RESUMO
Guchang Zhixie Wan (GZW) is a commonly used Chinese medicine for the treatment of ulcerative colitis (UC). This research explored the potential pharmacological mechanism of GZW in UC. The active ingredients, potential targets, and UC-related genes of GZW were retrieved from public databases. The pharmacological mechanisms including key components, potential targets and signal pathways were determined through bioinformatics analysis. The results of this study were verified through virtual molecular docking and cell experiments. Network analysis revealed that 26 active GZW compounds and 148 potential GZW target proteins were associated with UC. Quercetin, kaempferol and ß-sitosterol were identified as the core active ingredients of GZW. IFNG, IL-1A, IL-1B, JUN, RELA, and STAT1 were indicated as key targets of GZW. These key targets have a strong affinity for quercetin, kaempferol, and ß-sitosterol. GO and KEGG enrichment analysis showed that GZW target proteins are highly enriched in inflammatory, immune, and oxidative stress-related pathways. This study confirmed the therapeutic effect and revealed potential molecular mechanism of GZW on UC. And the protective effects of GZW on inflammatory bowel disease pathway were also revealed through STAT3/NF-κB/IL-6 pathway. The findings of this study enhanced our understanding of GZW in the treatment of UC and provided a feasible method for discovering potential drugs from traditional Chinese medicine formulations.
Assuntos
Medicamentos de Ervas Chinesas/metabolismo , Animais , Sítios de Ligação , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Interleucina-6/sangue , Interleucina-6/metabolismo , Medicina Tradicional Chinesa , Camundongos , Simulação de Acoplamento Molecular , Mapas de Interação de Proteínas , Células RAW 264.7 , Fator de Transcrição STAT3/sangue , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/sangue , Fator de Transcrição RelA/metabolismoRESUMO
Heat shock proteins play an important role in immune inflammation and the formation and restoration of proteins. In recent years, the importance of heat shock protein 90 (Hsp90) in the activation of immune inflammation through nuclear factor kB (NFkB) has been discussed. To assess the activation of the Hsp90-NFkB system by measuring serum and urinary levels in patients with chronic glomerulonephritis (CGN). This study included 32 patients with active forms of CGN and 14 patients with Fabry nephropathy. The control group included 10 healthy individuals. Twenty-one out of 32 CGN patients had nephrotic syndrome (NS). Eleven out of 32 CGN patients had proteinuria levels from 1 to 3 g/day without nephrotic syndrome. A total of 17 patients had renal dysfunction (estimated glomerular filtration rate < 60 ml/min/1.73m2). Fourteen patients with Fabry nephropathy had proteinuria without nephrotic syndrome. Serum and urine HSP-90 and NFkB p65 levels were determined using an enzyme-linked immunosorbent assay. The levels of HSP-90 and NFkB in the serum of patients with CGN were significantly higher than in healthy individuals and patients with Fabry nephropathy. In patients with Fabry nephropathy, the HSP-90 and NFkB levels in the urine and serum did not significantly differ from those in the control subjects. Serum Hsp90 levels were significantly higher in the CGN patients with NS than in patients without NS, as well as in patients with normal renal function compared with patients with an eGFR < 60 ml/min/1.73 m2 and patients with tubulo-interstitial fibrosis. Higher levels of HSP-90 and NFkB in serum were observed in patients with nephrotic forms of CGN, including focal segmental glomerulosclerosis, minimal change disease and membranous nephropathy. There were no correlations between the clinical signs of CGN and urinary HSP90/NFkB levels. Activation of the HSP-90-NFkB system, which is directly involved in the development of immune inflammation in CGN, was found in patients with an active course of CGN, especially in those with nephrotic syndrome.
