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1.
Lancet ; 395(10221): 371-383, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007172

RESUMO

Asthma is a disease of reversible airflow obstruction characterised clinically by wheezing, shortness of breath, and coughing. Increases in airway type 2 cytokine activity, including interleukin-4 (IL-4), IL-5, and IL-13, are now established biological mechanisms in asthma. Inhaled corticosteroids have been the foundation for asthma treatment, in a large part because they decrease airway type 2 inflammation. However, inhaled or systemic corticosteroids are ineffective treatments in many patients with asthma and few treatment options exist for patients with steroid resistant asthma. Although mechanisms for corticosteroid refractory asthma are likely to be numerous, the development of a new class of biologic agents that target airway type 2 inflammation has provided a new model for treating some patients with corticosteroid refractory asthma. The objective of this Therapeutic paper is to summarise the new type 2 therapeutics, with an emphasis on the biological rationale and clinical efficacy of this new class of asthma therapeutics.


Assuntos
Antiasmáticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Adulto , Biomarcadores/metabolismo , Ensaios Clínicos Fase III como Assunto , Citocinas/antagonistas & inibidores , Citocinas/fisiologia , Eosinófilos/fisiologia , Previsões , Humanos , Ácidos Indolacéticos/uso terapêutico , Interleucina-4/antagonistas & inibidores , Interleucina-5/antagonistas & inibidores , Omalizumab/uso terapêutico , Piridinas/uso terapêutico , Células Th2/fisiologia , Resultado do Tratamento
2.
J Orthop Res ; 38(1): 139-149, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31441099

RESUMO

Secondary joint damage is the process by which a single injury can lead to detrimental changes in adjacent tissue structures, typically through the spread of inflammatory responses. We recently developed an in vitro model of secondary joint damage using a murine rotator cuff explant system, in which injuries to muscle and bone cause massive cell death in otherwise uninjured tendon. The purpose of the present study was to test the ability cytokine-targeted and broad-spectrum therapeutics to prevent cell death and tissue degeneration associated with secondary joint damage. We treated injured bone-tendon-muscle explants with either interleukin-1 receptor antagonist, etanercept, or dexamethasone (DEX) for up to 7 days in culture. Only the low-dose DEX treatment was able to prevent cell death and tissue degeneration. We then identified a critical window between 24 and 72 h following injury for maximal benefit of DEX treatment through timed administration experiments. Finally, we performed two tendon-only explant studies to identify mechanistic effects on tendon health. Interestingly, DEX did not prevent cell death and degeneration in a model of cytokine-induced damage, suggesting other targets of DEX activity. Future studies will aim to identify factors in joint inflammation that may be targeted by DEX treatment, as well as to investigate novel delivery strategies. Statement of clinical significance: Overall, this work demonstrates beneficial effects of DEX administration on preventing tenocyte death and extracellular matrix degeneration in an explant model of secondary joint damage, supporting the clinical use of low-dose glucocorticoids for short-term treatment of joint inflammation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:139-149, 2020.


Assuntos
Dexametasona/uso terapêutico , Lesões do Manguito Rotador/prevenção & controle , Animais , Morte Celular/efeitos dos fármacos , Citocinas/antagonistas & inibidores , Citocinas/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Lesões do Manguito Rotador/cirurgia , Estresse Mecânico
3.
Int J Oral Sci ; 11(3): 30, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31685798

RESUMO

Periodontitis is an inflammatory disease involving the destruction of both soft and hard tissue in the periodontal region. Although dysbiosis of the local microbial community initiates local inflammation, over-activation of the host immune response directly activates osteoclastic activity and alveolar bone loss. Many studies have reported on the cytokine network involved in periodontitis and its crucial and pleiotropic effect on the recruitment of specific immunocytes, control of pathobionts and induction or suppression of osteoclastic activity. Nonetheless, particularities in the stimulation of pathogens in the oral cavity that lead to the specific and complex periodontal cytokine network are far from clarified. Thus, in this review, we begin with an up-to-date aetiological hypothesis of periodontal disease and summarize the roles of cytokines in the host immune response. In addition, we also summarize the latest cytokine-related therapeutic measures for periodontal disease.


