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1.
Mol Biol Rep ; 50(1): 97-106, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36308582

RESUMO

BACKGROUND: Carbon tetrachloride (CCl4) is highly toxic to animal liver and is a major contributor to liver injury. Gomphrena globosa L. (GgL) is an edible plant with anti-inflammation and antioxidation properties. The aim of this study was to investigate the potential therapeutic effects of GgL on liver injury. METHODS AND RESULTS: A model of chronic liver injury in mice was established by intraperitoneal injection of CCl4 (0.4 mL/kg) for 3 weeks, and the mice were treated intraperitoneally with different concentrations of GgL crude extract (GgCE; 100, 200, 300 mg/kg) or Bifendatatum (Bif; 20 mg/kg) in the last 2 weeks. The results showed that GgCE treatment alleviated the liver injury, improved the pathological changes caused by CCl4 on the mice liver, and enhance the antioxidant capacity. We also found that GgCE increased the expression of antioxidant stress related proteins, decreased the phosphorylation levels of autophagy related proteins PI3K and mTOR, and decreased the expression of LC3 II and P62 proteins. CONCLUSION: These results suggest that GgCE alleviated CCl4-induced chronic liver injury in mice by activating antioxidant signaling pathways and promoting autophagy, indicating a potential therapeutic effect of GgCE on liver injury.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Doença Hepática Induzida por Substâncias e Drogas , Camundongos , Animais , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Fígado/metabolismo , Transdução de Sinais , Tetracloreto de Carbono/farmacologia , Autofagia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Estresse Oxidativo
2.
J Appl Microbiol ; 134(12)2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38017630

RESUMO

AIMS: Clostridium perfringens infections affect food safety, human health, and the development of the poultry feed industry. Anti-virulence is an alternative strategy to develop new drug. Perfringolysin O (PFO) is an exotoxin of C. perfringens that has been demonstrated to play critical roles in the pathogenesis of this organism, promising it an attractive target to explore drugs to combat C. perfringens infection. METHODS AND RESULTS: Based on an activity-based screening, we identified six PFO inhibitors from the Food and Drug Administration (FDA)-approved drug library, among which rabeprazole sodium (RS) showed an optimal inhibitory effect with an IC50 of 1.82 ± 0.746 µg ml-1. The GLY57, ASP58, SER190, SER193-194, ASN199, GLU204, ASN377, THR379, and ALA200 in PFO interacted with RS during binding based on an energy analysis and H-bond analysis. This interaction blocked the oligomer formation of PFO, thereby inhibiting its cytotoxicity. RS treatment significantly increased the survival rate and alleviated pathological damage in C. perfringens or PFO-treated Galleria mellonella. CONCLUSIONS: RS could potentially be used as a candidate drug for treating C. perfringens infection.


Assuntos
Infecções por Clostridium , Clostridium perfringens , Humanos , Rabeprazol/farmacologia , Rabeprazol/metabolismo , Reposicionamento de Medicamentos , Proteínas Hemolisinas/farmacologia , Proteínas Hemolisinas/metabolismo
3.
Acta Biochim Biophys Sin (Shanghai) ; 55(5): 842-852, 2023 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-37227155

