|
1
|
Guo J, Xu Y, Liu J, Hou X. The involvement of lidocaine in amyloid-β1-42-dependent mitochondrial dysfunction and apoptosis in hippocampal neurons via nerve growth factor-protein kinase B pathway. Neuroreport 2024; 35:1123-1132. [PMID: 39445521 DOI: 10.1097/wnr.0000000000002105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
This project is conceived to reveal the role of lidocaine in the process of Alzheimer's disease (AD) and its possible downstream targets. After the employment of AD cell model in mice hippocampal neuronal HT-22 cells in the presence of amyloid-β1-42 (Aβ1-42), Cell Counting Kit-8 method investigated cell viability. Oxidative damage was assayed based on a dichloro-dihydro-fluorescein diacetate fluorescent probe and commercially available kits. The 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide fluorescent probe estimated mitochondrial function. Terminal-deoxynucleotidyl transferase mediated nick end labeling, western blotting, and immunofluorescence appraised the apoptotic level. Western blot also ascertained the alternations of nerve growth factors (NGF)-protein kinase B (Akt) pathway-related proteins. Aβ1-42 concentration dependently triggered the viability loss, oxidative damage, and apoptosis in HT-22 cells. Lidocaine promoted the viability and reduced the mitochondrial impairment and mitochondria-dependent apoptosis in Aβ1-42-treated HT-22 cells in a concentration-dependent manner. Besides, lidocaine activated the NGF-Akt pathway and NGF absence blocked NGF-Akt pathway, aggravated mitochondrial dysfunction as well as mitochondria-dependent apoptosis in lidocaine-administrated HT-22 cells in response to Aβ1-42. Altogether, these observations concluded that lidocaine might stimulate NGF-Akt pathway to confer protection against mitochondrial impairment and apoptosis in Aβ1-42-mediated cellular model of AD.
Collapse
Affiliation(s)
- Jianlian Guo
- Department of Surgical Anesthesiology, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | | | | | | |
Collapse
|
|
2
|
Tan B, Chiranthanut N, Chansakaow S, Sireeratawong S, Khonsung P, Nimlamool W, Takuathung MN, Lertprasertsuke N. Gastroprotective effects of Pikad Tri-phol-sa-mut-than herbal remedy on multiple gastric ulcer models in rats. Heliyon 2023; 9:e19297. [PMID: 37654455 PMCID: PMC10466925 DOI: 10.1016/j.heliyon.2023.e19297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 08/05/2023] [Accepted: 08/17/2023] [Indexed: 09/02/2023] Open
Abstract
In Thai traditional medicine, Pikad Tri-phol-sa-mut-than has long been used to alleviate gastrointestinal symptoms, renal disease, inflammation-related disorders, and severe malady. This recipe is composed of dried fruits of Morinda citrifolia L., Coriandrum sativum L., and Aegle marmelos (L.) Corrêa. The aim of this study was to assess the anti-gastric ulcer property of the water extract of Pikad Tri-phol-sa-mut-than (TS), using various animal models with different inducers, including restraint water immersion stress, indomethacin, and ethanol/hydrochloric acid (EtOH/HCl). Its mechanisms of anti-gastric ulcer actions were also elucidated using both in vitro and in vivo experiments. When compared with the control groups, the oral pretreatment of TS at the doses of 150, 300 and 600 mg/kg significantly reduced the gastric ulcer formation in all models. It was also found that TS at the dose of 600 mg/kg could increase gastric wall mucus in rats but could not produce the significant reduction of the gastric volume or total acidity of gastric content. Results from hematoxylin and eosin (H&E) and Periodic acid-Schiff (PAS) staining examinations of gastric tissues confirmed that TS visibly reduced gastric mucosal damage, while immunohistochemistry revealed that TS remarkably suppressed the protein expression of Bcl-2-associated X (BAX), a regulator of apoptosis, compared to those of the control group. The DPPH, ABTS, and FRAP assays showed antioxidant effects of TS. All of these findings demonstrated that TS has gastroprotective effects, which may be related to the increase in the gastric wall mucus secretion, not anti-secretory activity, as well as its antioxidant and antiapoptotic activities.
Collapse
Affiliation(s)
- Bing Tan
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Graduate School, Chiang Mai University, Chiang Mai, 50200, Thailand
- Department of Pharmacy, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, China
| | - Natthakarn Chiranthanut
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Sunee Chansakaow
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Seewaboon Sireeratawong
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Parirat Khonsung
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Wutigri Nimlamool
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Mingkwan Na Takuathung
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nirush Lertprasertsuke
- Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| |
Collapse
|
|
3
|
Nuñez A, Zegarra-Valdivia J, Fernandez de Sevilla D, Pignatelli J, Torres Aleman I. The neurobiology of insulin-like growth factor I: From neuroprotection to modulation of brain states. Mol Psychiatry 2023; 28:3220-3230. [PMID: 37353586 DOI: 10.1038/s41380-023-02136-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 05/30/2023] [Accepted: 06/13/2023] [Indexed: 06/25/2023]
Abstract
After decades of research in the neurobiology of IGF-I, its role as a prototypical neurotrophic factor is undisputed. However, many of its actions in the adult brain indicate that this growth factor is not only involved in brain development or in the response to injury. Following a three-layer assessment of its role in the central nervous system, we consider that at the cellular level, IGF-I is indeed a bona fide neurotrophic factor, modulating along ontogeny the generation and function of all the major types of brain cells, contributing to sculpt brain architecture and adaptive responses to damage. At the circuit level, IGF-I modulates neuronal excitability and synaptic plasticity at multiple sites, whereas at the system level, IGF-I intervenes in energy allocation, proteostasis, circadian cycles, mood, and cognition. Local and peripheral sources of brain IGF-I input contribute to a spatially restricted, compartmentalized, and timed modulation of brain activity. To better define these variety of actions, we consider IGF-I a modulator of brain states. This definition aims to reconcile all aspects of IGF-I neurobiology, and may provide a new conceptual framework in the design of future research on the actions of this multitasking neuromodulator in the brain.