Assuntos
Citocinas/metabolismo , Inflamação , Periodontite/imunologia , Periodontite/microbiologia , Perda do Osso Alveolar/etiologia , Citocinas/fisiologia , Humanos , Doenças Periodontais , Fator de Necrose Tumoral alfa/fisiologia
4.
Adv Clin Chem ; 93: 63-113, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31655733

RESUMO

The natural history of heart failure (HF) is not linear, because changes in the heart structure and function start long before the disease becomes clinically evident. Many different cytokines originating from intracardiac tissues (cardiomyocytes, cardiac endothelial cells, cardiac fibroblasts, and cardiac infiltrated immune cells) or extracardiac tissues (adipose tissue, gut, and lymphoid organs) have been identified in HF. Because the levels of circulating cytokines correlate with the development and severity of HF, these mediators may have both pathophysiological importance, through their ability to modulate inflammation, myocyte stress/stretch, myocyte injury and apoptosis, fibroblast activation and extracellular matrix remodeling, and utility as clinical predictive biomarkers. A greater understanding of the mechanisms mediated by the multifaceted network of cytokines, leading to distinct HF phenotypes (HF with reduced or preserved ejection fraction), is urgently needed for the development of new treatment strategies. In this chapter, all these issues were thoroughly discussed, pointing on the practical considerations concerning the clinical use of the cytokines as prognostic biomarkers and potential therapeutic targets in HF.


Assuntos
Citocinas/fisiologia , Insuficiência Cardíaca/fisiopatologia , Biomarcadores/sangue , Citocinas/sangue , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/classificação , Humanos , Mediadores da Inflamação/sangue
5.
Orthopade ; 48(11): 911-916, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31531702

RESUMO

Inflammatory rheumatic diseases are often associated with secondary osteoporosis, as many inflammatory messengers can interfere with bone metabolism and adversely affect it. In addition to a decrease in densitometric bone density, remodeling occurs in the trabecular bone, which can lead to a disturbed microarchitecture and increase the risk of fracture.Central to this is the close integration of bone metabolism and the immune system. Proinflammatory cytokines play an important role not only in the inflammatory process, but also as mediators of bone resorption because they stimulate osteoclastogenesis and induce further signal transduction cascades with negative influence on the bone. The understanding gained in recent years of the underlying immunological processes has led to the development of new and targeted treatment approaches.


Assuntos
Reabsorção Óssea/imunologia , Citocinas/fisiologia , Osteoporose , Doenças Reumáticas/imunologia , Remodelação Óssea , Reabsorção Óssea/metabolismo , Humanos , Mediadores da Inflamação/fisiologia , Osteoblastos/fisiologia , Osteoclastos/fisiologia , Doenças Reumáticas/metabolismo
6.
Med Hypotheses ; 131: 109313, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443758