RESUMO

Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents. In clinical treatments, the insensitivity of OS to conventional radiotherapy regimens significantly contributes to poor patient prognosis and survival. EXO1 is responsible for DNA repair pathways and telomere maintenance. Meanwhile, ATM and ATR are considered switches because they can regulate the expression of EXO1. However, their expression and interaction in OS cells under irradiation (IR) remain unclear. This study aims to investigate the roles of FBXO32, ATM, ATR and EXO1 in OS radiotherapy insensitivity and poor patient prognosis and explore potential pathogenic mechanisms. Bioinformatics is employed to analyse differential gene expression and correlations with prognosis in OS. Cell counting kit 8 assay, clone formation assay, and flow cytometry are used to evaluate cell survival and apopotosis under IR. Co-IP assay is used to detect protein‒protein interactions. Bioinformatics analysis reveals that EXO1 is closely related to survival, apoptosis and poor prognosis in OS. Silencing of EXO1 suppresses cell proliferation and increases the sensitivity of OS cells. Molecular biological experiments show that ATM and ATR act as switches to regulate EXO1 expression under IR. Higher expression of EXO1, which is closely correlated with IR insensitivity and poorer prognosis, might be used as a prognostic indicator for OS. Phosphorylated ATM enhances the expression of EXO1, and phosphorylated ATR induces the degradation of EXO1. More importantly, FBXO32 degrades ATR via ubiquitination in a time-dependent manner. Our data may provide a reference for future research in the mechanisms, clinical diagnosis, and treatment of OS.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Criança , Humanos , Adolescente , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Osteossarcoma/genética , Osteossarcoma/radioterapia , Osteossarcoma/metabolismo , Sobrevivência Celular , Proliferação de Células/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Exodesoxirribonucleases/genética , Exodesoxirribonucleases/metabolismo , Enzimas Reparadoras do DNA/genética , Proteínas Musculares/metabolismo , Proteínas Ligases SKP Culina F-Box/metabolismo
4.
Opt Express ; 30(24): 43384-43397, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36523037

RESUMO

The undesired distribution of irregular surface astigmatism (SA) on the freeform surface has been the major concern of progressive addition lens (PAL) design. Herein, we proposed a segmented freeform surface (SFS) construction method, which relies on the lines of curvature to rule the surface segmentation and then eliminates the difference between principal curvatures to correct the SA. Based on ray tracing and numerical simulation results, the SFS-PAL design has superior performance in image quality within a dynamic field of view over the conventional freeform PAL. To verify the feasibility and the real performance of the new design, we used the diamond turning method with a fast tool servo to realize the rapid prototyping, and then used injection molding for the mass production of the high-quality SFS-PALs.

5.
Nucleic Acids Res ; 48(19): 10940-10952, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33010150

RESUMO

ATR functions as a master regulator of the DNA-damage response. ATR activation requires the ATR activator, topoisomerase IIß-binding protein 1 (TopBP1). However, the underlying mechanism of TopBP1 regulation and how its regulation affects DNA replication remain unknown. Here, we report a specific interaction between TopBP1 and the histone demethylase PHF8. The TopBP1/PHF8 interaction is mediated by the BRCT 7+8 domain of TopBP1 and phosphorylation of PHF8 at Ser854. This interaction is cell-cycle regulated and phosphorylation-dependent. PHF8 is phosphorylated by CK2, which regulates binding of PHF8 to TopBP1. Importantly, PHF8 regulates TopBP1 protein level by preventing its ubiquitination and degradation mediated by the E3 ligase UBR5. Interestingly, PHF8pS854 is likely to contribute to regulation of TopBP1 stability and DNA replication checkpoint. Further, both TopBP1 and PHF8 are required for efficient replication fork restart. Together, these data identify PHF8 as a TopBP1-binding protein and provide mechanistic insight into how PHF8 regulates TopBP1 stability to maintain DNA replication.


Assuntos
Proteínas de Transporte/metabolismo , Replicação do DNA , Proteínas de Ligação a DNA/metabolismo , Histona Desmetilases/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Caseína Quinase II/metabolismo , Linhagem Celular , Humanos , Fosforilação , Ligação Proteica , Domínios Proteicos
6.
Molecules ; 27(16)2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-36014383

RESUMO

Clostridium perfringens (C. perfringens) is an important foodborne pathogen that can cause diseases such as gas gangrene and necrotizing enteritis in a variety of economic animals, seriously affecting public health and the economic benefits and healthy development of the livestock and poultry breeding industry. Perfringolysin O (PFO) is an important virulence factor of C. perfringens and plays critical roles in necrotic enteritis and gas gangrene, rendering it an ideal target for developing new drugs against infections caused by this pathogen. In this study, based on biological activity inhibition assays, oligomerization tests and computational biology assays, we found that the foodborne natural component piceatannol reduced pore-forming activity with an inhibitory ratio of 83.84% in the concentration of 16 µg/mL (IC50 = 7.83 µg/mL) by binding with PFO directly and changing some of its secondary structures, including 3-Helix, A-helix, bend, and in turn, ultimately affecting oligomer formation. Furthermore, we confirmed that piceatannol protected human intestinal epithelial cells from the damage induced by PFO with LDH release reduced by 38.44% at 16 µg/mL, based on a cytotoxicity test. By performing an animal experiment, we found the C. perfringens clones showed an approximate 10-fold reduction in infected mice. These results suggest that piceatannol may be a candidate for anti-C. perfringens drug development.


