gynecology and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences "M. Serio, " University of Florence, Florence, Italy
| | - Felice Petraglia
- Obstetrics and Gynecology and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences "M. Serio, " University of Florence, Florence, Italy.
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28
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Lee D, Hong HS. Substance P Alleviates Retinal Pigment Epithelium Dysfunction Caused by High Glucose-Induced Stress. Life (Basel) 2023; 13:life13051070. [PMID: 37240715 DOI: 10.3390/life13051070] [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: 04/10/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023] Open
Abstract
When the retina is constantly affected by high glucose (HG) due to diabetes, the barrier function of the retinal pigment epithelium (RPE) is impaired, accompanied by unnecessary vascularization. This eventually leads to the development of diabetic retinopathy (DR). This study investigated the recovery effect of substance P (SP) on RPE injured by HG. RPE was treated with HG for 24 h, and HG-induced cellular injuries were confirmed. SP was added to the dysfunctional RPE. Compared to RPE in low glucose (LG) conditions, HG-damaged RPE had large, fibrotic cell shapes, and its cellular viability decreased. HG treatment reduced tight junction protein expression levels and caused oxidative stress by interrupting the antioxidant system; this was followed by inflammatory factor intracellular adhesion molecule-1 (ICAM-1), Monocyte chemotactic protein-1 (MCP-1), and angiogenesis factor vascular endothelial growth factor (VEGF) expression. SP treatment contributed to RPE recovery by enhancing cell viability, tight junction protein expression, and RPE function under HG conditions, possibly by activating the Akt signaling pathway. Importantly, SP treatment reduced ICAM-1, MCP-1, and VEGF expression. Collectively, SP activated survival signals to suppress oxidative stress and improve retinal barrier function in RPE, accompanied by immune suppression. This suggests the possible application of SP to diabetic retinal injuries.
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Affiliation(s)
- Dahyeon Lee
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hyun Sook Hong
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- East-West Medical Research Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Kyung Hee Institute of Regenerative Medicine (KIRM), Medical Science Research Institute, Kyung Hee University Medical Center, Seoul 02447, Republic of Korea
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29
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Hanč P, Messou MA, Wang Y, von Andrian UH. Control of myeloid cell functions by nociceptors. Front Immunol 2023; 14:1127571. [PMID: 37006298 PMCID: PMC10064072 DOI: 10.3389/fimmu.2023.1127571] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/23/2023] [Indexed: 03/19/2023] Open
Abstract
The immune system has evolved to protect the host from infectious agents, parasites, and tumor growth, and to ensure the maintenance of homeostasis. Similarly, the primary function of the somatosensory branch of the peripheral nervous system is to collect and interpret sensory information about the environment, allowing the organism to react to or avoid situations that could otherwise have deleterious effects. Consequently, a teleological argument can be made that it is of advantage for the two systems to cooperate and form an “integrated defense system” that benefits from the unique strengths of both subsystems. Indeed, nociceptors, sensory neurons that detect noxious stimuli and elicit the sensation of pain or itch, exhibit potent immunomodulatory capabilities. Depending on the context and the cellular identity of their communication partners, nociceptors can play both pro- or anti-inflammatory roles, promote tissue repair or aggravate inflammatory damage, improve resistance to pathogens or impair their clearance. In light of such variability, it is not surprising that the full extent of interactions between nociceptors and the immune system remains to be established. Nonetheless, the field of peripheral neuroimmunology is advancing at a rapid pace, and general rules that appear to govern the outcomes of such neuroimmune interactions are beginning to emerge. Thus, in this review, we summarize our current understanding of the interaction between nociceptors and, specifically, the myeloid cells of the innate immune system, while pointing out some of the outstanding questions and unresolved controversies in the field. We focus on such interactions within the densely innervated barrier tissues, which can serve as points of entry for infectious agents and, where known, highlight the molecular mechanisms underlying these interactions.
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Affiliation(s)
- Pavel Hanč
- Department of Immunology, Harvard Medical School, Boston, MA, United States
- The Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- *Correspondence: Pavel Hanč, ; Ulrich H. von Andrian,
| | - Marie-Angèle Messou
- Department of Immunology, Harvard Medical School, Boston, MA, United States
- The Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
| | - Yidi Wang
- Department of Immunology, Harvard Medical School, Boston, MA, United States
- The Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
| | - Ulrich H. von Andrian
- Department of Immunology, Harvard Medical School, Boston, MA, United States
- The Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- *Correspondence: Pavel Hanč, ; Ulrich H. von Andrian,
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30
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Zhang W, Lyu M, Bessman NJ, Xie Z, Arifuzzaman M, Yano H, Parkhurst CN, Chu C, Zhou L, Putzel GG, Li TT, Jin WB, Zhou J, Hu H, Tsou AM, Guo CJ, Artis D. Gut-innervating nociceptors regulate the intestinal microbiota to promote tissue protection. Cell 2022; 185:4170-4189.e20. [PMID: 36240781 PMCID: PMC9617796 DOI: 10.1016/j.cell.2022.09.008] [Citation(s) in RCA: 91] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/14/2022] [Accepted: 08/29/2022] [Indexed: 11/06/2022]
Abstract
Nociceptive pain is a hallmark of many chronic inflammatory conditions including inflammatory bowel diseases (IBDs); however, whether pain-sensing neurons influence intestinal inflammation remains poorly defined. Employing chemogenetic silencing, adenoviral-mediated colon-specific silencing, and pharmacological ablation of TRPV1+ nociceptors, we observed more severe inflammation and defective tissue-protective reparative processes in a murine model of intestinal damage and inflammation. Disrupted nociception led to significant alterations in the intestinal microbiota and a transmissible dysbiosis, while mono-colonization of germ-free mice with Gram+Clostridium spp. promoted intestinal tissue protection through a nociceptor-dependent pathway. Mechanistically, disruption of nociception resulted in decreased levels of substance P, and therapeutic delivery of substance P promoted tissue-protective effects exerted by TRPV1+ nociceptors in a microbiota-dependent manner. Finally, dysregulated nociceptor gene expression was observed in intestinal biopsies from IBD patients. Collectively, these findings indicate an evolutionarily conserved functional link between nociception, the intestinal microbiota, and the restoration of intestinal homeostasis.
