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1.
FASEB J ; 35(10): e21852, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34499774

RESUMO

Postoperative pain and delayed healing in surgical wounds, which require complex management strategies have understudied complicated mechanisms. Here we investigated temporal changes in behavior, tissue structure, and transcriptomic profiles in a rat model of a surgical incision, using hyperalgesic behavioral tests, histological analyses, and next-generation RNA sequencing, respectively. The most rapidly (1 hour) expressed genes were the chemokines, Cxcl1 and Cxcl2. Consequently, infiltrating leukocytes were abundantly observed starting at 6 and peaking at 24 hours after incising which was supported by histological analysis and appearance of the neutrophil markers, S100a8 and S100a9. At this time, hyperalgesia was at a peak and overall transcriptional activity was most highly activated. At the 1-day timepoint, Nppb, coding for natriuretic peptide precursor B, was the most strongly upregulated gene and was localized by in situ hybridization to the epidermal keratinocytes at the margins of the incision. Nppb was basically unaffected in a peripheral inflammation model transcriptomic dataset. At the late phase of wound healing, five secreted, incision-specific peptidases, Mmp2, Aebp1, Mmp23, Adamts7, and Adamtsl1, showed increased expression, supporting the idea of a sustained tissue remodeling process. Transcripts that are specifically upregulated at each timepoint in the incision model may be potential candidates for either biomarkers or therapeutic targets for wound pain and wound healing. This study incorporates the examination of longitudinal temporal molecular responses, corresponding anatomical localization, and hyperalgesic behavioral alterations in the surgical incision model that together provide important and novel foundational knowledge to understand mechanisms of wound pain and wound healing.


Assuntos
Hiperalgesia/patologia , Dor Pós-Operatória/patologia , Placa Plantar/fisiologia , RNA-Seq/métodos , Ferida Cirúrgica/complicações , Transcriptoma , Cicatrização , Animais , Comportamento Animal , Edema/etiologia , Edema/metabolismo , Edema/patologia , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/metabolismo , Ratos , Ratos Sprague-Dawley
2.
Pan Afr Med J ; 39: 116, 2021.
Artigo em Francês | MEDLINE | ID: mdl-34512852

RESUMO

Ballantyne syndrome or mirror syndrome was first described in 1892. It is a disorder affecting pregnant women describing the association of fetal anasarca complicated by more or less generalized maternal edema and albuminuria (and sometimes anemia). It is a rare clinical entity. Diagnosis is based on a triad consisting of fetal hydrops, generalized maternal edema and placentomegaly. It can be associated with fetal hydrops from any cause. Diagnostic should be suspected in patients with maternal edema syndrome associated with fetal anasarca. Guarded fetal prognosis can be associated with high maternal morbidity; hence the need for early diagnosis, resting on a clear determination of its cause, and aimed to implement antenatal treatment improving maternal and fetal prognosis. We here report a unique case of Ballantyne syndrome which has never been described in the literature. The study involved a 32-year-old female patient with fetal hydrops caused by fetal cardiac rhabdomyoma.


Assuntos
Doenças Fetais/diagnóstico , Neoplasias Cardíacas/diagnóstico , Complicações na Gravidez/diagnóstico , Rabdomioma/diagnóstico , Adulto , Edema/diagnóstico , Edema/patologia , Feminino , Doenças Fetais/fisiopatologia , Neoplasias Cardíacas/patologia , Humanos , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/etiologia , Doenças Placentárias/diagnóstico , Doenças Placentárias/patologia , Gravidez , Complicações na Gravidez/fisiopatologia , Prognóstico , Rabdomioma/patologia , Síndrome
3.
Cells ; 10(8)2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34440665

RESUMO

The coronavirus disease 2019 (COVID-19) has spread over the world for more than one year. COVID-19 often develops life-threatening hypoxemia. Endothelial injury caused by the viral infection leads to intravascular coagulation and ventilation-perfusion mismatch. However, besides above pathogenic mechanisms, the role of alveolar edema in the disease progression has not been discussed comprehensively. Since the exudation of pulmonary edema fluid was extremely serious in COVID-19 patients, we bring out a hypothesis that severity of alveolar edema may determine the size of poorly-ventilated area and the blood oxygen content. Treatments to pulmonary edema (conservative fluid management, exogenous surfactant replacements and ethanol-oxygen vapor therapy hypothetically) may be greatly helpful for reducing the occurrences of severe cases. Given that late mechanical ventilation may cause mucus (edema fluid) to be blown deep into the small airways, oxygen therapy should be given at the early stages. The optimal time and blood oxygen saturation (SpO2) threshold for oxygen therapy are also discussed.