Assuntos
Enterite , Gangrena Gasosa , Doenças das Aves Domésticas , Animais , Toxinas Bacterianas , Clostridium perfringens , Proteínas Hemolisinas , Humanos , Camundongos , Estilbenos , Virulência
7.
J Cell Mol Med ; 24(9): 5097-5108, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32293113

RESUMO

Non-alcohol fatty liver disease (NAFLD) is a common disease which causes serious liver damage. Geniposide (GEN), a kind of iridoid glycoside extracted from Gardenia jasminoides fruit, has many biological effects, such as resistance to cell damage and anti-neurodegenerative disorder. Lipid accumulation was obvious in tyloxapol-induced liver and oil acid (OA) with palmitic acid (PA)-induced HepG2 cells compared with the control groups while GEN improved the increasing conditions. GEN significantly lessened the total cholesterol (TC), the triglyceride (TG), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), myeloperoxidase (MPO), reactive oxygen species (ROS) and increased high-density lipoprotein (HDL), superoxide dismutase (SOD) to response the oxidative stress via activating nuclear factor erythroid-2-related factor 2 (Nrf2), haeme oxygenase (HO)-1 and peroxisome proliferator-activated receptor (PPAR)α which may influence the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) signalling pathway in mice and cells. Additionally, GEN evidently decreased the contents of sterol regulatory element-binding proteins (SREBP)-1c, phosphorylation (P)-mechanistic target of rapamycin complex (mTORC), P-S6K, P-S6 and high mobility group protein (HMGB) 1 via inhibiting the expression of phosphoinositide 3-kinase (PI3K), and these were totally abrogated in Nrf2-/- mice. Our study firstly proved the protective effect of GEN on lipid accumulation via enhancing the ability of antioxidative stress and anti-inflammation which were mostly depend on up-regulating the protein expression of Nrf2/HO-1 and AMPK signalling pathways, thereby suppressed the phosphorylation of mTORC and its related protein.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Iridoides/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Células Hep G2 , Humanos , Inflamação , Lipídeos/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Ácido Palmítico/química , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Polietilenoglicóis , Transdução de Sinais
8.
J Cell Mol Med ; 24(5): 3022-3033, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31989756

RESUMO

Chicoric acid is polyphenol of natural plant and has a variety of bioactivity. Caused by various kinds of stimulating factors, acute liver injury has high fatality rate. The effect of chicoric acid in acute liver injury induced by Lipopolysaccharide (LPS) and d-galactosamine (d-GalN) was investigated in this study. The results showed that CA decreased the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum and reduced the mortality induced by LPS/d-GalN. CA can restrain mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) to alleviate inflammation. Meanwhile, the results indicated CA can active nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway with increasing the level of AMP-activated protein kinase (AMPK). And with the treatment of CA, protein levels of autophagy genes were obvious improved. The results of experiments indicate that CA has protective effect in liver injury, and the activation of AMPK and autophagy may make sense.