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Affiliation(s)
- Wen Zhang
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Mengze Lyu
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Nicholas J Bessman
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Zili Xie
- Department of Anesthesiology, The Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA
| | - Mohammad Arifuzzaman
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Hiroshi Yano
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Christopher N Parkhurst
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Coco Chu
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Lei Zhou
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Gregory G Putzel
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Ting-Ting Li
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Wen-Bing Jin
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Jordan Zhou
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Hongzhen Hu
- Department of Anesthesiology, The Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA
| | - Amy M Tsou
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Friedman Center for Nutrition and Inflammation, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Division of Pediatric Gastroenterology, Hepatology and Nutrition, Weill Cornell Medical College, New York, NY, USA
| | - Chun-Jun Guo
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Friedman Center for Nutrition and Inflammation, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - David Artis
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Friedman Center for Nutrition and Inflammation, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.
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31
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Gheorghe RO, Grosu AV, Bica-Popi M, Ristoiu V. The Yin/Yang Balance of Communication between Sensory Neurons and Macrophages in Traumatic Peripheral Neuropathic Pain. Int J Mol Sci 2022; 23:ijms232012389. [PMID: 36293246 PMCID: PMC9603877 DOI: 10.3390/ijms232012389] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/07/2022] [Accepted: 10/11/2022] [Indexed: 11/06/2022] Open
Abstract
Traumatic peripheral neuropathic pain is a complex syndrome caused by a primary lesion or dysfunction of the peripheral nervous system. Secondary to the lesion, resident or infiltrating macrophages proliferate and initiate a cross-talk with the sensory neurons, at the level of peripheral nerves and sensory ganglia. The neuron–macrophage interaction, which starts very early after the lesion, is very important for promoting pain development and for initiating changes that will facilitate the chronicization of pain, but it also has the potential to facilitate the resolution of injury-induced changes and, consequently, promote the reduction of pain. This review is an overview of the unique characteristics of nerve-associated macrophages in the peripheral nerves and sensory ganglia and of the molecules and signaling pathways involved in the neuro-immune cross-talk after a traumatic lesion, with the final aim of better understanding how the balance between pro- and anti-nociceptive dialogue between neurons and macrophages may be modulated for new therapeutic approaches.
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Sipka AS, Chandler TL, Weichhart T, Schuberth HJ, Mann S. Inhibition of mTOR in bovine monocyte derived macrophages and dendritic cells provides a potential mechanism for postpartum immune dysfunction in dairy cows. Sci Rep 2022; 12:15084. [PMID: 36064574 PMCID: PMC9445052 DOI: 10.1038/s41598-022-19295-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 08/26/2022] [Indexed: 11/29/2022] Open
Abstract
Dairy cattle experience a profound nutrient deficit postpartum that is associated with immune dysfunction characterized by heightened inflammation and reduced pathogen clearance. The activation of the central nutrient-sensing mTOR pathway is comparatively reduced in leukocytes of early postpartum dairy cows during this time of most pronounced nutrient deficit. We assessed the effect of pharmacological mTOR inhibition (Torin-1, rapamycin) on differentiation of monocyte derived classically (M1) and alternatively (M2) activated macrophages (MPh) and dendritic cells (moDC) from 12 adult dairy cows. Treatment with mTOR inhibitors generated M1 MPh with increased oxidative burst and expression of IL12 subunits but decreased phagocytosis and expression of IL1B, IL6, and IL10. In M2 MPh, treatment inhibited expression of regulatory features (CD163, ARG2, IL10) skewing the cells toward an M1-like phenotype. In moDC, mTOR inhibition increased expression of pro-inflammatory cytokines (IL12A, IL12B, IL1B, IL6) and surface CD80. In co-culture with mixed lymphocytes, mTOR-inhibited moDC exhibited a cytokine profile favoring a Th1 response with increased TNF and IFNG production and decreased IL10 concentrations. We conclude that mTOR inhibition in vitro promoted differentiation of inflammatory macrophages with reduced regulatory features and generation of Th1-favoring dendritic cells. These mechanisms could contribute to immune dysregulation in postpartum dairy cows.
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Affiliation(s)
- Anja S Sipka
- Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, 231 Farrier Road, Ithaca, NY, 14853, USA.
| | - Tawny L Chandler
- Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, 231 Farrier Road, Ithaca, NY, 14853, USA
| | - Thomas Weichhart
- Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Straße 10, 1090, Vienna, Austria
| | - Hans-Joachim Schuberth
- Institute for Immunology, University of Veterinary Medicine, Buenteweg 2, 30559, Hannover, Germany
| | - Sabine Mann
- Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, 231 Farrier Road, Ithaca, NY, 14853, USA.
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Wu Y, Berisha A, Borniger JC. Neuropeptides in Cancer: Friend and Foe? Adv Biol (Weinh) 2022; 6:e2200111. [PMID: 35775608 DOI: 10.1002/adbi.202200111] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 05/31/2022] [Indexed: 01/28/2023]
Abstract
Neuropeptides are small regulatory molecules found throughout the body, most notably in the nervous, cardiovascular, and gastrointestinal systems. They serve as neurotransmitters or hormones in the regulation of diverse physiological processes. Cancer cells escape normal growth control mechanisms by altering their expression of growth factors, receptors, or intracellular signals, and neuropeptides have recently been recognized as mitogens in cancer growth and development. Many neuropeptides and their receptors exist in multiple subtypes, coupling with different downstream signaling pathways and playing distinct roles in cancer progression. The consideration of neuropeptide/receptor systems as anticancer targets is already leading to new biological and diagnostic knowledge that has the potential to enhance the understanding and treatment of cancer. In this review, recent discoveries regarding neuropeptides in a wide range of cancers, emphasizing their mechanisms of action, signaling cascades, regulation, and therapeutic potential, are discussed. Current technologies used to manipulate and analyze neuropeptides/receptors are described. Applications of neuropeptide analogs and their receptor inhibitors in translational studies and radio-oncology are rapidly increasing, and the possibility for their integration into therapeutic trials and clinical treatment appears promising.