Assuntos
COVID-19/patologia , Edema/patologia , Alvéolos Pulmonares/patologia , Humanos
4.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445584

RESUMO

There are a large number of remedies in traditional medicine focused on relieving pain and inflammation. Flavanones have been a potential source in the search for leading compounds and biologically active components, and they have been the focus of much research and development in recent years. Eysenhardtia platycarpa is used in traditional medicine for the treatment of kidney diseases, bladder infections, and diabetes mellitus. Many compounds have been isolated from this plant, such as flavones, flavanones, phenolic compounds, triterpenoid acids, chalcones, sugars, and fatty acids, among others. In this paper, natural flavanone 1 (extracted from Eysenhardtia platycarpa) as lead compound and flavanones 1a-1d as its structural analogues were screened for anti-inflammatory activity using Molinspiration® and PASS Online in a computational study. The hydro alcoholic solutions (FS) of flavanones 1, 1a-1d (FS1, FS1a-FS1d) were also assayed to investigate their in vivo anti-inflammatory cutaneous effect using two experimental models, a rat ear edema induced by arachidonic acid (AA) and a mouse ear edema induced by 12-O-tetradecanoylphorbol acetate (TPA). Histological studies and analysis of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6 were also assessed in AA-inflamed rat ear tissue. The results showed that the flavanone hydro alcoholic solutions (FS) caused edema inhibition in both evaluated models. This study suggests that the evaluated flavanones will be effective when used in the future in skin pathologies with inflammation, with the results showing 1b and 1d to be the best.


Assuntos
Anti-Inflamatórios/farmacologia , Otopatias/tratamento farmacológico , Edema/tratamento farmacológico , Fabaceae/química , Flavanonas/farmacologia , Inflamação/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Otopatias/patologia , Edema/patologia , Ensaios de Triagem em Larga Escala , Inflamação/patologia , Camundongos , Ratos , Ratos Wistar
5.
Life Sci ; 284: 119910, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34453939

RESUMO

AIMS: Quercetin has been investigated as an agent to treat rheumatoid arthritis. At high doses it improves inflammation and the antioxidant status of arthritic rats, but it also exerts mitochondriotoxic and pro-oxidant activities. Beneficial effects of quercetin have not been found at low doses because of its chemical instability and low bioavailability. In the hope of overcoming these problems this study investigated the effects of long-term administration of quercetin-loaded pectin/casein microparticles on the oxidative status of liver and brain of rats with adjuvant-induced arthritis. MAIN METHODS: Particle morphology was viewed with transmission electron microscopy and the encapsulation efficiency was measured indirectly by X-ray diffraction. Quercetin microcapsules (10 mg/Kg) were orally administered to rats during 60 days. Inflammation indicators and oxidative stress markers were measured in addition to the respiratory activity and ROS production in isolated mitochondria. KEY FINDINGS: Quercetin was efficiently encapsulated inside the polymeric matrix, forming a solid amorphous solution. The administration of quercetin microparticles to arthritic rats almost normalized protein carbonylation, lipid peroxidation, the levels of reactive oxygen species as well as the reduced glutathione content in both liver and brain. The paw edema in arthritic rats was not responsive, but the plasmatic activity of ALT and the mitochondrial respiration were not affected by quercetin, indicating absence of mitochondriotoxic or hepatotoxic actions. SIGNIFICANCE: Quercetin-loaded pectin/casein microcapsules orally administered at a low dose improve oxidative stress of arthritic rats without a strong anti-inflammatory activity. This supports the long-term use of quercetin as an antioxidant agent to treat rheumatoid arthritis.


