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1.
Sci Rep ; 11(1): 7777, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33833346

RESUMO

Due to frequent and often severe lung affections caused by COVID-19, murine models of acute respiratory distress syndrome (ARDS) are increasingly used in experimental lung research. The one induced by a single lipopolysaccharide (LPS) exposure is practical. However, whether it is preferable to administer LPS intranasally or intratracheally remains an open question. Herein, female C57Bl/6 J mice were exposed intranasally or intratracheally to one dose of either saline or 3 mg/kg of LPS. They were studied 24 h later. The groups treated with LPS, either intranasally or intratracheally, exhibited a pronounced neutrophilic inflammation, signs of lung tissue damage and protein extravasation into the alveoli, and mild lung dysfunction. The magnitude of the response was generally not different between groups exposed intranasally versus intratracheally. However, the variability of some the responses was smaller in the LPS-treated groups exposed intranasally versus intratracheally. Notably, the saline-treated mice exposed intratracheally demonstrated a mild neutrophilic inflammation and alterations of the airway epithelium. We conclude that an intranasal exposure is as effective as an intratracheal exposure in a murine model of ARDS induced by LPS. Additionally, the groups exposed intranasally demonstrated less variability in the responses to LPS and less complications associated with the sham procedure.


Assuntos
Inflamação/induzido quimicamente , Lipopolissacarídeos/efeitos adversos , Pulmão/patologia , /induzido quimicamente , Administração Intranasal , Animais , Modelos Animais de Doenças , Feminino , Inflamação/patologia , Lipopolissacarídeos/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Proteínas/análise , /patologia
2.
Nat Chem Biol ; 17(3): 307-316, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33510451

RESUMO

Glucocorticoids display remarkable anti-inflammatory activity, but their use is limited by on-target adverse effects including insulin resistance and skeletal muscle atrophy. We used a chemical systems biology approach, ligand class analysis, to examine ligands designed to modulate glucocorticoid receptor activity through distinct structural mechanisms. These ligands displayed diverse activity profiles, providing the variance required to identify target genes and coregulator interactions that were highly predictive of their effects on myocyte glucose disposal and protein balance. Their anti-inflammatory effects were linked to glucose disposal but not muscle atrophy. This approach also predicted selective modulation in vivo, identifying compounds that were muscle-sparing or anabolic for protein balance and mitochondrial potential. Ligand class analysis defined the mechanistic links between the ligand-receptor interface and ligand-driven physiological outcomes, a general approach that can be applied to any ligand-regulated allosteric signaling system.


Assuntos
Anti-Inflamatórios/farmacologia , Transportador de Glucose Tipo 4/genética , Atrofia Muscular/tratamento farmacológico , Receptores de Glucocorticoides/química , Transdução de Sinais/efeitos dos fármacos , Células A549 , Regulação Alostérica , Animais , Anti-Inflamatórios/síntese química , Linhagem Celular Transformada , Regulação da Expressão Gênica , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Humanos , Lipopolissacarídeos/administração & dosagem , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Ratos , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade
3.
Carbohydr Polym ; 255: 117392, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33436221

RESUMO

Fructooligosaccharide was isolated from Polygonatum Cyrtonema Hua (PFOS) for the first time. Structure characterized using FT-IR, MALDI-TOF-MS, NMR, AFM, and TEM, indicated that PFOS was graminan-type fructan with a degree of polymerization ranging from 5 to 10. A murine model of lipopolysaccharide (LPS)-induced peritonitis was used to evaluate the in vivo anti-inflammatory and lung protective efficacy of PFOS. The result shown that pretreatment with PFOS (1.0 mg/mL) in peritonitis-induced mice could significantly inhibit the level of pro-inflammatory cytokines (TNF-α, IL-1ß) in serum (P < 0.001), increase mice survival rate from 12.5 % to 54 % (P < 0.05), and alleviated lung injury through ameliorating the damage of the pulmonary cellular architecture and reducing inflammatory monocyte accumulation in lung tissue. This effect of oligosaccharides could explain the traditional usage of P. cyrtonema as a tonic medicine for respiratory problems and it could be used as a potential natural ingredient with anti-inflammatory activity.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Pulmão/efeitos dos fármacos , Oligossacarídeos/farmacologia , Peritonite/tratamento farmacológico , Polygonatum/química , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/mortalidade , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Expressão Gênica , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Lipopolissacarídeos/administração & dosagem , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/patologia , Oligossacarídeos/química , Oligossacarídeos/isolamento & purificação , Peritonite/induzido quimicamente , Peritonite/imunologia , Peritonite/mortalidade , Análise de Sobrevida , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
4.
Molecules ; 26(3)2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499133

