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1.
Chem Pharm Bull (Tokyo) ; 68(1): 96-99, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902905

RESUMO

Chemical investigation of the aerial parts of Andrographis paniculata resulted in isolation of nine compounds, including a new ent-labdane diterpenoid, andrographic acid methyl ester (1), a new chalcone glucoside, pashanone glucoside (5), and seven known metabolites, andrograpanin (2), andrographolide (3), andropanolide (4), andrographidine A (6), andrographidine F (7), 6-epi-8-O-acetyl-harpagide (8), and curvifloruside F (9). Their chemical structures were elucidated based on comprehensive analyses of the spectroscopic data, including NMR and MS. Among the isolated compounds, andropanolide exerted cytotoxicity toward LNCaP, HepG2, KB, MCF7, and SK-Mel2 carcinoma cells, with IC50 values ranging from 31.8 to 45.9 µM. In addition, andropanolide significantly inhibited the overproduction of nitric oxide (NO) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, with an IC50 value of 13.4 µM.


Assuntos
Andrographis/química , Diterpenos/química , Flavonoides/química , Andrographis/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Humanos , Lipopolissacarídeos/toxicidade , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Conformação Molecular , Óxido Nítrico/metabolismo , Componentes Aéreos da Planta/química , Componentes Aéreos da Planta/metabolismo , Células RAW 264.7
2.
Chem Commun (Camb) ; 56(3): 399-402, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31820751

RESUMO

A combinatorial approach using a one-bead-one-compound method and a screening based on a SOD-activity assay was set up for the discovery of an efficient peptidyl copper complex. The complex exhibited good stability constants, suitable redox potentials and excellent intrinsic activity. This complex was further assayed in cells for its antioxidant properties and showed beneficial effects when cells were subjected to oxidative stress.


Assuntos
Materiais Biocompatíveis/metabolismo , Cobre/química , Peptídeos/química , Sequência de Aminoácidos , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Colo/citologia , Colo/efeitos dos fármacos , Colo/metabolismo , Cobre/metabolismo , Células HT29 , Humanos , Interleucina-8/metabolismo , Lipopolissacarídeos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Peptídeos/metabolismo , Superóxido Dismutase/metabolismo
3.
Vet Res Commun ; 43(4): 239-247, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31760569

RESUMO

Sickness behavior (SB) is considered part of the adaptive behavioral and neuroimmune changes that occur in response to inflammatory processes. However, SB is a motivational state modulated by the environmental context. The objective of this study was to evaluate if selenium could ameliorate symptoms of SB and if stress would affect these responses. We induced SB in rats using lipopolysaccharide (LPS). We choose selenium based on our findings of LPS-exposure decreasing selenium levels in rats. We exposed these rats to a psychogenic stress and studied motivational modulation paradigms, such as cure of the organism, preservation of the species, and fight or flight. We studied ultrasonic vocalizations, open-field behaviors, body weight, and IL-1 beta and IFN-gamma serum levels. LPS-induced SB was evidenced by decreased motor/exploratory activity and increased proinflammatory mediators' levels. Selenium treatment did not exert beneficial effects on SB, revealing that probably the selenium deficiency was not related to SB. When analyzed with the stress paradigm, the behavior of rats was differentially affected. LPS did not affect behavior in the presence of stress. SB was abrogated during stressor events to prioritize survival behaviors, such as fight-or-flight. Contrarily, the association of LPS, selenium, and stress induced SB even during stressor events, revealing that this combination induced a cumulative toxic effect.


Assuntos
Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Comportamento de Doença/efeitos dos fármacos , Estresse Psicológico/psicologia , Animais , Lipopolissacarídeos/toxicidade , Ratos , Selênio/farmacologia
4.
Life Sci ; 238: 116976, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634464