Assuntos
Artrite Experimental/patologia , Caseínas/química , Microesferas , Estresse Oxidativo , Pectinas/química , Quercetina/farmacologia , Alanina Transaminase/sangue , Animais , Antioxidantes/farmacologia , Artrite Experimental/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Varredura Diferencial de Calorimetria , Respiração Celular/efeitos dos fármacos , Edema/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxirredutases/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
6.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443414

RESUMO

Natural antioxidants, especially those of plant origins, have shown a plethora of biological activities with substantial economic value, as they can be extracted from agro-wastes and/or under exploited plant species. The perennial hydrophyte, Potamogeton perfoliatus, has been used traditionally to treat several health disorders; however, little is known about its biological and its medicinal effects. Here, we used an integrated in vitro and in vivo framework to examine the potential effect of P. perfoliatus on oxidative stress, nociception, inflammatory models, and brewer's yeast-induced pyrexia in mice. Our results suggested a consistent in vitro inhibition of three enzymes, namely 5-lipoxygenase, cyclooxygenases 1 and 2 (COX-1 and COX-2), as well as a potent antioxidant effect. These results were confirmed in vivo where the studied extract attenuated carrageenan-induced paw edema, carrageenan-induced leukocyte migration into the peritoneal cavity by 25, 44 and 64% at 200, 400 and 600 mg/kg, p.o., respectively. Moreover, the extract decreased acetic acid-induced vascular permeability by 45% at 600 mg/kg, p.o., and chemical hyperalgesia in mice by 86% by 400 mg/kg, p.o., in acetic acid-induced writhing assay. The extract (400 mg/kg) showed a longer response latency at the 3 h time point (2.5 fold of the control) similar to the nalbuphine, the standard opioid analgesic. Additionally, pronounced antipyretic effects were observed at 600 mg/kg, comparable to paracetamol. Using LC-MS/MS, we identified 15 secondary metabolites that most likely contributed to the obtained biological activities. Altogether, our findings indicate that P. perfoliatus has anti-inflammatory, antioxidant, analgesic and antipyretic effects, thus supporting its traditional use and promoting its valorization as a potential candidate in treating oxidative stress-associated diseases.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Antipiréticos/farmacologia , Extratos Vegetais/farmacologia , Potamogetonaceae/química , Ácido Acético , Animais , Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Carragenina , Movimento Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos , Edema/patologia , Febre/patologia , Glucosídeos Iridoides/farmacologia , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Cavidade Peritoneal/patologia , Fenilpropionatos/farmacologia , Compostos Fitoquímicos/análise , Ratos , Saccharomyces cerevisiae
7.
Am J Hematol ; 96(10): 1241-1252, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34265103

RESUMO

Thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (TAFRO) syndrome is a heterogeneous entity manifesting with a constellation of symptoms described above that can occur in the context of idiopathic multicentric Castleman disease (iMCD) as well as infectious diseases, malignancies, and rheumatologic disorders. So, iMCD-TAFRO is an aggressive subtype of iMCD with TAFRO syndrome and often hyper-vascularized lymph nodes. Since we proposed diagnostic criteria of iMCD-TAFRO in 2016, we have accumulated new insights on the disorder and additional cases have been reported worldwide. In this systematic review and cohort analysis, we established and validated a definition for iMCD-TAFRO. First, we searched PubMed and Japan Medical Abstracts Society databases using the keyword "TAFRO" to extract cases. Patients with possible systemic autoimmune diseases and hematologic malignancies were excluded. Our search identified 54 cases from 50 articles. We classified cases into three categories: (1) iMCD-TAFRO (TAFRO syndrome with lymph node histopathology consistent with iMCD), (2) possible iMCD-TAFRO (TAFRO syndrome with no lymph node biopsy performed and no other co-morbidities), and (3) TAFRO without iMCD or other co-morbidities (TAFRO syndrome with lymph node histopathology not consistent with iMCD or other comorbidities). Based on the findings, we propose an international definition requiring four clinical criteria (thrombocytopenia, anasarca, fever/hyperinflammatory status, organomegaly), renal dysfunction or characteristic bone marrow findings, and lymph node features consistent with iMCD. The definition was validated with an external cohort (the ACCELERATE Natural History Registry). The present international definition will facilitate a more precise and comprehensive approach to the diagnosis of iMCD-TAFRO.