Assuntos
Glomerulonefrite/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Fator de Transcrição RelA/metabolismo , Adulto , Doença Crônica , Doença de Fabry/sangue , Doença de Fabry/urina , Feminino , Glomerulonefrite/sangue , Glomerulonefrite/urina , Proteínas de Choque Térmico HSP90/sangue , Proteínas de Choque Térmico HSP90/urina , Humanos , Masculino , Pessoa de Meia-Idade , Fator de Transcrição RelA/sangue , Fator de Transcrição RelA/urina , Adulto JovemRESUMO
PROBLEM: Vitamin D is well-known for having anti-inflammatory and immunomodulatory properties. Impaired maternal vitamin D status has been known to increase the risk of adverse pregnancy outcomes like pre-term birth. The present study aims to evaluate the impact of fetal cord serum 25-hydroxyvitamin D-mediated signaling in mediating inflammatory responses in placenta during pre-term birth. METHOD OF STUDY: For the above purpose, cord serum 25 hydroxyvitamin D 25(OH)D were measured in term (n = 20) and pre-term (n = 20) born babies using ELISA. Vitamin D downstream signaling has also been checked in placenta (VDR, CYP27B1, cathelicidin LL37) along with expression of inflammatory markers (S100A8, HMGB1, TLR2, p-NF-kappaB) using Western blotting and immunohistochemistry. Pearson correlation model was used to do correlation study. RESULTS: Compared with term born babies (59.31 ± 3.476), decline in cord serum 25(OH)D levels is observed in pre-term born babies (22.26 ± 1.083, P = <0.0001) that showed strong positive correlation with gestational age (r = .9368***) and birthweight (r = .9559***). On the other hand, vitamin D signaling markers were found to be downregulated and inflammatory markers were upregulated in placental tissue of pre-term born babies. CONCLUSION: Thus, our study demonstrated that insufficient cord 25(OH)D levels may disturb the homeostasis of inflammation in placenta. Altered cord serum 25(OH)D mediated anti-inflammatory signaling may be acting as trigger signals in modulating inflammatory responses in placenta and eliciting premature activation of spontaneous labor in pre-term birth.
Assuntos
Sangue Fetal/química , Recém-Nascido Prematuro/sangue , Inflamação/sangue , Doenças Placentárias/sangue , Nascimento Prematuro/sangue , Vitamina D/análogos & derivados , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/biossíntese , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Adulto , Peso ao Nascer , Vilosidades Coriônicas/metabolismo , Vilosidades Coriônicas/patologia , Feminino , Idade Gestacional , Humanos , Lactente , Inflamação/patologia , Mediadores da Inflamação/análise , Doenças Placentárias/patologia , Gravidez , Complicações na Gravidez/sangue , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Calcitriol/biossíntese , Receptores de Calcitriol/genética , Fator de Transcrição RelA/sangue , Vitamina D/sangue , Deficiência de Vitamina D/sangueRESUMO
BACKGROUND: Our present study aimed to unravel the therapeutic biotargets of vitamin C (VC) against cystitis glandularis (CG), and to elucidate the molecular mechanisms for VC treating CG. METHODS: Network pharmacology was used to predict therapeutic targets of VC against CG, and to identify molecular mechanisms. In addition, further human and animal studies were designed to validate the bioinformatic findings through biochemical tests, computerized tomography scans, and immunostaining assays. RESULTS: In bioinformatic analyses, pathogenic targets of CG and putative targets of VC were identified, respectively. An interaction network between biological target and functional protein was produced before screening and collecting the key therapeutic targets of VC against CG, biological processes, and signaling pathways. In addition, ingenuity pathway analysis with cloud platform indicated that anti-CG mechanisms of VC were achieved through modulating a cluster of molecular pathways, such as tumor necrosis factor (TNF) pathway. Meanwhile, 18 core targets of VC against CG were identified, and the most important TNF, interleukin-6 (IL6), and Jun biotargets were obtained, respectively. In further validation in human study, cellular TNF-α, IL6, and c-Jun expressions in patient's CG samples were elevated significantly, accompanied with detectable urinary tract infection. Beneficially, VC-dosed CG mice resulted in downregulated expressions of endogenous TNF-α, IL6, and c-Jun in blood and bladder samples. CONCLUSION: Collectively, these bioinformatic findings and experimentative data uncover the therapeutic targets and biological mechanisms of VC for treating CG, in which the key biomarkers of TNF-α, IL6, and c-Jun may be the potential molecules for treating CG in clinical application.