RESUMO

Low-molecular-weight chitosan (LMWC), a product of chitosan deacetylation, possesses anti-inflammatory effects. In the present study, a porcine small intestinal epithelial cell line, IPEC-J2, was used to assess the protective effects of LMWC on lipopolysaccharide (LPS)-induced intestinal epithelial cell injury. IPEC-J2 cells were pretreated with or without LMWC (400 µg/mL) in the presence or absence of LPS (5 µg/mL) for 6 h. LMWC pretreatment increased (p < 0.05) the occludin abundance and decreased (p < 0.05) the tumour necrosis factor-α (TNF-α) production, apoptosis rate and cleaved cysteinyl aspartate-specific protease-3 (caspase-3) and -8 contents in LPS-treated IPEC-J2 cells. Moreover, LMWC pretreatment downregulated (p < 0.05) the expression levels of TNF receptor 1 (TNFR1) and TNFR-associated death domain and decreased (p < 0.05) the nuclear and cytoplasmic abundance of nuclear factor-κB (NF-κB) p65 in LPS-stimulated IPEC-J2 cells. These results suggest that LMWC exerts a mitigation effect on LPS-induced intestinal epithelial cell damage by suppressing TNFR1-mediated apoptosis and decreasing the production of proinflammatory cytokines via the inhibition of NF-κB signalling pathway.


Assuntos
Quitosana/farmacologia , Inflamação/prevenção & controle , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Caspases/metabolismo , Linhagem Celular , Quitosana/administração & dosagem , Quitosana/química , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Lipopolissacarídeos/administração & dosagem , Peso Molecular , NF-kappa B/metabolismo , Ocludina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Suínos
5.
Stem Cell Res Ther ; 12(1): 72, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33468250

RESUMO

BACKGROUND: One of the most severe complications of the current COVID-19 pandemic is acute respiratory distress syndrome (ARDS). ARDS is caused by increased amounts of pro-inflammatory cytokines, leading to lung damage and loss of lung function. There are currently no effective therapies for combatting ARDS. Mesenchymal stem cells (MSCs) have been suggested as a potential treatment for ARDS due to their significant immunomodulatory properties. MSC small extracellular vesicles (sEVs), including exosomes, modulate the immune response as effectively as MSCs themselves, with the added advantages of increased safety and tissue penetration. METHODS: We isolated sEVs from MSCs induced to secrete increased levels of neurotrophic and immunomodulatory factors, termed Exo MSC-NTF, and compared their ability to treat ARDS, in a lung injury LPS mouse model, to sEVs isolated from naïve MSCs (Exo MSC). Measurments of lung histopathological changes and neutrophil infiltration, blood oxygen saturation, and bronchoalveolar lavge fluid (BALF) proinflammatory cytokines and coagulation related factors were performed. RESULTS: We found that Exo MSC-NTF was superior to Exo MSC in reducing LPS-induced ARDS markers, including physiological lung damage such as alveolar wall thickness, fibrin presence, and neutrophil accumulation, as well as increasing oxygenation levels. Furthermore, Exo MSC-NTF reversed the imbalance in the host immune response, seen as decreased IFN-γ, IL-6, TNF-α, and RANTES levels in the bronchoalveolar lavage fluid. CONCLUSIONS: These positive preclinical results suggest that Exo MSC-NTF may be suitable as a therapy for COVID-19-induced ARDS and are more effective at combatting ARDS physiological, pathological, and biochemical symptoms than sEVs isolated from non-induced MSCs.


Assuntos
Exossomos/imunologia , Transplante de Células-Tronco Mesenquimais/métodos , /terapia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Imunomodulação , Lipopolissacarídeos/administração & dosagem , Células-Tronco Mesenquimais/imunologia , Camundongos , /imunologia
6.
Artigo em Inglês | MEDLINE | ID: mdl-33010450

RESUMO

Toll-like receptors (TLR) are crucial for recognizing bacterial, viral or fungal pathogens and to orchestrate the appropriate immune response. The widely expressed TLR2 and TLR4 differentially recognize various pathogens to initiate partly overlapping immune cascades. To better understand the physiological consequences of both immune responses, we performed comparative lipidomic analyses of local paw inflammation in mice induced by the TLR2 and TLR4 agonists, zymosan and lipopolysaccharide (LPS), respectively, which are commonly used in models for inflammation and inflammatory pain. Doses for both agonists were chosen to cause mechanical hypersensitivity with identical strength and duration. Lipidomic analysis showed 5 h after LPS or zymosan injection in both models an increase of ether-phosphatidylcholines (PC O) and their corresponding lyso species with additional lipids being increased only in response to LPS. However, zymosan induced stronger immune cell recruitment and edema formation as compared to LPS. Importantly, only in LPS-induced inflammation the lipid profile in the contralateral paw was altered. Fittingly, the plasma level of various cytokines and chemokines, including IL-1ß and IL-6, were significantly increased only in LPS-treated mice. Accordingly LPS induced distinct changes in the lipid profiles of ipsilateral and contralateral paws. Here, oxydized fatty acids, phosphatidylcholines and phosphatidylethanolamines were uniquely upregulated on the contralateral side. Thus, both models cause increased levels of PC O and lyso-PC O lipids at the site of inflammation pointing at a common role in inflammation. Also, LPS initiates systemic changes, which can be detected by changes in the lipid profiles.