Assuntos
Trombocitopenia/diagnóstico , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/patologia , Edema/diagnóstico , Edema/patologia , Fibrose , Humanos , Linfonodos/patologia , Insuficiência Renal/diagnóstico , Insuficiência Renal/patologia , Trombocitopenia/patologia
8.
J Histochem Cytochem ; 69(8): 511-522, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34291686

RESUMO

Induction of severe inflammatory arthritis in the collagen antibody-induced arthritis (CAIA) murine model causes extensive joint damage and pain-like behavior compromising analysis. While mild models are less severe, their reduced, variable penetrance makes assessment of treatment efficacy difficult. This study aimed to compare macroscopic and microscopic changes in the paws, along with central nervous system activation between a mild and moderate CAIA model. Balb/c mice (n=18) were allocated to control, mild, and moderate CAIA groups. Paw inflammation, bone volume (BV), and paw volume (PV) were assessed. Histologically, the front paws were assessed for joint inflammation, cartilage damage, and pre/osteoclast-like cells and the lumbar spinal cord and the periaqueductal gray (PAG) region of the brain for glial reactivity. A moderate CAIA dose induced (1) significantly greater local paw inflammation, inflammatory cell infiltration, and PV; (2) significantly more osteoclast-like cells on the bone surface and within the surrounding soft tissue; and (3) significantly greater glial reactivity within the PAG compared with the mild CAIA model. These findings support the use of a moderate CAIA model (higher dose of monoclonal antibodies with low-dose lipopolysaccharide) to induce more consistent histopathological features, without excessive joint destruction.


Assuntos
Artrite Experimental/patologia , Reabsorção Óssea/patologia , Cartilagem Articular/patologia , Modelos Animais de Doenças , Edema/patologia , Animais , Anticorpos Monoclonais/administração & dosagem , Artrite Experimental/induzido quimicamente , Artrite Experimental/diagnóstico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/patologia , Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/diagnóstico , Cartilagem Articular/efeitos dos fármacos , Edema/induzido quimicamente , Edema/diagnóstico , Feminino , Membro Anterior/efeitos dos fármacos , Membro Anterior/patologia , Histocitoquímica , Lipopolissacarídeos/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/patologia , Índice de Gravidade de Doença , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia
9.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203675

RESUMO

Recently, we found that the deletion of TRPC5 leads to increased inflammation and pain-related behaviour in two animal models of arthritis. (-)-Englerin A (EA), an extract from the East African plant Phyllanthus engleri has been identified as a TRPC4/5 agonist. Here, we studied whether or not EA has any anti-inflammatory and analgesic properties via TRPC4/5 in the carrageenan model of inflammation. We found that EA treatment in CD1 mice inhibited thermal hyperalgesia and mechanical allodynia in a dose-dependent manner. Furthermore, EA significantly reduced the volume of carrageenan-induced paw oedema and the mass of the treated paws. Additionally, in dorsal root ganglion (DRG) neurons cultured from WT 129S1/SvIm mice, EA induced a dose-dependent cobalt uptake that was surprisingly preserved in cultured DRG neurons from 129S1/SvIm TRPC5 KO mice. Likewise, EA-induced anti-inflammatory and analgesic effects were preserved in the carrageenan model in animals lacking TRPC5 expression or in mice treated with TRPC4/5 antagonist ML204.This study demonstrates that while EA activates a sub-population of DRG neurons, it induces a novel TRPC4/5-independent analgesic and anti-inflammatory effect in vivo. Future studies are needed to elucidate the molecular and cellular mechanisms underlying EA's anti-inflammatory and analgesic effects.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Sesquiterpenos de Guaiano/farmacologia , Canais de Cátion TRPC/metabolismo , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Carragenina , Células Cultivadas , Cobalto/metabolismo , Modelos Animais de Doenças , Edema/patologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hiperalgesia/tratamento farmacológico , Inflamação/complicações , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Camundongos Knockout , Dor/complicações , Dor/tratamento farmacológico , Dor/patologia , Fenótipo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Sesquiterpenos de Guaiano/uso terapêutico
10.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068193

RESUMO

In this study, we investigate the immunomodulatory effects of a novel antimicrobial peptide, YD1, isolated from Kimchi, in both in vitro and in vivo models. We establish that YD1 exerts its anti-inflammatory effects via up-regulation of the Nrf2 pathway, resulting in the production of HO-1, which suppresses activation of the NF-κB pathway, including the subsequent proinflammatory cytokines IL-1ß, IL-6, and TNF-α. We also found that YD1 robustly suppresses nitric oxide (NO) and prostaglandin E2 (PGE2) production by down-regulating the expression of the upstream genes, iNOS and COX-2, acting as a strong antioxidant. Collectively, YD1 exhibits vigorous anti-inflammatory and antioxidant activity, presenting it as an interesting potential therapeutic agent.


