Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 33.846
Filtrar
1.
Biomed Pharmacother ; 139: 111557, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243621

RESUMO

Migraine is a neurological ailment that is characterized by severe throbbing unilateral headache and associated with nausea, photophobia, phonophobia and vomiting. A full and clear mechanism of the pathogenesis of migraine, though studied extensively, has not been established yet. The current available information indicates an intracranial network activation that culminates in the sensitization of the trigemino-vascular system, release of inflammatory markers, and initiation of meningeal-like inflammatory reaction that is sensed as headache. Genetic factors might play a significant role in deciding an individual's susceptibility to migraine. Twin studies have revealed that a single gene polymorphism can lead to migraine in individuals with a monogenic migraine disorder. In this review, we describe recent advancements in the genetics, pathophysiology, diagnosis, treatment, management, and prevention of migraine. We also discuss the potential roles of genetic and abnormal factors, including some of the metabolic triggering factors that result in migraine attacks. This review will help to accumulate current knowledge about migraine and understanding of its pathophysiology, and provides up-to-date prevention strategies.


Assuntos
Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/patologia , Animais , Genética , Humanos , Inflamação/diagnóstico , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/patologia , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/tratamento farmacológico , Polimorfismo de Nucleotídeo Único/genética
2.
FASEB J ; 35(8): e21761, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34245616

RESUMO

Uremic cardiomyopathy is a common complication in chronic kidney disease (CKD) patients, accounting for a high mortality rate. Several mechanisms have been proposed to link CKD and cardiac alterations; however, the early cardiac modifications that occur in CKD that may trigger cardiac remodeling and dysfunction remain largely unexplored. Here, in a mouse model of CKD induced by 5/6 nephrectomy, we first analyzed the early transcriptional and inflammatory changes that occur in the heart. Five days after 5/6 nephrectomy, RNA-sequencing showed the upregulation of 54 genes in the cardiac tissue of CKD mice and the enrichment of biological processes related to immune system processes. Increased cardiac infiltration of T-CD4+ lymphocytes, myeloid cells, and macrophages during early CKD was observed. Next, since CC chemokine ligand-8 (CCL8) was one of the most upregulated genes in the heart of mice with early CKD, we investigated the effect of acute and transient CCL8 inhibition on uremic cardiomyopathy severity. An increase in CCL8 protein levels was confirmed in the heart of early CKD mice. CCL8 inhibition attenuated the early infiltration of T-CD4+ lymphocytes and macrophages to the cardiac tissue, leading to a protection against chronic cardiac fibrotic remodeling, inflammation and cardiac dysfunction induced by CKD. Altogether, our data show the occurrence of transcriptional and inflammatory changes in the heart during the early phases of CKD and identify CCL8 as a key contributor to the early cardiac inflammatory state that triggers further cardiac remodeling and dysfunction in uremic cardiomyopathy.


Assuntos
Cardiomiopatias/metabolismo , Quimiocina CCL8/biossíntese , Miocárdio/metabolismo , Insuficiência Renal Crônica/metabolismo , Regulação para Cima , Uremia/metabolismo , Animais , Cardiomiopatias/patologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Miocárdio/patologia , Insuficiência Renal Crônica/patologia , Uremia/patologia
3.
AAPS PharmSciTech ; 22(5): 204, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34258696

RESUMO

Hirsutism is a dermatological condition that refers to the excessive growth of hair in androgen-sensitive areas in women. Recently, the enhancement of the visible signs of a hairy female has taken special concern that affected the quality of life. The present study was developed to compare the follicular targeting effect of topical spironolactone (SP) or progesterone (PG)-loaded nanostructured lipid carrier (NLC) on the management of hirsutism. Four NLC formulations were prepared using cold homogenization techniques and pharmaceutically evaluated. SP-NLC and PG-NLC topical hydrogels were prepared to explore their pharmacological effect on letrozole induced polycystic ovarian syndrome (PCOS) in rats. Inflammatory mediators, antioxidant, and hormonal parameters were assayed. Additionally, histopathological examination was carried out to confirm the successful induction of PCOS. Results confirmed that all NLC formulations have a spherical shape with particle size ranged from 225.92 ± 0.41 to 447.80 ± 0.66 nm, entrapment efficiency > 75%, and zeta potential (- 31.4 to - 36.5 mV). F1 and F3 NLCs were considered as selected formulations for SP and PG, respectively. Female Wistar rats treated with F1 formulation for 3 weeks displayed better outcomes as manifested by the measured parameters as compared to the other tested groups. A significant reduction in hair follicle diameter and density was observed after topical application of SP or PG nano-gels. Finally, the outcomes pose a strong argument that the development of topically administered SP-NLC can be explored as a promising carrier over PG-NLC for more effectual improvement in the visible sign of hirsutism.