Assuntos
Reação de Fase Aguda/sangue , Edema/sangue , Lipopolissacarídeos/administração & dosagem , Fosfatidilcolinas/sangue , Fosfatidiletanolaminas/sangue , Zimosan/administração & dosagem , Reação de Fase Aguda/induzido quimicamente , Reação de Fase Aguda/genética , Reação de Fase Aguda/patologia , Animais , Edema/induzido quimicamente , Edema/genética , Edema/patologia , Ácidos Graxos/sangue , Ácidos Graxos/classificação , Regulação da Expressão Gênica , Membro Posterior/irrigação sanguínea , Membro Posterior/efeitos dos fármacos , Membro Posterior/metabolismo , Interleucina-1beta/sangue , Interleucina-1beta/genética , Interleucina-6/sangue , Interleucina-6/genética , Lipidômica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilcolinas/classificação , Fosfatidiletanolaminas/classificação , Transdução de Sinais , Receptor 2 Toll-Like/sangue , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/sangue , Receptor 4 Toll-Like/genética
7.
Life Sci ; 258: 118197, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32781059

RESUMO

AIMS: Patients with neurodevelopmental disorders, usually suffer from bone diseases. Many studies have revealed a higher risk of fracture after atypical antipsychotic drug Risperidone (RIS) treatment, which is usually used to treat such disorders. It remains debatable whether neurodevelopmental disorders by itself are the cause of bone diseases or pharmacotherapy may be the reason. MATERIALS AND METHODS: This study attempts to evaluate the biomechanical, histological, stereological, and molecular properties of bones in the offspring of Lipopolysaccharide (LPS) and saline-treated mothers that received saline, drug vehicle or the atypical antipsychotic drug risperidone (RIS) at different days of postnatal development. After postnatal drug treatment, animals were assessed for autistic-like behaviors. Then their bones were taken for evaluations. RESULTS: Maternal LPS exposure resulted in deficits in all behavioral tests and RIS ameliorated these behaviors (p < 0.01& p < 0.05). The administration of LPS and RIS individually led to a significant decrease in the biomechanical parameters such as bone stiffness, strength and the energy used to fracture of bone. The numerical density of osteocalcin-positive cells were significantly decreased in these groups. These rats also had decreased RUNX2 and osteocalcin gene expression. When LPS rats were treated with RIS, these conditions were accelerated (p < 0.001). DISCUSSIONS: The results of our preclinical study, consistent with previous studies in animals, explore that autistic-like deficits induced by prenatal exposure to LPS, can reduce bone stability and bone mass similar to those observed in neurodevelopmental disorders, and, for the first time, reveal that this condition worsened when these animals were treated with RIS.


Assuntos
Transtorno Autístico/induzido quimicamente , Reabsorção Óssea/induzido quimicamente , Exposição Materna , Efeitos Tardios da Exposição Pré-Natal/patologia , Risperidona/efeitos adversos , Animais , Animais Recém-Nascidos , Transtorno Autístico/sangue , Transtorno Autístico/complicações , Comportamento Animal , Fenômenos Biomecânicos , Reabsorção Óssea/sangue , Reabsorção Óssea/fisiopatologia , Citocinas/sangue , Citocinas/genética , Feminino , Lipopolissacarídeos/administração & dosagem , Masculino , Atividade Motora , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Risperidona/administração & dosagem , Comportamento Estereotipado
8.
Anticancer Res ; 40(8): 4457-4464, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727775

RESUMO

BACKGROUND/AIM: Our previous studies suggested that oral administration of lipopolysaccharide (LPS) regulates the progression of various diseases via transformation of tissue-resident macrophages (MΦ). Recently, we characterized microglia transformed by repetitive low-dose LPS treatment (REPELL-microglia) in vitro, and this response was similar to that observed in response to oral administration of LPS in vivo. Here, we examined the characteristics of peritoneal tissue-resident MΦ (pMΦ) transformed by repetitive low-dose LPS treatment (REPELL-pMΦ). MATERIALS AND METHODS: Primary pMΦ were treated with low-dose LPS (1 ng/ml) three times; subsequently, phagocytic activity and gene expression were evaluated. RESULTS: REPELL-pMΦ exhibited high phagocytic activity and elevated expression of Arg1, Gipr, Gdnf, and Fpr2. The gene expression profiles observed in REPELL-pMΦ were distinct from those of REPELL-microglia. CONCLUSION: REPELL-pMΦ have the potential to promote clearance of xenobiotics and to suppress inflammation. The present study also demonstrates the diversity of tissue-resident MΦ transformation that reflect their tissue origin.