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Affiliation(s)
- Yue Wu
- Cold Spring Harbor Laboratory, One Bungtown Rd, Cold Spring Harbor, NY, 11724, USA
| | - Adrian Berisha
- Cold Spring Harbor Laboratory, One Bungtown Rd, Cold Spring Harbor, NY, 11724, USA
| | - Jeremy C Borniger
- Cold Spring Harbor Laboratory, One Bungtown Rd, Cold Spring Harbor, NY, 11724, USA
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Fehér J, Élő Á, István L, Nagy ZZ, Radák Z, Scuderi G, Artico M, Kovács I. Microbiota mitochondria disorders as hubs for early age-related macular degeneration. GeroScience 2022; 44:2623-2653. [PMID: 35978068 PMCID: PMC9385247 DOI: 10.1007/s11357-022-00620-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 07/01/2022] [Indexed: 01/07/2023] Open
Abstract
Age-related macular degeneration (AMD) is a progressive neurodegenerative disease affecting the central area (macula lutea) of the retina. Research on the pathogenic mechanism of AMD showed complex cellular contribution governed by such risk factors as aging, genetic predisposition, diet, and lifestyle. Recent studies suggested that microbiota is a transducer and a modifier of risk factors for neurodegenerative diseases, and mitochondria may be one of the intracellular targets of microbial signaling molecules. This review explores studies supporting a new concept on the contribution of microbiota-mitochondria disorders to AMD. We discuss metabolic, vascular, immune, and neuronal mechanism in AMD as well as key alterations of photoreceptor cells, retinal pigment epithelium (RPE), Bruch's membrane, choriocapillaris endothelial, immune, and neuronal cells. Special attention was paid to alterations of mitochondria contact sites (MCSs), an organelle network of mitochondria, endoplasmic reticulum, lipid droplets (LDs), and peroxisomes being documented based on our own electron microscopic findings from surgically removed human eyes. Morphometry of Bruch's membrane lipids and proteoglycans has also been performed in early AMD and aged controls. Microbial metabolites (short-chain fatty acids, polyphenols, and secondary bile acids) and microbial compounds (lipopolysaccharide, peptidoglycan, and bacterial DNA)-now called postbiotics-in addition to local effects on resident microbiota and mucous membrane, regulate systemic metabolic, vascular, immune, and neuronal mechanisms in normal conditions and in various common diseases. We also discuss their antioxidant, anti-inflammatory, and metabolic effects as well as experimental and clinical observations on regulating the main processes of photoreceptor renewal, mitophagy, and autophagy in early AMD. These findings support an emerging concept that microbiota-mitochondria disorders may be a crucial pathogenic mechanism of early AMD; and similarly, to other age-related neurodegenerative diseases, new treatment approaches should be targeted at these disorders.
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Affiliation(s)
- János Fehér
- PRIMAVERA Program, Nutripharma Hungaria Ltd., Budapest, Hungary
| | - Ágnes Élő
- grid.11804.3c0000 0001 0942 9821Department of Ophthalmology, Semmelweis University, Budapest, Hungary
| | - Lilla István
- grid.11804.3c0000 0001 0942 9821Department of Ophthalmology, Semmelweis University, Budapest, Hungary
| | - Zoltán Zsolt Nagy
- grid.11804.3c0000 0001 0942 9821Department of Ophthalmology, Semmelweis University, Budapest, Hungary
| | - Zsolt Radák
- grid.472475.70000 0000 9243 1481Research Institute of Sport Science, University of Physical Education, Budapest, Hungary
| | - Gianluca Scuderi
- grid.7841.aOphthalmology Unit, NESMOS Department, Sant’Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy
| | - Marco Artico
- grid.417007.5Department of Sensory Organs, “Sapienza” University of Rome, Roma, Italy
| | - Illés Kovács
- grid.11804.3c0000 0001 0942 9821Department of Ophthalmology, Semmelweis University, Budapest, Hungary ,grid.5386.8000000041936877XDepartment of Ophthalmology, Weill Cornell Medical College, New York City, NY USA
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Zhu Y, Duan S, Wang M, Deng Z, Li J. Neuroimmune Interaction: A Widespread Mutual Regulation and the Weapons for Barrier Organs. Front Cell Dev Biol 2022; 10:906755. [PMID: 35646918 PMCID: PMC9130600 DOI: 10.3389/fcell.2022.906755] [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: 03/29/2022] [Accepted: 04/26/2022] [Indexed: 12/12/2022] Open
Abstract
Since the embryo, the nervous system and immune system have been interacting to regulate each other’s development and working together to resist harmful stimuli. However, oversensitive neural response and uncontrolled immune attack are major causes of various diseases, especially in barrier organs, while neural-immune interaction makes it worse. As the first defense line, the barrier organs give a guarantee to maintain homeostasis in external environment. And the dense nerve innervation and abundant immune cell population in barrier organs facilitate the neuroimmune interaction, which is the physiological basis of multiple neuroimmune-related diseases. Neuroimmune-related diseases often have complex mechanisms and require a combination of drugs, posing challenges in finding etiology and treatment. Therefore, it is of great significance to illustrate the specific mechanism and exact way of neuro-immune interaction. In this review, we first described the mutual regulation of the two principal systems and then focused on neuro-immune interaction in the barrier organs, including intestinal tract, lungs and skin, to clarify the mechanisms and provide ideas for clinical etiology exploration and treatment.
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Affiliation(s)
- Yan Zhu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
| | - Shixin Duan
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
| | - Mei Wang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
| | - Zhili Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Zhili Deng, ; Ji Li,
| | - Ji Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Zhili Deng, ; Ji Li,
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Erin N, Shurin GV, Baraldi JH, Shurin MR. Regulation of Carcinogenesis by Sensory Neurons and Neuromediators. Cancers (Basel) 2022; 14:2333. [PMID: 35565462 PMCID: PMC9102554 DOI: 10.3390/cancers14092333] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/26/2022] [Accepted: 05/05/2022] [Indexed: 12/12/2022] Open
Abstract
Interactions between the immune system and the nervous system are crucial in maintaining homeostasis, and disturbances of these neuro-immune interactions may participate in carcinogenesis and metastasis. Nerve endings have been identified within solid tumors in humans and experimental animals. Although the involvement of the efferent sympathetic and parasympathetic innervation in carcinogenesis has been extensively investigated, the role of the afferent sensory neurons and the neuropeptides in tumor development, growth, and progression is recently appreciated. Similarly, current findings point to the significant role of Schwann cells as part of neuro-immune interactions. Hence, in this review, we mainly focus on local and systemic effects of sensory nerve activity as well as Schwann cells in carcinogenesis and metastasis. Specific denervation of vagal sensory nerve fibers, or vagotomy, in animal models, has been reported to markedly increase lung metastases of breast carcinoma as well as pancreatic and gastric tumor growth, with the formation of liver metastases demonstrating the protective role of vagal sensory fibers against cancer. Clinical studies have revealed that patients with gastric ulcers who have undergone a vagotomy have a greater risk of stomach, colorectal, biliary tract, and lung cancers. Protective effects of vagal activity have also been documented by epidemiological studies demonstrating that high vagal activity predicts longer survival rates in patients with colon, non-small cell lung, prostate, and breast cancers. However, several studies have reported that inhibition of sensory neuronal activity reduces the development of solid tumors, including prostate, gastric, pancreatic, head and neck, cervical, ovarian, and skin cancers. These contradictory findings are likely to be due to the post-nerve injury-induced activation of systemic sensory fibers, the level of aggressiveness of the tumor model used, and the local heterogeneity of sensory fibers. As the aggressiveness of the tumor model and the level of the inflammatory response increase, the protective role of sensory nerve fibers is apparent and might be mostly due to systemic alterations in the neuro-immune response. Hence, more insights into inductive and permissive mechanisms, such as systemic, cellular neuro-immunological mechanisms of carcinogenesis and metastasis formation, are needed to understand the role of sensory neurons in tumor growth and spread.