RESUMO

Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary disease caused by a mutation in the intracellular domain of the activin A receptor type I and is characterized by episodes (flare-ups) of progressive heterotopic endochondral ossification (HO) in the soft tissues. The mutation alone is not sufficient for the occurrence of HO since flare-ups are triggered by inflammation and activation of the innate immune system. A number of cellular and humoral mediators have been implicated in animal and in vitro models. Observations in humans support the inflammatory nature of the condition, but data on the involved mediators are variable. We hypothesize that for induction of flare-ups in patients with FOP increase in at least one of the pro-inflammatory cytokines is both essential and sufficient to trigger the entire process of the inflammatory cells influx resulting in the novel ectopic bone formation and we suggest that C-C motif ligand 5 (CCL5), a pro-inflammatory chemokine also known as Regulated on activation, normal T-cell expressed and secreted (RANTES), might be the key candidate. CCL5 is a chemoattractant for all cellular types implicated in HO and is produced by the cells of the tissue microenvironment at the sites of HO as well as by the pro-inflammatory cellular mediators. CCL5 induces ossification in cultured human pluripotent mesenchymal cells (hMSCs) and in the primary culture of monocytes from FOP patients (but not from their healthy relatives), stimulation with lipopolysaccharide induces CCL5 expression. Finally, in a pilot study we used a panel of 23 cytokines and chemokines to screen the plasma samples of three subjects: a female patient with FOP during a flare-up; a female patient with hyperostosis corticalis generalisata (van Buchem disease), another rare disease characterized by excessive bone formation at the sites where it regularly occurs that does not include inflammatory events; and a healthy woman without bone disorders. There appeared a rather clear-cut signal of a 2-fold higher level of CCL5 in the FOP patient vs. the healthy subject and the van Buchem patient. Evaluation of the hypothesis would require an international prospective study, with main motivation being the lack of a conclusive treatment as the major unmet need in FOP. A treatment targeting CCL5 receptor already exists and is used in HIV-infected patients.


Assuntos
Quimiocina CCL5/sangue , Terapia de Alvo Molecular , Miosite Ossificante/sangue , Ossificação Heterotópica/sangue , Quimiocina CCL5/antagonistas & inibidores , Citocinas/fisiologia , Feminino , Humanos , Inflamação , Lipopolissacarídeos/farmacologia , Células-Tronco Mesenquimais/metabolismo , Modelos Imunológicos , Monócitos/metabolismo , Miosite Ossificante/tratamento farmacológico , Miosite Ossificante/imunologia , Ossificação Heterotópica/imunologia , Osteocondrodisplasias/sangue , Células-Tronco Pluripotentes/metabolismo
7.
Med Hypotheses ; 131: 109294, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443760

RESUMO

Narcolepsy type 1 is a lifelong sleep disorder characterized by the loss of hypocretin-producing neurons in the brain. Environmental agents, including influenza, neurotoxic metals, and combustion smoke, have been implicated in the pathogenesis, especially in carriers of the human leukocyte antigen class II DQB1*06:02 allele. Sensitive experimental approaches have recently revealed hypocretin-autoreactive CD4+ and CD8+ T cells in the blood of narcoleptic patients. However, such potentially harmful cells are also detectable, to a lesser degree, in control DQB1*06:02 carriers, suggesting that the integrity of the blood-brain barrier (BBB) provides a neuroprotective effect. Here, we present the hypothesis that external toxic agents induce neuroinflammation in the olfactory bulb and concomitant overproduction of proinflammatory cytokines (e.g., tumor necrosis factor-α and interferon-γ); this, in turn, compromises the BBB, allowing autoimmune cells to access and kill hypocretinergic neurons. Such sequential pathological alterations could occur insidiously, passing unnoticed and consequently being underestimated. The elevated number of autoreactive T cells in narcoleptics relative to controls might reflect externally induced immunomodulation rather than a direct disease trigger.


Assuntos
Barreira Hematoencefálica/fisiologia , Cadeias beta de HLA-DQ/imunologia , Modelos Imunológicos , Narcolepsia/imunologia , Bulbo Olfatório/fisiopatologia , Animais , Autoantígenos/imunologia , Autoantígenos/metabolismo , Citocinas/fisiologia , Poluentes Ambientais/farmacocinética , Poluentes Ambientais/toxicidade , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Mimetismo Molecular , Narcolepsia/etiologia , Narcolepsia/fisiopatologia , Neurônios/metabolismo , Neurônios/patologia , Bulbo Olfatório/efeitos dos fármacos , Orexinas/imunologia , Orexinas/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/imunologia
8.
Med Hypotheses ; 131: 109287, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443764

RESUMO

Sarcoidosis is a multisystem disorder with non-caseating granulomas in various organs. The etiology of sarcoid granuloma formation is not clear and likely an antigen-induced process. We came across a previously treated sarcoidosis patient who presented with worsening dyspnea on exertion for several months and several days of difficulty swallowing. On Chest CT imaging, large posterior mediastinal mass was found that subsequently diagnosed as macrocystic lymphatic malformation after surgical resection. Pathophysiology of development of acquired lymphatic malformations in a sarcoidosis patient is currently not clear. We hypothesize there might be a complex interplay of Toll-like receptors, IFN-γ and the phosphatidylinositol 3-kinase pathway in the pathogenesis.