Assuntos
Portadores de Fármacos/administração & dosagem , Hirsutismo/sangue , Hirsutismo/tratamento farmacológico , Nanoestruturas/administração & dosagem , Progesterona/administração & dosagem , Espironolactona/administração & dosagem , Animais , Portadores de Fármacos/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Hidrogéis/administração & dosagem , Hidrogéis/síntese química , Inflamação/tratamento farmacológico , Inflamação/patologia , Nanoestruturas/química , Tamanho da Partícula , Progesterona/síntese química , Ratos , Ratos Wistar , Espironolactona/síntese química
4.
PLoS Pathog ; 17(7): e1009705, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34265022

RESUMO

COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is a disease affecting several organ systems. A model that captures all clinical symptoms of COVID-19 as well as long-haulers disease is needed. We investigated the host responses associated with infection in several major organ systems including the respiratory tract, the heart, and the kidneys after SARS-CoV-2 infection in Syrian hamsters. We found significant increases in inflammatory cytokines (IL-6, IL-1beta, and TNF) and type II interferons whereas type I interferons were inhibited. Examination of extrapulmonary tissue indicated inflammation in the kidney, liver, and heart which also lacked type I interferon upregulation. Histologically, the heart had evidence of myocarditis and microthrombi while the kidney had tubular inflammation. These results give insight into the multiorgan disease experienced by people with COVID-19 and possibly the prolonged disease in people with post-acute sequelae of SARS-CoV-2 (PASC).


Assuntos
COVID-19/imunologia , Regulação para Baixo/imunologia , Interferon Tipo I/imunologia , Rim/imunologia , Miocárdio/imunologia , Sistema Respiratório/imunologia , SARS-CoV-2/imunologia , Animais , COVID-19/patologia , Cricetinae , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Inflamação/patologia , Rim/patologia , Rim/virologia , Masculino , Mesocricetus , Miocárdio/patologia , Sistema Respiratório/patologia , Sistema Respiratório/virologia
5.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281284

RESUMO

Progressive diabetic nephropathy (DN) in diabetes leads to major morbidity and mortality. The major pathological alterations of DN include mesangial expansion, extracellular matrix alterations, tubulointerstitial fibrosis, and glomerular sclerosis. Polygoni avicularis is widely used in traditional oriental medicine and has long been used as a diuretic, astringent, insecticide and antihypertensive. However, to the best of the authors' knowledge, the effects of the ethanolic extract from rhizome of Polygoni avicularis (ER-PA) on DN have not yet been assessed. The present study aimed to identify the effect of ER-PA on renal dysfunction, which has been implicated in DN in human renal mesangial cells and db/db mice and investigate its mechanism of action. The in vivo experiment was performed using Polygoni avicularis-ethanol soluble fraction (ER-PA) and was administrated to db/db mice at 10 and 50 mg/kg dose. For the in vitro experiments, the human renal mesangial cells were induced by high glucose (HG, 25 mM). The ER-PA group showed significant amelioration in oral glucose tolerance, and insulin resistance index. ER-PA significantly improved the albumin excretion and markedly reduced plasma creatinine, kidney injury molecule-1 and C-reactive protein. In addition, ER-PA significantly suppressed inflammatory cytokines. Histopathologically, ER-PA attenuated glomerular expansion and tubular fibrosis in db/db mice. Furthermore, ER-PA suppressed the expression of renal fibrosis biomarkers (TGF and Collagen IV). ER-PA also reduced the NLR family pyrin domain containing 3 inflammatory factor level. These results suggest that ER-PA has a protective effect against renal dysfunction through improved insulin resistance as well as the inhibition of nephritis and fibrosis in DN.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Fitoterapia , Polygonum/química , Animais , Células Cultivadas , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Fibrose , Glucose/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Resistência à Insulina , Masculino , Proteínas de Membrana/metabolismo , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Células Mesangiais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Rizoma/química
6.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199865