Assuntos
Anti-Inflamatórios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Inflamação/prevenção & controle , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Animais , Citocinas/metabolismo , Edema/induzido quimicamente , Edema/metabolismo , Edema/patologia , Edema/prevenção & controle , Heme Oxigenase-1/genética , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Proteínas de Membrana/genética , Camundongos , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
11.
Int J Mol Sci ; 22(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064436

RESUMO

2-Arachidonyl-lysophosphatidylethanolamine, shortly 2-ARA-LPE, is a polyunsaturated lysophosphatidylethanolamine. 2-ARA-LPE has a very long chain arachidonic acid, formed by an ester bond at the sn-2 position. It has been reported that 2-ARA-LPE has anti-inflammatory effects in a zymosan-induced peritonitis model. However, it's action mechanisms are poorly investigated. Recently, resolution of inflammation is considered to be an active process driven by M2 polarized macrophages. Therefore, we have investigated whether 2-ARA-LPE acts on macrophages for anti-inflammation, whether 2-ARA-LPE modulates macrophage phenotypes to reduce inflammation, and whether 2-ARA-LPE is anti-inflammatory in a carrageenan-induced paw edema model. In mouse peritoneal macrophages, 2-ARA-LPE was found to inhibit lipopolysaccharide (LPS)-induced M1 macrophage polarization, but not induce M2 polarization. 2-ARA-LPE inhibited the inductions of inducible nitric oxide synthase and cyclooxygenase-2 in mouse peritoneal macrophages at the mRNA and protein levels. Furthermore, products of the two genes, nitric oxide and prostaglandin E2, were also inhibited by 2-ARA-LPE. However, 1-oleoyl-LPE did not show any activity on the macrophage polarization and inflammatory responses. The anti-inflammatory activity of 2-ARA-LPE was also verified in vivo in a carrageenan-induced paw edema model. 2-ARA-LPE inhibits LPS-induced M1 polarization, which contributes to anti-inflammation and suppresses the carrageenan-induced paw edema in vivo.


Assuntos
Anti-Inflamatórios/farmacologia , Ácidos Araquidônicos/farmacologia , Edema/tratamento farmacológico , Lisofosfolipídeos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Ácidos Araquidônicos/química , Carragenina/administração & dosagem , Ciclo-Oxigenase 2/imunologia , Dinoprostona/antagonistas & inibidores , Dinoprostona/biossíntese , Edema/induzido quimicamente , Edema/imunologia , Edema/patologia , Membro Posterior/efeitos dos fármacos , Membro Posterior/imunologia , Membro Posterior/metabolismo , Subunidade p35 da Interleucina-12/antagonistas & inibidores , Subunidade p35 da Interleucina-12/imunologia , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/imunologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Lisofosfolipídeos/química , Macrófagos Peritoneais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/imunologia , Cultura Primária de Células , Resultado do Tratamento
12.
Nat Commun ; 12(1): 3447, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103494

RESUMO

Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene-environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women.


Assuntos
Sistema Cardiovascular/embriologia , Embrião de Mamíferos/patologia , Ferro/deficiência , Animais , Aorta Torácica/anormalidades , Biomarcadores/metabolismo , Diferenciação Celular , Vasos Coronários/embriologia , Vasos Coronários/patologia , Suplementos Nutricionais , Edema/patologia , Embrião de Mamíferos/anormalidades , Desenvolvimento Embrionário , Feminino , Perfilação da Expressão Gênica , Interação Gene-Ambiente , Proteínas de Fluorescência Verde/metabolismo , Ferro/metabolismo , Vasos Linfáticos/embriologia , Vasos Linfáticos/patologia , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Penetrância , Fenótipo , Gravidez , Transdução de Sinais , Células-Tronco/patologia , Transgenes , Tretinoína/metabolismo
13.
Biomed Pharmacother ; 140: 111771, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34058441