Assuntos
Arginase/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Lipopolissacarídeos/efeitos adversos , Macrófagos Peritoneais/fisiologia , Receptores de Formil Peptídeo/genética , Receptores dos Hormônios Gastrointestinais/genética , Administração Oral , Animais , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/administração & dosagem , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/efeitos dos fármacos , Masculino , Camundongos , Especificidade de Órgãos , Fagocitose/efeitos dos fármacos , Fenótipo , Cultura Primária de Células , Regulação para Cima
9.
Anticancer Res ; 40(8): 4755-4762, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727802

RESUMO

BACKGROUND: Developmental disorders are associated with microglial dysfunction. Oral administration of lipopolysaccharide derived from Pantoea agglomerans bacteria (LPSp) leads to normalization of phagocytic activity of microglia and suppression of inflammation in mice. In this article, we report on a successful trial in which we achieved a significant improvement of symptoms in patients with developmental disorders. PATIENTS AND METHODS: Five pediatric patients diagnosed with autism spectrum disorders (ASD)/attention deficit hyperactivity disorder (ADHD) who visited our clinic received either 0.75 or 1 mg/day LPSp for 6 months or more, in addition to our usual therapy regimens (detoxification therapy, nutritional therapy, and vibration therapy). A survey questionnaire was completed by the patients' parents and evaluated using the Numerical Rating Scale. RESULTS: Behavior, verbal ability, and communication disabilities associated with ASD/ADHD improved in all patients. CONCLUSION: Oral administration of LPSp may represent a new treatment option in the area of developmental disorders where there is currently no treatment available.


Assuntos
Deficiências do Desenvolvimento/tratamento farmacológico , Lipopolissacarídeos/administração & dosagem , Pantoea/química , Administração Oral , Criança , Pré-Escolar , Citocinas/metabolismo , Deficiências do Desenvolvimento/metabolismo , Feminino , Humanos , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fagocitose/efeitos dos fármacos
10.
Nat Immunol ; 21(7): 736-745, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32367036

RESUMO

Cytosolic sensing of pathogens and damage by myeloid and barrier epithelial cells assembles large complexes called inflammasomes, which activate inflammatory caspases to process cytokines (IL-1ß) and gasdermin D (GSDMD). Cleaved GSDMD forms membrane pores, leading to cytokine release and inflammatory cell death (pyroptosis). Inhibiting GSDMD is an attractive strategy to curb inflammation. Here we identify disulfiram, a drug for treating alcohol addiction, as an inhibitor of pore formation by GSDMD but not other members of the GSDM family. Disulfiram blocks pyroptosis and cytokine release in cells and lipopolysaccharide-induced septic death in mice. At nanomolar concentration, disulfiram covalently modifies human/mouse Cys191/Cys192 in GSDMD to block pore formation. Disulfiram still allows IL-1ß and GSDMD processing, but abrogates pore formation, thereby preventing IL-1ß release and pyroptosis. The role of disulfiram in inhibiting GSDMD provides new therapeutic indications for repurposing this safe drug to counteract inflammation, which contributes to many human diseases.


Assuntos
Dissulfiram/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas de Ligação a Fosfato/antagonistas & inibidores , Piroptose/efeitos dos fármacos , Sepse/tratamento farmacológico , Animais , Caspase 1/genética , Caspase 1/metabolismo , Inibidores de Caspase/farmacologia , Caspases/metabolismo , Caspases Iniciadoras/genética , Caspases Iniciadoras/metabolismo , Linhagem Celular Tumoral , Dissulfiram/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Feminino , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Lipossomos , Camundongos , Mutagênese Sítio-Dirigida , Proteínas de Ligação a Fosfato/genética , Proteínas de Ligação a Fosfato/metabolismo , Piroptose/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sepse/imunologia , Células Sf9 , Spodoptera
11.
J Dairy Sci ; 103(6): 5525-5531, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32253037

RESUMO

It is well established that intravenous administration of lipopolysaccharides (LPS)-cell wall components from gram-negative bacteria-induce acute inflammatory responses in dairy calves, but the effect of oral administration of LPS to dairy calves is currently unknown. To evaluate the effects of oral administration of LPS derived from Escherichia coli (serotype O111:B4) on innate immune responses in milk-fed Holstein calves, 20 visually healthy calves (34 ± 1 d) received 4 L of milk with LPS (12 µg/kg body weight; n = 10; LPS) or without LPS (n = 10; control) at the morning feeding. Samples were collected at 0.5 h before the morning feeding and at 3, 6, 24, 48, 72, and 168 h after the morning feeding to measure rectal temperature and heart rate, as well as plasma-negative and plasma-positive acute phase proteins (i.e., haptoglobin, serum amyloid A, albumin, total protein, and fibrinogen) and immunoglobulin concentrations (IgG, IgM, and IgA). None of these measurements was affected by the oral administration of LPS. Oral administration of LPS at 12 µg/kg of body weight did not induce an acute inflammatory response in visually healthy milk-fed Holstein calves when administered in milk.