RESUMO

In obese patients, enhanced serum levels of free fatty acids (FFA), such as palmitate (PA) or oleate (OA), are associated with an increase in systemic inflammatory markers. Bacterial infection during periodontal disease also promotes local and systemic low-grade inflammation. How both conditions concomitantly impact tooth movement is largely unknown. Thus, the aim of this study was to address the changes in cytokine expression and the secretion of human periodontal ligament fibroblasts (HPdLF) due to hyperlipidemic conditions, when additionally stressed by bacterial and mechanical stimuli. To investigate the impact of obesity-related hyperlipidemic FFA levels on HPdLF, cells were treated with 200 µM PA or OA prior to the application of 2 g/cm2 compressive force. To further determine the additive impact of bacterial infection, HPdLF were stimulated with lipopolysaccharides (LPS) obtained from Porphyromonas gingivalis. In mechanically compressed HPdLF, PA enhanced COX2 expression and PGE2 secretion. When mechanically stressed HPdLF were additionally stimulated with LPS, the PGE2 and IL6 secretion, as well as monocyte adhesion, were further increased in PA-treated cultures. Our data emphasize that a hyperlipidemic condition enhances the susceptibility of HPdLF to an excessive inflammatory response to compressive forces, when cells are concomitantly exposed to bacterial components.


Assuntos
Fibroblastos/imunologia , Hiperlipidemias/fisiopatologia , Inflamação/imunologia , Lipopolissacarídeos/farmacologia , Ligamento Periodontal/imunologia , Porphyromonas gingivalis/química , Estresse Mecânico , Força Compressiva , Citocinas/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Ligamento Periodontal/efeitos dos fármacos , Ligamento Periodontal/patologia , Pressão
7.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199845

RESUMO

Inflammasomes are molecular hubs that are assembled and activated by a host in response to various microbial and non-microbial stimuli and play a pivotal role in maintaining tissue homeostasis. The NLRP3 is a highly promiscuous inflammasome that is activated by a wide variety of sterile triggers, including misfolded protein aggregates, and drives chronic inflammation via caspase-1-mediated proteolytic cleavage and secretion of proinflammatory cytokines, interleukin-1ß and interleukin-18. These cytokines further amplify inflammatory responses by activating various signaling cascades, leading to the recruitment of immune cells and overproduction of proinflammatory cytokines and chemokines, resulting in a vicious cycle of chronic inflammation and tissue damage. Neuromuscular diseases are a heterogeneous group of muscle disorders that involve injury or dysfunction of peripheral nerves, neuromuscular junctions and muscles. A growing body of evidence suggests that dysregulation, impairment or aberrant NLRP3 inflammasome signaling leads to the initiation and exacerbation of pathological processes associated with neuromuscular diseases. In this review, we summarize the available knowledge about the NLRP3 inflammasome in neuromuscular diseases that affect the peripheral nervous system and amyotrophic lateral sclerosis, which affects the central nervous system. In addition, we also examine whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes.


Assuntos
Inflamassomos/metabolismo , Inflamação/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doenças Neuromusculares/patologia , Animais , Humanos , Inflamação/complicações , Inflamação/metabolismo , Doenças Neuromusculares/etiologia , Doenças Neuromusculares/metabolismo
8.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201218

RESUMO

Ocular graft-versus-host disease (oGVHD) is a fast progressing, autoimmunological disease following hematopoietic stem cell transplantation, leading to severe inflammation of the eye and destruction of the lacrimal functional unit with consecutive sight-threatening consequences. The therapeutic "window of opportunity" is narrow, and current treatment options are limited and often insufficient. To achieve new insights into the pathogenesis and to develop new therapeutic approaches, clinically relevant models of oGVHD are desirable. In this study, the ocular phenotype was described in a murine, chemotherapy-based, minor-mismatch GVHD model mimicking early-onset chronic oGVHD, with corneal epitheliopathy, inflammation of the lacrimal glands, and blepharitis. Additionally, corneal lymphangiogenesis was observed as part of oGVHD pathogenesis for the first time, thus opening up the investigation of lymphangiogenesis as a potential therapeutic and diagnostic tool.


