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Jiao B, Cao X, Zhang C, Zhang W, Yu S, Zhang M, Zhang X. Alterations of the gut microbiota in patients with postherpetic neuralgia. AMB Express 2023; 13:108. [PMID: 37803181 PMCID: PMC10558420 DOI: 10.1186/s13568-023-01614-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 09/24/2023] [Indexed: 10/08/2023] Open
Abstract
Postherpetic neuralgia (PHN) is a prevalent, intricate, and intractable form of neuropathic pain. The available evidence indicates that alterations in the gut microbiota are significant environmental determinants in the development of chronic neuropathic pain. Nevertheless, the correlation between the gut microbiota and PHN remains elusive. A cross-sectional study was performed on a cohort of 27 patients diagnosed with PHN and 27 matched healthy controls. Fecal samples were collected and subjected to microbiota analysis using 16S ribosomal RNA gene sequencing. Comparable levels of bacterial richness and diversity were observed in the gut microbiota of PHN patients and healthy controls. A significant difference was observed in 37 genera between the two groups. Furthermore, the LEfSe method revealed that the abundance levels of Escherichia-Shigella, Streptococcus, Ligilactobacillus, and Clostridia_UCG-014_unclassified were elevated in PHN patients, while Eubacterium_hallii_group, Butyricicoccus, Tyzzerella, Dorea, Parasutterella, Romboutsia, Megamonas, and Agathobacter genera were reduced in comparison to healthy controls. Significantly, the discriminant model utilizing the predominant microbiota exhibited efficacy in distinguishing PHN patients from healthy controls, with an area under the curve value of 0.824. Moreover, Spearman correlation analysis demonstrated noteworthy correlations between various gut microbiota and clinical symptoms, including disease course, anxiety state, sleep quality, heat pain, pain intensity, and itching intensity. Gut microbiota dysbiosis exists in PHN patients, microbiome differences could be used to distinguish PHN patients from normal healthy individuals with high sensitivity and specificity, and altered gut microbiota are related to clinical manifestations, suggesting potentially novel prevention and therapeutic directions of PHN.
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Affiliation(s)
- Bo Jiao
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xueqin Cao
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Caixia Zhang
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Wencui Zhang
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Shangchen Yu
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Mi Zhang
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province, China.
| | - Xianwei Zhang
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
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Wang S, Zhou Y, Huang J, Li H, Pang H, Niu D, Li G, Wang F, Zhou Z, Liu Z. Advances in experimental models of rheumatoid arthritis. Eur J Immunol 2023; 53:e2249962. [PMID: 36330559 DOI: 10.1002/eji.202249962] [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: 04/23/2022] [Revised: 10/16/2022] [Accepted: 11/02/2022] [Indexed: 11/06/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent articular inflammation and joint damage. RA was first described over 200 years ago; however, its etiology and pathophysiology remain insufficiently understood. The current treatment of RA is mainly empirical or based on the current understanding of etiology with limited efficacy and/or substantial side effects. Thus, the development of safer and more potent therapeutics, validated and optimized in experimental models, is urgently required. To improve the transition from bench to bedside, researchers must carefully select the appropriate experimental models as well as draw the right conclusions. Here, we summarize the establishment, pathological features, potential mechanisms, advantages, and limitations of the currently available RA models. The aim of the review is to help researchers better understand available RA models; discuss future trends in RA model development, which can help highlight new translational and human-based avenues in RA research.