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Affiliation(s)
- Nuray Erin
- Department of Medical Pharmacology, Immunopharmacology, and Immuno-Oncology Unit, School of Medicine, Akdeniz University, 07070 Antalya, Turkey
| | - Galina V. Shurin
- Department of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA; (G.V.S.); (M.R.S.)
| | - James H. Baraldi
- Department of Neuroscience, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA;
| | - Michael R. Shurin
- Department of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA; (G.V.S.); (M.R.S.)
- Department of Immunology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA
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Martin-Martin I, Valenzuela Leon PC, Amo L, Shrivastava G, Iniguez E, Aryan A, Brooks S, Kojin BB, Williams AE, Bolland S, Ackerman H, Adelman ZN, Calvo E. Aedes aegypti sialokinin facilitates mosquito blood feeding and modulates host immunity and vascular biology. Cell Rep 2022; 39:110648. [PMID: 35417706 PMCID: PMC9082008 DOI: 10.1016/j.celrep.2022.110648] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/01/2022] [Accepted: 03/17/2022] [Indexed: 11/28/2022] Open
Abstract
Saliva from mosquitoes contains vasodilators that antagonize vasoconstrictors produced at the bite site. Sialokinin is a vasodilator present in the saliva of Aedes aegypti. Here, we investigate its function and describe its mechanism of action during blood feeding. Sialokinin induces nitric oxide release similar to substance P. Sialokinin-KO mosquitoes produce lower blood perfusion than parental mosquitoes at the bite site during probing and have significantly longer probing times, which result in lower blood feeding success. In contrast, there is no difference in feeding between KO and parental mosquitoes when using artificial membrane feeders or mice that are treated with a substance P receptor antagonist, confirming that sialokinin interferes with host hemostasis via NK1R signaling. While sialokinin-KO saliva does not affect virus infection in vitro, it stimulates macrophages and inhibits leukocyte recruitment in vivo. This work highlights the biological functionality of salivary proteins in blood feeding.
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Affiliation(s)
- Ines Martin-Martin
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
| | - Paola Carolina Valenzuela Leon
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Laura Amo
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Gaurav Shrivastava
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Eva Iniguez
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Azadeh Aryan
- Department of Entomology and Fralin Life Science Institute, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA
| | - Steven Brooks
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Bianca B Kojin
- Department of Entomology, Texas A&M University, College Station, TX 77843, USA
| | - Adeline E Williams
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA; Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins 80523, CO, USA
| | - Silvia Bolland
- Department of Entomology and Fralin Life Science Institute, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA
| | - Hans Ackerman
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Zach N Adelman
- Department of Entomology and Fralin Life Science Institute, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA; Department of Entomology, Texas A&M University, College Station, TX 77843, USA
| | - Eric Calvo
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
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Li Q, Jiang B, Zhang Z, Huang Y, Xu Z, Chen X, Huang Y, Jian J. SP protects Nile tilapia (Oreochromis niloticus) against acute Streptococcus agalatiae infection. FISH & SHELLFISH IMMUNOLOGY 2022; 123:218-228. [PMID: 35257891 DOI: 10.1016/j.fsi.2022.03.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/16/2022] [Accepted: 03/03/2022] [Indexed: 06/14/2023]
Abstract
Substance P (SP) is a neuropeptide that involves in a wide variety of physiological and pathological events, mainly exerts its roles by neurokinin 1 receptor (NK1R), also modulates immune function. However, the roles of SP during immune response to acute bacterial infection of Nile tilapia (Oreochromis niloticus) remain unclear. In this study, the gene of SP precursor (tachykinin precursor 1, TAC1) and the gene of SP receptor (NK1R) from Nile tilapia were identified, and the roles of SP during an acute bacterial infection in a warm water environment were investigated. On-TAC1(Oreochromis niloticus-TAC1) contains conservative SP & NKA peptide sequences and On-NK1R contains seven conservative transmembrane domains. Their transcriptional levels were most abundant in brain and the On-TAC1 transcripts can be induced in the tilapia challenged with Streptococcus agalactiae. Furthermore, the experimental results revealed that On-SP could promote pyroptosis, suppress inflammation, and improve survival rate during acute bacterial infection. The present data lays a theoretical foundation to further elucidate the mechanism of SP protecting fish against pathogens.
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Affiliation(s)
- Qi Li
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China
| | - Baijian Jiang
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China
| | - Zhiqiang Zhang
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China
| | - Yongxiong Huang
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China
| | - Zhou Xu
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China
| | - Xinjin Chen
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China
| | - Yu Huang
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; Guangdong Provincial Engineering Research Center for Aquatic Animal Health Assessment, Shenzhen, China.
| | - Jichang Jian
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; Guangdong Provincial Engineering Research Center for Aquatic Animal Health Assessment, Shenzhen, China
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Tao R, Qu Z, Zhang K, Chen J, Wang X, Deng Y. Substance P modulates BMSCs migration for tissue repair through NK-1R/CXCR4/p-Akt signal activation. Mol Biol Rep 2022; 49:2227-2236. [PMID: 35034285 DOI: 10.1007/s11033-021-07044-y] [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: 09/02/2021] [Accepted: 12/02/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND The migration of bone marrow-derived mesenchymal stem cells (BMSCs) to the wound site played an important role in tissue repair. Substance P (SP) has been studied and reported to be involved in tissue repair by promoting the growth of endothelial cells and the migration of BMSCs. However, the complicated process and the molecular mechanisms were not fully understood. Thus, we aimed to investigate the effect of SP-induced BMSCs migration on tissue repair and its possible mechanism. METHODS AND RESULTS Western blot and q-PCR assay revealed that SP could induce the BMSCs migration through overexpression of CXCR4 and upregulation of Akt phosphorylation. And the upregulation was related to the activation of neurokinin-1 receptor (NK-1R). Besides, we found that the increased phosphorylation Akt caused by SP could be canceled by the inhibition of CXCR4 both in vitro and in vivo. Furthermore, a skin-injury animal model was established and used to observe the tissue repair process. Results showed that SP could accelerate wound closure, gain more granulation tissue accumulation, and more collagen deposition through the promotion of angiogenesis and induction of the BMSCs migration to the wound site. And these effects could be impaired by inhibition of CXCR4 and p-Akt. CONCLUSIONS Our results suggested that SP promoted tissue repair through BMSCs migration via upregulation of CXCR4 and p-Akt. The expression of CXCR4 and p-Akt were regulated by NK-1R activation. These findings add more evidence in understanding the mechanisms of SP-induced BMSCs migration and highlight the potential for clinical implementation of SP in tissue repair.