Assuntos
Ácidos Cafeicos/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Succinatos/farmacologia , Quinases Proteína-Quinases Ativadas por AMP , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Autofagia/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Galactosamina/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Inflamação/sangue , Inflamação/genética , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/lesões , Fígado/patologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Proteínas Quinases/genética
9.
J Cell Mol Med ; 23(6): 4063-4075, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30950217

RESUMO

Aucubin (AU) is the main active ingredient of Aucuba japonica which has showed many positive effects such as anti-inflammation and liver protection. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. In this research, we explored the effects of AU on the tyloxapol-induced NAFLD in mice and apolipoprotein C-III (apoC-III) induced-3T3L1 cells. Tyloxapol (300 mg/kg) was injected to C57BL/6 mice with aucubin. The differentiated 3T3-L1 cells were treated with or without aucubin after stimulation of apoC-III (100 µg/mL). In results, aucubin inhibited hyperlipidaemia, oxidative stress and inflammation by influencing the content of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), very low density lipoprotein (VLDL), myeloperoxidase (MPO), superoxide dismutase (SOD), tumour necrosis factor receptor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 in blood. AU activated NF-E2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor α (PPARα), PPARγ and hemeoxygenase-1 (HO-1) and promoted the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPKα), AMPKß, acetyl-CoA carboxylase (ACC) and protein kinase B (AKT). In conclusion, AU performed the function of hypolipidaemic by its obvious anti-inflammation and antioxidant activity, which may become a kind of new drug targeting at NAFLD.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Heme Oxigenase-1/metabolismo , Glucosídeos Iridoides/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células 3T3-L1 , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Linhagem Celular , Colesterol/metabolismo , Lipídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Triglicerídeos/metabolismo
10.
J Cell Physiol ; 234(11): 19785-19798, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30937936

RESUMO

Morin (MO), a natural bioflavinoid, exists in many herbs. Previous studies have acclaimed MO's anti-inflammatory, antidiabetic, antioxidant, antifibrotic, anticancer, and antihyperglycemic biological effects. This study aimed to assess the molecular mechanism of MO involved in the oleic acid (OA)-induced inflammatory damage and lipid accumulation in HepG2 cell and tyloxapol (Ty)-induced hyperlipidemia in mice. We found that MO can efficaciously mitigate reactive tumor necrosis factor-α (TNF-α) level and triglyceride (TG) accumulation in OA-induced HepG2 cell and in tyloxapol-induced mice. Next, the study testified that MO apparently suppressed OA-excited nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways in HepG2 cell. In addition, MO distinctly upregulated the expression of peroxisome proliferator-activated receptor α (PPARα) and decreased the expression of sterol regulatory element-binding protein 1c (SREBP-1c) in OA-induced HepG2 cell and in tyloxapol-induced mice, both of which are dependent upon the phosphorylation of acetyl-CoA carboxylase (ACC), adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and protein kinase B (AKT). In conclusion, these results suggest that MO has protective potential against hyperlipidemia and steatosis, and the potential mechanism may have a close relation with activation of PPARα and inhibition of SREBP-1c.


Assuntos
Flavonoides/farmacologia , Hiperlipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Quinases Proteína-Quinases Ativadas por AMP , Acetil-CoA Carboxilase/genética , Animais , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/genética , Inflamação/induzido quimicamente , Inflamação/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/genética , Ácido Oleico/toxicidade , PPAR alfa/genética , Fosforilação/efeitos dos fármacos , Polietilenoglicóis/toxicidade , Proteínas Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Triglicerídeos/metabolismo
11.
Cell Commun Signal ; 17(1): 2, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30630510