Assuntos
Interferon gama/fisiologia , Anormalidades Linfáticas/etiologia , Doenças do Mediastino/etiologia , Modelos Biológicos , Fosfatidilinositol 3-Quinase/fisiologia , Sarcoidose/complicações , Receptores Toll-Like/fisiologia , Citocinas/fisiologia , Transtornos de Deglutição/etiologia , Dispneia/etiologia , Feminino , Granuloma/fisiopatologia , Humanos , Anormalidades Linfáticas/fisiopatologia , Doenças do Mediastino/fisiopatologia , Transdução de Sinais/fisiologia
9.
J Appl Oral Sci ; 27: e20180365, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365708

RESUMO

OBJECTIVES: Visfatin is an adipokine that plays an important role in immune functions as a growth factor, enzyme, and pro-inflammatory mediator. We aimed to determine the levels of visfatin, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in gingival crevicular fluid (GCF) in both obese/non-obese patients, with/without generalized chronic periodontitis (GCP). METHODOLOGY: Patients were categorized as obese (O) (n=31) or non-obese (nO) (n=19). Groups were divided into four subgroups according to periodontal conditions: (1) periodontally healthy without obesity (nO-Ctrl); (2) GCP without obesity (nO-CP); (3) periodontally healthy with obesity (O-Ctrl); and (4) GCP with obesity (O-CP). Demographic variables, anthropometric and laboratory data were recorded. Periodontal parameters were measured at baseline and 3rd months after either non-surgical periodontal treatment or calorie -restricted diet therapy. At the same time, GCF samples were taken from patients to analyze TNF-alpha, IL-6,and visfatin levels. RESULTS: Periodontal parameters were significantly higher in the O group than in the nO group (P<0.05). IL-6 levels were higher in the O group than in the nO group (P<0.001). The visfatin levels of the obese patients were reduceddecreased following the treatments (P<0.05). Cholesterol levels were higher in the O group than in the nO groups (P<0.05). IL-6 levels were higher in O-CP and O-Ctrl groups than in the nO-Ctrl group (P<0.05). Compared to the other groups, visfatin levels were significantly higher in the O-CP group but decreased following treatment (P<0.05). CONCLUSIONS: Our findings suggest that visfatin and IL-6 levels in GCF are associated with the pathogenesis of obesity and periodontitis. Within the limits of this study, we considered that there might be an association between the lipid profile and periodontitis on systemically healthy individuals.


Assuntos
Citocinas/análise , Líquido do Sulco Gengival/química , Interleucina-6/análise , Nicotinamida Fosforribosiltransferase/análise , Obesidade/metabolismo , Periodontite/metabolismo , Fator de Necrose Tumoral alfa/análise , Adulto , Idoso , Biomarcadores/análise , Índice de Massa Corporal , Estudos de Casos e Controles , Citocinas/fisiologia , Feminino , Humanos , Interleucina-6/fisiologia , Masculino , Pessoa de Meia-Idade , Nicotinamida Fosforribosiltransferase/fisiologia , Índice Periodontal , Periodontite/diagnóstico por imagem , Radiografia Panorâmica , Valores de Referência , Estatísticas não Paramétricas , Fator de Necrose Tumoral alfa/fisiologia
10.
Nat Rev Neurol ; 15(8): 483-490, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263254

RESUMO

Migraine is a prevalent disorder, affecting 15.1% of the world's population. In most cases, the migraine attacks are sporadic; however, some individuals experience a gradual increase in attack frequency over time, and up to 2% of the general population develop chronic migraine. The mechanisms underlying this chronicity are unresolved but are hypothesized to involve a degree of inflammation. In this article, we review the relevant literature related to inflammation and migraine, from the initiation of attacks to chronification. We propose that the increase in migraine frequency leading to chronic migraine involves neurogenic neuroinflammation, possibly entailing increased expression of cytokines via activation of protein kinases in neurons and glial cells of the trigeminovascular system. We present evidence from preclinical research that supports this view and discuss the implications for migraine therapy.