Assuntos
Antineoplásicos/toxicidade , Blefarite/patologia , Córnea/irrigação sanguínea , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Inflamação/patologia , Aparelho Lacrimal/patologia , Animais , Blefarite/etiologia , Blefarite/metabolismo , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Aparelho Lacrimal/metabolismo , Linfangiogênese , Camundongos , Camundongos Endogâmicos C57BL
9.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201387

RESUMO

Inflammation worsens oxalate nephropathy by exacerbating tubular damage. The transient receptor potential vanilloid 1 (TRPV1) channel is present in kidney and has a polymodal sensing ability. Here, we tested whether TRPV1 plays a role in hyperoxaluria-induced renal inflammation. In TRPV1-expressed proximal tubular cells LLC-PK1, oxalate could induce cell damage in a time- and dose-dependent manner; this was associated with increased arachidonate 12-lipoxygenase (ALOX12) expression and synthesis of endovanilloid 12(S)-hydroxyeicosatetraenoic acid for TRPV1 activation. Inhibition of ALOX12 or TRPV1 attenuated oxalate-mediated cell damage. We further showed that increases in intracellular Ca2+ and protein kinase C α activation are downstream of TRPV1 for NADPH oxidase 4 upregulation and reactive oxygen species formation. These trigger tubular cell inflammation via increased NLR family pyrin domain-containing 3 expression, caspase-1 activation, and interleukin (IL)-1ß release, and were alleviated by TRPV1 inhibition. Male hyperoxaluric rats demonstrated urinary supersaturation, tubular damage, and oxidative stress in a time-dependent manner. Chronic TRPV1 inhibition did not affect hyperoxaluria and urinary supersaturation, but markedly reduced tubular damage and calcium oxalate crystal deposition by lowering oxidative stress and inflammatory signaling. Taking all these results together, we conclude that TRPV1 hyperfunction contributes to oxalate-induced renal inflammation. Blunting TRPV1 function attenuates hyperoxaluric nephropathy.


Assuntos
Injúria Renal Aguda/complicações , Hiperoxalúria/complicações , Inflamação/patologia , Nefrite/patologia , Oxalatos/toxicidade , Estresse Oxidativo , Canais de Cátion TRPV/metabolismo , Animais , Hiperoxalúria/induzido quimicamente , Inflamação/etiologia , Inflamação/metabolismo , Masculino , Nefrite/etiologia , Nefrite/metabolismo , Ratos , Ratos Wistar , Canais de Cátion TRPV/genética
10.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201404

RESUMO

Neurodegenerative-neuroinflammatory disorders of the retina seriously hamper human vision. In searching for key factors that contribute to the development of these pathologies, we considered potential interactions among purinergic neuromodulation, glycinergic neurotransmission, and microglia activity in the retina. Energy deprivation at cellular levels is mainly due to impaired blood circulation leading to increased release of ATP and adenosine as well as glutamate and glycine. Interactions between these modulators and neurotransmitters are manifold. First, P2Y purinoceptor agonists facilitate reuptake of glycine by glycine transporter 1, while its inhibitors reduce reverse-mode operation; these events may lower extracellular glycine levels. The consequential changes in extracellular glycine concentration can lead to parallel changes in the activity of NR1/NR2B type NMDA receptors of which glycine is a mandatory agonist, and thereby may reduce neurodegenerative events in the retina. Second, P2Y purinoceptor agonists and glycine transporter 1 inhibitors may indirectly inhibit microglia activity by decreasing neuronal or glial glycine release in energy-compromised retina. These inhibitions may have a role in microglia activation, which is present during development and progression of neurodegenerative disorders such as glaucomatous and diabetic retinopathies and age-related macular degeneration or loss of retinal neurons caused by thromboembolic events. We have hypothesized that glycine transporter 1 inhibitors and P2Y purinoceptor agonists may have therapeutic importance in neurodegenerative-neuroinflammatory disorders of the retina by decreasing NR1/NR2B NMDA receptor activity and production and release of a series of proinflammatory cytokines from microglial cells.