RESUMO

Danhong injection (DHI) is a compound Chinese medicine widely used in China for treatment of ischemic cardio-cerebrovascular diseases. However, limited data are available regarding the protective effect of DHI on the ischemic penumbra in ischemic stroke. This study aimed to investigate the effect of intravenous DHI on neuronal injure in the ischemic penumbra after cerebral ischemia/reperfusion (CI/R), focusing especially on the involvement of intracellular energy metabolism coupling. Male Sprague-Dawley rats were subjected to right middle cerebral artery occlusion for 60 min followed by reperfusion with or without intravenous DHI (0.5, 1.0, or 2.0 mL/kg) once daily for 7 days. Post-treatment with DHI ameliorated neurological defects, diminished cerebral infarction, alleviated cerebral edema, improved microcirculatory perfusion after 7days of reperfusion, and inhibited apoptosis and enhanced neuronal survival in the ischemic penumbra. In addition, DHI significantly ameliorated oxidative stress, reduced DNA damage, and inhibited the activation of PARP1/AIF pathway, thereby restoring cytoplasmic glycolytic activity. Furthermore, this drug increased PDH activity by inhibiting the HIF1α/PDK1 signaling pathway, thus eliminating the inhibitory effect of CI/R on mitochondrial metabolism. The results of this study suggest that DHI can alleviate cerebral edema after CI/R and rescue the ischemic penumbra, and these protective effects are due to the regulation of intracellular energy metabolic coupling.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Dano ao DNA , Medicamentos de Ervas Chinesas/farmacologia , Edema/tratamento farmacológico , Edema/metabolismo , Edema/patologia , Metabolismo Energético/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Cetona Oxirredutases/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Piruvato Desidrogenase Quinase de Transferência de Acetil/antagonistas & inibidores , Ratos Sprague-Dawley
14.
PLoS One ; 16(4): e0249276, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33793632

RESUMO

Aconitine (AC) is the primary bioactive and secondary metabolite alkaloidin of Aconitum species which is accounted for more than 60% of the total diester-diterpenoid alkaloids in Aconite. To evaluate the analgesic effects of AC, 4 different pain models including hot plate assay, acetic acid writhing assay, formalin and CFA induced pain models were adopted in this study. In hot plate experiment, AC treatment at concentration of 0.3 mg/kg and 0.9 mg/kg improved the pain thresholds of mice similar to the positive drug aspirin at the concentration of 200 mg/kg (17.12% and 20.27% VS 19.21%). In acetic acid writhing experiment, AC significantly reduced the number of mice writhing events caused by acetic acid, and the inhibition rates were 68% and 76%. These results demonstrated that AC treatment revealed significant analgesic effects in both acute thermal stimulus pain model and chemically-induced visceral pain model. The biphasic nociceptive responses induced by formalin were significantly inhibited after AC treatment for 1h or 2h. The inhibition rates were 33.23% and 20.25% of AC treatment for 1h at 0.3 mg/kg and 0.9 mg/kg in phase I. In phase II, the inhibition rates of AC and aspirin were 36.08%, 32.48% and 48.82% respectively, which means AC showed similar analgesic effect to non-steroidal anti-inflammatory compounds. In the chronic CFA-induced nociception model, AC treatment also improved mice pain threshold to 131.33% at 0.3 mg/kg, which was similar to aspirin group (152.03%). Above all, our results verified that AC had obviously analgesic effects in different mice pain models.


Assuntos
Aconitina/uso terapêutico , Analgésicos/uso terapêutico , Dor/tratamento farmacológico , Ácido Acético/toxicidade , Animais , Aspirina/uso terapêutico , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/patologia , Feminino , Formaldeído/toxicidade , Adjuvante de Freund/toxicidade , Temperatura Alta , Camundongos , Camundongos Endogâmicos C57BL , Dor/induzido quimicamente , Dor/patologia , Limiar da Dor
15.
Bioorg Chem ; 111: 104883, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33865053

RESUMO

A novel series of thiazolo-pyrazole hybrids has been prepared and assessed for their in vitro COX-1/COX-2 inhibitory activity. Compound 6c exhibited the most selective COX-2 inhibition profile (SI of 264) not far of Celecoxib (294). In-vivo anti-inflammatory activity revealed that compound 6d exhibited the highest activity (97.30% inhibition of edema) exceeding reference standard Indomethacin (84.62% inhibition of edema). The ulcerogenic liability tested, using gross, microscopic, biochemical analysis and apoptotic genes expression, showed that compound 6b matched the optimal candidate activity (ulcer index = 120, selectivity index of ~ 162 and 77% in-vivo inhibition of edema). Meanwhile, compound 6 m (ulcer index = 0) showcased the highest safety profile. Molecular modeling analysis and drug likeness studies presented appreciated agreement with the biological evaluation.