RESUMO

AIM: The purpose of the present study was to elucidate the protective effect of histone deacetylase 6 inhibitor ACY1215 on autophagy pathway in acute liver failure (ALF). MAIN METHODS: Lipopolysaccharide (LPS) and d-galactosamine (D-Gal) were used to induce ALF model in C57BL/6 mice. D-Gal and tumor necrosis factor alpha (TNF-α) were applied in L02 cell. Autophagy inhibitor 3-MA and ACY1215 were conducted to induce 3-MA group, ACY1215 group and ACY1215+3-MA group. RESULTS: ACY1215 improved liver histological and functional changes in ALF mice model, whereas the autophagy inhibitor 3-MA aggravated liver tissue pathological and functional damage in ALF mice model group. The apoptotic levels (including apoptotic index/rate and apoptotic proteins) in ALF mice and L02 cell were ameliorated with treatment ACY1215. 3-MA accentuated the apoptotic levels in ACY1215 group. D-Gal/TNF-α could reduce L02 cell mitochondrial membrane potential (ΔΨm) in control group. ACY1215 increased the ΔΨm in ALF model. 3-MA also further reduced the ΔΨm in ACY1215 group. ACY1215 could induce autophagy in ALF mice and cell model group accompanied with an increase in expression of LC3-II and beclin-1 proteins and down-regulation of p62 protein. Moreover, the expression of LC3-II and beclin1 proteins were greatly reduced and the expression of p62 protein was ascended after intervention with 3-MA in ACY1215 group. SIGNIFICANCE: Histone deacetylase 6 inhibitor ACY1215 could protect acute liver failure mice and L02 cell by inhibiting apoptosis pathway through enhancing autophagy way.


Assuntos
Autofagia , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Falência Hepática Aguda/prevenção & controle , Substâncias Protetoras/farmacologia , Pirimidinas/farmacologia , Animais , Apoptose , Autofagia/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Lipopolissacarídeos/toxicidade , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
5.
Life Sci ; 238: 116920, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610189

RESUMO

AIMS: Dendritic cells (DCs) and Toll-like receptor (TLR) participate in mediating inflammation process. However, the functional role of TLR expressed on DCs in osteoarthritis (OA) development has not been defined yet. The purpose of this study was to investigate the role and mechanism of TLR and DCs in the progression of experimental osteoarthritis (OA). MATERIALS AND METHODS: Experimental OA model was induced by iodoacetate injection. Expressions of toll-like receptors in DCs of OA mice were detected by qRT-PCR and flow cytometry. TLR agonists lipopolysaccharide (LPS) and R848 or TLR antagonist FP7 were used, and the levels of TLRs and inflammatory cytokines were examined by qRT-PCR and ELISA. KEY FINDINGS: The expression levels of TLR family members were increased in DCs derived from synovial fluid of OA mice compared with the sham mice. In vitro, OA mice-derived DCs had increased production of inflammatory cytokine after TLR agonists LPS and R848 challenge, while TLR challenges did not affect DCs maturation. Inhibition of TLR by TLR antagonist FP7 blocked TLR challenges-induced increased inflammation in DCs. In mice, administration of FP7 attenuated LPS-induced inflammatory response and OA condition. SIGNIFICANCE: Increased TLR expression in OA-derived DCs contributes to the inflammation condition and potentially acts as a therapeutic target for osteoarthritis.


Assuntos
Artrite Reumatoide/complicações , Células Dendríticas/imunologia , Inflamação/etiologia , Osteoartrite/complicações , Receptores Toll-Like/metabolismo , Animais , Citocinas/metabolismo , Células Dendríticas/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL
6.
Ecotoxicol Environ Saf ; 185: 109687, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31561077

RESUMO

Chronic inflammation has been shown to play a vital role in lung tumorigenesis. Recently, we have successfully developed a C57BL/6 mouse model of inflammation-related lung tumorigenesis induced by benzo(a)pyrene [B(a)p] and lipopolysaccharide (LPS), which will contribute to better understand the association between pulmonary inflammation and cancer. In this study, we aim to explore the role of NLRP3 and NLRP6 inflammasome in lung tumorigenesis in the animal model that we set up previously. Levels of NLRP3, NLRP6, interleukin-1ß (IL-1ß) and IL-18 protein in lung tissues were detected by using immunohistochemistry. The co-localization of NLRP3 or NLRP6 with caspase-1 was examined using immunofluorescence and confocal. Western blotting was used to evaluate the levels of caspase-1 p10 and cleaved-IL-1ß protein. The expression of IL-18 in bronchoalveolar lavage fluid (BALF) was measured using ELISA kit. The expression of NLRP3, NLRP6 and IL-18 protein in the lung tissues of mice exposed to B(a)p plus LPS was upregulated significantly compared with those in Vehicle control group. Immunofluorescent results indicated the co-localization of NLRP3 with caspase-1 was increased in the lung tissues of LPS-, B(a)p- or B(a)p plus LPS-exposed mice than that in Vehicle control group, but no co-localization of NLRP6 with caspase-1. Additionally, caspase-1 activation was induced, cleaved-IL-1ß in lung tissues and IL-18 protein in BALF were increased in B(a)p plus LPS-exposed mice compared with those in B(a)p group. In conclusion, our results from this study demonstrate that NLRP3 inflammasome, not NLRP6 inflammasome, activation is involved in B(a)p plus LPS-induced inflammation-related lung tumorigenesis in mice, but the mechanisms of NLRP6 participate in the development of lung cancer should be further investigated.