Assuntos
Bovinos/imunologia , Escherichia coli/química , Imunidade Inata/efeitos dos fármacos , Lipopolissacarídeos/imunologia , Proteínas da Fase Aguda/análise , Proteínas da Fase Aguda/efeitos dos fármacos , Administração Oral , Animais , Peso Corporal , Imunoglobulinas/sangue , Lipopolissacarídeos/administração & dosagem , Masculino , Leite/metabolismo , Sorogrupo
12.
Acta Cir Bras ; 35(2): e202000202, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32267288

RESUMO

PURPOSE: To investigate the effects of adalimumab pretreatment on the lipopolysaccharide-mediated myocardial injury. METHODS: Twenty-eight Wistar rats were randomized into four groups (n=7). Control (C) group animals were injected once a day with intraperitoneal (i.p) 0.9 % saline for two days. In the Adalimumab (Ada) group, adalimumab was injected at a dose of 10 mg/kg/ day (i.p) for two days. Lipopolysaccharide (Lps) group rats were injected with a dose of 5 mg/kg (i.p) lipopolysaccharide. Lipopolysaccharide + Adalimumab (Lps+Ada) group rats received adalimumab before the administration of lipopolysaccharide. The animals were sacrificed 24 h after the last injection and blood samples were obtained for determination of biochemical cardiac injury markers and circulating levels of TNF-α and interleukin-6 (IL-6). Hearts were harvested for histological examination. RESULTS: Endotoxin exposure resulted in significant increases in serum cardiac injury markers, serum cytokines and histological myocardial injury scores in the Lps group. The levels of circulating cytokines, cardiac injury markers and histological injury scores for myocardial necrosis, perivascular cell infiltration, and inflammation were significantly reduced in Lps+Ada as compared to Lps group (p<0.05). CONCLUSIONS: Adalimumab pretreatment reduces endotoxin-induced myocardial damage in rats. This beneficial effect is thought to be related to the reduction of cytokine release.


Assuntos
Adalimumab/administração & dosagem , Cardiopatias/tratamento farmacológico , Lipopolissacarídeos/administração & dosagem , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Endotoxinas , Feminino , Cardiopatias/induzido quimicamente , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/biossíntese
13.
J Surg Res ; 252: 231-239, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32299011

RESUMO

BACKGROUND: Standard treatment for diffuse peritonitis due to colorectal perforation may be insufficient to suppress inflammatory reaction in sepsis. Thus, developing new treatments is important. This study aimed to examine whether intraperitoneal irradiation by artificial sunlight suppresses inflammatory reaction in a lipopolysaccharide (LPS)-induced peritonitis model after surgical treatments. MATERIALS AND METHODS: Mice were divided into naive, nontreatment (NT), and phototherapy (PT) groups. In the latter two groups, LPS was intraperitoneally administered to induce peritonitis and removed by intraperitoneal lavage after laparotomy. The PT group was irradiated with artificial sunlight intraperitoneally. We evaluated the local and systemic inflammatory reactions. Murine macrophages were irradiated with artificial sunlight after stimulation by LPS, and cell viability and expression of tumor necrotizing factor-α (TNF-α) were evaluated. RESULTS: As a local inflammatory reaction, the whole cell count, the expression of interleukin-6 and TNF-α in the intra-abdominal fluid, and the peritoneal thickness were significantly lower in the PT group than in the NT group. As a systematic inflammatory reaction, the expression of serum TNF-α, granulocyte macrophage colony-stimulating factor, monocyte chemotactic protein-1, macrophage inflammatory protein (MIP)-1α, and MIP-1ß were significantly lower in the PT group than in the NT group. Irradiation by artificial sunlight suppressed the expression of TNF-α in murine macrophages without affecting cell viability. CONCLUSIONS: Intraperitoneal irradiation by artificial sunlight could suppress local and systemic inflammatory reactions in the LPS-induced peritonitis murine model. These effects may be associated with macrophage immune responses.