Collapse
Affiliation(s)
- A Nuñez
- Department of Anatomy, Histology and Neurosciences, Universidad Autónoma de Madrid, Madrid, Spain
| | - J Zegarra-Valdivia
- Achucarro Basque Center for Neuroscience, Leioa, Spain
- CIBERNED, Madrid, Spain
- Universidad Señor de Sipán, Chiclayo, Perú
| | - D Fernandez de Sevilla
- Department of Anatomy, Histology and Neurosciences, Universidad Autónoma de Madrid, Madrid, Spain
| | - J Pignatelli
- CIBERNED, Madrid, Spain
- Cajal Institute (CSIC), Madrid, Spain
| | - I Torres Aleman
- Achucarro Basque Center for Neuroscience, Leioa, Spain.
- CIBERNED, Madrid, Spain.
- Ikerbasque Science Foundation, Bilbao, Spain.
| |
Collapse
|
|
4
|
Single-cell transcriptome atlas of the human corpus cavernosum. Nat Commun 2022; 13:4302. [PMID: 35879305 PMCID: PMC9314400 DOI: 10.1038/s41467-022-31950-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 07/11/2022] [Indexed: 11/30/2022] Open
Abstract
The corpus cavernosum is the most important structure for penile erection, and its dysfunction causes many physiological and psychological problems. However, its cellular heterogeneity and signalling networks at the molecular level are poorly understood because of limited access to samples. Here, we profile 64,993 human cavernosal single-cell transcriptomes from three males with normal erection and five organic erectile dysfunction patients. Cell communication analysis reveals that cavernosal fibroblasts are central to the paracrine signalling network and regulate microenvironmental homeostasis. Combining with immunohistochemical staining, we reveal the cellular heterogeneity and describe a detailed spatial distribution map for each fibroblast, smooth muscle and endothelial subcluster in the corpus cavernosum. Furthermore, comparative analysis and related functional experiments identify candidate regulatory signalling pathways in the pathological process. Our study provides an insight into the human corpus cavernosum microenvironment and a reference for potential erectile dysfunction therapies. The corpus cavernosum is the most important structure for penile erection, and its dysfunction causes physiological and psychological problems. Here the authors perform single-cell RNA-sequencing on corpus cavernosum samples from males with normal erection and erectile dysfunction patients, providing insights into this pathology.
Collapse
|
|
5
|
Tarnawski AS, Ahluwalia A. Endothelial cells and blood vessels are major targets for COVID-19-induced tissue injury and spreading to various organs. World J Gastroenterol 2022; 28:275-289. [PMID: 35110950 PMCID: PMC8771611 DOI: 10.3748/wjg.v28.i3.275] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/02/2021] [Accepted: 01/11/2022] [Indexed: 02/06/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) infected so far over 250 million people and caused the death of over 5 million worldwide. Aging, diabetes, and cardiovascular diseases, conditions with preexisting impaired endothelial functions predispose to COVID-19. While respiratory epithelium is the main route of virus entry, the endothelial cells (ECs) lining pulmonary blood vessels are also an integral part of lung injury in COVID-19 patients. COVID-19 not only affects the lungs and respiratory system but also gastrointestinal (GI) tract, liver, pancreas, kidneys, heart, brain, and skin. Blood vessels are likely conduits for the virus dissemination to these distant organs. Importantly, ECs are also critical for vascular regeneration during injury/lesions healing and restoration of vascular network. The World Journal of Gastroenterology has published in last two years over 67 outstanding papers on COVID-19 infection with a focus on the GI tract, liver, pancreas, etc., however, the role of the endothelial and vascular components as major targets for COVID-19-induced tissue injury, spreading to various organs, and injury healing have not been sufficiently emphasized. In the present article, we focus on these subjects and on current treatments including the most recent oral drugs molnupiravir and paxlovid that show a dramatic, significant efficacy in controlling severe COVID-19 infection.
Collapse
Affiliation(s)
- Andrzej S Tarnawski
- Gastroenterology Research Department, University of California Irvine and the Veterans Administration Long Beach Healthcare System, Long Beach, CA 90822, United States
| | - Amrita Ahluwalia
- Research Service, Veterans Administration Long Beach Healthcare System, Long Beach, CA 90822, United States
| |
Collapse
|
|
6
|
Alastra G, Aloe L, Baldassarro VA, Calzà L, Cescatti M, Duskey JT, Focarete ML, Giacomini D, Giardino L, Giraldi V, Lorenzini L, Moretti M, Parmeggiani I, Sannia M, Tosi G. Nerve Growth Factor Biodelivery: A Limiting Step in Moving Toward Extensive Clinical Application? Front Neurosci 2021; 15:695592. [PMID: 34335170 PMCID: PMC8319677 DOI: 10.3389/fnins.2021.695592] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/21/2021] [Indexed: 12/11/2022] Open
Abstract
Nerve growth factor (NGF) was the first-discovered member of the neurotrophin family, a class of bioactive molecules which exerts powerful biological effects on the CNS and other peripheral tissues, not only during development, but also during adulthood. While these molecules have long been regarded as potential drugs to combat acute and chronic neurodegenerative processes, as evidenced by the extensive data on their neuroprotective properties, their clinical application has been hindered by their unexpected side effects, as well as by difficulties in defining appropriate dosing and administration strategies. This paper reviews aspects related to the endogenous production of NGF in healthy and pathological conditions, along with conventional and biomaterial-assisted delivery strategies, in an attempt to clarify the impediments to the clinical application of this powerful molecule.