RESUMO

BACKGROUND: Acetaminophen (APAP) overdose-induced acute liver failure (ALF) is mainly resulted from uncontrolled oxidative stress. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a key antioxidant transcription factor, is essential for alleviating APAP-induced hepatotoxicity. Corilagin (Cori) is a natural polyphenol compound that possesses effective antioxidant activity; however, the protective effect of Cori on APAP-induced hepatotoxicity is still unknown. The current study aimed to explore whether Cori could mitigate hepatotoxicity caused by APAP and the underlying molecular mechanisms of action. METHODS: Cell counting kit-8 (CCK-8) assays, Western blotting analysis, dual-luciferase reporter assays, a mouse model, CRISPR/Cas9 knockout technology, and hematoxylin-eosin (H & E) staining were employed to explore the mechanisms by which Cori exerts a protective effect on hepatotoxicity in HepG2 cells and in a mouse model. RESULTS: Our findings suggested that Cori efficiently decreased APAP-triggered the generation of reactive oxygen species (ROS) and cell death in HepG2 cells. Additionally, Cori significantly induced the expression of several antioxidant enzymes, and this induced expression was closely linked to the upregulation of Nrf2, inhibition of Keap1 protein expression, and promotion of antioxidant response element (ARE) activity in HepG2 cells. Moreover, Cori clearly induced the phosphorylation of AMP-activated protein kinase (AMPK), glycogen synthase kinase-3ß (GSK3ß), liver kinase B1 (LKB1) and acetyl-CoA carboxylase (ACC). Furthermore, Cori-mediated GSK3ß inactivation, Nrf2 upregulation and cytoprotection were abolished by an AMPK inhibitor (Compound C) in HepG2 cells. Lastly, we found that Cori inhibited APAP-induced hepatotoxicity and mediated the expression of many antioxidant enzymes; these results were reversed in Nrf2 -/- HepG2 cells. In vivo, Cori significantly protected against APAP-induced ALF by reducing mortality and alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, attenuating histopathological liver changes, inhibiting myeloperoxidase (MPO) and malondialdehyde (MDA) levels, and increasing the superoxide dismutase (SOD) content and GSH-to-GSSG ratio as well as suppressing c-jun N-terminal kinase (JNK) phosphorylation. However, Cori-induced reductions in mortality, AST and ALT levels, and histopathological liver changes induced by APAP were clearly abrogated in Nrf2-deficienct mice. CONCLUSIONS: These findings principally indicated that Cori effectively protects against APAP-induced ALF via the upregulation of the AMPK/GSK3ß-Nrf2 signaling pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Acetaminofen/efeitos adversos , Glucosídeos/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Taninos Hidrolisáveis/farmacologia , Fígado/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Animais , Elementos de Resposta Antioxidante/genética , Morte Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucosídeos/química , Células Hep G2 , Humanos , Taninos Hidrolisáveis/química , Fígado/efeitos dos fármacos , Fígado/lesões , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/patologia , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
13.
J Infect Dis ; 211(9): 1376-87, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25231018

RESUMO

Listeriolysin O (LLO), an essential virulence determinant of Listeria monocytogenes, is a pore-forming toxin whose primary function is to facilitate cytosolic bacterial replication by breaching the phagosomal membranes, which is critical for the pathogen to evade host immune recognition. The critical role of LLO in the virulence of L. monocytogenes renders it an ideal target for designing novel antivirulence therapeutics. We found that fisetin, a natural flavonoid without antimicrobial activity, is a potent antagonist of LLO-mediated hemolysis. Fisetin effectively inhibits L. monocytogenes infection in both tissue culture and animal infection models. Molecular modeling and mutational analysis revealed that fisetin directly engages loop 2 and loop 3 of LLO, leading to the blockage of cholesterol binding and the reduction of its oligomerization, thus inhibiting its hemolytic activity. Our results establish fisetin as an effective antitoxin agent for LLO, which can be further developed into novel therapeutics against infections caused by L. monocytogenes.


Assuntos
Toxinas Bacterianas/metabolismo , Flavonoides/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico/metabolismo , Proteínas Hemolisinas/metabolismo , Listeria monocytogenes/efeitos dos fármacos , Listeria monocytogenes/patogenicidade , Animais , Toxinas Bacterianas/genética , Feminino , Flavonoides/química , Flavonóis , Proteínas de Choque Térmico/genética , Proteínas Hemolisinas/genética , Listeria monocytogenes/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Virulência
14.
Neurobiol Dis ; 73: 296-306, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25315683