Assuntos
Perfuração Intestinal/complicações , Peritônio/efeitos da radiação , Peritonite/terapia , Fototerapia/métodos , Luz Solar , Animais , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Perfuração Intestinal/imunologia , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/efeitos da radiação , Masculino , Camundongos , Peritônio/imunologia , Peritonite/imunologia , Células RAW 264.7
14.
Biochem Pharmacol ; 177: 113992, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32335141

RESUMO

IL-17A combined with TNF-α plays a vital role in inflammatory response and interference of the synergistic effect is an effective strategy for treating inflammatory diseases. Ellipticine, a natural alkaloid, has biological activities on anti-tumor and anti-HIV. However, it is still unknown whether ellipticine can inhibit IL-17A and TNF-α-mediated signaling and has treatment effect on PALI. Here, we reported that ellipticine significantly inhibited the production of pro-inflammatory cytokines and chemokines in pulmonary epithelial cell BEAS-2B treated with IL-17A and TNF-α, but not IL-17A or TNF-α alone. Meanwhile, ellipticine attenuated NF-κB and MAPKs activation in response to IL-17A and TNF-α treatment, inhibited Act1 and TRAF6-mediated NF-κB activation, and blocked the interaction of Act1 with TRAF6. Furthermore, we found that ellipticine significantly alleviated CAE and LPS-induced SAP/PALI. Ellipticine treatment dramatically reduced inflammatory cells infiltration, MPO activity, serum amylase and lipase activity and the protein concentration of BALF. Collectively, our findings indicate that ellipticine inhibits the synergistic effect of IL-17A and TNF-α by targeting on Act1 and TRAF6 interaction and is a potential therapeutic agent for the treatment of SAP/PALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Elipticinas/farmacologia , Interleucina-17/antagonistas & inibidores , Pancreatite/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Amilases/antagonistas & inibidores , Amilases/genética , Amilases/metabolismo , Animais , Linhagem Celular Transformada , Ceruletídeo/administração & dosagem , Modelos Animais de Doenças , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Interleucina-17/farmacologia , Lipase/antagonistas & inibidores , Lipase/genética , Lipase/metabolismo , Lipopolissacarídeos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Pancreatite/induzido quimicamente , Pancreatite/complicações , Pancreatite/genética , Peroxidase/antagonistas & inibidores , Peroxidase/genética , Peroxidase/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/antagonistas & inibidores , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
15.
Biochem Biophys Res Commun ; 524(4): 876-882, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32057359

RESUMO

Sepsis is a progressive disease characterized by excessive inflammatory responses, severe tissue injury and organ dysfunction, ultimately leading to mortality. In this study, we demonstrated that thioredoxin-2 (TRX-2) expression is reduced in macrophages stimulated with lipopolysaccharide (LPS). Overexpression of TRX-2 significantly attenuated interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) production induced by LPS. TRX-2 inhibited LPS-induced inflammatory responses through suppressing activation of the NF-κB and MAPK signaling pathways. Furthermore, TRX-2 induced a significant decrease in mortality in mouse sepsis models in association with reduced inflammatory cytokine production and attenuation of organ injury. Our data collectively support a role of TRX-2 as a critical regulator of sepsis that influences survival by protecting the host from excessive inflammatory damage.


Assuntos
Macrófagos Peritoneais/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , NF-kappa B/genética , Choque Séptico/genética , Tiorredoxinas/genética , Animais , Regulação da Expressão Gênica , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Células RAW 264.7 , Choque Séptico/induzido quimicamente , Choque Séptico/mortalidade , Choque Séptico/patologia , Transdução de Sinais , Análise de Sobrevida , Tioglicolatos/farmacologia , Tiorredoxinas/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
16.
Cancer Immunol Immunother ; 69(5): 745-758, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32047957

RESUMO

BACKGROUND: Osteosarcoma (OS) is the most common malignant bone tumor and the prognosis of advanced cases is still poor. Recently, there have been several reports suggesting the relationship between innate immunity and OS, but the detailed mechanism is unknown. We demonstrate the relationship between OS and Toll-like receptor 4 (TLR4) which is one of the most important factors in innate immunity. METHODS: We established a syngenic mouse tumor model using C3H/HeN, C3H/HeJ mouse and a highly metastatic OS cell line, LM8. TLR4 activation with lipopolysaccharide (LPS) was performed on both mice and its influence on the progression of OS was evaluated. We also performed CD8 + cells depletion to examine the influence on TLR4 activation effects. RESULTS: Tumor volume of C3H/HeN mice was significantly smaller and overall survival of C3H/HeN mice was significantly longer than C3H/HeJ mice. We found more CD8+ cells infiltrating in lung metastases of C3H/HeN mice and depletion of CD8+ cells canceled the antitumor effects of LPS. CONCLUSION: TLR4 activation by LPS increased CD8+ cells infiltrating into lung metastases and suppressed OS progression in the mouse model. TLR4 activation may suppress the progression of OS via stimulating CD8+ cells and can be expected as a novel treatment for OS.