Assuntos
Ácido Ascórbico/administração & dosagem , Biomarcadores/sangue , Cistite/tratamento farmacológico , Mapas de Interação de Proteínas/efeitos dos fármacos , Animais , Cistite/sangue , Cistite/genética , Cistite/patologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/sangue , Interleucina-6/genética , Proteínas Quinases JNK Ativadas por Mitógeno/sangue , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/sangue , Fator de Transcrição RelA/genética , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genéticaRESUMO
Long noncoding RNAs (lncRNAs) are dysregulated in cancer and involved in oncogenic or tumor inhibitory processes. The aim of the study was to investigate the expression pattern of lncRNA XLOC_013703 in multiple myeloma (MM) and to evaluate its biological role and potential significance. We found that XLOC_013703 was significantly decreased in CD138 positive plasma cells and serum of MM patients compared to normal controls, and the decreased XLOC_013703 expression was correlated with ß2-MG, serum-free light chain (s-FLC) and revised international staging system. RNA-fluorescence in situ hybridization results revealed that XLOC_013703 was distributed both in the nucleus and in the cytoplasm of MM cells including H929, RPMI8226, and U266. Overexpression of XLOC_013703 inhibited the proliferation of U266 cells and blocked the cell cycle in G1 stage, thus contributing to MM cell apoptosis. By contrast, knockdown of XLOC_013703 promoted the growth of H929 cells. Western blot analysis confirmed that the expression of p-IκBα and nuclear P65 was substantially increased in shRNA transfection groups compared to control groups, whereas overexpression of XLOC_013703 reduced these expressions. In conclusion, we confirmed that the decreased expression of a novel lncRNA, XLOC_013703, in MM. XLOC_013703 was involved in MM cell survival and proliferation via nuclear factor-κB pathway which represents a potential therapeutic target for MM. © 2019 IUBMB Life, 71(9):1240-1251, 2019.
Assuntos
Proliferação de Células/genética , Mieloma Múltiplo/genética , NF-kappa B/genética , RNA Longo não Codificante/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Hibridização in Situ Fluorescente , Metástase Linfática/genética , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/patologia , Inibidor de NF-kappaB alfa/genética , RNA Longo não Codificante/sangue , Transdução de Sinais/genética , Fator de Transcrição RelA/sangue , Fator de Transcrição RelA/genéticaRESUMO
AIM: The aim of the present study was to investigate the effect of cold atmospheric discharge plasma-activated saline (DPAS) on abdominal sepsis. METHODS: For in vitro research, Methicillin-resistant Staphylococcus aureus (MRSA) was treated with DPAS, and the survival was detected. For in vivo research, male C57BL/6 mice were induced to sepsis by cecal ligation and puncture (CLP) and were randomly allocated into saline and DPAS control groups, CLP group, and low or high doses of DPAS (CLPâ+âDPAS 5 and CLPâ+âDPAS 10) groups. In experiment 1, mice were monitored for 120âh to conduct a Kaplan-Meier survival curve analysis. In experiment 2, blood, peritoneal fluid, and lung and intestinal tissues in experimental groups were collected at 4, 8, and 24âh after the CLP/sham operation to determine the severity of sepsis. RESULTS: In vitro results showed that DPAS significantly inhibited MRSA proliferation. In vivo results showed that both low and high doses of DPAS could significantly improve septic survival in the mice. DPAS treatment also significantly attenuated the lung and intestine histopathological injuries; lung wet/dry ratio; inflammatory reaction; bacterial load in the peritoneal cavity, blood, and lungs; HMGB1 and NF-κB p65 expression levels; cell apoptosis in the lung and intestine. However, there was no difference between CLPâ+âDPAS 5 and CLPâ+âDPAS 10 groups. CONCLUSION: In conclusion, DPAS had markedly protective effects on abdominal sepsis in mice, and the potential mechanism was associated with the ability of reactive species in DPAS to promote bacterial clearance, inhibit the inflammatory response and cell apoptosis.