Assuntos
Benzo(a)pireno/toxicidade , Inflamassomos/metabolismo , Lipopolissacarídeos/toxicidade , Neoplasias Pulmonares/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia/imunologia , Receptores de Superfície Celular/metabolismo , Animais , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/metabolismo
7.
Life Sci ; 236: 116860, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518605

RESUMO

AIMS: Intrathecal injection of morphine presents analgesic and antiedematogenic effects in rats. However, it is unknown whether tramadol, which possess a mixed mechanism of action, can also produce analgesic and antiedematogenic effects similarly. MAIN METHODS: Male Wistar rats received carrageenan and LPS in the right knee joint. Tramadol (10 µg) was injected intrathecally 20 min before articular LPS injection. Incapacitation and articular edema were measured 5 h after LPS stimulation. Synovial fluid was collected for leukocyte counting and western blot analysis. Whole joint and lumbar spinal cord were also collected for histology and immunohistochemistry, respectively. Intrathecal pretreatments groups were with the NKCC1 blocker bumetanide, TRPV1 agonist resiniferatoxin, µ-opioid receptor antagonist CTOP and serotonergic neurotoxin 5,7-DHT, all previously to tramadol. KEY FINDINGS: Tramadol treatment caused the reduction of incapacitation and edema. It also reduced c-Fos protein expression in the spinal cord dorsal horn and slightly reduced TNF-α levels in synovial fluid, but neither reduced cell migration nor tissue damage. Bumetanide and resiniferatoxin prevented the analgesic and antiedematogenic effects of tramadol. CTOP prevented the analgesic and the antiedematogenic effects, but 5,7-DHT prevented only tramadol-induced analgesia. SIGNIFICANCE: Spinal NKCC1 cotransporter and peptidergic peripheral afferents seem to be important for the analgesic and antiedematogenic effects of tramadol, as well as µ-opioid receptor. However, the monoamine uptake inhibition effect of tramadol seems to be important only to the analgesic effect.


Assuntos
Analgésicos Opioides/administração & dosagem , Artralgia/prevenção & controle , Artrite Experimental/complicações , Artrite Reativa/complicações , Edema/prevenção & controle , Lipopolissacarídeos/toxicidade , Tramadol/administração & dosagem , Animais , Artralgia/etiologia , Artralgia/patologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/fisiopatologia , Artrite Reativa/induzido quimicamente , Artrite Reativa/fisiopatologia , Modelos Animais de Doenças , Edema/etiologia , Edema/patologia , Injeções Espinhais , Masculino , Ratos , Ratos Wistar
8.
Molecules ; 24(18)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547327

RESUMO

Previous studies have revealed the anti-inflammatory and neuroprotective properties of Hericium erinaceus extracts, including the fact that the active ingredient erinacine C (EC) can induce the synthesis of nerve growth factor. However, there is limited research on the use and mechanisms of action of EC in treating neuroinflammation. Hence, in this study, the inflammatory responses of human BV2 microglial cells induced by LPS were used to establish a model to assess the anti-neuroinflammatory efficacy of EC and to clarify its possible mechanisms of action. The results showed that EC was able to reduce the levels of nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor (TNF)-α, and inducible nitric oxide synthase (iNOS) proteins produced by LPS-induced BV2 cells, in addition to inhibiting the expression of NF-κB and phosphorylation of IκBα (p-IκBα) proteins. Moreover, EC was found to inhibit the Kelch-like ECH-associated protein 1 (Keap1) protein, and to enhance the nuclear transcription factor erythroid 2-related factor (Nrf2) and the expression of the heme oxygenase-1 (HO-1) protein. Taken together, these data suggest that the mechanism of action of EC involves the inhibition of IκB, p-IκBα, and iNOS expressions and the activation of the Nrf2/HO-1 pathway.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diterpenos/farmacologia , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Proteínas de Membrana/metabolismo , Camundongos , Microglia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
Int J Med Sci ; 16(8): 1149-1156, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31523178