Assuntos
Glicinérgicos/metabolismo , Inflamação/patologia , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Receptores Purinérgicos/metabolismo , Doenças Retinianas/patologia , Animais , Humanos , Inflamação/complicações , Inflamação/metabolismo , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Doenças Retinianas/complicações , Doenças Retinianas/metabolismo
11.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202516

RESUMO

Cognitive and motor impairment in minimal hepatic encephalopathy (MHE) are mediated by neuroinflammation, which is induced by hyperammonemia and peripheral inflammation. GABAergic neurotransmission in the cerebellum is altered in rats with chronic hyperammonemia. The mechanisms by which hyperammonemia induces neuroinflammation remain unknown. We hypothesized that GABAA receptors can modulate cerebellar neuroinflammation. The GABAA antagonist bicuculline was administrated daily (i.p.) for four weeks in control and hyperammonemic rats. Its effects on peripheral inflammation and on neuroinflammation as well as glutamate and GABA neurotransmission in the cerebellum were assessed. In hyperammonemic rats, bicuculline decreases IL-6 and TNFα and increases IL-10 in the plasma, reduces astrocyte activation, induces the microglia M2 phenotype, and reduces IL-1ß and TNFα in the cerebellum. However, in control rats, bicuculline increases IL-6 and decreases IL-10 plasma levels and induces microglial activation. Bicuculline restores the membrane expression of some glutamate and GABA transporters restoring the extracellular levels of GABA in hyperammonemic rats. Blocking GABAA receptors improves peripheral inflammation and cerebellar neuroinflammation, restoring neurotransmission in hyperammonemic rats, whereas it induces inflammation and neuroinflammation in controls. This suggests a complex interaction between GABAergic and immune systems. The modulation of GABAA receptors could be a suitable target for improving neuroinflammation in MHE.


Assuntos
Hiperamonemia/complicações , Hiperamonemia/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Animais , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Imuno-Histoquímica , Inflamação/patologia , Modelos Biológicos , Doenças do Sistema Nervoso/patologia , Transporte Proteico , Ratos , Transdução de Sinais
12.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206441

RESUMO

DJ-1 was originally identified as an oncogene product while mutations of the gene encoding DJ-1/PARK7 were later associated with a recessive form of Parkinson's disease. Its ubiquitous expression and diversity of function suggest that DJ-1 is also involved in mechanisms outside the central nervous system. In the last decade, the contribution of DJ-1 to the protection from ischemia-reperfusion injury has been recognized and its involvement in the pathophysiology of cardiovascular disease is attracting increasing attention. This review describes the current and gaps in our knowledge of DJ-1, focusing on its role in regulating cardiovascular function. In parallel, we present original data showing an association between increased DJ-1 expression and antiapoptotic and anti-inflammatory markers following cardiac and vascular surgical procedures. Future studies should address DJ-1's role as a plausible novel therapeutic target for cardiovascular disease.


Assuntos
Coração/fisiopatologia , Traumatismo por Reperfusão Miocárdica , Miocárdio , Proteína Desglicase DJ-1/metabolismo , Animais , Biomarcadores/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia
13.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198614