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Affiliation(s)
- Ran Tao
- Day Surgery Center, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, People's Republic of China
| | - Zhan Qu
- Department of Essential Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, People's Republic of China
| | - Ke Zhang
- Day Surgery Center, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, People's Republic of China
| | - Jie Chen
- Day Surgery Center, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, People's Republic of China
| | - Xinyu Wang
- Department of Gastrointestinal Surgery, The First Hospital of Changsha, Changsha, 410008, Hunan Province, People's Republic of China
| | - Youming Deng
- Department of Essential Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, People's Republic of China.
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40
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Hong JY, Kim SH, Seo Y, Jeon J, Davaa G, Hyun JK, Kim SH. Self-assembling peptide gels promote angiogenesis and functional recovery after spinal cord injury in rats. J Tissue Eng 2022; 13:20417314221086491. [PMID: 35340425 PMCID: PMC8943448 DOI: 10.1177/20417314221086491] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 02/23/2022] [Indexed: 12/30/2022] Open
Abstract
Spinal cord injury (SCI) leads to disruption of the blood–spinal cord barrier,
hemorrhage, and tissue edema, which impair blood circulation and induce
ischemia. Angiogenesis after SCI is an important step in the repair of damaged
tissues, and the extent of angiogenesis strongly correlates with the neural
regeneration. Various biomaterials have been developed to promote angiogenesis
signaling pathways, and angiogenic self-assembling peptides are useful for
producing diverse supramolecular structures with tunable functionality. RADA16
(Ac-RARADADARARADADA-NH2), which forms nanofiber networks under physiological
conditions, is a self-assembling peptide that can provide mechanical support for
tissue regeneration and reportedly has diverse roles in wound healing. In this
study, we applied an injectable form of RADA16 with or without the neuropeptide
substance P to the contused spinal cords of rats and examined angiogenesis
within the damaged spinal cord and subsequent functional improvement.
Histological and immunohistochemical analyses revealed that the inflammatory
cell population in the lesion cavity was decreased, the vessel number and
density around the damaged spinal cord were increased, and the levels of
neurofilaments within the lesion cavity were increased in SCI rats that received
RADA16 and RADA16 with substance P (rats in the RADA16/SP group). Moreover,
real-time PCR analysis of damaged spinal cord tissues showed that IL-10
expression was increased and that locomotor function (as assessed by the Basso,
Beattie, and Bresnahan (BBB) scale and the horizontal ladder test) was
significantly improved in the RADA16/SP group compared to the control group. Our
findings indicate that RADA16 modified with substance P effectively stimulates
angiogenesis within the damaged spinal cord and is a candidate agent for
promoting functional recovery post-SCI.
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Affiliation(s)
- Jin Young Hong
- Department of Nanobiomedical Science
and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University,
Cheonan, Republic of Korea
- Institute of Tissue Regeneration
Engineering, Dankook University, Cheonan, Republic of Korea
| | - Su Hee Kim
- Center for Biomaterials, Biomedical
Research Institute, Korea Institute of Science and Technology, Seoul, Republic of
Korea
- Medifab Ltd., Seoul, Republic of
Korea
| | - Yoojin Seo
- Center for Biomaterials, Biomedical
Research Institute, Korea Institute of Science and Technology, Seoul, Republic of
Korea
| | - Jooik Jeon
- Department of Nanobiomedical Science
and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University,
Cheonan, Republic of Korea
- Institute of Tissue Regeneration
Engineering, Dankook University, Cheonan, Republic of Korea
| | - Ganchimeg Davaa
- Department of Nanobiomedical Science
and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University,
Cheonan, Republic of Korea
- Institute of Tissue Regeneration
Engineering, Dankook University, Cheonan, Republic of Korea
| | - Jung Keun Hyun
- Department of Nanobiomedical Science
and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University,
Cheonan, Republic of Korea
- Institute of Tissue Regeneration
Engineering, Dankook University, Cheonan, Republic of Korea
- Department of Rehabilitation Medicine,
College of Medicine, Dankook University, Cheonan, Republic of Korea
- Jung Keun Hyun, Department of
Rehabilitation Medicine, College of Medicine, Dankook University, 119 Dandae-ro,
Anseo-dong, Dongnam-gu, Cheonan 31116, Republic of Korea.
| | - Soo Hyun Kim
- Center for Biomaterials, Biomedical
Research Institute, Korea Institute of Science and Technology, Seoul, Republic of
Korea
- Korea Institute of Science and
Technology Europe, Saarbrücken, Germany
- NBIT, KU-KIST Graduate School of
Converging Science and Technology, Korea University, Seoul, Republic of Korea
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41
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Yu Q, Liao M, Sun C, Zhang Q, Deng W, Cao X, Wang Q, Omari-Siaw E, Bi S, Zhang Z, Yu J, Xu X. LBO-EMSC Hydrogel Serves a Dual Function in Spinal Cord Injury Restoration via the PI3K-Akt-mTOR Pathway. ACS APPLIED MATERIALS & INTERFACES 2021; 13:48365-48377. [PMID: 34633177 DOI: 10.1021/acsami.1c12013] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
It is critical to obtain an anti-inflammatory microenvironment when curing spinal cord injury (SCI). On the basis of this, we prepared Lycium barbarum oligosaccharide (LBO)-nasal mucosa-derived mesenchymal stem cells (EMSCs) fibronectin hydrogel for SCI restoration via inflammatory license effect and M2 polarization of microglias. LBO exhibited remarkable M2 polarization potential for microglia. However, EMSCs primed by LBO generated enhanced paracrine effects through the inflammatory license-like process. The observed dual function is likely based on the TNFR2 pathway. In addition, LBO-EMSC hydrogel possesses a synergistic effect on M2 polarization of microglia through the PI3K-Akt-mTOR signaling pathway. The obtained findings provide a simple approach for MSC-based therapies for SCI and shed more light on the role of TNFR2 on bidirectional regulation in tissue regeneration.