RESUMO

Background Sepsis, a leading cause of death in intensive care units, is generally associated with vascular dysfunction. However, its pathophysiological process has not been fully clarified, lacking in-depth knowledge of its pathophysiological process may hinder the improvement of diagnosis and therapy for sepsis. Hence, as the key parts of the vascular wall, the interaction between endothelial cells (ECs) and smooth muscle cells (SMCs) under septic situation need to be further studied. Methods ECs and SMCs were co-cultured using Transwell plates. Lipopolysaccharide (LPS) was used to induce sepsis. A scratch-wound assay was used to assess cell migration, and western blotting was used to assess the level of redifferentiation of SMCs as well as the expression of PDGFR-ß and IQGAP1. Results Co-culture with ECs reduced the redifferentiation of SMCs induced by LPS (10 µg/ml), which was characterized by increased migration ability and decreased expression of contractile proteins (e.g., SM22 and α-SMA). The production of TNF-α could decrease the level of PDGFR-ß in SMCs. Treatment of SMCs with the PDGFR-ß inhibitor imatinib (5 µM) was able to counteract LPS-induced SMC redifferentiation and reduce IQGAP1 protein expression, especially when SMCs were co-cultured with ECs. Conclusion The phenotype of vascular SMCs co-cultured with ECs was modulated by IQGAP1 through the PDGFR-ß pathway, which may lead to vascular remodeling and homeostasis in LPS-induced intravascular injury. This pathway could be a novel target for the treatment of vascular damage.


Assuntos
Músculo Liso Vascular/citologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Técnicas de Cocultura , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Humanos , Lipopolissacarídeos/toxicidade , Músculo Liso Vascular/efeitos dos fármacos , Fenótipo , Sepse/metabolismo , Sepse/patologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
10.
Life Sci ; 236: 116865, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525428

RESUMO

AIMS: Endothelial dysfunction is one of the earliest symptoms in septic patients and plays an important role in the cardiovascular alterations. However, the endothelial mechanisms involved in the impaired sympathetic regulation of the cardiovascular system are not clear. This study aimed to determine the role of the endocardial endothelium (EE) in the cardiac ß-adrenergic (ß-AR) remodeling at the early phase of endotoxemic shock. MAIN METHODS: Rats received either lipopolysaccharide (LPS) or saline (control) intravenously. Three hours later, ß-AR cardiac contractility was evaluated on papillary muscles with or without a functional EE. KEY FINDINGS: Isoproterenol-induced contractility was strongly increased in papillary muscles from LPS rats. A similar increase was observed with a ß1-AR stimulation, whereas ß2-AR and ß3-AR produced similar contractility in control and LPS treatments. The removal of the EE did not modify ß1-AR-induced contractility in controls, whereas it abolished the increased ß1-AR response in LPS-treated muscles. In LPS-treated papillary muscle, the increased ß1-AR-induced contractility was not modified by pretreatment with a NOS inhibitor or an endothelin receptor antagonist. Conversely, the increased ß1-AR-induced contractility was abolished by indomethacin, a non-selective cyclooxygenase (COX) inhibitor, as well as by selective inhibitors of COX1 and COX2. An early treatment with indomethacin improved the survival of LPS rat. SIGNIFICANCE: Our results suggest that the EE is involved in the increased cardiac ß1-AR contractility in the early phase of endotoxemic shock. This effect is mediated through the activation of COX1 and COX2 and suggests these may be novel putative therapeutic targets during endotoxemic shock.


Assuntos
Ciclo-Oxigenase 1/metabolismo , Endotélio Vascular/fisiopatologia , Endotoxemia/fisiopatologia , Proteínas de Membrana/metabolismo , Contração Miocárdica , Músculos Papilares/fisiopatologia , Receptores Adrenérgicos beta 1/metabolismo , Animais , Modelos Animais de Doenças , Endotoxemia/induzido quimicamente , Lipopolissacarídeos/toxicidade , Masculino , Ratos , Ratos Sprague-Dawley
11.
EMBO J ; 38(20): e101266, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31544965

RESUMO

Inflammasomes are cytosolic protein complexes, which orchestrate the maturation of active IL-1ß by proteolytic cleavage via caspase-1. Although many principles of inflammasome activation have been described, mechanisms that limit inflammasome-dependent immune responses remain poorly defined. Here, we show that the thiol-specific peroxidase peroxiredoxin-4 (Prdx4) directly regulates IL-1ß generation by interfering with caspase-1 activity. We demonstrate that caspase-1 and Prdx4 form a redox-sensitive regulatory complex via caspase-1 cysteine 397 that leads to caspase-1 sequestration and inactivation. Mice lacking Prdx4 show an increased susceptibility to LPS-induced septic shock. This effect was phenocopied in mice carrying a conditional deletion of Prdx4 in the myeloid lineage (Prdx4-ΔLysMCre). Strikingly, we demonstrate that Prdx4 co-localizes with inflammasome components in extracellular vesicles (EVs) from inflammasome-activated macrophages. Purified EVs are able to transmit a robust IL-1ß-dependent inflammatory response in vitro and also in recipient mice in vivo. Loss of Prdx4 boosts the pro-inflammatory potential of EVs. These findings identify Prdx4 as a critical regulator of inflammasome activity and provide new insights into remote cell-to-cell communication function of inflammasomes via macrophage-derived EVs.