Collapse
Affiliation(s)
- Giuseppe Alastra
- Interdepartmental Centre for Industrial Research in Health Sciences and Technologies, University of Bologna, Bologna, Italy
| | | | - Vito Antonio Baldassarro
- Interdepartmental Centre for Industrial Research in Health Sciences and Technologies, University of Bologna, Bologna, Italy
| | - Laura Calzà
- Interdepartmental Centre for Industrial Research in Health Sciences and Technologies, University of Bologna, Bologna, Italy
- IRET Foundation, Bologna, Italy
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | | | - Jason Thomas Duskey
- Nanotech Laboratory, TeFarTI Center, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Maria Letizia Focarete
- Interdepartmental Centre for Industrial Research in Health Sciences and Technologies, University of Bologna, Bologna, Italy
- Department of Chemistry “Giacomo Ciamician”, University of Bologna, Bologna, Italy
| | - Daria Giacomini
- Interdepartmental Centre for Industrial Research in Health Sciences and Technologies, University of Bologna, Bologna, Italy
- Department of Chemistry “Giacomo Ciamician”, University of Bologna, Bologna, Italy
| | - Luciana Giardino
- IRET Foundation, Bologna, Italy
- Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy
| | - Valentina Giraldi
- Interdepartmental Centre for Industrial Research in Health Sciences and Technologies, University of Bologna, Bologna, Italy
- Department of Chemistry “Giacomo Ciamician”, University of Bologna, Bologna, Italy
| | - Luca Lorenzini
- Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy
| | | | - Irene Parmeggiani
- Nanotech Laboratory, TeFarTI Center, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Michele Sannia
- Interdepartmental Centre for Industrial Research in Health Sciences and Technologies, University of Bologna, Bologna, Italy
| | - Giovanni Tosi
- Nanotech Laboratory, TeFarTI Center, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| |
Collapse
|
|
7
|
Li R, Xu J, Rao Z, Deng R, Xu Y, Qiu S, Long H, Zhu Q, Liu X, Bai Y, Quan D. Facilitate Angiogenesis and Neurogenesis by Growth Factors Integrated Decellularized Matrix Hydrogel. Tissue Eng Part A 2020; 27:771-787. [PMID: 33107410 DOI: 10.1089/ten.tea.2020.0227] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Neurological functional recovery depends on the synergistic interaction between angiogenesis and neurogenesis after peripheral nerve injury (PNI). Decellularized nerve matrix hydrogels have drawn much attention and been considered as potential therapeutic biomaterials for neurovascularization, due to their intrinsic advantages in construction of a growth-permissive microenvironment, strong affinity to multiple growth factors (GFs), and promotion of neurite outgrowth. In the present study, nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) were incorporated into porcine decellularized nerve matrix hydrogel (pDNM-gel) for PNI treatment. Both GFs bound strongly to pDNM-gel and underwent a controlled release manner, which showed facilitated axonal extension and vascular-like tube formation in vitro. Especially, a companion growth was identified when human umbilical vein endothelial cells and neurons were cocultured on the GFs containing pDNM-gel. In a crushed rat sciatic nerve model, the incorporated NGF and VEGF appeared to contribute for axonal growth and neovascularization correspondingly but separately. Both GFs were equally important in improving nerve functional recovery after in situ administration. These findings indicate that pDNM-gel is not only a bioactive hydrogel-based material that can be used alone, but also serves as suitable carrier of multiple GFs for promoting an effective PNI repair. Impact statement Decellularized matrix hydrogel derived from nerve tissue has demonstrated its effectiveness in promoting nerve reinnervation, remyelination, and functionalization. Meanwhile, angiogenesis is highly desirable for treatment of long-distance peripheral nerve defects. To this end, we incorporated both vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) into porcine decellularized nerve matrix hydrogel (pDNM-gel) to induce neovascularization and neuroregeneration. At the cellular level, the pDNM-gel with both growth factors (GFs) exhibited significant capability in promoting axonal elongation, Schwann cell proliferation and migration, as well as vessel/nerve interaction. In crushed peripheral nerve injury (PNI) rat model, the integrated VEGF was more favorable for angiogenesis, whereas NGF mainly contributed to neurogenesis. However, the combination of both GFs in pDNM-gel highly facilitated motor functional recovery, highlighting the therapeutic promise of decellularized matrix hydrogel for growth factor delivery toward neuroprotection and neuroregeneration after PNI.
Collapse
Affiliation(s)
- Rui Li
- PCFM Lab, GD HPPC Lab, School of Chemistry, Sun Yat-sen University, Guangzhou, China.,Guangdong Functional Biomaterials Engineering Technology Research Center, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, China
| | - Jinghui Xu
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zilong Rao
- PCFM Lab, GD HPPC Lab, School of Chemistry, Sun Yat-sen University, Guangzhou, China.,Guangdong Functional Biomaterials Engineering Technology Research Center, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, China
| | - Rongli Deng
- PCFM Lab, GD HPPC Lab, School of Chemistry, Sun Yat-sen University, Guangzhou, China
| | - Yiwei Xu
- PCFM Lab, GD HPPC Lab, School of Chemistry, Sun Yat-sen University, Guangzhou, China
| | - Shuai Qiu
- Guangdong Peripheral Nerve Tissue Engineering and Technology Research Center, Department of Orthopedic and Microsurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Houqing Long
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qingtang Zhu
- Guangdong Peripheral Nerve Tissue Engineering and Technology Research Center, Department of Orthopedic and Microsurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaolin Liu
- Guangdong Peripheral Nerve Tissue Engineering and Technology Research Center, Department of Orthopedic and Microsurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ying Bai