Assuntos
Staphylococcus aureus Resistente à Meticilina/patogenicidade , Plasma , Solução Salina/uso terapêutico , Sepse/microbiologia , Sepse/prevenção & controle , Animais , Ceco/lesões , Proteína HMGB1/sangue , Intestinos/microbiologia , Estimativa de Kaplan-Meier , Ligadura/efeitos adversos , Pulmão/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Punções/efeitos adversos , Sepse/sangue , Fator de Transcrição RelA/sangueRESUMO
BACKGROUND/OBJECTIVES: Given their role in female reproduction, the effects of progesterone on arginine and related amino acids, polyamines and NF-κB p65 activation were studied across the menstrual cycle. METHODS: Arginine, ornithine and citrulline as well as putrescine, spermidine, spermine, and N-acetyl-putrescine were determined in plasma, NF-κB p65 activation in peripheral blood mononuclear cells and progesterone in serum of 28 women at early (T1) and late follicular (T2) and mid (T3) and late (T4) luteal phase. RESULTS: Arginine and related amino acids declined from T1 and T2 to T3 and T4, while progesterone increased. At T3, arginine, ornithine, and citrulline were inversely related with progesterone. Changes (ΔT3-T2) in arginine, ornithine, and citrulline were inversely related with changes (ΔT3-T2) in progesterone. Ornithine and citrulline were positively related with arginine, as were changes (ΔT3-T2) in ornithine and citrulline with changes (ΔT3-T2) in arginine. At T2, NF-κB p65 activation was positively related with arginine. Polyamines did not change and were not related to progesterone. All results described were significant at P < 0.001. CONCLUSIONS: This study for the first time provides data, at the plasma and PBMC level, supporting a proposed regulatory node of arginine and related amino acids, progesterone and NF-κB p65 at luteal phase of the menstrual cycle, aimed at successful preparation of pregnancy.
Assuntos
Arginina/sangue , Fase Luteal/sangue , Progesterona/fisiologia , Adulto , Aminoácidos/sangue , Citrulina/metabolismo , Feminino , Fase Folicular , Voluntários Saudáveis , Humanos , Leucócitos Mononucleares/citologia , Subunidade p50 de NF-kappa B/sangue , Ornitina/metabolismo , Putrescina/metabolismo , Valores de Referência , Espermidina/metabolismo , Espermina/metabolismo , Fator de Transcrição RelA/sangueRESUMO
Background To investigate the relationship between the levels of nuclear factor (NF)-κB p50 and NF-κB p65 and tumour characteristics in patients with thyroid carcinoma. Methods This prospective study enrolled consecutive patients with thyroid carcinoma. Tumour samples were collected and the levels of NF-κB p50 and NF-κB p65 protein and mRNA were measured using immunohistochemistry and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Results A total of 73 patients with thyroid carcinoma were included in the study (20 males; 53 females; mean ± SD age, 44.8 ± 12.7 years, range, 18-76 years). There were no significant differences in sex, age and pathological type between the NF-κB p50 positive group and the NF-κB p50 negative group, but tumour diameter and lymph node metastasis were significantly higher in the NF-κB p50 positive group compared with the NF-κB p50 negative group. Similar findings were observed for NF-κB p65. The levels of NF-κB p50 were positively correlated with NF-κB p65 in samples of thyroid carcinoma ( rs = 0.653). Conclusion The levels of NF-κB p50 and NF-κB p65 in samples of thyroid carcinoma were positively associated with tumour diameter and the presence of lymph node metastasis.
Assuntos
Subunidade p50 de NF-kappa B/sangue , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/patologia , Fator de Transcrição RelA/sangue , Adolescente , Adulto , Idoso , China , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Mensageiro/sangue , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias da Glândula Tireoide/metabolismo , Adulto JovemRESUMO
BACKGROUND: Few studies have examined anti-inflammatory effects of pomegranate juice (PJ). The present study aimed to evaluate the effect of PJ on nuclear factor kappa B (NF-κB) p65 and sirtuin1 in peripheral blood mononuclear cell (PBMC), and plasma vascular inflammation biomarkers. METHODS: Patients with type 2 diabetes were randomly assigned to either the PJ (n = 22) or the placebo group (n = 22). The patients in the PJ group received 250 mL of PJ daily for 12 weeks, whereas the placebo group received corresponding control beverages of similar color and energy content. At baseline and at the end of week 12, fasting plasma concentrations of soluble intercellular adhesion molecule type 1 (sICAM-1), soluble vascular cell adhesion molecule type 1 (sVCAM-1), and soluble E-selectin (sE-selectin) were measured. NF-κB p65 and SIRT1 were measured in the PBMC. RESULTS: Plasma sE-selectin concentration decreased significantly in the PJ group at the end of week 12 compared to baseline (P < 0.001 for treatment effect), and the reduction was significant in comparison with the placebo group (P < 0.05 for treatment effect). There were no significant differences between the two groups in plasma sICAM-1 and sVCAM-1. At the end of the study, compared with the placebo group, NF-κB p65 in PBMC was significantly lower (P < 0.01 for treatment effect) and SIRT1 was significantly higher (P < 0.0001 for treatment effect) in the PJ group. CONCLUSION: This study supports the PJ consumption as a food with potential benefits in individuals with type 2 diabetes as evidenced by improvements in NF-κB and SIRT1 levels in PBMC of study participants.