Assuntos
Caspase 1/metabolismo , Vesículas Extracelulares/metabolismo , Inflamassomos/imunologia , Macrófagos/imunologia , Peroxirredoxinas/fisiologia , Choque Séptico/prevenção & controle , Animais , Caspase 1/genética , Citocinas/metabolismo , Feminino , Inflamassomos/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Choque Séptico/induzido quimicamente , Choque Séptico/imunologia , Choque Séptico/patologia , Transdução de Sinais
12.
Chemosphere ; 236: 124413, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31545206

RESUMO

TBBPA is one of the main brominated flame retardants and is ubiquitous in the environment. TBBPA can directly encounter immune cells via the bloodstream, posing potential immunotoxicity. To understand the immunomodulating effect of TBBPA on macrophages, the murine macrophages, RAW 264.7, were exposed to TBBPA at environmentally relevant concentrations (1-100 nM). The results showed that TBBPA at the selected concentrations did not alter cell viability of RAW 264.7 cells with or without LPS stimulation. TBBPA upregulated the expression of pro-inflammatory cytokines, including IL-1ß, IL-6, and TNF-α, whereas it attenuated the LPS-stimulated expression of these pro-inflammatory cytokines, and the expression of anti-inflammatory cytokines, including IL-4, IL-10, and IL-13. In addition, TBBPA reduced the mRNA levels of antigen-presenting-related genes, including H2-K2, H2-Aa, Cd80, and Cd86. Moreover, TBBPA impaired the phagocytic activity of macrophages. Furthermore, exposure to TBBPA significantly elevated the protein levels of phosphorylated NF-κB p65 (p-p65), while it reduced LPS-stimulated p-p65 protein levels. DCFH-DA staining assays showed that TBBPA caused a slight but significant elevation in reactive oxygen species levels. The data obtained in the present study demonstrated that exposure to environmentally relevant concentrations of TBBPA posed immunotoxicity in macrophages and unveiled a potential health risk of TBBPA.


Assuntos
Poluentes Ambientais/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Bifenil Polibromatos/toxicidade , Animais , Antígeno B7-2/genética , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Retardadores de Chama/toxicidade , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
13.
Gene ; 721: 144095, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31476403

RESUMO

Penehyclidine hydrochloride (PHC) is a novel anticholinergic drug applied broadly in surgeries as a preanesthetic medication. A substantial amount of research indicates that PHC has lung defensive properties. Considering that endoplasmic reticulum (ER) stress exerts a crucial function in cell apoptosis associated with the lipopolysaccharides (LPS)-induced acute lung injury (ALI) model, we aimed to determine whether regulation of ER stress in the LPS-induced ALI model was associated with the lung defensive role of PHC. Adult male SD rats were administered LPS (5 mg/kg, intratracheally) followed by PHC (1.0 mg/kg, intravenously) for 24 h. The NR8383 alveolar macrophages were randomly separated into Sham, LPS (100 ng/mL), and PHC (1, 2.5, or 5 µg/mL) + LPS groups. PHC (1, 2.5, or 5 µg/mL) + LPS groups were treated with PHC alone for 1 h after LPS exposure. Posttreatment with PHC relieved LPS-induced pulmonary impairment and blocked LPS-mediated lung apoptosis, indicated by the downregulation of the lung apoptotic indicators malondialdehyde and superoxide dismutase in serum at 24 h after LPS-induced ALI. PHC (1-5 µg/mL) did not influence the activity of cultivated NR8383 alveolar macrophages in vitro. However, postconditioning with PHC dosage-dependently reduced LPS-mediated cell apoptosis. Additionally, many studies have indicated that PHC administration inhibits ER stress and initiates hairy and enhancer of split 1 (Hes1)/(Notch1) signaling by decreasing phosphorylated α subunit of eukaryotic initiation factor 2α (p-eIF2α)/eukaryotic translation initiation factor 2α (eIF2α) and Phospho-protein kinase R-like ER kinase (p-PERK)/ protein kinase R-like ER kinase (PERK) proportions; inhibiting C/EBP-homologous protein (CHOP), activating transcription factor 4 (ATF4), caspase-3, and Bcl2-associated x (Bax) activity; and enhancing notch1 intracellular domain (NICD), Notch1, B-cell lymphoma-2 (Bcl-2), and Hes1 activity in vivo and in vitro. In addition, the defensive functions of PHC on LPS-activated NR8383 alveolar macrophages were abrogated through the Notch1 pathway antagonist [(3,5-difluorophenacetyl)-1-alanyl] -phenylglycine-butyl ester (DAPT). In conclusion, PHC alleviates LPS-induced ALI by ameliorating ER stress-mediated apoptosis and promoting Hes1/Notch1 signaling in vivo and in vitro.