- Guangdong Functional Biomaterials Engineering Technology Research Center, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, China
| | - Daping Quan
- PCFM Lab, GD HPPC Lab, School of Chemistry, Sun Yat-sen University, Guangzhou, China.,Guangdong Functional Biomaterials Engineering Technology Research Center, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
8
|
Giuliani A, Lorenzini L, Baldassarro VA, Pannella M, Cescatti M, Fernandez M, Alastra G, Flagelli A, Villetti G, Imbimbo BP, Giardino L, Calzà L. Effects of Topical Application of CHF6467, a Mutated Form of Human Nerve Growth Factor, on Skin Wound Healing in Diabetic Mice. J Pharmacol Exp Ther 2020; 375:317-331. [PMID: 32948647 DOI: 10.1124/jpet.120.000110] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 08/26/2020] [Indexed: 12/16/2022] Open
Abstract
Nerve growth factor (NGF) is the protein responsible for the development and maintenance of sensory skin innervation. Given the role of appropriate innervation in skin healing, NGF has been indicated as a possible prohealing treatment in pathologic conditions characterized by nerve-ending loss, such as chronic ulcers in diabetes; however, its use as a therapeutic agent is limited by its hyperalgesic effect. We tested the effect of topical application of the nonalgogenic NGF derivative hNGFP61S/R100E in two models of skin ulcer induced in dbdb diabetic mice, investigating healing time, skin histology, reinnervation, and angiogenesis using morphologic and molecular approaches. We showed that the topical administration of CHF6467, a recombinant human NGF in which an amino acid substitution (R100E) abolished the hyperalgesic effect usually associated with NGF, accelerated skin repair in experimental wounds (full-excision and pressure-ulcer) induced in diabetic mice (dbdb). CHF6467-induced acceleration of wound healing was accompanied by increased re-epithelization, reinnervation, and revascularization as assessed by histology, immunohistochemistry, and image analysis. Bioinformatic analysis of differentially expressed genes and signaling pathways in the wound tissues showed that protein kinase B-mammalian target of rapamycin was the most regulated pathway. In spite of the transdermal absorption leading to measurable, dose-dependent increases in CHF6467 plasma levels, no systemic thermal or local mechanical hyperalgesia was observed in treated mice. When tested in vitro in human cell lines, CHF6467 stimulated keratinocyte and fibroblast proliferation and tube formation by endothelial cells. Collectively, these results support a possible use of CHF6467 as a prohealing agent in skin lesions in diabetes. SIGNIFICANCE STATEMENT: Topical application of CHF6467 accelerates reinnervation, neoangiogenesis, and wound healing in diabetic mice in both full-thickness skin-excision and pressure-ulcer models through the protein kinase B/mammalian target of rapamycin pathway and does not induce hyperalgesia.
Collapse
Affiliation(s)
- A Giuliani
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - L Lorenzini
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - V A Baldassarro
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - M Pannella
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - M Cescatti
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - M Fernandez
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - G Alastra
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - A Flagelli
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - G Villetti
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - B P Imbimbo
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - L Giardino
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| | - L Calzà
- Department of Veterinary Medical Science, University of Bologna, Italy (A.G., L.L., M.F., L.G.); Interdepartmental Center for Industrial Research in Life Sciences and Technologies University of Bologna, Italy (L.L., V.A.B., G.A., A.F, L.G., L.C.); Department of of Pharmacy and Biotechnology, University of Bologna, Italy (L.C.); Fondazione IRET, Ozzano Emilia, Italy (M.P., M.C.); Chiesi Farmaceutici, Parma, Italy (G.V., B.P.I.)
| |
Collapse
|
|
9
|
Hu Y, Xiong J, Wen H, Wei H, Zeng X. MiR-98-5p promotes ischemia/reperfusion-induced microvascular dysfunction by targeting NGF and is a potential biomarker for microvascular reperfusion. Microcirculation 2020; 28:e12657. [PMID: 32892409 DOI: 10.1111/micc.12657] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 08/18/2020] [Accepted: 08/26/2020] [Indexed: 12/29/2022]
Abstract
OBJECTIVE This study examined the correlation between serum miR-98-5p levels and indices of microvascular reperfusion in patients undergoing primary percutaneous coronary intervention (pPCI) after ST-segment elevation myocardial infarction (STEMI). Additionally, we evaluated the mechanisms by which miR-98-5p promoted ischemia/reperfusion (I/R)-induced injury in both cultured cell lines and an animal model. METHODS Circulating miR-98-5p levels were measured and compared from 171 STEMI patients undergoing pPCI, who were divided into two groups: no-reflow and reflow. The levels of miR-98-5p, nerve growth factor (NGF), and transient receptor potential vanilloid 1 (TRPV1) were analyzed in cultured human coronary endothelial cells (HCECs) exposed to hypoxia/reoxygenation (H/R). The effects of antagomir-98-5p on myocardial I/R-induced microvascular dysfunction in vivo were evaluated. Target gene expression and activity were assessed. RESULTS Higher miR-98-5p levels were associated with compromised indices of microvascular reperfusion. In vitro experiments on HCECs showed that exposure to H/R significantly increased miR-98-5p levels. We identified NGF as a novel target of miR-98-5p. Further, antagomir-98-5p relieved microvascular dysfunction and enhanced the expression of NGF and TRPV1 in the rat myocardial I/R model. CONCLUSIONS MiR-98-5p promotes microvascular dysfunction by targeting the NGF-TRPV1 axis. Serum miR-98-5p serves as a potential biomarker for microvascular reperfusion.