Assuntos
Encéfalo/fisiopatologia , Encefalite/fisiopatologia , Transtornos de Enxaqueca/fisiopatologia , Animais , Citocinas/fisiologia , Progressão da Doença , Encefalite/complicações , Humanos , Transtornos de Enxaqueca/complicações , Neuroglia/fisiologia , Neurônios/fisiologia
11.
Neurosci Bull ; 35(4): 595-607, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31214924

RESUMO

Neuroimmune system may be involved in the pathological process of bipolar disorder (BD), but the essential association is not fully understood. Accumulating evidence has shown that BD involves the activation of immune cells and the release of inflammatory substances in the central nerve system (CNS). Meanwhile, neuroimmune responses also interact with other hypothesis of the etiology of BD that are widely recognized, such as neurotransmitter systems, neuroendocrine systems, neurotrophic factors, and oxidative stress. Simultaneously, related genes and immune changes in peripheral blood vary with it. Overall, neuroimmunity may play an important role in the pathogenesis of BD, and the inflammatory cytokines, especially interleukin-6 and tumor necrosis factor-alpha, have potential value for the clinical diagnosis and prognosis of BD, as well as predicting the therapeutic effects of drugs. Large-scale studies are needed to extend the evidence on neuroimmunity in BD, and to examine its clinical value for applications such as early prediction and treatment.


Assuntos
Transtorno Bipolar/fisiopatologia , Citocinas/fisiologia , Sistema Imunitário/fisiopatologia , Neuroglia/fisiologia , Neuroimunomodulação/fisiologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Citocinas/metabolismo , Humanos , Inflamação/fisiopatologia , Fatores de Crescimento Neural/fisiologia , Sistemas Neurossecretores/fisiopatologia , Neurotransmissores/fisiologia , Estresse Oxidativo/fisiologia
12.
Nat Neurosci ; 22(7): 1089-1098, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31235908

RESUMO

Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here we generate an inducible pericyte-specific Cre line and cross pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor. After pericyte ablation with diphtheria toxin, mice showed acute blood-brain barrier breakdown, severe loss of blood flow, and a rapid neuron loss that was associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing of pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade that links pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings may have implications for the pathogenesis and treatment of neurological disorders that are associated with pericyte loss and/or neurovascular dysfunction.


Assuntos
Proteínas de Transporte/fisiologia , Citocinas/fisiologia , Degeneração Neural/fisiopatologia , Proteínas do Tecido Nervoso/fisiologia , Neurônios/patologia , Pericitos/fisiologia , Choque/fisiopatologia , Animais , Isquemia Encefálica/fisiopatologia , Capilares/fisiopatologia , Proteínas de Transporte/uso terapêutico , Células Cultivadas , Circulação Cerebrovascular/fisiologia , Citocinas/deficiência , Citocinas/uso terapêutico , Células Endoteliais/citologia , Feminino , Genes Reporter , Infusões Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Degeneração Neural/tratamento farmacológico , Neuroglia/metabolismo , Neurônios/metabolismo , Neurotoxinas/toxicidade , Regiões Promotoras Genéticas , Proteínas Recombinantes de Fusão/metabolismo , Choque/metabolismo , Choque/patologia
13.
Nat Neurosci ; 22(7): 1053-1056, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209376

RESUMO

The lateral habenula encodes aversive stimuli contributing to negative emotional states during drug withdrawal. Here we report that morphine withdrawal in mice leads to microglia adaptations and diminishes glutamatergic transmission onto raphe-projecting lateral habenula neurons. Chemogenetic inhibition of this circuit promotes morphine withdrawal-like social deficits. Morphine withdrawal-driven synaptic plasticity and reduced sociability require tumor necrosis factor-α (TNF-α) release and neuronal TNF receptor 1 activation. Hence, habenular cytokines control synaptic and behavioral adaptations during drug withdrawal.