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Affiliation(s)
- Siwei Wang
- School of Basic Medicine, Yangtze University, Jingzhou, Hubei Province, China.,Honghu Hospital of Traditional Chinese Medicine, Affiliated Hospital of Yangtze University, Honghu, Hubei Province, China
| | - Yanhua Zhou
- School of Basic Medicine, Yangtze University, Jingzhou, Hubei Province, China.,Honghu Hospital of Traditional Chinese Medicine, Affiliated Hospital of Yangtze University, Honghu, Hubei Province, China
| | - Jiangrong Huang
- School of Basic Medicine, Yangtze University, Jingzhou, Hubei Province, China
| | - Huilin Li
- School of Basic Medicine, Yangtze University, Jingzhou, Hubei Province, China
| | - Huidan Pang
- School of Basic Medicine, Yangtze University, Jingzhou, Hubei Province, China
| | - Dandan Niu
- School of Basic Medicine, Yangtze University, Jingzhou, Hubei Province, China
| | - Guangyao Li
- School of Basic Medicine, Yangtze University, Jingzhou, Hubei Province, China
| | - Fei Wang
- Department of Experiment and Training, Hubei College of Chinese Medicine, Hubei Province, China
| | - Zushan Zhou
- School of Basic Medicine, Yangtze University, Jingzhou, Hubei Province, China.,Honghu Hospital of Traditional Chinese Medicine, Affiliated Hospital of Yangtze University, Honghu, Hubei Province, China
| | - Zhenzhen Liu
- School of Basic Medicine, Yangtze University, Jingzhou, Hubei Province, China
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Chen P, Wang C, Ren YN, Ye ZJ, Jiang C, Wu ZB. Alterations in the gut microbiota and metabolite profiles in the context of neuropathic pain. Mol Brain 2021; 14:50. [PMID: 33750430 PMCID: PMC7941960 DOI: 10.1186/s13041-021-00765-y] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 02/25/2021] [Indexed: 12/17/2022] Open
Abstract
The aim of this study was to explore the relationships among gut microbiota disturbances and serum and spinal cord metabolic disorders in neuropathic pain. 16S rDNA amplicon sequencing and serum and spinal cord metabolomics were used to identify alterations in the microbiota and metabolite profiles in the sham rats and the chronic constriction injury (CCI) model rats. Correlations between the abundances of gut microbiota components at the genus level, the levels of serum metabolites, and pain-related behavioural parameters were analysed. Ingenuity pathway analysis (IPA) was applied to analyse the interaction networks of the differentially expressed serum metabolites. First, we found that the composition of the gut microbiota was different between rats with CCI-induced neuropathic pain and sham controls. At the genus level, the abundances of Helicobacter, Phascolarctobacterium, Christensenella, Blautia, Streptococcus, Rothia and Lactobacillus were significantly increased, whereas the abundances of Ignatzschineria, Butyricimonas, Escherichia, AF12, and Corynebacterium were significantly decreased. Additionally, 72 significantly differentially expressed serum metabolites and 17 significantly differentially expressed spinal cord metabolites were identified between the CCI rats and the sham rats. Finally, correlation analysis showed that changes in the gut microbiota was significantly correlated with changes in serum metabolite levels, suggesting that dysbiosis of the gut microbiota is an important factor in modulating metabolic disturbances in the context of neuropathic pain. In conclusion, our research provides a novel perspective on the potential roles of the gut microbiota and related metabolites in neuropathic pain.
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Affiliation(s)
- Peng Chen
- Basic Medical School, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Chen Wang
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yan-Na Ren
- Basic Medical School, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Zeng-Jie Ye
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chao Jiang
- Department of Neurology, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, China.
| | - Zhi-Bing Wu
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China.
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Understanding the Molecular Mechanisms Underlying the Pathogenesis of Arthritis Pain Using Animal Models. Int J Mol Sci 2020; 21:ijms21020533. [PMID: 31947680 PMCID: PMC7013391 DOI: 10.3390/ijms21020533] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 12/27/2019] [Accepted: 01/09/2020] [Indexed: 12/22/2022] Open
Abstract
Arthritis, including osteoarthritis (OA) and rheumatoid arthritis (RA), is the leading cause of years lived with disability (YLD) worldwide. Although pain is the cardinal symptom of arthritis, which is directly related to function and quality of life, the elucidation of the mechanism underlying the pathogenesis of pain in arthritis has lagged behind other areas, such as inflammation control and regulation of autoimmunity. The lack of therapeutics for optimal pain management is partially responsible for the current epidemic of opioid and narcotic abuse. Recent advances in animal experimentation and molecular biology have led to significant progress in our understanding of arthritis pain. Despite the inherent problems in the extrapolation of data gained from animal pain studies to arthritis in human patients, the critical assessment of molecular mediators and translational studies would help to define the relevance of novel therapeutic targets for the treatment of arthritis pain. This review discusses biological and molecular mechanisms underlying the pathogenesis of arthritis pain determined in animal models of OA and RA, along with the methodologies used.
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Ignatowski TA, Spengler RN. Targeting tumor necrosis factor in the brain relieves neuropathic pain. World J Anesthesiol 2018; 7:10-19. [DOI: 10.5313/wja.v7.i2.10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/28/2018] [Accepted: 06/02/2018] [Indexed: 02/06/2023] Open
Abstract
Neuropathic pain is a chronic syndrome caused by direct damage to or disease of the somatosensory nervous system. The lack of safe, adequate and sustained pain relief offered by present analgesic treatments is most alarming. While many treatment options are available to manage chronic pain, such as antidepressants, non-steroidal anti-inflammatory agents, opioids, and anticonvulsants, chronic neuropathic pain remains largely unmanaged. Compounding the dilemma of ineffective chronic pain treatments is the need to provide relief from suffering and yet not contribute to the scourge of drug abuse. A recent epidemic of addiction and accidental drug prescription overdoses parallel the increased use of opioid treatment, even though opioids are rarely an effective treatment of relieving chronic pain. To make matters worse, opioids may contribute to exacerbating pain, and side-effects such as cognitive impairment, nausea, constipation, development of tolerance, as well as their potential for addiction and overdose deaths exist. Clearly, there is an urgent need for alternative, non-opiate treatment of chronic pain. Innovative discoveries of pertinent brain mechanisms and functions are key to developing effective, safe treatments. Pioneering work has revealed the essential effects of the pleiotropic mediator tumor necrosis factor (TNF) on brain functioning. These studies establish that TNF inhibits norepinephrine release from hippocampal neurons, and show that excess TNF production within the hippocampus occurs during neuropathic pain, which mobilizes additional mechanisms that further inhibit norepinephrine release. Significantly, it has been verified that elevated levels of TNF in the brain are actually required for neuropathic pain development. Since TNF decreases norepinephrine release in the brain, enhanced TNF levels would prevent engagement of the norepinephrine descending inhibitory neuronal pain pathways. Increased levels of TNF in the brain are therefore critical to the development of neuropathic pain. Therefore, strategies that decrease this enhanced TNF expression in the brain will have superior analgesic efficacy. We propose this novel approach of targeting the pathologically high levels of brain TNF as an effective strategy in the treatment of the devastating syndrome of chronic pain.