Assuntos
Lesão Pulmonar Aguda , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hialuronan Sintases/metabolismo , Lipopolissacarídeos/toxicidade , Quinuclidinas/farmacologia , Receptor Notch1/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
14.
Int. microbiol ; 22(3): 317-323, sept. 2019. graf
Artigo em Inglês | IBECS | ID: ibc-184838

RESUMO

In recent years, the beneficial impact of targeted gut microbiota manipulation in various neurological disorders has become more evident. Therefore, probiotics have been considered as a promising approach to modulate brain gene expression and neuronal pathways even in some neurodegenerative diseases. The purpose of this study was to determine the effect of probiotic biotherapy with combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 on the expression levels of proteins critical to neuronal apoptosis in hippocampus of lipopolysaccharide (LPS)-exposed rats. Four groups of animals (Control, LPS, Probiotic + LPS, and Probiotic) were treated with maltodextrin (placebo) or probiotic (109 CFU/ml/rat) for 2 weeks by gavage. On the 15th day, a single intraperitoneal dose of saline or LPS (1 mg/kg) was injected and 4 h later, protein assessment was performed by western blotting in hippocampal tissues. LPS significantly increased the Bax, Bax/Bcl-2 ratio, and cleaved caspase-3 expression along with decreased the Bcl-2 and procaspase-3 protein levels. However, probiotic pretreatment (L. helveticus R0052 + B. longum R0175) significantly downregulated the Bax and Bax/Bcl-2 ratio accompanied with upregulated Bcl-2 expression. Prophylactic treatment with these bacteria also attenuated LPS-induced caspase-3 activation by remarkably increasing the expression of procaspase-3 while reducing the level of cleaved caspase-3 in target tissues. Our data indicate that probiotic formulation (L. helveticus R0052 + B. longum R0175) alleviated hippocampal apoptosis induced by LPS in rats via the gut-brain axis and suggest that this probiotic could play a beneficial role in some neurodegenerative conditions


No disponible


Assuntos
Animais , Ratos , Apoptose , Bifidobacterium longum/crescimento & desenvolvimento , Hipocampo/patologia , Lactobacillus helveticus/crescimento & desenvolvimento , Probióticos/administração & dosagem , Western Blotting , Caspase 3/análise , Hipocampo/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Placebos/administração & dosagem , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteína X Associada a bcl-2/análise
15.
Life Sci ; 233: 116731, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31394128

RESUMO

AIMS: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by widespread inflammation. LncRNA taurine-up-regulated gene 1 (TUG1) has been reported to be involved in multiple biological processes and human diseases. The aim of this study was to investigate the role of lncRNA TUG1 in MS and the underlying mechanism. MAIN METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in mice by immunization with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55). Lentiviral vectors encoding sh-TUG1 was constructed to silence TUG1 in MOG-EAE mice by intracerebroventricular (ICV) injection. The effect of TUG1 on inflammation in MS was evaluated by real-time PCR, Western blot, ELISA and Hematoxylin-eosin staining. To further study the mechanism of TUG1 in MS, TUG1 knockdown and miR-9-5p overexpression were performed in LPS-induced BV2 cells. KEY FINDINGS: Down-regulation of TUG1 improved mice behavior, reduced granulocyte-macrophage colony stimulating factor (GM-CSF) level, decreased the levels of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin (IL)-6 and IL-17, and increased IL-10 in EAE mice. Notably, TUG1 expression was negatively correlated with miR-9-5p expression, while positively correlated with NF-κB1/p50. Knockdown of TUG1 or enforced expression of miR-9-5p inhibited LPS-induced inflammation in BV2 cells, while these effects were abolished by inhibition of miR-9-5p. We further verified that TUG1 negatively regulated miR-9-5p expression and NF-κB1/p50 is a direct target of miR-9-5p. SIGNIFICANCE: Down-regulation of TUG1 attenuates MS through inhibition of inflammation by sponging miR-9-5p via targeting NF-κB1/p50, suggesting that TUG1 is a potential therapeutic target for MS treatment.