RESUMO

Epilepsy and autism spectrum disorder (ASD) are common comorbidities of one another. Despite the prevalent correlation between the two disorders, few studies have been able to elucidate a mechanistic link. We demonstrate that forebrain specific Tsc1 deletion in mice causes epilepsy and autism-like behaviors, concomitant with disruption of 5-HT neurotransmission. We find that epileptiform activity propagates to the raphe nuclei, resulting in seizure-dependent hyperactivation of mTOR in 5-HT neurons. To dissect whether mTOR hyperactivity in 5-HT neurons alone was sufficient to recapitulate an autism-like phenotype we utilized Tsc1flox/flox;Slc6a4-cre mice, in which mTOR is restrictively hyperactivated in 5-HT neurons. Tsc1flox/flox;Slc6a4-cre mice displayed alterations of the 5-HT system and autism-like behaviors, without causing epilepsy. Rapamycin treatment in these mice was sufficient to rescue the phenotype. We conclude that the spread of seizure activity to the brainstem is capable of promoting hyperactivation of mTOR in the raphe nuclei, which in turn promotes autism-like behaviors. Thus our study provides a novel mechanism describing how epilepsy can contribute to the development of autism-like behaviors, suggesting new therapeutic strategies for autism.


Assuntos
Transtorno Autístico/tratamento farmacológico , Transtorno Autístico/metabolismo , Comportamento Animal/fisiologia , Epilepsia/metabolismo , Neurônios/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Núcleos da Rafe/metabolismo , Serotonina/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteína 1 do Complexo Esclerose Tuberosa
15.
Microb Pathog ; 75: 21-8, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25173422

RESUMO

Betulin, a naturally occurring triterpene, has shown anti-HIV activity, but details on the anti-inflammatory activity are scanty. In this study, we sought to investigate the effect of Betulin on LPS-induced activation of cell lines with relevance for lung inflammation in vitro and on lung inflammation elicited by either LPS or viable Escherichia coli (E. coli) in vivo. In vitro, Betulin inhibited LPS-induced tumor necrosis factor α (TNF-α) and (interleukin) IL-6 levels and up-regulated the level of IL-10. Also Betulin suppressed the phosphorylation of nuclear factor-κB (NF-κB) p65 protein in LPS-stimulated RAW 264.7 cells. In vivo, Betulin alleviated LPS-induced acute lung injury. Treatment with Betulin diminished pro-inflammatory cytokines, myeloperoxidase activity and bacterial loads in lung tissue during gram-negative pneumonia. Our findings demonstrated that Betulin inhibits pro-inflammatory responses induced by the gram-negative stimuli LPS and E. coli, suggesting that Betulin may represent a novel strategy for the treatment of lung inflammation.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Toxinas Botulínicas/farmacologia , Pneumonia Bacteriana/prevenção & controle , Animais , Anti-Inflamatórios/administração & dosagem , Carga Bacteriana , Toxinas Botulínicas/administração & dosagem , Linhagem Celular , Citocinas/análise , Modelos Animais de Doenças , Infecções por Escherichia coli/patologia , Infecções por Escherichia coli/prevenção & controle , Lipopolissacarídeos/toxicidade , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL
16.
Inflamm Res ; 63(6): 429-39, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24487736

RESUMO

OBJECTIVE: We investigated whether p-synephrine exerts potent anti-inflammatory effects against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in vivo, and we further investigated the inhibitory mechanism of p-synephrine in LPS-induced ALI. METHODS: Lipopolysaccharide (0.5 mg/kg) was instilled intranasally in phosphate-buffered saline to induce acute lung injury, and 6, 24, and 48 h after LPS was given, bronchoalveolar lavage fluid was obtained to measure pro-inflammatory mediator. We also evaluated the effects of p-synephrine on LPS-induced the severity of pulmonary injury. The phosphorylation of nuclear factor-κB (NF-κB) p65 protein was analyzed by Western blotting. RESULTS: Our data showed that p-synephrine significantly reduced the amount of inflammatory cells, the lung wet-to-dry weight (W/D) ratio, reactive oxygen species, myeloperoxidase activity and enhanced superoxide dismutase (SOD) in mice with LPS-induced ALI. Tumor necrosis factor α and interleukin (IL)-6 concentrations decreased significantly while the concentration of IL-10 was significantly increased after p-synephrine pretreatment. In addition, p-synephrine suppressed not only the phosphorylation of NF-κB but also the degradation of its inhibitor (IκBα). CONCLUSIONS: These results suggested that the inhibition of NF-κB activation and the regulation of SOD are involved in the mechanism of p-synephrine's protection against ALI.