Assuntos
Anti-Inflamatórios/farmacologia , Antiulcerosos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Edema/tratamento farmacológico , Úlcera Gástrica/tratamento farmacológico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Antiulcerosos/síntese química , Antiulcerosos/química , Apoptose/efeitos dos fármacos , Apoptose/genética , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Edema/induzido quimicamente , Edema/patologia , Formaldeído , Masculino , Modelos Moleculares , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia
16.
Nutrition ; 89: 111238, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33895558

RESUMO

OBJECTIVES: Changes in muscle mass and quality are important targets for nutritional intervention in critical illness. Effects of such interventions may be assessed using sequential computed tomography (CT) scans. However, fluid and lipid infiltration potentially affects muscle area measurements. The aim of this study was to evaluate changes in muscle mass and quality in critical illness with special emphasis on the influence of edema on this assessment. METHODS: Changes in skeletal muscle area index (SMI) and radiation attenuation (RA) at the level of vertebra L3 were analyzed using sequential CT scans of 77 patients with abdominal sepsis. Additionally, the relation between these changes and disease severity using the maximum Sequential Organ Failure Assessment (SOFA) score and change in edema were studied. RESULTS: SMI declined on average 0.35%/d (±1.22%; P = 0.013). However, SMI increased in 41.6% of the study population. Increasing edema formation was significantly associated with increased SMI and with a higher SOFA score. Muscle RA decreased during critical illness, but was not significantly associated with changes in SMI or changes in edema. CONCLUSION: In critically ill patients, edema affects skeletal muscle area measurements, which leads to an overestimation of skeletal muscle area. A higher SOFA score was associated with edema formation. Because both edema and fat infiltration may affect muscle RA, the separate effects of these on muscle quality are difficult to distinguish. When using abdominal CT scans to changes in muscle mass and quality in critically ill patients, researchers must be aware and careful with the interpretation of the results.


Assuntos
Estado Terminal , Sarcopenia , Edema/diagnóstico por imagem , Edema/patologia , Humanos , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Escores de Disfunção Orgânica , Estudos Retrospectivos , Sarcopenia/patologia , Tomografia Computadorizada por Raios X
17.
Int J Legal Med ; 135(4): 1455-1460, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33890166

RESUMO

Scopolamine is an alkaloid which acts as competitive antagonists to acetylcholine at central and peripheral muscarinic receptors. We report the case of a 41-year-old male convict with a 27-year history of cannabis abuse who suddenly died in the bed of his cell after having smoked buscopan® tablets. Since both abuse of substances and recent physical assaults had been reported, we opted for a comprehensive approach (post-mortem computed tomography CT (PMCT), full forensic autopsy, and toxicology testing) to determine which was the cause of the death. Virtopsy found significant cerebral edema and lungs edema that were confirmed at the autopsy and at the histopathological examination. Scopolamine was detected in peripheral blood at the toxic concentration of 14 ng/mL in blood and at 263 ng/mL in urine, and scopolamine butyl bromide at 17 ng/mL in blood and 90 ng/mL in urine. Quetiapine, mirtazapine, lorazepam, diazepam, and metabolites and valproate were also detected (at therapeutic concentrations). Inmates, especially when they have a history of drug abuse, are at risk to use any substance they can find for recreational purposes. In prisons, active surveillance on the management and assumption of prescribed drugs could avoid fatal acute intoxication.


Assuntos
Brometo de Butilescopolamônio/envenenamento , Toxicologia Forense , Prisioneiros , Escopolamina/envenenamento , Adulto , Autopsia , Edema/patologia , Evolução Fatal , Humanos , Masculino , Detecção do Abuso de Substâncias
18.
Biomed Res Int ; 2021: 6624347, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33880371

RESUMO

Distichochlamys benenica is a native black ginger that grows in Vietnam. In point of fact, there is limitation of available information in the literature making mention of the chemical constituents and bioactive properties of this plant. This study is aimed at isolating trans-o-coumaric acid (1), trans-cinnamic acid (2), and borneol (3) from the rhizomes of D. benenica Q.B.Nguyen & Skornick and evaluate the anti-inflammatory and antimicrobial activities of 1-3 using the carrageenan paw edema model and the dilution broth method, respectively. This revealed that 1 was as effective as diclofenac in reducing the intensity of the edema development. The in silico research showed that the activity of 1 might be derived from inhibiting COX-2 by generating h-bonds at the positions of Arg 120, Tyr 355, and Arg 513 residues. The antimicrobial activities against Gram-positive strains (Staphylococcus aureus and Bacillus subtilis) were comparable, with the minimum inhibitory concentrations ranging from 1.52 to 3.37 mM. This is the first study of the bioactivity of compounds isolated from D. benenica Q.B.Nguyen & Skornick. Our results suggest that 1 may be a nature-derived compound which demonstrates the anti-inflammatory properties and inhibit the proliferation of several Gram-positive bacteria.