Collapse
Affiliation(s)
- Yisen Hu
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, & Guangxi Key Laboratory Base of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, Nanning, Guangxi, P.R. China
| | - Jingjie Xiong
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, & Guangxi Key Laboratory Base of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, Nanning, Guangxi, P.R. China
| | - Hong Wen
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, & Guangxi Key Laboratory Base of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, Nanning, Guangxi, P.R. China
| | - Heng Wei
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, & Guangxi Key Laboratory Base of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, Nanning, Guangxi, P.R. China
| | - Xiaocong Zeng
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, & Guangxi Key Laboratory Base of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, Nanning, Guangxi, P.R. China
| |
Collapse
|
|
10
|
Mu M, Gao P, Yang Q, He J, Wu F, Han X, Guo S, Qian Z, Song C. Alveolar Epithelial Cells Promote IGF-1 Production by Alveolar Macrophages Through TGF-β to Suppress Endogenous Inflammatory Signals. Front Immunol 2020; 11:1585. [PMID: 32793225 PMCID: PMC7385185 DOI: 10.3389/fimmu.2020.01585] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 06/15/2020] [Indexed: 12/22/2022] Open
Abstract
To maintain alveolar gas exchange, the alveolar surface has to limit unnecessary inflammatory responses. This involves crosstalk between alveolar epithelial cells (AECs) and alveolar macrophages (AMs) in response to damaging factors. We recently showed that insulin-like growth factor (IGF)-1 regulates the phagocytosis of AECs. AMs secrete IGF-1 into the bronchoalveolar lavage fluid (BALF) in response to inflammatory stimuli. However, whether AECs regulate the production of IGF-1 by AMs in response to inflammatory signals remains unclear, as well as the role of IGF-1 in controlling the alveolar balance in the crosstalk between AMs and AECs under inflammatory conditions. In this study, we demonstrated that IGF-1 was upregulated in BALF and lung tissues of acute lung injury (ALI) mice, and that the increased IGF-1 was mainly derived from AMs. In vitro experiments showed that the production and secretion of IGF-1 by AMs as well as the expression of TGF-β were increased in LPS-stimulated AEC-conditioned medium (AEC-CM). Pharmacological blocking of TGF-β in AECs and addition of TGF-β neutralizing antibody to AEC-CM suggested that this AEC-derived cytokine mediates the increased production and secretion of IGF-1 from AMs. Blocking TGF-β synthesis or treatment with TGF-β neutralizing antibody attenuated the increase of IGF-1 in BALF in ALI mice. TGF-β induced the production of IGF-1 by AMs through the PI3K/Akt signaling pathway. IGF-1 prevented LPS-induced p38 MAPK activation and the expression of the inflammatory factors MCP-1, TNF-α, and IL-1β in AECs. However, IGF-1 upregulated PPARγ to increase the phagocytosis of apoptotic cells by AECs. Intratracheal instillation of IGF-1 decreased the number of polymorphonuclear neutrophils in BALF of ALI model mice, reduced alveolar congestion and edema, and suppressed inflammatory cell infiltration in lung tissues. These results elucidated a mechanism by which AECs used TGF-β to regulate IGF-1 production from AMs to attenuate endogenous inflammatory signals during alveolar inflammation.
Collapse
Affiliation(s)
- Mimi Mu
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, China.,Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, China.,Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Peiyu Gao
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, China.,Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, China.,Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Qian Yang
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, China.,Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, China.,Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Jing He
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, China.,Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, China.,Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Fengjiao Wu
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, China.,Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, China.,Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Xue Han
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, China.,Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, China.,Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Shujun Guo
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, China.,Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, China.,Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Zhongqing Qian
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, China.,Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, China.,Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Chuanwang Song
- Department of Immunology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, China.,Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, China.,Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| |
Collapse
|
|
11
|
Guo L, Davis BM, Ravindran N, Galvao J, Kapoor N, Haamedi N, Shamsher E, Luong V, Fico E, Cordeiro MF. Topical recombinant human Nerve growth factor (rh-NGF) is neuroprotective to retinal ganglion cells by targeting secondary degeneration. Sci Rep 2020; 10:3375. [PMID: 32099056 PMCID: PMC7042238 DOI: 10.1038/s41598-020-60427-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 01/16/2020] [Indexed: 12/13/2022] Open
Abstract
Optic neuropathy is a major cause of irreversible blindness worldwide, and no effective treatment is currently available. Secondary degeneration is believed to be the major contributor to retinal ganglion cell (RGC) death, the endpoint of optic neuropathy. Partial optic nerve transection (pONT) is an established model of optic neuropathy. Although the mechanisms of primary and secondary degeneration have been delineated in this model, until now how this is influenced by therapy is not well-understood. In this article, we describe a clinically translatable topical, neuroprotective treatment (recombinant human nerve growth factor, rh-NGF) predominantly targeting secondary degeneration in a pONT rat model. Topical application of rh-NGF twice daily for 3 weeks significantly improves RGC survival as shown by reduced RGC apoptosis in vivo and increased RGC population in the inferior retina, which is predominantly affected in this model by secondary degeneration. Topical rh-NGF also promotes greater axonal survival and inhibits astrocyte activity in the optic nerve. Collectively, these results suggest that topical rh-NGF exhibits neuroprotective effects on retinal neurons via influencing secondary degeneration process. As topical rh-NGF is already involved in early clinical trials, this highlights its potential in multiple indications in patients, including those affected by glaucomatous optic neuropathy.
Collapse
Affiliation(s)
- Li Guo
- Glaucoma & Retinal Neurodegeneration Research Group, Institute of Ophthalmology, University College London, London, United Kingdom.
| | - Benjamin M Davis
- Glaucoma & Retinal Neurodegeneration Research Group, Institute of Ophthalmology, University College London, London, United Kingdom
| | - Nivedita Ravindran
- Glaucoma & Retinal Neurodegeneration Research Group, Institute of Ophthalmology, University College London, London, United Kingdom
| | - Joana Galvao
- Glaucoma & Retinal Neurodegeneration Research Group, Institute of Ophthalmology, University College London, London, United Kingdom
| | - Neel Kapoor
- Glaucoma & Retinal Neurodegeneration Research Group, Institute of Ophthalmology, University College London, London, United Kingdom
| | - Nasrin Haamedi
- Glaucoma & Retinal Neurodegeneration Research Group, Institute of Ophthalmology, University College London, London, United Kingdom
| | - Ehtesham Shamsher
- Glaucoma & Retinal Neurodegeneration Research Group, Institute of Ophthalmology, University College London, London, United Kingdom
| | - Vy Luong
- Glaucoma & Retinal Neurodegeneration Research Group, Institute of Ophthalmology, University College London, London, United Kingdom
| | - Elena Fico
- Glaucoma & Retinal Neurodegeneration Research Group, Institute of Ophthalmology, University College London, London, United Kingdom.,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - M Francesca Cordeiro
- Glaucoma & Retinal Neurodegeneration Research Group, Institute of Ophthalmology, University College London, London, United Kingdom. .,Western Eye Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom.