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Affiliation(s)
| | | | | | | | | | - Xia Cao
- Jiangsu University, 212013 Zhenjiang, China
| | | | | | - Shiqi Bi
- Affiliated Hospital of Jiangsu University, 212001 Zhenjiang, China
| | | | | | - Ximing Xu
- Jiangsu University, 212013 Zhenjiang, China
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Widiapradja A, Kasparian AO, McCaffrey SL, Kolb LL, Imig JD, Lacey JL, Melendez GC, Levick SP. Replacement of Lost Substance P Reduces Fibrosis in the Diabetic Heart by Preventing Adverse Fibroblast and Macrophage Phenotype Changes. Cells 2021; 10:2659. [PMID: 34685639 PMCID: PMC8534147 DOI: 10.3390/cells10102659] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/27/2021] [Accepted: 09/29/2021] [Indexed: 01/05/2023] Open
Abstract
Reduced levels of the sensory nerve neuropeptide substance P (SP) have been reported in the diabetic rat heart, the consequence being a loss of cardioprotection in response to ischemic post-conditioning. We considered whether this loss of SP also predisposes the heart to non-ischemic diabetic cardiomyopathy in the form of fibrosis and hypertrophy. We report that diabetic Leprdb/db mice have reduced serum SP and that administration of exogenous replacement SP ameliorated cardiac fibrosis. Cardiac hypertrophy did not occur in Leprdb/db mice. Cardiac fibroblasts exposed to high glucose converted to a myofibroblast phenotype and produced excess extracellular matrix proteins; this was prevented by the presence of SP in the culture media. Cardiac fibroblasts exposed to high glucose produced increased amounts of the receptor for advanced glycation end products, reactive oxygen species and inflammatory cytokines, all of which were prevented by SP. Cultured macrophages assumed an M1 pro-inflammatory phenotype in response to high glucose as indicated by increased TNF-α, CCL2, and IL-6. SP promoted a shift to the reparative M2 macrophage phenotype characterized by arginase-1 and IL-10. Leprdb/db mice showed increased left ventricular M1 phenotype macrophages and an increase in the M1/M2 ratio. Replacement SP in Leprdb/db mice restored a favorable M1 to M2 balance. Together these findings indicate that a loss of SP predisposes the diabetic heart to developing fibrosis. The anti-fibrotic actions of replacement SP involve direct effects on cardiac fibroblasts and macrophages to oppose adverse phenotype changes. This study identifies the potential of replacement SP to treat diabetic cardiomyopathy.
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Affiliation(s)
- Alexander Widiapradja
- Kolling Institute, St Leonards, NSW 2065, Australia; (A.W.); (A.O.K.); (S.L.M.)
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia
| | - Ainsley O. Kasparian
- Kolling Institute, St Leonards, NSW 2065, Australia; (A.W.); (A.O.K.); (S.L.M.)
- School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Samuel L. McCaffrey
- Kolling Institute, St Leonards, NSW 2065, Australia; (A.W.); (A.O.K.); (S.L.M.)
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia
| | - Lauren L. Kolb
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (L.L.K.); (J.D.I.)
| | - John D. Imig
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (L.L.K.); (J.D.I.)
| | - Jessica L. Lacey
- Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (J.L.L.); (G.C.M.)
- Section on Comparative Medicine, Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Giselle C. Melendez
- Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (J.L.L.); (G.C.M.)
- Section on Comparative Medicine, Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Scott P. Levick
- Kolling Institute, St Leonards, NSW 2065, Australia; (A.W.); (A.O.K.); (S.L.M.)
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia
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43
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Hwang DDJ, Lee SJ, Kim JH, Lee SM. The Role of Neuropeptides in Pathogenesis of Dry Dye. J Clin Med 2021; 10:4248. [PMID: 34575359 PMCID: PMC8471988 DOI: 10.3390/jcm10184248] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/07/2021] [Accepted: 09/14/2021] [Indexed: 12/29/2022] Open
Abstract
Neuropeptides are known as important mediators between the nervous and immune systems. Recently, the role of the corneal nerve in the pathogenesis of various ocular surface diseases, including dry eye disease, has been highlighted. Neuropeptides are thought to be important factors in the pathogenesis of dry eye disease, as suggested by the well-known role between the nervous and immune systems, and several recently published studies have elucidated the previously unknown pathogenic mechanisms involved in the role of the neuropeptides secreted from the corneal nerves in dry eye disease. Here, we reviewed the emerging concept of neurogenic inflammation as one of the pathogenic mechanisms of dry eye disease, the recent results of related studies, and the direction of future research.
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Affiliation(s)
- Daniel Duck-Jin Hwang
- Department of Ophthalmology, HanGil Eye Hospital, Incheon 21388, Korea;
- Department of Ophthalmology, College of Medicine, Catholic Kwandong University, Incheon 21388, Korea
| | - Seok-Jae Lee
- Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul 03080, Korea; (S.-J.L.); (J.-H.K.)
- Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea
| | - Jeong-Hun Kim
- Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul 03080, Korea; (S.-J.L.); (J.-H.K.)
- Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea
- Department of Ophthalmology, College of Medicine, Seoul National University, Seoul 03080, Korea
- Advanced Biomedical Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon 34141, Korea
| | - Sang-Mok Lee
- Department of Ophthalmology, HanGil Eye Hospital, Incheon 21388, Korea;
- Department of Ophthalmology, College of Medicine, Catholic Kwandong University, Incheon 21388, Korea
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Stanojević S, Blagojević V, Ćuruvija I, Vujić V. Lactobacillus rhamnosus Affects Rat Peritoneal Cavity Cell Response to Stimulation with Gut Microbiota: Focus on the Host Innate Immunity. Inflammation 2021; 44:2429-2447. [PMID: 34505975 DOI: 10.1007/s10753-021-01513-z] [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: 04/18/2021] [Accepted: 07/05/2021] [Indexed: 12/01/2022]
Abstract
Gut microbiota contribute to shaping the immune repertoire of the host, whereas probiotics may exert beneficial effects by modulating immune responses. Having in mind the differences in both the composition of gut microbiota and the immune response between rats of Albino Oxford (AO) and Dark Agouti (DA) rat strains, we investigated if intraperitoneal (i.p.) injection of live Lactobacillus rhamnosus (LB) may influence peritoneal cavity cell response to in vitro treatments with selected microbiota in the rat strain-dependent manner. Peritoneal cavity cells from AO and DA rats were lavaged two (d2) and seven days (d7) following i.p. injection with LB and tested for NO, urea, and H2O2 release basally, or upon in vitro stimulation with autologous E.coli and Enterococcus spp. Whereas the single i.p. injection of LB nearly depleted resident macrophages and increased the proportion of small inflammatory macrophages and monocytes on d2 in both rat strains, greater proportion of MHCIIhiCD163- and CCR7+ cells and increased NO/diminished H2O2 release in DA compared with AO rats suggest a more intense inflammatory priming by LB in this rat strain. Even though E.coli- and/or Enterococcus spp.-induced rise in H2O2 release in vitro was abrogated by LB in cells from both rat strains, LB prevented microbiota-induced increase in NO/urea ratio only in cells from AO and augmented it in cells from DA rats. Thus, the immunomodulatory properties may not be constant for particular probiotic bacteria, but shaped by innate immunity of the host.