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Affiliation(s)
- Tracey A Ignatowski
- Department of Pathology and Anatomical Sciences and Program for Neuroscience, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14203, United States
- NanoAxis, LLC, Clarence, NY 14031, United States
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Lim MA, Louie B, Ford D, Heath K, Cha P, Betts-Lacroix J, Lum PY, Robertson TL, Schaevitz L. Development of the Digital Arthritis Index, a Novel Metric to Measure Disease Parameters in a Rat Model of Rheumatoid Arthritis. Front Pharmacol 2017; 8:818. [PMID: 29184498 PMCID: PMC5694443 DOI: 10.3389/fphar.2017.00818] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 10/30/2017] [Indexed: 12/29/2022] Open
Abstract
Despite a broad spectrum of anti-arthritic drugs currently on the market, there is a constant demand to develop improved therapeutic agents. Efficient compound screening and rapid evaluation of treatment efficacy in animal models of rheumatoid arthritis (RA) can accelerate the development of clinical candidates. Compound screening by evaluation of disease phenotypes in animal models facilitates preclinical research by enhancing understanding of human pathophysiology; however, there is still a continuous need to improve methods for evaluating disease. Current clinical assessment methods are challenged by the subjective nature of scoring-based methods, time-consuming longitudinal experiments, and the requirement for better functional readouts with relevance to human disease. To address these needs, we developed a low-touch, digital platform for phenotyping preclinical rodent models of disease. As a proof-of-concept, we utilized the rat collagen-induced arthritis (CIA) model of RA and developed the Digital Arthritis Index (DAI), an objective and automated behavioral metric that does not require human-animal interaction during the measurement and calculation of disease parameters. The DAI detected the development of arthritis similar to standard in vivo methods, including ankle joint measurements and arthritis scores, as well as demonstrated a positive correlation to ankle joint histopathology. The DAI also determined responses to multiple standard-of-care (SOC) treatments and nine repurposed compounds predicted by the SMarTRTM Engine to have varying degrees of impact on RA. The disease profiles generated by the DAI complemented those generated by standard methods. The DAI is a highly reproducible and automated approach that can be used in-conjunction with standard methods for detecting RA disease progression and conducting phenotypic drug screens.
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Affiliation(s)
| | - Brenton Louie
- Capella Biosciences Inc., Palo Alto, CA, United States
| | | | | | | | | | - Pek Yee Lum
- Capella Biosciences Inc., Palo Alto, CA, United States
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Tumor Necrosis Factor-Alpha Inhibitor Etanercept Does Not Alter Methotrexate-Induced Gastrointestinal Mucositis in Rats. J Pediatr Gastroenterol Nutr 2017; 65:e28-e34. [PMID: 27861204 DOI: 10.1097/mpg.0000000000001469] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Gastrointestinal (GI) mucositis is a severe adverse effect of chemotherapy and radiotherapy. Proinflammatory cytokines are thought to play an important role in the pathophysiology of GI mucositis. We aimed to determine the effect of the tumor necrosis factor-alpha (TNF-α) inhibitor etanercept on the severity of mucositis in a previously established methotrexate (MTX)-induced GI mucositis rat model. METHODS Male Wistar rats received 60 mg/kg MTX on day 0 intravenously. Rats were treated daily with either etanercept (TNF-α inhibitor) 5 mg/kg or NaCl 0.9% subcutaneously from day -3 till day 3. Control rats received NaCl 0.9% intravenously and etanercept subcutaneously. The severity of mucositis was determined by intake, bodyweight, plasma citrulline, and by a function test (absorption of an oral glucose bolus). On day 4 and day 10 rats were terminated. Villus length, crypt length, intestinal myeloperoxidase, and plasma etanercept levels were determined. RESULTS The administration of MTX induced mucositis in all rats. Etanercept did not cause a change in the degree of mucositis. Bodyweight, intake, and glucose levels were not altered by etanercept; villus length was comparable; and there was no difference in myeloperoxidase and citrulline level. Etanercept levels in plasma were significantly increased in the etanercept rats (P < 0.05). CONCLUSIONS TNF-α inhibitor etanercept did not alter the severity of mucositis in the rat, suggesting that targeting only the inflammatory pathway of TNF-α is not effective for decreasing the severity of GI mucositis induced by high-dose MTX. Etanercept alone is not useful for the treatment of MTX-induced GI mucositis.