Assuntos
Encefalomielite Autoimune Experimental/prevenção & controle , Regulação da Expressão Gênica , Inflamação/prevenção & controle , MicroRNAs/genética , Esclerose Múltipla/prevenção & controle , Subunidade p50 de NF-kappa B/metabolismo , RNA Longo não Codificante/antagonistas & inibidores , Animais , Apoptose , Proliferação de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Inflamação/induzido quimicamente , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Subunidade p50 de NF-kappa B/genética , RNA Longo não Codificante/genética , Ativação Transcricional
16.
Pain Res Manag ; 2019: 6393150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428213

RESUMO

Migraine is one of the most common neurological disorders which poses significant socioeconomic burden worldwide. Neuroinflammation and oxidative stress both play important roles in the pathogenesis of migraine. Human urinary kallidinogenase (UK) is a tissue kallikrein derived from human urine. Increasing evidence suggests that UK may protect against ischemic stroke, but UK's treatment potential against migraine remains to be explored. Immortal BV-2 murine microglial cells were treated with UK (125 nM, 250 nM, and 500 nM) and then given lipopolysaccharides (LPS, 1000 ng/mL). Cell viability of BV-2 cells was tested by the CCK-8 assay. Expressions of tumor necrosis factor-α (TNFα), prostaglandin E2 (PGE2), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) were examined with the ELISA method and western blot. Intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) were measured to determine oxidative stress. Our results showed that LPS administration increased the levels of proinflammatory cytokines (TNFα, PGE2, IL-6, and IL-1ß) and oxidative stress (ROS and MDA) when compared with the control group and decreased significantly upon introduction with UK. Taken together, UK treatment reduced LPS-induced neuroinflammation and oxidative stress in a dose-dependent manner, which might be a potential treatment of migraine.


Assuntos
Microglia/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Calicreínas Teciduais/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Transtornos de Enxaqueca/metabolismo , Transtornos de Enxaqueca/fisiopatologia
17.
Oxid Med Cell Longev ; 2019: 3614960, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428223

RESUMO

Depression is a mental disorder that affects 300 million people of all ages worldwide, but fewer than half of those with the condition receive adequate treatment. In addition, the high pharmacological refractoriness (affecting 30%-50% of patients) and toxicity of some classical antidepressants support the pursuit of new therapies. People with this condition show depressed mood, loss of pleasure, high levels of oxidative stress, and accelerated biological aging (decreased telomere length and expression of the telomerase reverse transcriptase (TERT), the enzyme responsible for telomere maintenance). Because of the close relationship between depression and oxidative stress, nutraceuticals with antioxidant properties are excellent candidates for therapy. This study represents the first investigation of the possible antidepressant and antiaging effects of commercial samples of clarified açaí (Euterpe oleracea) juice (EO). This fruit is rich in antioxidants and widely consumed. In this study, mice were treated with saline or EO (10 µL/g, oral) for 4 days and then with saline or lipopolysaccharide (0.5 mg/kg, i.p.) to induce depressive-like behavior. Only four doses of EO were enough to abolish the despair-like and anhedonia behaviors and alterations observed in electromyographic measurements. The antidepression effect of EO was similar to that of imipramine and associated with antioxidant and antiaging effects (preventing lipid peroxidation and increasing TERT mRNA expression, respectively) in three major brain regions involved in depression (hippocampus, striatum, and prefrontal cortex). Additionally, EO significantly protected hippocampal cells, preventing neuronal loss associated with the depressive-like state and nitrite level increases (an indirect marker of nitric oxide production). Moreover, EO alone significantly increased TERT mRNA expression, revealing for the first time a potent antiaging action in the brain that suggests neuroprotection against long-term age-related consequences.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Euterpe/química , Extratos Vegetais/química , Animais , Antidepressivos/química , Antidepressivos/uso terapêutico , Antioxidantes/química , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Transtorno Depressivo/patologia , Transtorno Depressivo/prevenção & controle , Euterpe/metabolismo , Frutas/química , Frutas/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Telomerase/genética , Telomerase/metabolismo , Regulação para Cima/efeitos dos fármacos
18.
Mediators Inflamm ; 2019: 7823069, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467487