| |
Collapse
|
|
12
|
Ahluwalia A, Hoa N, Jones MK, Tarnawski AS. NSAID-induced injury of gastric epithelial cells is reversible: roles of mitochondria, AMP kinase, NGF, and PGE 2. Am J Physiol Gastrointest Liver Physiol 2019; 317:G862-G871. [PMID: 31545918 PMCID: PMC6962499 DOI: 10.1152/ajpgi.00192.2019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/03/2019] [Accepted: 09/16/2019] [Indexed: 02/06/2023]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (DFN) and indomethacin (INDO) are extensively used worldwide. Their main side effects are injury of the gastrointestinal tract, including erosions, ulcers, and bleeding. Since gastric epithelial cells (GEPCs) are crucial for mucosal defense and are the major target of injury, we examined the extent to which DFN- and INDO-induced GEPC injury can be reversed by nerve growth factor (NGF), 16,16 dimethyl prostaglandin E2 (dmPGE2), and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), the pharmacological activator of the metabolic sensor AMP kinase (AMPK). Cultured normal rat gastric mucosal epithelial (RGM1) cells were treated with PBS (control), NGF, dmPGE2, AICAR, and/or NSAID (DFN or INDO) for 1-4 h. We examined cell injury by confocal microscopy, cell death/survival using calcein AM, mitochondrial membrane potential using MitoTracker, and phosphorylation of AMPK by Western blotting. DFN and INDO treatment of RGM1 cells for 2 h decreased mitochondrial membrane potential and cell viability. NGF posttreatment (initiated 1 or 2 h after DFN or INDO) reversed the dissipation of mitochondrial membrane potential and cell injury caused by DFN and INDO and increased cell viability versus cells treated for 4 h with NSAID alone. Pretreatment with dmPGE2 and AICAR significantly protected these cells from DFN- and INDO-induced injury, whereas dmPGE2 and AICAR posttreatment (initiated 1 h after NSAID treatment) reversed cell injury and significantly increased cell viability and rescued the cells from NSAID-induced mitochondrial membrane potential reduction. DFN and INDO induce extensive mitochondrial injury and GEPC death, which can be significantly reversed by NGF, dmPGE2, and AICAR.NEW & NOTEWORTHY This study demonstrated that mitochondria are key targets of diclofenac- and indomethacin-induced injury of gastric epithelial cells and that diclofenac and indomethacin injury can be prevented and, importantly, also reversed by treatment with nerve growth factor, 16,16 dimethyl prostaglandin E2, and 5-aminoimidazole-4-carboxamide ribonucleotide.
Collapse
Affiliation(s)
- Amrita Ahluwalia
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
| | - Neil Hoa
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
| | - Michael K Jones
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
- Department of Medicine, University of California, Irvine, California
| | - Andrzej S Tarnawski
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
- Department of Medicine, University of California, Irvine, California
| |
Collapse
|
|
13
|
Mu M, Wu F, He J, Tang X, Ma H, Guo S, Song C. Insulin‑like growth factor 1 inhibits phagocytosis of alveolar epithelial cells in asthmatic mice. Mol Med Rep 2019; 20:2381-2388. [PMID: 31322198 DOI: 10.3892/mmr.2019.10456] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 06/04/2019] [Indexed: 11/06/2022] Open
Abstract
The phagocytosis of apoptotic cells by alveolar epithelial cells helps to eliminate airway inflammation. Insulin‑like growth factor 1 (IGF‑1) regulates cell metabolism and proliferation, and promotes cell survival, while it may also promote the proliferation and differentiation of alveolar epithelial cells during the repair of lung injury. The present study investigated the effect of IGF‑1 on the phagocytic activity of alveolar epithelial cells, a nonprofessional phagocyte. IGF‑1 was elevated in lung tissue and bronchoalveolar lavage fluid obtained from mice with ovalbumin‑induced asthma. IGF‑1 was reduced by 50% in the lung tissue and by nearly 100% in the bronchoalveolar lavage fluid in asthmatic mice established by depletion of alveolar macrophages using 2‑chloroadenosine. In addition, interleukin‑33 induced IGF‑1 production in primary alveolar macrophages. It was also observed that IGF‑1 inhibited the phagocytosis of fluorescent microspheres and apoptotic cells by MLE‑12 alveolar epithelial cells. Antibody blocking of IGF‑1 enhanced the phagocytosis of fluorescent microspheres and apoptotic cells, and significantly reduced inflammatory cell infiltration in airway and perivascular tissues. The elevated IGF‑1 level in the lungs of asthma model mice was mainly produced in alveolar macrophages. Taken together, the current study demonstrated that IGF‑1 inhibited phagocytosis by alveolar epithelial cells, and that IGF‑1 blockade enhanced the phagocytic activity and alleviated airway inflammation. These results support the potential use of IGF‑1 as a target in the treatment of asthma.
Collapse
Affiliation(s)
- Mimi Mu
- Department of Immunology, Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Fengjiao Wu
- Department of Immunology, Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Jing He
- Department of Immunology, Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Xu Tang
- Department of Clinical Laboratory Medicine, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Hua Ma
- Department of Immunology, Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Shujun Guo
- Department of Immunology, Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Chuanwang Song
- Department of Immunology, Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| |
Collapse
|
|
14
|
Ahluwalia A, Jones MK, Hoa N, Tarnawski AS. Mitochondria in gastric epithelial cells are the key targets for NSAIDs-induced injury and NGF cytoprotection. J Cell Biochem 2019; 120:11651-11659. [PMID: 30790334 DOI: 10.1002/jcb.28445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/05/2018] [Accepted: 12/10/2018] [Indexed: 02/05/2023]
Abstract
Gastric epithelial cells are important components of mucosal protection and targets of nonsteroidal anti-inflammatory drugs (NSAIDs)-induced injury. Diclofenac (DFN) is one of the most widely used NSAIDs; however, even its short-term use can induce gastric erosions and ulcers. Nerve growth factor (NGF) has been reported to act not only on neuronal cells but also on endothelial cells; however, its action on gastric epithelial cells is unknown. This study was aimed to determine, whether NGF can protect gastric epithelial cells against DFN-induced injury, and to determine the underlying molecular mechanisms with a focus on mitochondria, survivin, and insulin-like growth factor 1 (IGF-1). Cultured normal rat gastric mucosal epithelial cells 1 (RGM1) were treated with phosphate-buffered saline (PBS; control), NGF (100 ng/mL) and/or DFN (0.25-1.00 mM) for 4 hours. We examined: (1) cell injury by confocal microscopy; (2) cell death/survival using Calcein AM live cell tracking dye; (3) mitochondrial structure and membrane potential function using MitoTracker in live cells; and (4) expression of NGF, its receptor - tropomyosin receptor kinase A (TrkA), survivin and IGF-1 by immunostaining. DFN treatment of RGM1 cells for 4 hours caused extensive cell injury, mitochondrial disintegration, reduced cell viability (from 94 ± 3% in controls to 14 ± 4% in 0.5 mM DFN-treated cells; P < 0.001), and expression of survivin and IGF-1. NGF treatment significantly increased survivin and IGF-1 expression by 41% and 75%, respectively versus PBS controls. Pretreatment with NGF before DFN treatment reduced mitochondrial damage and cell death by 73% and 82%, respectively versus treatment with DFN alone (all P < 0.001). This study also showed the presence of high-affinity TrkA receptors in the plasma membrane and mitochondria of RGM1 cells indicating novel actions of NGF.