Assuntos
Citocinas/fisiologia , Habenula/fisiologia , Morfina/efeitos adversos , Comportamento Social , Síndrome de Abstinência a Substâncias/fisiopatologia , Transmissão Sináptica/fisiologia , Adaptação Psicológica , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/fisiologia , Naloxona/toxicidade , Plasticidade Neuronal , Distribuição Aleatória , Receptores de Glutamato/análise , Receptores de N-Metil-D-Aspartato/análise , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/fisiologia , Síndrome de Abstinência a Substâncias/psicologia , Fator de Necrose Tumoral alfa/fisiologia
14.
Yakugaku Zasshi ; 139(6): 853-859, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31155525

RESUMO

In most mammalian species, adult neurogenesis appears to occur only in the olfactory bulb and hippocampal dentate gyrus, where neural stem/progenitor cells exist to create new neurons. The discovery of multi-potential neural stem/progenitor cells (NPCs) in the adult brain has precipitated a novel therapeutic strategy for harnessing these endogenous cells to aid in recovery from neurodegenerative disorders. During neurodegeneration, a plethora of endogenous factors, including cytokines, chemokines, neurotransmitters, blood-derived factors, and reactive oxygen species, are released by the activation of resident microglia, astrocytes, and infiltrating peripheral macrophages. It is interesting that these endogenous factors affect the proliferation, migration, differentiation, and survival of newly generated cells involved in the incorporation of newly generated neurons into the brain's circuitry. The unique profile of these endogenous factors can vary the degree of neuroregeneration after neurodegeneration. We show that adult neurogenesis-activating signals are regulated by endogenous factors produced during neurodegeneration.


Assuntos
Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Terapia de Alvo Molecular , Células-Tronco Multipotentes/fisiologia , Células-Tronco Neurais/fisiologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/terapia , Neurogênese/genética , Neurogênese/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Animais , Encéfalo/citologia , Quimiocinas/fisiologia , Citocinas/fisiologia , Humanos , Camundongos , Regeneração Nervosa/genética , Regeneração Nervosa/fisiologia , Neurotransmissores/fisiologia , Espécies Reativas de Oxigênio
15.
Forensic Sci Int ; 302: 109856, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31247451

RESUMO

The assessment and interpretation of the timing of skeletal trauma can be of extreme difficulty in post-mortem specimens, especially because of post-mortem processes and taphonomic events. The chronological diagnosis of bone trauma, consisting usually in the gross distinction between antemortem, perimortem and post-mortem, is based almost uniquely on macroscopic and morphologic parameters in the anthropological field. However, both the interference of taphonomy and the scarce persistence of specific features indicating vitality (meaning etymologically "produced in life") and/or some very early bone healing reactions, make it extremely difficult. In this perspective, it is important not only to distinguish between peri and post-mortem lesions, but also to interpret perimortem lesions with respect to vitality and time elapsed since the trauma which may change the course of the investigations. And techniques of forensic pathology applied to forensic anthropology can come in extremely handy. If any traces of vital blood extravasation, haemorrhage, hematoma, inflammation, and biomarkers of early healing reaction are found in the bone tissue of a skeletal lesion (regardless the state of preservation of the body), then can they be used as a diagnostic tool or marker of vitality for that lesion? In these terms, vital reactions like bleeding or any early sign of bone healing can be the only evidence for demonstrating that a traumatic event was prior the death. Nevertheless, very little information, or research for that matter, is available in literature concerning persistence and detectability of vitality markers during the bone decomposition process. A fundamental point for properly determining the vitality of a fracture and estimating the post-traumatic time interval in skeletal lesions is the physio-pathological picture of the very initial healing process. This article attempts to provide a review of the physiopathological current knowledge available and applicable to osteology.