RESUMO

Macrophages have variable functional phenotypes, high diversity, and plasticity and are involved in the pathogenesis of sepsis-induced liver injury. Alteration of macrophage polarization through activated (M1) macrophage to alternatively activated (M2) macrophage has emerged as a potential therapeutic strategy. This study was designed to explore the effect of a benzenediamine analog FC-99 on macrophage polarization in vitro and lipopolysaccharide- (LPS-) induced liver injury followed by the underlying mechanisms. For in vitro experiments, FC-99 inhibited M1-related macrophage factors and promoted M2-related markers induced by IL-4 in the mouse macrophage cell line RAW264.7. Moreover, FC-99-induced macrophages polarized to M2 phenotype which could be repressed by a PPAR-γ inhibitor but not STAT6 siRNA knockdown, indicating FC-99-induced M2 macrophage polarization through PPAR-γ rather than STAT6 signal. In LPS-induced septic mice, FC-99 pretreated mice displayed lower expression of M1 markers together with the increased M2 marker CD206 and improvement of liver injury. These findings illustrated that FC-99 could promote M2 macrophage polarization via PPAR-γ signaling and seemed to be a potential therapeutic candidate for inflammatory liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Compostos de Diazônio/uso terapêutico , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Animais , Western Blotting , Citometria de Fluxo , Imunofluorescência , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , RNA Interferente Pequeno , Transdução de Sinais/efeitos dos fármacos
19.
Biomed Res Int ; 2019: 9573248, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467920

RESUMO

The neonatal immune system is still immature, which makes it more susceptible to the infectious agents. Neonatal immune activation is associated with increased permeability of the blood-brain barrier, causing an inflammatory cascade in the CNS and altering behavioral and neurochemical parameters. One of the hypotheses that has been studied is that neuroinflammation may be involved in neurodegenerative processes, such as Alzheimer's disease (AD). We evaluate visuospatial memory, cytokines levels, and the expression of tau and GSK-3ß proteins in hippocampus and cortex of animals exposed to neonatal endotoxemia. C57BL/6 mice aging two days received a single injection of subcutaneous lipopolysaccharide (LPS). At 60,120, and 180 days of age, visual-spatial memory was evaluated and the hippocampus and cortex were dissected to evaluate the cytokines levels and expression of tau and GSK-3ß proteins. The animals exposed to LPS in the neonatal period present with visuospatial memory impairment at 120 and 180 days of age. Here there was an increase of TNF-α and IL-1ß levels in the hippocampus and cortex only at 60 days of age. Here there was an increase in the expression of GSK-3ß in hippocampus of the animals at 60, 120, and 180 days of age. In the cortex, this increase occurred in the 120 and 180 days of age. Tau protein expression was high in hippocampus and cortex at 120 days of age and in hippocampus at 180 days of age. The data observed show that neonatal immune activation may be associated with visuospatial memory impairment, neuroinflammation, and increased expression of GSK-3ß and Tau proteins in the long term.


Assuntos
Animais Recém-Nascidos/imunologia , Encéfalo/imunologia , Endotoxemia/imunologia , Inflamação/imunologia , Animais , Animais Recém-Nascidos/genética , Barreira Hematoencefálica/imunologia , Encéfalo/crescimento & desenvolvimento , Córtex Cerebelar/imunologia , Endotoxemia/induzido quimicamente , Glicogênio Sintase Quinase 3 beta/genética , Hipocampo/imunologia , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Lipopolissacarídeos/toxicidade , Camundongos , Proteínas tau/genética
20.
Mol Cell ; 75(6): 1147-1160.e5, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31420217

RESUMO

Activated macrophages adapt their metabolic pathways to drive the pro-inflammatory phenotype, but little is known about the biochemical underpinnings of this process. Here, we find that lipopolysaccharide (LPS) activates the pentose phosphate pathway, the serine synthesis pathway, and one-carbon metabolism, the synergism of which drives epigenetic reprogramming for interleukin-1ß (IL-1ß) expression. Glucose-derived ribose and one-carbon units fed by both glucose and serine metabolism are synergistically integrated into the methionine cycle through de novo ATP synthesis and fuel the generation of S-adenosylmethionine (SAM) during LPS-induced inflammation. Impairment of these metabolic pathways that feed SAM generation lead to anti-inflammatory outcomes, implicating SAM as an essential metabolite for inflammatory macrophages. Mechanistically, SAM generation maintains a relatively high SAM:S-adenosylhomocysteine ratio to support histone H3 lysine 36 trimethylation for IL-1ß production. We therefore identify a synergistic effect of glucose and amino acid metabolism on orchestrating SAM availability that is intimately linked to the chromatin state for inflammation.


Assuntos
Histonas/metabolismo , Macrófagos Peritoneais/metabolismo , S-Adenosilmetionina/metabolismo , Trifosfato de Adenosina/metabolismo , Adulto , Animais , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos Peritoneais/patologia , Masculino , Metilação/efeitos dos fármacos , Camundongos
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