RESUMO

Systemic autoinflammatory diseases are a heterogeneous family of disorders characterized by a dysregulation of the innate immune system, in which sterile inflammation primarily develops through antigen-independent hyperactivation of immune pathways. In most cases, they have a strong genetic background, with mutations in single genes involved in inflammation. Therefore, they can derive from different pathogenic mechanisms at any level, such as dysregulated inflammasome-mediated production of cytokines, intracellular stress, defective regulatory pathways, altered protein folding, enhanced NF-kappaB signalling, ubiquitination disorders, interferon pathway upregulation and complement activation. Since the discover of pathogenic mutations of the pyrin-encoding gene MEFV in Familial Mediterranean Fever, more than 50 monogenic autoinflammatory diseases have been discovered thanks to the advances in genetic sequencing: the advent of new genetic analysis techniques and the discovery of genes involved in autoinflammatory diseases have allowed a better understanding of the underlying innate immunologic pathways and pathogenetic mechanisms, thus opening new perspectives in targeted therapies. Moreover, this field of research has become of great interest, since more than a hundred clinical trials for autoinflammatory diseases are currently active or recently concluded, allowing us to hope for considerable acquisitions for the next few years. General paediatricians need to be aware of the importance of this group of diseases and they should consider autoinflammatory diseases in patients with clinical hallmarks, in order to guide further examinations and refer the patient to a specialist rheumatologist. Here we resume the pathogenesis, clinical aspects and diagnosis of the most important autoinflammatory diseases in children.


Assuntos
Inflamação/patologia , Animais , Citocinas/metabolismo , Humanos , Imunidade Inata , Inflamassomos/metabolismo , Inflamação/imunologia , NF-kappa B/metabolismo
14.
Int J Mol Sci ; 22(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204101

RESUMO

Histamine is a pleiotropic mediator involved in a broad spectrum of (patho)-physiological processes, one of which is the regulation of inflammation. Compounds acting on three out of the four known histamine receptors are approved for clinical use. These approved compounds comprise histamine H1-receptor (H1R) antagonists, which are used to control allergic inflammation, antagonists at H2R, which therapeutically decrease gastric acid release, and an antagonist at H3R, which is indicated to treat narcolepsy. Ligands at H4R are still being tested pre-clinically and in clinical trials of inflammatory diseases, including rheumatoid arthritis, asthma, dermatitis, and psoriasis. These trials, however, documented only moderate beneficial effects of H4R ligands so far. Nevertheless, pre-clinically, H4R still is subject of ongoing research, analyzing various inflammatory, allergic, and autoimmune diseases. During inflammatory reactions in gut tissues, histamine concentrations rise in affected areas, indicating its possible biological effect. Indeed, in histamine-deficient mice experimentally induced inflammation of the gut is reduced in comparison to that in histamine-competent mice. However, antagonists at H1R, H2R, and H3R do not provide an effect on inflammation, supporting the idea that H4R is responsible for the histamine effects. In the present review, we discuss the involvement of histamine and H4R in inflammatory and inflammation-associated diseases of the gut.


Assuntos
Gastroenteropatias/metabolismo , Gastroenteropatias/patologia , Inflamação/metabolismo , Inflamação/patologia , Receptores Histamínicos H4/metabolismo , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Histamina/metabolismo , Humanos , Leucócitos/patologia
15.
Int J Mol Sci ; 22(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204159

RESUMO

By upregulation of cell adhesion molecules and secretion of proinflammatory cytokines, cells of the neurovascular unit, including pericytes and endothelial cells, actively participate in neuroinflammatory reactions. As previously shown, both cell types can activate inflammasomes, cerebral endothelial cells (CECs) through the canonical pathway, while pericytes only through the noncanonical pathway. Using complex in vitro models, we demonstrate here that the noncanonical inflammasome pathway can be induced in CECs as well, leading to a further increase in the secretion of active interleukin-1ß over that observed in response to activation of the canonical pathway. In parallel, a more pronounced disruption of tight junctions takes place. We also show that CECs respond to inflammatory stimuli coming from both the apical/blood and the basolateral/brain directions. As a result, CECs can detect factors secreted by pericytes in which the noncanonical inflammasome pathway is activated and respond with inflammatory activation and impairment of the barrier properties. In addition, upon sensing inflammatory signals, CECs release inflammatory factors toward both the blood and the brain sides. Consequently, CECs activate pericytes by upregulating their expression of NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3), an inflammasome-forming pattern recognition receptor. In conclusion, cerebral pericytes and endothelial cells mutually activate each other in inflammation.