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Methods for Testing Immunological Factors. DRUG DISCOVERY AND EVALUATION: PHARMACOLOGICAL ASSAYS 2016. [PMCID: PMC7122208 DOI: 10.1007/978-3-319-05392-9_45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Hypersensitivity reactions can be elicited by various factors: either immunologically induced, i.e., allergic reactions to natural or synthetic compounds mediated by IgE, or non-immunologically induced, i.e., activation of mediator release from cells through direct contact, without the induction of, or the mediation through immune responses. Mediators responsible for hypersensitivity reactions are released from mast cells. An important preformed mediator of allergic reactions found in these cells is histamine. Specific allergens or the calcium ionophore 48/80 induce release of histamine from mast cells. The histamine concentration can be determined with the o-phthalaldehyde reaction.
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Yamacita-Borin FY, Zarpelon AC, Pinho-Ribeiro FA, Fattori V, Alves-Filho JC, Cunha FQ, Cunha TM, Casagrande R, Verri WA. Superoxide anion-induced pain and inflammation depends on TNFα/TNFR1 signaling in mice. Neurosci Lett 2015; 605:53-8. [PMID: 26291484 DOI: 10.1016/j.neulet.2015.08.015] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 08/11/2015] [Accepted: 08/11/2015] [Indexed: 11/27/2022]
Abstract
Inhibition of tumor necrosis factor-alpha (TNFα) and superoxide anion production reduces inflammation and pain. The present study investigated whether superoxide anion-induced pain depends on TNFα signaling and the role of superoxide anion in TNFα-induced hyperalgesia to clarify the interrelation between these two mediators in the context of pain. Intraplantar injection of a superoxide anion donor (potassium superoxide) induced mechanical hyperalgesia (0.5-5h after injection), neutrophil recruitment (myeloperoxidase activity), and overt pain-like behaviors (paw flinching, paw licking, and abdominal writhings) in wild-type mice. Tumor necrosis factor receptor 1 deficiency (TNFR1-/-) and treatment of wild-type mice with etanercept (a soluble TNFR2 receptor that inhibits TNFα actions) inhibited superoxide anion-induced pain-like behaviors. TNFR1(-/-) mice were also protected from superoxide anion donor-induced oxidative stress, suggesting the role of this pathway in the maintenance of oxidative stress. Finally, we demonstrated that Apocynin (an NADPH oxidase inhibitor) or Tempol (a superoxide dismutase mimetic) treatment inhibited TNFα-induced paw mechanical hyperalgesia and neutrophil recruitment (myeloperoxidase activity). These results demonstrate that TNFα/TNFR1 signaling is important in superoxide anion-triggered pain and that TNFα/TNFR1 signaling amplifies the oxidative stress triggered by superoxide anion, which contributes to sustaining pain and inflammation.
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Affiliation(s)
- Fabiane Y Yamacita-Borin
- Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid KM380 PR445, Cx Postal 10.011, Londrina, Paraná, CEP 86057-970, Brazil; Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Estadual de Londrina, Av. Robert Koch 60, Londrina, Paraná, CEP 86038-350, Brazil
| | - Ana C Zarpelon
- Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid KM380 PR445, Cx Postal 10.011, Londrina, Paraná, CEP 86057-970, Brazil
| | - Felipe A Pinho-Ribeiro
- Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid KM380 PR445, Cx Postal 10.011, Londrina, Paraná, CEP 86057-970, Brazil
| | - Victor Fattori
- Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid KM380 PR445, Cx Postal 10.011, Londrina, Paraná, CEP 86057-970, Brazil
| | - Jose C Alves-Filho
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, CEP 14049-900, Brazil
| | - Fernando Q Cunha
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, CEP 14049-900, Brazil
| | - Thiago M Cunha
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, CEP 14049-900, Brazil
| | - Rubia Casagrande
- Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Estadual de Londrina, Av. Robert Koch 60, Londrina, Paraná, CEP 86038-350, Brazil
| | - Waldiceu A Verri
- Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid KM380 PR445, Cx Postal 10.011, Londrina, Paraná, CEP 86057-970, Brazil.
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