Assuntos
Diabetes Mellitus Tipo 2/dietoterapia , Sucos de Frutas e Vegetais , Leucócitos Mononucleares/enzimologia , Lythraceae , Sirtuína 1/sangue , Adulto , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/enzimologia , Selectina E/sangue , Feminino , Humanos , Molécula 1 de Adesão Intercelular/sangue , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Fator de Transcrição RelA/sangue , Resultado do Tratamento , Regulação para Cima , Molécula 1 de Adesão de Célula Vascular/sangueRESUMO
McKinley-Barnard, SK, Andre, TL, Gann, JJ, Hwang, PS, and Willoughby, DS. Effectiveness of fish oil supplementation in attenuating exercise-induced muscle damage in females during midfollicular and midluteal menstrual phases. J Strength Cond Res 32(6): 1601-1612, 2018-The purpose of this study was to determine whether the differences in estrogen levels during the female menstrual cycle and fish oil supplementation would attenuate eccentric exercise-induced muscle damage and delayed-onset muscle soreness (DOMS). In a double-blind fashion, 22 physically active females (20.9 ± 1.4 years, 63.5 ± 9.0 kg, 165.2 ± 7.5 cm) were randomly assigned to ingest either 6 g of fish oil (n = 11) or placebo (n = 11) daily for 21 days. Participants underwent an eccentric exercise bout of the knee extensors on 2 occasions during the midfollicular (MF) and midluteal (ML) phases of the 28-day menstrual cycle. Before (PRE), at 6 (6HRPOST), and at 24 hours postexercise (24HRPOST) for each session, participants underwent assessments of DOMS, muscle strength, and had venous blood samples and muscle biopsies obtained. Data were analyzed using a 2 × 2 × 3 repeated-measures multivariate analysis of variance for each criterion variable (p ≤ 0.05). Further analysis of the main effects for the test was performed using separate 1-way analyses of variance. Delayed-onset muscle soreness was significantly greater at the 6HRPOST and 24HRPOST timepoints compared with PRE (p < 0.001). Superoxide dismutase and tumor necrosis factor-alpha (TNF-α) concentrations were significantly higher at the MF phase compared with the ML phase (p < 0.001 and p = 0.05, respectively). There were no statistically significant differences observed for muscle strength, myoglobin, NF-Kß p50, or NF-Kß p65. This study demonstrates that higher levels of estrogen may exert a cytoprotective effect on the sarcolemma.
Assuntos
Exercício Físico , Óleos de Peixe/uso terapêutico , Fase Folicular/sangue , Fase Luteal/sangue , Mialgia/prevenção & controle , Músculo Quadríceps/patologia , Adulto , Biópsia , Suplementos Nutricionais , Método Duplo-Cego , Estradiol/sangue , Feminino , Humanos , Masculino , Força Muscular , Mialgia/etiologia , Mioglobina/sangue , Subunidade p50 de NF-kappa B/sangue , Músculo Quadríceps/fisiologia , Superóxido Dismutase/sangue , Fator de Transcrição RelA/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto JovemRESUMO
To observe the protective effects of Lycium barbarum polysaccharides (LBP) on cerebral ischemia reperfusion injury in mice and explore its mechanism. Common carotid artery thread was used to cause middle cerebral artery ischemia, and the thread was taken out after 2 h ischemia to achieve cerebral ischemia reperfusion injury in mice. Therefore, the transient middle cerebral artery occlusion (tMCAO) models were established to observe the effects of LBP (25,50, 100 mgâ¢kg⻹) on neurological outcome, infarct size and water contents. HE staining was used to observe its effects on neurocytes of cerebral tissues in mice. Western blotting was used to evaluate the protein expression levels of NF-κB p65. ELISA was used to evaluate the levels of TNF-α, IL-6 and IL-1ß in the serum. According to the results, LBP markedly improved neurologic deficits, and decreased infarct size and water contents at 24 h after reperfusion in mice. Pathological section of brain tissues also proved its protective effects on neurocytes. Western blot analysis indicated that LBP markedly down-regulated the protein level of NF-κB p65. ELISA indicated that LBP decreased the levels of TNF-α, IL-6 and IL-1ß in the serum 24 h after reperfusion.In conclusion, LBP has protective effects on cerebral ischemia reperfusion injury in mice, and this effect may be associated with inhibiting NF-κB and inflammatory reactions.