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Affiliation(s)
- Stanislava Stanojević
- Immunology Research Centre "Branislav Janković, Institute of Virology, Vaccines and Sera "Torlak, Belgrade, Serbia. .,Immunology Research Centre "Branislav Janković, Institute of Virology, Vaccines and Sera "Torlak, Belgrade, Serbia.
| | - Veljko Blagojević
- Immunology Research Centre "Branislav Janković, Institute of Virology, Vaccines and Sera "Torlak, Belgrade, Serbia
| | - Ivana Ćuruvija
- Immunology Research Centre "Branislav Janković, Institute of Virology, Vaccines and Sera "Torlak, Belgrade, Serbia
| | - Vesna Vujić
- Department of Chemistry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
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Kim DY, Piao J, Park JS, Lee D, Hong HS. Substance P ameliorates TNF-α-mediated impairment of human aortic vascular cells in vitro. Clin Exp Pharmacol Physiol 2021; 48:1288-1297. [PMID: 34060109 DOI: 10.1111/1440-1681.13533] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/24/2021] [Accepted: 05/28/2021] [Indexed: 11/26/2022]
Abstract
Vascular diseases are caused by endothelial dysfunction due to inflammation. On endothelial injury, the expression of extracellular matrix (ECM) is enhanced and nitric oxide (NO) bioavailability becomes deficient. This condition affects endothelial metabolism and leads to vascular destruction. The aim of this investigation was to determine whether substance P (SP) is able to protect the endothelium against inflammatory stress. To this end, aortic endothelial cells were pre-treated with SP, followed by tumour necrosis factor α (TNF-α), and cellular responses were evaluated using a combination of cell biology and quantification assays, as well as western blot analyses. Our results show that TNF-α enhanced ECM expression and reduced NO production within 4 hours, promoting immune cell adhesion to the endothelium and monocyte chemoattractant protein-1 (MCP-1) secretion from aortic smooth muscle cells. However, SP treatment ameliorated TNF-α-induced endothelial impairment by maintaining low ECM levels. Our data suggest that this protective effect is mediated by Akt activation and NO-enriched conditions. The inhibition of aortic endothelial cell injury by SP also reduced MCP-1 production in aortic smooth muscle cells. Together, our data indicate that SP can protect aortic endothelial and smooth muscle cells from inflammatory injury, which suggests that SP may prevent cardiovascular disease.
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Affiliation(s)
- Do Young Kim
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, South Korea
| | - Jiyuan Piao
- Department of Genetic Engineering, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Seoul, South Korea
| | - Jeong Seop Park
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, South Korea
| | - Dahyeon Lee
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, South Korea
| | - Hyun Sook Hong
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, South Korea
- East-West Medical Research Institute, Kyung Hee University, Seoul, South Korea
- Kyung Hee Institute of Regenerative Medicine (KIRM), Medical Science Research institute, Kyung Hee University Medical Center, Seoul, South Korea
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46
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Kim S, Son Y. Astrocytes Stimulate Microglial Proliferation and M2 Polarization In Vitro through Crosstalk between Astrocytes and Microglia. Int J Mol Sci 2021; 22:ijms22168800. [PMID: 34445510 PMCID: PMC8396240 DOI: 10.3390/ijms22168800] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/05/2021] [Accepted: 08/11/2021] [Indexed: 12/15/2022] Open
Abstract
Microglia are resident immune cells of the central nervous system that act as brain-specific macrophages and are also known to regulate the innate immune functions of astrocytes through secretory molecules. This communication plays an important role in brain functions and homeostasis as well as in neuropathologic disease. In this study, we aimed to elucidate whether astrocytes and microglia could crosstalk to induce microglial polarization and proliferation, which can be further regulated under a microenvironment mimicking that of brain stroke. Microglia in a mixed glial culture showed increased survival and proliferation and were altered to M2 microglia; CD11b−GFAP+ astrocytes resulted in an approximately tenfold increase in microglial cell proliferation after the reconstitution of astrocytes. Furthermore, GM-CSF stimulated microglial proliferation approximately tenfold and induced them to become CCR7+ M1 microglia, which have a phenotype that could be suppressed by anti-inflammatory cytokines such as IL-4, IL-10, and substance P. In addition, the astrocytes in the microglial co-culture showed an A2 phenotype; they could be activated to A1 astrocytes by TNF-α and IFN-γ under the stroke-mimicking condition. Altogether, astrocytes in the mixed glial culture stimulated the proliferation of the microglia and M2 polarization, possibly through the acquisition of the A2 phenotype; both could be converted to M1 microglia and A1 astrocytes under the inflammatory stroke-mimicking environment. This study demonstrated that microglia and astrocytes could be polarized to M2 microglia and A2 astrocytes, respectively, through crosstalk in vitro and provides a system with which to explore how microglia and astrocytes may behave in the inflammatory disease milieu after in vivo transplantation.
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Affiliation(s)
- Sumin Kim
- Department of Genetics and Biotechnology, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Yong In 17104, Korea;
| | - Youngsook Son
- Department of Genetics and Biotechnology, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Yong In 17104, Korea;
- Kyung Hee Institute of Regenerative Medicine (KIRM), KHU Medical Science Research Institute, Kyung Hee University Medical Center, Seoul 02447, Korea
- Correspondence: ; Tel.: +82-31-201-3822
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47
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Macrophage as a Peripheral Pain Regulator. Cells 2021; 10:cells10081881. [PMID: 34440650 PMCID: PMC8392675 DOI: 10.3390/cells10081881] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/22/2021] [Accepted: 07/22/2021] [Indexed: 12/30/2022] Open
Abstract
A neuroimmune crosstalk is involved in somatic and visceral pathological pain including inflammatory and neuropathic components. Apart from microglia essential for spinal and supraspinal pain processing, the interaction of bone marrow-derived infiltrating macrophages and/or tissue-resident macrophages with the primary afferent neurons regulates pain signals in the peripheral tissue. Recent studies have uncovered previously unknown characteristics of tissue-resident macrophages, such as their origins and association with regulation of pain signals. Peripheral nerve macrophages and intestinal resident macrophages, in addition to adult monocyte-derived infiltrating macrophages, secrete a variety of mediators, such as tumor necrosis factor-α, interleukin (IL)-1β, IL-6, high mobility group box 1 and bone morphogenic protein 2 (BMP2), that regulate the excitability of the primary afferents. Neuron-derived mediators including neuropeptides, ATP and macrophage-colony stimulating factor regulate the activity or polarization of diverse macrophages. Thus, macrophages have multitasks in homeostatic conditions and participate in somatic and visceral pathological pain by interacting with neurons.