Assuntos
Lesão Pulmonar Aguda/imunologia , Anti-Inflamatórios/farmacologia , NF-kappa B/antagonistas & inibidores , Sinefrina/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/uso terapêutico , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Contagem de Células , Interleucina-10/imunologia , Interleucina-6/imunologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , NF-kappa B/imunologia , Peroxidase/imunologia , Espécies Reativas de Oxigênio/imunologia , Superóxido Dismutase/imunologia , Sinefrina/uso terapêutico , Fator de Necrose Tumoral alfa/imunologia
17.
J Surg Res ; 186(1): 436-45, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24120240

RESUMO

BACKGROUND: Bornyl acetate is a bicyclic monoterpene present in numerous conifer oils. In this study, we aimed at clarifying the potential anti-inflammatory function and mechanism of bornyl acetate by using lipopolysaccharide (LPS)-induced acute lung injury murine model and RAW 264.7 cells. MATERIALS AND METHODS: RAW 264.7 cells were pretreated with bornyl acetate 1 h before LPS stimulation and cell-free super supernatants were collected to measure cytokine concentrations. To induce acute lung injury, BALB/c mice were injected intranasally with LPS and treated with bornyl acetate 1 h before LPS stimulation. Seven hours after administration, the bronchoalveolar lavage fluid (BALF) was collected for measuring the cell count and cytokine production. We collected lungs for assaying wet-to-dry weight ratio, myeloperoxidase activity, and histologic changes. The extent of phosphorylation of mitogen-activated protein kinases and nuclear factor κB was detected by Western blot. RESULTS: Our results showed that bornyl acetate downregulated the levels of proinflammatory cytokines in vitro and in vivo; reduced the number of total cells, neutrophils, and macrophages in BALF; attenuated the histologic alterations in the lung; decreased the wet-to-dry weight ratio in BALF; and suppressed NF-kappa-B inhibitor alpha, extracellular regulated protein kinases, c-JunN-terminal kinase, p38 mitogen-activated protein kinase activation. CONCLUSIONS: These findings suggested that bornyl acetate may be developed as a preventive agent for lung inflammatory diseases.


Assuntos
Canfanos/farmacologia , Peroxidase/metabolismo , Pneumonia/prevenção & controle , Lesão Pulmonar Aguda/patologia , Animais , Células Cultivadas , Citocinas/biossíntese , Pulmão/efeitos dos fármacos , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo
18.
Microbiol Spectr ; 12(1): e0240623, 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38078719

RESUMO

IMPORTANCE: Salmonella spp. remains a major worldwide health concern that causes significant morbidity and mortality in both humans and animals. The spread of antimicrobial resistant strains has declined the efficacy of conventional chemotherapy. Thus, novel anti-infection drugs or strategies are needed. Anti-virulence strategy represents one of the promising means for the treatment of bacterial infections. In this study, we found that the natural compound fisetin could inhibit Salmonella invasion of host cells by targeting SPI-1 regulation. Fisetin treatment impaired the interaction of the regulatory protein HilD with the promoters of its target genes, thereby suppressing the expression of T3SS-1 effectors as well as structural proteins. Moreover, fisetin treatment could reduce pathology in the Salmonella murine infection model. Collectively, our results suggest that fisetin may serve as a promising lead compound for the development of anti-Salmonella drugs.