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Polissacarídeos/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Interleucina-1beta/sangue , Interleucina-6/sangue , Lycium/química , Camundongos , Fator de Transcrição RelA/sangue , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Studies showed that the use of cyclic adenosine monophosphate (cAMP) substitutes or intracellular cAMP activators increased intracellular cAMP level, causing anti-inflammatory effects. This study was to investigate the effects of pretreatment with meglumine cyclic adenylate (MCA), a compound of meglumine and cAMP, on systemic inflammation induced by lipopolysaccharide (LPS) in rats. Eighteen adult male Sprague-Dawley rats were randomly divided into 3 groups (n=6 each): control group (NS group), LPS group (LPS group) and LPS with MCA pretreatment group (MCA group). Systemic inflammation was induced with LPS 10 mg/kg injected via the femoral vein in LPS and MCA groups. In MCA group, MCA 2 mg/kg was injected via the femoral vein 20 min before LPS injection, and the equal volume of normal saline was given in NS and LPS groups at the same time. Three hours after LPS injection, the blood samples were taken from the abdominal aorta for determination of plasma concentrations of TNF-α, IL-1, IL-6, IL-10, cAMP by ELISA and NF-κBp65 expression by Western blotting. The experimental results showed that inflammatory and antiinflammatory indices were increased in LPS group compared to NS group; inflammatory indices were declined and anti-inflammatory indices were increased in MCA group relative to LPS group. Our study suggested that MCA pretreatment may attenuate LPS-induced systemic inflammation.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , AMP Cíclico/análogos & derivados , Meglumina/análogos & derivados , Síndrome de Resposta Inflamatória Sistêmica/prevenção & controle , Animais , Biomarcadores/sangue , AMP Cíclico/sangue , AMP Cíclico/imunologia , AMP Cíclico/farmacologia , Injeções Intravenosas , Interleucina-1/sangue , Interleucina-1/imunologia , Interleucina-10/sangue , Interleucina-10/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Lipopolissacarídeos , Masculino , Meglumina/farmacologia , Ratos , Ratos Sprague-Dawley , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/induzido quimicamente , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Fator de Transcrição RelA/sangue , Fator de Transcrição RelA/imunologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologiaRESUMO
PROBLEM: The aim of this study was to investigate the levels of nuclear factor kappa B-p65 (NF-κB p65) and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in maternal blood with premature rupture of membranes (PROM) and to assess their values for prediction of subclinical chorioamnionitis. METHOD: NF-κB p65 and sTREM-1 levels were measured in maternal blood and cord blood by fluorescence quantitative RT-PCR assay. According to the placental membranes pathological examination, pregnant women with PROM were divided into chorioamnionitis group (n=28) and non-chorioamnionitis group (n=22). RESULTS: In the PROM group,the NF-κB p65 and sTREM-1 levels in maternal blood were significantly higher in women with chorioamnionitis than women without chorioamnionitis (P<.05). The cutoff value of maternal NF-κB p65, sTREM-1, C-reactive protein (CRP), and WBC level were 6.73, 2.93, 6.75 mg/L, and 10.8×10(9) /L, respectively, through analysis of the area under the ROC curve (AUC). The optimal combination test was detection of maternal blood NF-κB p65 and CRP levels, which resulted in a sensitivity of 89.3% and a specificity of 72.7% for the prediction of subclinical chorioamnionitis. CONCLUSION: Combined measurements of maternal NF-κB p65 and CRP levels may be used as early biological indicators that predict subclinical chorioamnionitis in premature rupture of membranes.