Assuntos
Neoplasias Ósseas/imunologia , Neoplasias Pulmonares/imunologia , Osteossarcoma/imunologia , Linfócitos T Citotóxicos/imunologia , Receptor 4 Toll-Like/metabolismo , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Linhagem Celular Tumoral/transplante , Quimioterapia Adjuvante , Criança , Pré-Escolar , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Lipídeo A/administração & dosagem , Lipídeo A/análogos & derivados , Lipopolissacarídeos/administração & dosagem , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Depleção Linfocítica , Masculino , Camundongos , Pessoa de Meia-Idade , Osteossarcoma/mortalidade , Osteossarcoma/secundário , Osteossarcoma/terapia , Prognóstico , Intervalo Livre de Progressão , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/metabolismo , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/imunologia , Carga Tumoral/imunologia , Adulto Jovem
17.
Mol Med Rep ; 21(3): 1077-1088, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016449

RESUMO

Osteoarthritis (OA) is a degenerative joint disease that affects the physical, and mental health of middle­aged and elderly people. The aims of the present study were to determine the biological function and molecular mechanisms of miR­363­3p in chondrocyte apoptosis. Exploration of the molecular mechanisms of OA may be helpful in the understand of the causes, and facilitating the prevention and treatment of OA. In the present study, the expression of nuclear respiratory factor1 (NRF1) was downregulated in the articular cartilage of OA rats in vivo and lipopolysaccharide (LPS)­treated chondrocytes in vitro. MicroRNAs (miRNA) are regulators of gene expression in the progression of OA. TargetScan software was used to predict that NRF1 was a potential target for miRNA (miR)­363, and this was confirmed in subsequent experiments. The expression of miR­363­3p was negatively correlated with the expression of NRF1, and its expression was significantly upregulated in OA model rats and in LPS­induced chondrocytes compared with the expression in the respective controls. In addition, the overexpression of miR­363­3p increased the levels of interleukin (IL)­1ß, IL­6 and tumor necrosis factor­α in vivo, and was demonstrated to promote chondrocyte injury and apoptosis by Safranin O staining and TUNEL. Moreover, the inhibition of miR­363­3p expression increased the expression of NRF1 and protected chondrocytes from apoptosis in vitro and in vivo, whereas the overexpression of miR­363­3p downregulated NRF1 expression and promoted LPS­induced chondrocyte apoptosis through the p53 pathway in vitro. The results of this study suggested that miR­363­3p­mediated inhibition of NRF1may be associated with chondrocyte apoptosis in OA.


Assuntos
Apoptose , MicroRNAs/genética , Fator 1 Relacionado a NF-E2/metabolismo , Osteoartrite/genética , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Animais , Cartilagem Articular/fisiologia , Condrócitos/fisiologia , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Lipopolissacarídeos/administração & dosagem , Masculino , Fator 1 Relacionado a NF-E2/genética , Ratos , Ratos Wistar , Proteína Supressora de Tumor p53/genética , Regulação para Cima
18.
Sci Rep ; 10(1): 1887, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024889

RESUMO

It is widely accepted that enhanced uterine inflammation associated with microbial infection is a main causative factor for preterm birth. However, little is known about the molecular basis by which inflammation is associated with preterm birth. Here, we demonstrate that apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein 3-kinase family, facilitates inflammation-induced preterm birth and that inhibition of ASK1 activity is sufficient to suppress preterm birth. ASK1-deficient pregnant mice exhibited reduced incidence of lipopolysaccharide (LPS)-induced preterm birth. ASK1 was required for the induction of LPS-induced inflammatory responses related to preterm birth, including pro-inflammatory cytokine production in the uterus and peritoneal cavities. In addition, selective suppression of uterine ASK1 activity through a chemical genetic approach reduced the incidence of LPS-induced preterm birth. Moreover, translational studies with human choriodecidua demonstrated that ASK1 was required for LPS-induced activation of JNK and p38 and pro-inflammatory cytokine production. Our findings suggest that ASK1 activation is responsible for the induction of inflammation that leads to preterm birth and that the blockade of ASK1 signaling might be a promising therapeutic target for preventing preterm birth.