Assuntos
Flavonóis , Infecções por Salmonella , Salmonella typhimurium , Humanos , Animais , Camundongos , Salmonella typhimurium/genética , Sistemas de Secreção Tipo III/metabolismo , Infecções por Salmonella/tratamento farmacológico , Infecções por Salmonella/microbiologia , Fatores de Transcrição/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica
19.
Br J Pharmacol ; 181(1): 54-69, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37539785

RESUMO

BACKGROUND AND PURPOSE: The production of metallo-ß-lactamases is a major mechanisms adopted by bacterial pathogens to resist carbapenems. Repurposing approved drugs to restore the efficacy of carbapenems represents an efficient and cost-effective approach to fight infections caused by carbapenem resistant pathogens. EXPERIMENTAL APPROACH: The nitrocefin hydrolysis assay was employed to screen potential New Delhi metallo-lactamase-1 (NDM-1) inhibitors from a commercially available U.S. Food and Drug Administration (FDA) approved drug library. The mechanism of inhibition was clarified by metal restoration, inductively coupled plasma mass spectrometry (ICP-MS) and molecular dynamics simulation. The in vitro synergistic antibacterial effect of the identified inhibitors with meropenem was determined by the checkerboard minimum inhibitory concentration (MIC) assay, time-dependent killing assay and combined disc test. Three mouse infection models were used to further evaluate the in vivo therapeutic efficacy of combined therapy. KEY RESULTS: Twelve FDA-approved compounds were initially screened to inhibit the ability of NDM-1 to hydrolyse nitrocefin. Among these compounds, dexrazoxane, embelin, candesartan cilexetil and nordihydroguaiaretic acid were demonstrated to inhibit all tested metallo-ß-lactamases and showed an in vitro synergistic bactericidal effect with meropenem against metallo-ß-lactamases-producing bacteria. Dexrazoxane, embelin and candesartan cilexetil are metal ion chelating agents, while the inhibition of NDM-1 by nordihydroguaiaretic acid involves its direct binding to the active region of NDM-1. Furthermore, these four drugs dramatically rescued the treatment efficacy of meropenem in three infection models. CONCLUSIONS AND IMPLICATIONS: Our observations indicated that dexrazoxane, embelin, candesartan cilexetil and nordihydroguaiaretic acid are promising carbapenem adjuvants against metallo-ß-lactamases-positive carbapenem resistant bacterial pathogens.


Assuntos
Carbapenêmicos , Dexrazoxano , Animais , Camundongos , Carbapenêmicos/farmacologia , Carbapenêmicos/química , Meropeném/farmacologia , Inibidores de beta-Lactamases/farmacologia , Masoprocol , Antibacterianos/farmacologia , beta-Lactamases/metabolismo , Bactérias/metabolismo , Testes de Sensibilidade Microbiana
20.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1869(5): 159497, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38649009

RESUMO

BACKGROUNDS: Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases. The leaves of Broussonetia papyrifera contain a large number of flavonoids, which have a variety of biological functions. METHODS: In vitro experiments, free fatty acids were used to stimulate HepG2 cells. NAFLD model was established in vivo in mice fed with high fat diet (HFD) or intraperitoneally injected with Tyloxapol (Ty). At the same time, Total flavonoids of Broussonetia papyrifera (TFBP) was used to interfere with HepG2 cells or mice. RESULTS: The results showed that TFBP significantly decreased the lipid accumulation induced by oil acid (OA) with palmitic acid (PA) in HepG2 cells. TFBP decreased the total cholesterol (TC), the triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and increased high-density lipoprotein cholesterol (HDLC) in serum. TFBP could also effectively inhibit the generation of reactive oxygen species (ROS) and restrained the level of myeloperoxidase (MPO), and enhance the activity of superoxide dismutase (SOD) to alleviate the injury from oxidative stress in the liver. Additionally, TFBP activated nuclear factor erythroid-2-related factor 2 (Nrf2) pathway to increasing the phosphorylation of AMP-activated protein kinase (AMPK). Meanwhile, protein levels of mTORC signaling pathway were evidently restrained with the treatment of TFBP. CONCLUSION: Our experiments proved that TFBP has the therapeutic effect in NAFLD, and the activation of Nrf2 and AMPK signaling pathways should make sense.


Assuntos
Proteínas Quinases Ativadas por AMP , Broussonetia , Flavonoides , Fator 2 Relacionado a NF-E2 , Hepatopatia Gordurosa não Alcoólica , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Humanos , Camundongos , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Broussonetia/química , Dieta Hiperlipídica/efeitos adversos , Flavonoides/farmacologia , Células Hep G2/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
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