Collapse
Affiliation(s)
- Amrita Ahluwalia
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
| | - Michael K Jones
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
- Department of Medicine, University of California, Irvine, California
| | - Neil Hoa
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
| | - Andrzej S Tarnawski
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
- Department of Medicine, University of California, Irvine, California
| |
Collapse
|
|
15
|
He J, Mu M, Wang H, Ma H, Tang X, Fang Q, Guo S, Song C. Upregulated IGF‑1 in the lungs of asthmatic mice originates from alveolar macrophages. Mol Med Rep 2018; 19:1266-1271. [PMID: 30535455 DOI: 10.3892/mmr.2018.9726] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 11/02/2018] [Indexed: 11/06/2022] Open
Abstract
Asthma is characterized by inflammation and remodeling of the airways. Insulin‑like growth factor-1 (IGF‑1) serves an important role in the repair of lung tissue injury and airway remodeling by elevating collagen and elastin content, increasing the thickness of smooth muscle and promoting the proliferation of lung epithelial and interstitial cells, as well as fibroblasts; however, the content of IGF‑1 and its cellular origin in the lungs of patients with asthma remain unknown. In the present study, a mouse model of asthma was constructed. Following isolation of alveolar macrophages (AMs), the content of IGF‑1 in lung tissue and bronchoalveolar lavage fluid (BALF) was detected by ELISA. The proliferation and phagocytosis of alveolar epithelial cells (AECs) stimulated by IGF‑1 were detected by Cell Counting Kit‑8 method and flow cytometry, respectively. In the present study, IGF‑1 was upregulated in the lung tissues of asthmatic mice, and the content of IGF‑1 in BALF was also elevated. Depletion of AMs by treating mice with 2‑chloroadenosine via nose dripping reversed the increase of IGF‑1 by 80% in lung tissues and by ~100% in BALF of asthmatic mice, suggesting that elevated IGF‑1 in asthmatic mice predominantly originated from AMs. As IGF‑1 promotes the proliferation and phagocytosis of AECs, AM‑derived IGF‑1 may serve an important role in the regulation of airway inflammation and remodeling in asthmatic mice.
Collapse
Affiliation(s)
- Jing He
- Department of Immunology, Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Mimi Mu
- Department of Immunology, Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Helong Wang
- Department of Immunology, Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Hua Ma
- Department of Immunology, Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Xu Tang
- Department of Clinical Laboratory of Medicine, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Qiang Fang
- Department of Microbiology and Parasitology, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Shujun Guo
- Department of Immunology, Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Chuanwang Song
- Department of Immunology, Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| |
Collapse
|
|
16
|
Tarnawski AS, Ahluwalia A. Increased susceptibility of aging gastric mucosa to injury and delayed healing: Clinical implications. World J Gastroenterol 2018; 24:4721-4727. [PMID: 30479459 PMCID: PMC6235800 DOI: 10.3748/wjg.v24.i42.4721] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 10/12/2018] [Accepted: 10/21/2018] [Indexed: 02/06/2023] Open
Abstract
In this editorial we comment on the article by Fukushi K et al published in the recent issue of the World Journal of Gastroenterology 2018; 24(34): 3908-3918. We focus specifically on the mechanisms of the anti-thrombotic action of aspirin, gastric mucosal injury and aging-related increased susceptibility of gastric mucosa to injury. Aspirin is widely used not only for the management of acute and chronic pain and arthritis, but also importantly for the primary and secondary prevention of cardiovascular events such as myocardial infarcts and strokes. Clinical trials have consistently shown that antiplatelet therapy with long term, low dose aspirin (LDA) - 75 to 325 mg daily, dramatically reduces the risk of non-fatal myocardial infarcts, stroke and mortality in patients with established arterial diseases. However, such treatment considerably increases the risk of gastrointestinal (GI) ulcerations and serious bleeding by > 2-4 fold, especially in aging individuals. This risk is further increased in patients using LDA together with other antiplatelet agents, other nonsteroidal anti-inflammatory agents (NSAIDs) and/or alcohol, or in patients with Helicobacter pylori (H. pylori) infection. Previous studies by our group and others have demonstrated prominent structural and functional abnormalities in gastric mucosa of aging individuals (which we refer to as aging gastric mucosa or “aging gastropathy”) compared to the gastric mucosa of younger individuals. Aging gastric mucosa has impaired mucosal defense, increased susceptibility to injury by a variety of noxious agents such as aspirin, other NSAIDs and ethanol, and delayed and impaired healing of injury. The mechanism underlying these abnormalities of aging gastric mucosa include reduced mucosal blood flow causing hypoxia, upregulation of PTEN, activation of pro-apoptotic caspase-3 and caspase-9, and reduced survivin (anti-apoptosis protein), importin-α (nuclear transport protein), vascular endothelial growth factor, and nerve growth factor. The decision regarding initiation of a long-term LDA therapy should be made after a careful consideration of both cardiovascular and GI risk factors. The latter include a previous history of GI bleeding and/or ulcers, age ≥ 70, male gender, concurrent use of other NSAIDs, alcohol consumption and H. pylori infection. Furthermore, the incidence of GI ulcers and bleeding can be reduced in patients on long term LDA treatment by several measures. Clinicians treating such patients should test for and eradicate H. pylori, instruct patients to avoid alcohol and non-aspirin NSAIDs, including cyclooxygenase-2-selective NSAIDs, and prescribe proton pump inhibitors in patients on LDA therapy. In the future, clinicians may be able to prescribe one of several potential new drugs, which include aspirin associated with phosphatidylcholine (PL2200), which retains all property of aspirin but reduces by approximately 50% LDA-induced GI ulcerations.