Assuntos
Encéfalo/patologia , Comunicação Celular , Células Endoteliais/patologia , Inflamassomos/metabolismo , Pericitos/patologia , Transdução de Sinais , Animais , Inflamação/metabolismo , Inflamação/patologia , Suínos , Junções Íntimas/metabolismo
16.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204710

RESUMO

Autophagy is a major self-degradative process through which cytoplasmic material, including damaged organelles and proteins, are delivered and degraded in the lysosome. Autophagy represents a dynamic recycling system that produces new building blocks and energy, essential for cellular renovation, physiology, and homeostasis. Principal autophagy triggers include starvation, pathogens, and stress. Autophagy plays also a pivotal role in immune response regulation, including immune cell differentiation, antigen presentation and the generation of T effector responses, the development of protective immunity against pathogens, and the coordination of immunometabolic signals. A plethora of studies propose that both impaired and overactive autophagic processes contribute to the pathogenesis of human disorders, including infections, cancer, atherosclerosis, autoimmune and neurodegenerative diseases. Autophagy has been also implicated in the development and progression of allergen-driven airway inflammation and remodeling. Here, we provide an overview of recent studies pertinent to the biology of autophagy and molecular pathways controlling its activation, we discuss autophagy-mediated beneficial and detrimental effects in animal models of allergic diseases and illuminate new advances on the role of autophagy in the pathogenesis of human asthma. We conclude contemplating the potential of targeting autophagy as a novel therapeutic approach for the management of allergic responses and linked asthmatic disease.


Assuntos
Asma/complicações , Asma/patologia , Autofagia , Hipersensibilidade/complicações , Hipersensibilidade/patologia , Animais , Asma/imunologia , Autofagia/genética , Humanos , Hipersensibilidade/imunologia , Inflamação/patologia , Modelos Biológicos , Transcrição Genética
17.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204767

RESUMO

Increased airway wall thickness and remodeling of bronchial mucosa are characteristic of asthma and may arise from altered integrin signaling on airway cells. Here, we analyzed the expression of ß1-subfamily integrins on blood and airway cells (flow cytometry), inflammatory biomarkers in serum and bronchoalveolar lavage, reticular basement membrane (RBM) thickness and collagen deposits in the mucosa (histology), and airway geometry (CT-imaging) in 92 asthma patients (persistent airflow limitation subtype: n = 47) and 36 controls. Persistent airflow limitation was associated with type-2 inflammation, elevated soluble α2 integrin chain, and changes in the bronchial wall geometry. Both subtypes of asthma showed thicker RBM than control, but collagen deposition and epithelial α1 and α2 integrins staining were similar. Type-I collagen accumulation and RBM thickness were inversely related to the epithelial expression of the α2 integrin chain. Expression of α2ß1 integrin on T-cells and eosinophils was not altered in asthma. Collagen I deposits were, however, more abundant in patients with lower α2ß1 integrin on blood and airway CD8+ T-cells. Thicker airway walls in CT were associated with lower α2 integrin chain on blood CD4+ T-cells and airway eosinophils. Our data suggest that α2ß1 integrin on inflammatory and epithelial cells may protect against airway remodeling advancement in asthma.


Assuntos
Asma/metabolismo , Asma/patologia , Progressão da Doença , Integrina alfa2beta1/metabolismo , Pulmão/patologia , Substâncias Protetoras/metabolismo , Adulto , Idoso , Remodelação das Vias Aéreas , Asma/sangue , Asma/imunologia , Membrana Basal/patologia , Brônquios/diagnóstico por imagem , Brônquios/patologia , Brônquios/fisiopatologia , Lavagem Broncoalveolar , Feminino , Humanos , Inflamação/patologia , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/patologia , Subunidades Proteicas/metabolismo , Ventilação Pulmonar , Solubilidade , Linfócitos T/metabolismo , Tomografia Computadorizada por Raios X
18.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208040

RESUMO

(1) Background: The pro-resolving lipid mediator Resolvin D1 (RvD1) has already shown protective effects in animal models of diabetic retinopathy. This study aimed to investigate the retinal levels of RvD1 in aged (24 months) and younger (3 months) Balb/c mice, along with the activation of macro- and microglia, apoptosis, and neuroinflammation. (2) Methods: Retinas from male and female mice were used for immunohistochemistry, immunofluorescence, transmission electron microscopy, Western blotting, and enzyme-linked immunosorbent assays. (3) Results: Endogenous retinal levels of RvD1 were reduced in aged mice. While RvD1 levels were similar in younger males and females, they were markedly decreased in aged males but less reduced in aged females. Both aged males and females showed a significant increase in retinal microglia activation compared to younger mice, with a more marked reactivity in aged males than in aged females. The same trend was shown by astrocyte activation, neuroinflammation, apoptosis, and nitrosative stress, in line with the microglia and Müller cell hypertrophy evidenced in aged retinas by electron microscopy. (4) Conclusions: Aged mice had sex-related differences in neuroinflammation and apoptosis and low retinal levels of endogenous RvD1.