Assuntos
MAP Quinase Quinase Quinase 5/metabolismo , Nascimento Prematuro/imunologia , Útero/imunologia , Animais , Apoptose/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , MAP Quinase Quinase Quinase 5/genética , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Knockout , Cavidade Peritoneal/patologia , Gravidez , Nascimento Prematuro/patologia , Útero/patologia
19.
J Nutr ; 150(5): 1116-1125, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32101618

RESUMO

BACKGROUND: Liver dysfunction impairs immunological homeostasis. Glycine (Gly) has been reported to have antioxidative and anti-inflammatory effects and to regulate apoptosis in various models. OBJECTIVES: The aim of the present study was to determine whether Gly could attenuate LPS-induced liver injury. METHODS: In Experiment 1, 48 6-week-old male C57BL/6 mice were randomly assigned into one of 4 groups: CON (control), GLY [orally administered Gly, 5 g · kg body weight (BW)-1 · d-1 for 6 d], LPS (5 mg/kg BW, intraperitoneally administered), and GLY + LPS (Gly supplementation, and on day 7 LPS treatment). In Experiment 2, mice were untreated, pretreated with Gly as above, or pretreated with Gly + l-buthionine sulfoximine (BSO) (0.5 g/kg BW, intraperitoneally administered every other day) for 6 d. On day 7, mice were injected with LPS as above. Histological alterations, activities of antioxidative enzymes, apoptosis, and immune cell infiltration were analyzed. RESULTS: In Experiment 1, compared with CON, LPS administration resulted in increased karyolysis and karyopyknosis in the liver by 8- to 10-fold, enhanced serum activities of alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) by 1- to 1.8-fold, and increased hepatic apoptosis by 5.5-fold. Furthermore, LPS exposure resulted in increased infiltration of macrophages and neutrophils in the liver by 3.2- to 7.5-fold, elevated hepatic concentrations of malondialdehyde and hydrogen peroxide (H2O2), and elevated myeloperoxidase (MPO) activity by 1.5- to 6.3-fold. In Experiment 2, compared with the LPS group, mice in the GLY + LPS group had fewer histological alterations (68.5%-75.9%); lower serum ALT, AST, and LDH activities (24.3%-64.7%); and lower hepatic malondialdehyde and H2O2 concentrations (46.1%-80.2%), lower MPO activity (39.2%), immune cell infiltration (52.3%-85.3%), and apoptosis (69.6%), which were abrogated by BSO. Compared with the GLY + LPS group, mice in the GLY + BSO + LPS group had lower hepatic activities of catalase, superoxide dismutase, and glutathione peroxidase by 33.5%-48.5%; increased activation of NF-κB by 2.3-fold; and impaired nuclear factor (erythroid-derived 2)-like 2 signaling by 38.9%. CONCLUSIONS: Gly is a functional amino acid with an ability to protect the liver against LPS-induced injury in mice.


Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Glicina/farmacologia , Inflamação/prevenção & controle , Lipopolissacarídeos/administração & dosagem , Fígado/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Peróxido de Hidrogênio/análise , L-Lactato Desidrogenase/sangue , Fígado/química , Macrófagos/patologia , Masculino , Malondialdeído/análise , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/patologia , Peroxidase/metabolismo
20.
J Anim Sci ; 98(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31909792

RESUMO

An isotope tracer study was conducted to evaluate the effects of immune system stimulation (ISS) on the irreversible loss of cysteine (Cys) to taurine (Tau) and sulfate (SO4), as well as glutathione (GSH) synthesis, during the fed state in pigs. We previously have reported that ISS increases plasma Cys flux and the GSH synthesis rate at the tissue and whole-body levels in growing pigs. Thus, the current article presents the data on the irreversible loss of Cys during ISS in pigs. Ten gilts (BW: 7.0 ±â€…0.12 kg) were feed restricted a sulfur amino acids (SAA) limiting diet and injected twice with either saline (n = 4) or increasing amounts of E. coli lipopolysaccharide (n = 6). The day after the second injection, a 5-h primed continuous intravenous infusion of 35S-Cys was conducted. ISS reduced plasma Cys and total SAA concentrations (16% and 21%, respectively; P < 0.05). However, ISS had no effect on the plasma concentrations of Tau and SO4, nor did it affect the appearance of 35S in plasma Tau, plasma SO4, urinary Tau, or urinary SO4 (P > 0.19). On a whole-body basis and including urinary excretion, ISS increased the appearance of 35S in Tau by 67% (P < 0.05), but tended to decrease the appearance of 35S in SO4 by 22% (P < 0.09). Overall, the current findings indicate that during ISS, decreased plasma SAA concentrations and increased plasma Cys flux are attributed in part to increased rates of Cys conversion to Tau, but not Cys catabolism to SO4. Thus, increased utilization of Cys for the synthesis of immune system metabolites, such as GSH and Tau, is likely the main contributor to increased Cys flux during ISS in pigs. In addition, the irreversible loss of Cys during ISS is small and has a minimal impact on the daily SAA requirements of starter pigs.


Assuntos
Cisteína/metabolismo , Sistema Imunitário/efeitos dos fármacos , Suínos/fisiologia , Taurina/metabolismo , Ração Animal , Animais , Dieta/veterinária , Escherichia coli/química , Feminino , Glutationa/metabolismo , Lipopolissacarídeos/administração & dosagem , Sulfatos/metabolismo , Suínos/imunologia
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