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48
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Substance-P Inhibits Cardiac Microvascular Endothelial Dysfunction Caused by High Glucose-Induced Oxidative Stress. Antioxidants (Basel) 2021; 10:antiox10071084. [PMID: 34356317 PMCID: PMC8301094 DOI: 10.3390/antiox10071084] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 06/25/2021] [Accepted: 07/01/2021] [Indexed: 12/13/2022] Open
Abstract
Diabetes is characterized by high glucose (HG) levels in the blood circulation, leading to exposure of the vascular endothelium to HG conditions. Hyperglycemia causes oxidative stress via excessive reactive oxygen species (ROS) production in the endothelium, which leads to cellular dysfunction and the development of diabetic vascular diseases. Substance-P (SP) is an endogenous peptide involved in cell proliferation and migration by activating survival-related signaling pathways. In this study, we evaluated the role of SP in cardiac microvascular endothelial cells (CMECs) in HG-induced oxidative stress. CMECs were treated with diverse concentrations of glucose, and then the optimal dose was determined. Treatment of CMECs with HG reduced their viability and induced excessive ROS secretion, inactivation of PI3/Akt signaling, and loss of vasculature-forming ability in vitro. Notably, HG treatment altered the cytokine profile of CMECs. However, SP treatment inhibited the HG-mediated aggravation of CMECs by restoring viability, free radical balance, and paracrine potential. SP-treated CMECs retained the capacity to form compact and long stretching-tube structures. Collectively, our data provide evidence that SP treatment can block endothelial dysfunction in hyperglycemia and suggest the possibility of using SP for treating diabetic complications as an antioxidant.
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49
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Li H, Li M, Liu P, Wang K, Fang H, Yin J, Zhu D, Yang Q, Gao J, Ke Q, Yu H, Guo Y, Gao Y, Zhang C. A multifunctional substance P-conjugated chitosan hydrochloride hydrogel accelerates full-thickness wound healing by enhancing synchronized vascularization, extracellular matrix deposition, and nerve regeneration. Biomater Sci 2021; 9:4199-4210. [PMID: 33989376 DOI: 10.1039/d1bm00357g] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Due to the native skin limitations and the complexity of reconstructive microsurgery, advanced biomaterials are urgently required to promote wound healing for severe skin defects caused by accidents and disasters. Accumulating evidence has supported that substance P (SP) has a potential effect on skin regeneration. However, SP application is seriously impeded by its poor stability and oxidative reactions occurring during production, transportation, and storage. An SP-conjugated chitosan hydrochloride hydrogel (CSCl-SP) fabricated in this study demonstrated an enhanced capacity to repair full-thickness skin defects. CSCl-SP provided a stable in vitro delivery system for SP. The dissolution of CSCl-SP promoted the proliferation, migration, and tube formation, as well as angiogenesis-related gene and protein expression in human umbilical vein endothelial cells. CSCI-SP also stimulated the proliferation, migration, and production of anabolic growth factor in human fibroblasts. Moreover, CSCl-SP significantly promoted the neurite outgrowth in Neuro-2A cells. In vivo, CSCl-SP dramatically strengthened the vascularization, extracellular matrix deposition and remodeling, and nerve regeneration, thereby promoting efficient recovery of the full-thickness skin defect. Thus, synchronized multifunction of the CSCl-SP hydrogel makes it a promising and smart material for intractable skin defects.
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Affiliation(s)
- Hao Li
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| | - Mengna Li
- The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, China.
| | - Pei Liu
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| | - Kaiyang Wang
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| | - Haoyu Fang
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| | - Junhui Yin
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Daoyu Zhu
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| | - Qianhao Yang
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| | - Junjie Gao
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. and Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Qinfei Ke
- The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, China.
| | - Hongping Yu
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. and The First Affiliated Hospital of Xiamen University, Xiamen 361005, China
| | - Yaping Guo
- The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, China.
| | - Youshui Gao
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| | - Changqing Zhang
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
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50
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Yang F, Cai H, Zhang X, Sun J, Feng X, Yuan H, Zhang X, Xiao B, Li Q. An active marine halophenol derivative attenuates lipopolysaccharide-induced acute liver injury in mice by improving M2 macrophage-mediated therapy. Int Immunopharmacol 2021; 96:107676. [PMID: 34023550 DOI: 10.1016/j.intimp.2021.107676] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/09/2021] [Accepted: 04/11/2021] [Indexed: 12/11/2022]
Abstract
2,4',5'-Trihydroxyl-5,2'-dibromo diphenylmethanone (LM49), an active halophenol derivative synthesized by our group, which exhibits a broad spectrum of therapeutic properties, such as antioxidant and anti-inflammatory activities. In this study, we found LM49 could obviously attenuate acute liver injury induced by lipopolysaccharide (LPS) in mice by polarizing macrophages. The protective effect was described by reducing the hepatic inflammation and improving hepatic function using aspartate transaminase (AST) and alanine transaminase (ALT) assay. Further study revealed that LM49 pretreatment induced the Kupffer cells (KCs) to M2 polarization and decreased the production of inflammatory cytokines. The action mechanism in RAW 264.7 macrophages showed that LM49 could induce the activation of JAK1/STAT6 signaling pathway and the inhibition of TLR-4/NF-kB axis. Morever, LM49 also upregulated the expression of SOCS1 and FLK-4, which can promote M2 polarization by cooperating with STAT6 and inhibit M1 formation by reducing JAK1/STAT1. Our results suggested that LM49 could protect against LPS-induced acute liver injury in mice via anti-inflammatory signaling pathways and subsequent induction of M2 Kupffer cells. The results provided the first experimental evidence of active halophenols for the anti-inflammatory therapy by targeting M2 macrophages.
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Affiliation(s)
- Fan Yang
- School of Pharmaceutical Science, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China
| | - HongHong Cai
- School of Pharmaceutical Science, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China
| | - Xuan Zhang
- Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030001, PR China
| | - Jian Sun
- Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation,Shanxi University of Chinese Medicine, Taiyuan 030619, PR China
| | - XiuE Feng
- School of Pharmaceutical Science, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China
| | - HongXia Yuan
- Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation,Shanxi University of Chinese Medicine, Taiyuan 030619, PR China
| | - XiaoYan Zhang
- School of Pharmaceutical Science, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China
| | - BaoGuo Xiao
- Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation,Shanxi University of Chinese Medicine, Taiyuan 030619, PR China
| | - QingShan Li
- School of Pharmaceutical Science, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation,Shanxi University of Chinese Medicine, Taiyuan 030619, PR China.
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