Assuntos
Envelhecimento/patologia , Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação/patologia , Retina/patologia , Caracteres Sexuais , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Caspase 3/metabolismo , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/metabolismo , Células Ependimogliais/patologia , Células Ependimogliais/ultraestrutura , Feminino , Masculino , Camundongos Endogâmicos BALB C , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Microglia/ultraestrutura , NF-kappa B/metabolismo , Retina/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo
19.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208064

RESUMO

Febrile Infection-Related Epilepsy Syndrome (FIRES) is a unique catastrophic epilepsy syndrome, and the development of drug-resistant epilepsy (DRE) is inevitable. Recently, anakinra, an interleukin-1 receptor antagonist (IL-1RA), has been increasingly used to treat DRE due to its potent anticonvulsant activity. We here summarized its effects in 38 patients (32 patients with FIRES and six with DRE). Of the 22 patients with FIRES, 16 (73%) had at least short-term seizure control 1 week after starting anakinra, while the remaining six suspected anakinra-refractory cases were male and had poor prognoses. Due to the small sample size, an explanation for anakinra refractoriness was not evident. In all DRE patients, seizures disappeared or improved, and cognitive function improved in five of the six patients following treatment. Patients showed no serious side effects, although drug reactions with eosinophilia and systemic symptoms, cytopenia, and infections were observed. Thus, anakinra has led to a marked improvement in some cases, and functional deficiency of IL-1RA was indicated, supporting a direct mechanism for its therapeutic effect. This review first discusses the effectiveness of anakinra for intractable epileptic syndromes. Anakinra could become a new tool for intractable epilepsy treatment. However, it does not currently have a solid evidence base.


Assuntos
Encéfalo/patologia , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Inflamação/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Humanos , Inflamação/patologia , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem
20.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208173

RESUMO

Maternal malnutrition in critical periods of development increases the risk of developing short- and long-term diseases in the offspring. The alterations induced by this nutritional programming in the hypothalamus of the offspring are of special relevance due to its role in energy homeostasis, especially in the endocannabinoid system (ECS), which is involved in metabolic functions. Since astrocytes are essential for neuronal energy efficiency and are implicated in brain endocannabinoid signaling, here we have used a rat model to investigate whether a moderate caloric restriction (R) spanning from two weeks prior to the start of gestation to its end induced changes in offspring hypothalamic (a) ECS, (b) lipid metabolism (LM) and/or (c) hypothalamic astrocytes. Monitorization was performed by analyzing both the gene and protein expression of proteins involved in LM and ECS signaling. Offspring born from caloric-restricted mothers presented hypothalamic alterations in both the main enzymes involved in LM and endocannabinoids synthesis/degradation. Furthermore, most of these changes were similar to those observed in hypothalamic offspring astrocytes in culture. In conclusion, a maternal low caloric intake altered LM and ECS in both the hypothalamus and its astrocytes, pointing to these glial cells as responsible for a large part of the alterations seen in the total hypothalamus and suggesting a high degree of involvement of astrocytes in nutritional programming.


Assuntos
Astrócitos/metabolismo , Restrição Calórica , Endocanabinoides/metabolismo , Hipotálamo/metabolismo , Metabolismo dos Lipídeos , Transdução de Sinais , Animais , Animais Recém-Nascidos , Peso Corporal , Encéfalo/patologia , Feminino , Regulação da Expressão Gênica , Gliose/genética , Gliose/patologia , Inflamação/genética , Inflamação/patologia , Metabolismo dos Lipídeos/genética , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...