Assuntos
Remodelação Óssea/fisiologia , Fraturas Ósseas/patologia , Osteogênese/fisiologia , Biomarcadores/metabolismo , Coagulação Sanguínea/fisiologia , Citocinas/fisiologia , Hematoma/patologia , Hemorragia/patologia , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Neovascularização Fisiológica/fisiologia , Osteoblastos/fisiologia , Osteoclastos/fisiologia
16.
Clin Rheumatol ; 38(7): 1889-1895, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31127464

RESUMO

To report the simultaneous occurrence of psoriatic arthritis (PsA) and chronic regional pain syndrome type I (CRPS I) both triggered by intense walking in a male golfer with a history of scalp psoriasis. Sequential existence of these two conditions have been reported in the literature; however, to our knowledge, this is the first report of a simultaneous occurrence of PsA and CRPS I. This case illustrates the complex interplay between genetic predisposition and environmental risk factors with the central nervous and immune systems. As the pathogenesis of PsA has been better understood in recent years, we propose a mechanism that explains how the release of pro-inflammatory cytokines and neuropeptides following a traumatic event elicits a vicious cycle that is a common ground for the development of both PsA and CRPS I. Even unperceived trauma, such as intense walking, when directed to the synovio-entheseal complex, can precipitate the development of PsA and CRPS I in predisposed individuals.


Assuntos
Artrite Psoriásica/diagnóstico , Artrite Psoriásica/etiologia , Síndromes da Dor Regional Complexa/diagnóstico , Síndromes da Dor Regional Complexa/etiologia , Traumatismos do Pé/complicações , Doença Crônica , Citocinas/fisiologia , Traumatismos do Pé/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Neuropeptídeos/fisiologia
17.
Best Pract Res Clin Endocrinol Metab ; 33(3): 101275, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31047817

RESUMO

Pubertal disorders in the context of chronic disease especially in those with chronic inflammatory disorders or those requiring prolonged periods of treatment with glucocorticoid are common reasons for referral to the paediatric endocrine clinic. Disorders of puberty are also common in adolescents with disability requiring management by paediatric endocrinologists. In these adolescents, impaired skeletal development is also observed and this can be associated with fragility fractures. Chronic inflammation, glucocorticoid and sub-optimal nutrition all impact on the hypothalamic-pituitary gonadal axis, and can also impact on skeletal development locally by their effects on the growth plate and bone. Addressing pubertal disorders is important to ensure adolescents with chronic disease are matched with their peers, promote adequate bone mass accrual and linear growth. Careful discussion with primary clinicians, the young person and the family is needed when instituting endocrine therapies to address puberty and manage bone health.


Assuntos
Puberdade Tardia/etiologia , Adolescente , Densidade Óssea , Desenvolvimento Ósseo , Paralisia Cerebral/complicações , Doença Crônica , Citocinas/fisiologia , Feminino , Glucocorticoides/efeitos adversos , Humanos , Doenças Inflamatórias Intestinais/complicações , Distrofia Muscular de Duchenne/complicações , Estado Nutricional
18.
Minerva Endocrinol ; 44(3): 264-272, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30991794

RESUMO

Incretin hormones, namely glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gastro-intestinal hormones released from different enteroendocrine cells after nutrient intake. Incretins exert their actions though binding to and activation of specific GIP and GLP-1 receptors which are present in several target tissues. Incretin receptor activation in the pancreas leads to the incretin effect and other significant non-insulinotropic effects. Extra-pancreatic effects of incretin hormones in several other target tissues, such as their role in the pathophysiology of obesity and their potential relation with cardiovascular function, cognitive function, triglyceride storage in adipose tissue and bone metabolism, have attracted scientific interest. In the current review we intend to summarize existing knowledge on specific effects of GIP and GLP-1 in bone cells and bone metabolism. Starting from the identification of GIP receptor and GLP-1 receptor in animal and human bone cells, continuing with the skeletal effects of incretin deficiency or overexpression in animals, ending to the latest data on incretin and incretin agonists administration in cells, animals and humans, incretins play a significant yet complex role in the pathophysiology of bone metabolism affecting both formation and resorption. Although existing evidence seem strong and concrete, there is still a long way to go until their possible therapeutic or adjuvant use as bone modulating drugs can be considered.