Collapse
Affiliation(s)
- Andrzej S Tarnawski
- Department of Gastroenterology Research, University of California Irvine and the Veterans Administration Long Beach Healthcare System, Long Beach, CA 90822, United States
| | - Amrita Ahluwalia
- Department of Gastroenterology Research, University of California Irvine and the Veterans Administration Long Beach Healthcare System, Long Beach, CA 90822, United States
| |
Collapse
|
|
17
|
Savoia F, Sechi A, Tabanelli M, Zago S, Leuzzi M, Baraldi C, Patrizi A. Multiple perianal ulcers due to suppositories. Australas J Dermatol 2018; 60:50-52. [PMID: 30039854 DOI: 10.1111/ajd.12888] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 06/16/2018] [Indexed: 11/30/2022]
Abstract
We report a case of long-standing inexplicable perianal ulcers. After exclusion of an inflammatory, infectious or neoplastic origin, a thorough personal history revealed that for many years the patient had been using analgesic suppositories containing indomethacin, caffeine, and prochlorperazine dimaleate, four to five times a week, for migraine. On stopping the suppositories, there was complete healing within 12 weeks. We hypothesize that vasoconstriction and vascular damage were the pathogenetic mechanisms behind the perianal ulcers.
Collapse
Affiliation(s)
- Francesco Savoia
- Unit of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Andrea Sechi
- Unit of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | | | - Silvia Zago
- Pathologic Anatomy Unit, AUSL della Romagna, Ravenna, Italy
| | - Miriam Leuzzi
- Unit of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Carlotta Baraldi
- Unit of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Annalisa Patrizi
- Unit of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| |
Collapse
|
|
18
|
Ahluwalia A, Jones MK, Hoa N, Zhu E, Brzozowski T, Tarnawski AS. Reduced NGF in Gastric Endothelial Cells Is One of the Main Causes of Impaired Angiogenesis in Aging Gastric Mucosa. Cell Mol Gastroenterol Hepatol 2018; 6:199-213. [PMID: 29992182 PMCID: PMC6037903 DOI: 10.1016/j.jcmgh.2018.05.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 05/10/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Aging gastric mucosa has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully known. We examined whether impairment of angiogenesis in aging gastric mucosa is caused by deficiency of nerve growth factor (NGF) in gastric endothelial cells (ECs), and whether NGF therapy could reverse this impairment. METHODS In gastric mucosal ECs (GECs) isolated from young and aging rats we examined the following: (1) in vitro angiogenesis, (2) NGF expression, and (3) the effect of NGF treatment on angiogenesis, GEC proliferation and migration, and dependence on serum response factor. In in vivo studies in young and aging rats, we examined NGF expression in gastric mucosa and the effect of NGF treatment on angiogenesis and gastric ulcer healing. To determine human relevance, we examined NGF expression in gastric mucosal biopsy specimens of aging (≥70 y) and young (≤40 y) individuals. RESULTS In cultured aging GECs, NGF expression and angiogenesis were reduced significantly by 3.0-fold and 4.1-fold vs young GECs. NGF therapy reversed impairment of angiogenesis in aging GECs, and serum response factor silencing completely abolished this response. In gastric mucosa of aging rats, NGF expression in GECs was reduced significantly vs young rats. In aging rats, local NGF treatment significantly increased angiogenesis and accelerated gastric ulcer healing. In aging human subjects, NGF expression in ECs of gastric mucosal vessels was 5.5-fold reduced vs young individuals. CONCLUSIONS NGF deficiency in ECs is a key mechanism underlying impaired angiogenesis and delayed ulcer healing in aging gastric mucosa. Local NGF therapy can reverse these impairments.
Collapse
Key Words
- Aging
- Akt, serine threonine kinase signaling protein
- Angiogenesis
- BrdU, bromodeoxyuridine
- EC, endothelial cell
- Endothelial Cells
- FITC, fluorescein isothiocyanate
- GEC, gastric mucosal microvascular endothelial cells isolated from rats
- GU, gastric ulcer
- Gene Therapy
- LV-GFP, lentiviral green fluorescent protein
- LV-NGF, lentiviral nerve growth factor
- NGF, nerve growth factor
- NSAID, nonsteroidal anti-inflammatory drug
- Nerve Growth Factor
- PBS, phosphate-buffered saline
- PCNA, proliferating cell nuclear antigen
- PCR, polymerase chain reaction
- PI3, phosphoinositide-3
- SRF, serum response factor
- Ulcer Healing
- VEGF, vascular endothelial growth factor
- mRNA, messenger RNA
- mTOR, mammalian target of rapamycin
- siRNA, small interfering RNA
Collapse
Affiliation(s)
- Amrita Ahluwalia
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
| | - Michael K. Jones
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
- Department of Medicine, University of California, Irvine, California
| | - Neil Hoa
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
| | - Ercheng Zhu
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
| | - Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, Krakow, Poland
| | - Andrzej S. Tarnawski
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System, Long Beach, California
- Department of Medicine, University of California, Irvine, California
- Correspondence Address correspondence to: Andrzej S. Tarnawski, MD, PhD, AGAF, FACG, Veterans Affairs Long Beach Healthcare System, 5901 East 7th Street, 09/151, Long Beach, California 90822. fax: (562) 826-5675.
| |
Collapse
|