Assuntos
Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Zingiberaceae/química , Animais , Anti-Infecciosos/química , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Bactérias/efeitos dos fármacos , Sítios de Ligação , Carragenina , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Ácidos Cumáricos/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Diclofenaco/administração & dosagem , Diclofenaco/farmacologia , Diclofenaco/uso terapêutico , Edema/tratamento farmacológico , Edema/patologia , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/uso terapêutico
19.
Carbohydr Polym ; 262: 117972, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33838788

RESUMO

In order to improve the anti-inflammatory activity of chitosan oligosaccharide (COS), chitosan oligosaccharide graft citronellol derivatives (COS-g-Cit1-3) were successfully synthesized via grafting citronellol (Cit) onto COS backbone. The degrees of substitution (DS) of COS-g-Cit1-3 were 0.165, 0.199 and 0.182, respectively. The structure of COS-g-Cit1-3 was confirmed by UV-vis, FT-IR, 1H NMR and elemental analysis. The in vivo anti-inflammatory activity evaluation results displayed that COS-g-Cit1-3 drastically reduced the paw swelling, and the oedema inhibitions were 22.58 %, 29.03 % and 25.81 %, respectively. The results indicated that the anti-inflammatory effects of COS-g-Cit1-3 were significantly higher than COS and COS-g-Cit2 exhibited the highest anti-inflammatory ability. The results also presented that COS-g-Cit1-3 reduced the expression levels of TNF-α by promoting the secretion of IL-4 and IL-10. Moreover, western blot analysis data proved that COS-g-Cit1-3 inactivated the NF-κB signaling pathway via inhibiting the phosphorylation of p65, IKBα and IKKß.


Assuntos
Monoterpenos Acíclicos/química , Monoterpenos Acíclicos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Quitosana/química , Oligossacarídeos/química , Animais , Edema/tratamento farmacológico , Edema/patologia , Feminino , Espectroscopia de Ressonância Magnética/métodos , Masculino , Camundongos , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Fator de Necrose Tumoral alfa/metabolismo
20.
J Biol Chem ; 296: 100670, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33864815

RESUMO

The voltage-gated potassium (Kv) 1.3 channel plays a crucial role in the immune responsiveness of T-lymphocytes and macrophages, presenting a potential target for treatment of immune- and inflammation related-diseases. FS48, a protein from the rodent flea Xenopsylla cheopis, shares the three disulfide bond feature of scorpion toxins. However, its three-dimensional structure and biological function are still unclear. In the present study, the structure of FS48 was evaluated by circular dichroism and homology modeling. We also described its in vitro ion channel activity using patch clamp recording and investigated its anti-inflammatory activity in LPS-induced Raw 264.7 macrophage cells and carrageenan-induced paw edema in mice. FS48 was found to adopt a common αßß structure and contain an atypical dyad motif. It dose-dependently exhibited the Kv1.3 channel in Raw 264.7 and HEK 293T cells, and its ability to block the channel pore was demonstrated by the kinetics of activation and competition binding with tetraethylammonium. FS48 also downregulated the secretion of proinflammatory molecules NO, IL-1ß, TNF-α, and IL-6 by Raw 264.7 cells in a manner dependent on Kv1.3 channel blockage and the subsequent inactivation of the MAPK/NF-κB pathways. Finally, we observed that FS48 inhibited the paw edema formation, tissue myeloperoxidase activity, and inflammatory cell infiltrations in carrageenan-treated mice. We therefore conclude that FS48 identified from the flea saliva is a novel potassium channel inhibitor displaying anti-inflammatory activity. This discovery will promote understanding of the bloodsucking mechanism of the flea and provide a new template molecule for the design of Kv1.3 channel blockers.


Assuntos
Anti-Inflamatórios/farmacologia , Edema/tratamento farmacológico , Inflamação/tratamento farmacológico , Canal de Potássio Kv1.3/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Glândulas Salivares/metabolismo , Venenos de Escorpião/química , Animais , Edema/imunologia , Edema/metabolismo , Edema/patologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , NF-kappa B/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Xenopsylla
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