Assuntos
Osso e Ossos/metabolismo , Incretinas/fisiologia , Animais , Citocinas/fisiologia , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Humanos
19.
Nat Commun ; 10(1): 1796, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30996264

RESUMO

Metabolic reprogramming is an active regulator of stem cell fate choices, and successful stem cell differentiation in different compartments requires the induction of oxidative phosphorylation. However, the mechanisms that promote mitochondrial respiration during stem cell differentiation are poorly understood. Here we demonstrate that Stat3 promotes muscle stem cell myogenic lineage progression by stimulating mitochondrial respiration in mice. We identify Fam3a, a cytokine-like protein, as a major Stat3 downstream effector in muscle stem cells. We demonstrate that Fam3a is required for muscle stem cell commitment and skeletal muscle development. We show that myogenic cells secrete Fam3a, and exposure of Stat3-ablated muscle stem cells to recombinant Fam3a in vitro and in vivo rescues their defects in mitochondrial respiration and myogenic commitment. Together, these findings indicate that Fam3a is a Stat3-regulated secreted factor that promotes muscle stem cell oxidative metabolism and differentiation, and suggests that Fam3a is a potential tool to modulate cell fate choices.


Assuntos
Diferenciação Celular , Citocinas/fisiologia , Desenvolvimento Muscular/fisiologia , Mioblastos/fisiologia , Fator de Transcrição STAT3/fisiologia , Células-Tronco/fisiologia , Animais , Animais Recém-Nascidos , Linhagem da Célula/fisiologia , Células Cultivadas , Embrião de Mamíferos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Músculo Estriado/citologia , Músculo Estriado/crescimento & desenvolvimento , Fosforilação Oxidativa , Transdução de Sinais/fisiologia
20.
Metabolism ; 96: 46-55, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31029770

RESUMO

The incretin effect, the amplification of insulin secretion occurring when glucose is taken in orally as compared to infused intravenously, is one of the factors that help the body to tolerate carbohydrate/glucose ingestion. These include 1) amount and type of carbohydrates; 2) gastric emptying rate; 3) digestion and absorption of the carbohydrates; 4) secretion and effect of the incretin hormones; 5) disposition of absorbed nutrients/glucose. The incretin effect can also be viewed as the fraction of the ingested glucose load handled via gastrointestinal mechanisms (including the incretin effect); it is calculated by comparison of the amount of glucose required to copy, by intravenous infusion, the oral load. Typically, for 75 g of oral glucose, about 25 g are required. This means that the GastroIntestinal Glucose Disposal (GIGD) is 66%. Both the GIGD and the incretin effect depend on the amount of glucose ingested: for higher doses the GIGD may amount to 80%, which shows that this effect is a major contributor to glucose tolerance. The main mechanism behind it is stimulation of insulin secretion by a proportional secretion of the insulinotropic hormones GIP and GLP-1. Recently it has become possible to estimate their contributions in healthy humans using specific and potent receptor antagonists. Both hormones act to improve glucose tolerance (i.e. the antagonists impair tolerance) and their effects are additive. GIP seems to be quantitatively the most important, particularly regarding insulin secretion, whereas the action of GLP-1 is mainly displayed via inhibition of glucagon secretion.


Assuntos
Citocinas/fisiologia , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Incretinas/fisiologia , Nível de Saúde , Humanos , Insulina/metabolismo , Transdução de Sinais/fisiologia
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