Assuntos
Corioamnionite/sangue , Ruptura Prematura de Membranas Fetais/sangue , Fator de Transcrição RelA/sangue , Receptor Gatilho 1 Expresso em Células Mieloides/sangue , Adulto , Biomarcadores/sangue , Corioamnionite/imunologia , Feminino , Ruptura Prematura de Membranas Fetais/imunologia , Humanos , Valor Preditivo dos Testes , Gravidez , Fator de Transcrição RelA/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/imunologiaRESUMO
Using the menstrual cycle as a model, this study focused on longitudinal changes and associations within a physiological network known to play a role in female fertility, including, as biologically active nodes, NF-κB, leptin and adiponectin, ß-carotene, adipose tissue, and progesterone. In 28 women, leptin, adiponectin, ß-carotene, and progesterone concentrations, NF-κB p65 and p50 activation in peripheral blood mononuclear cells (known to possess estrogen, progesterone and leptin receptors), total body fat (TBF) and subcutaneous adipose tissue (SAT) mass were determined at early (T1) and late follicular (T2) and mid (T3) and late (T4) luteal phase. Leptin and adiponectin concentrations were higher, while NF-κB p65 activation was lower at T3 compared with T1. NF-κB p65 activation was inversely related to leptin concentrations at T1, T3, and T4. ß-Carotene was inversely related to leptin (T1,T2,T4) and SAT (T1,T3,T4). NF-κB p50 activation was inversely related to TBF (T4) and SAT (T3,T4), and leptin was positively related to TBF and SAT (T1-T4). Progesterone was inversely related to leptin (T2,T3), adiponectin (T3), TBF (T3,T4), and SAT (T2,T3,T4). By providing evidence of luteal phase-specific reduced NF-κB p65 activation in women under physiological conditions, this study bridges the gap between existing evidence of a Th1-Th2 immune response shift induced by reduced NF-κB p65 activation and a Th1-Th2 shift previously observed at luteal phase. For the first time, inverse regressions suggest inhibitory effects of leptin on NF-κB p65 activation at luteal phase, along with inhibitory effects of leptin as well as adiponectin on progesterone production in corpus luteum. © 2016 The Authors BioFactors published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology. 24(4):376-387, 2016.
Assuntos
Fase Folicular/sangue , Leptina/sangue , Leucócitos Mononucleares/metabolismo , Fase Luteal/sangue , Fator de Transcrição RelA/sangue , Adipocinas/sangue , Adiposidade , Adulto , Células Cultivadas , Feminino , Humanos , Estudos Longitudinais , Progesterona/sangue , beta Caroteno/sangueRESUMO
The effect of recombinant human soluble thrombomodulin (TM-α) on acute liver failure (ALF) is unclear, and we elucidated the effect of TM-α in lipopolysaccharide (LPS)/d-galactosamine (GalN)-induced ALF in mice. Placebo (saline) or TM-α (100 mg/kg) was administered 1 h after LPS/GalN administration. Survival rates were evaluated for 24 h after LPS/GalN administration. Plasma and liver samples were evaluated 1, 3, and 7 h after LPS/GalN administration. Survival rates were significantly higher in the TM-α-treated group than in the placebo group. A significant augmentation of plasma high-mobility group box 1 protein (HMGB1) was observed 7 h after LPS/GalN administration. In the TM-α-treated mice, plasma HMGB1 was significantly lower than in the placebo group. A significant augmentation of hepatic nuclear factor (NF)-κB p65 was observed in the placebo-treated group, whereas a significant reduction, relative to placebo, was observed in the TM-α-treated group. Hepatic expression of tumor necrosis factor (TNF)-α and myeloperoxidase were significantly increased in the placebo group, and were similarly significantly attenuated in the TM-α-treated group. TM-α treatment also produced a significant attenuation of liver neutrophil accumulation after LPS/GalN administration. Thus, TM-α may become a useful treatment strategy for reducing the symptoms of ALF via the attenuation of LPS/GalN-induced HMGB1 levels.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Trombomodulina/administração & dosagem , Animais , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Modelos Animais de Doenças , Galactosamina/toxicidade , Proteína HMGB1/sangue , Lipopolissacarídeos/toxicidade , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/patologia , Peroxidase/sangue , Proteínas Recombinantes/administração & dosagem , Solubilidade , Taxa de Sobrevida , Fator de Transcrição RelA/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
The aim of this study was to characterize variations in Raf kinase inhibitor protein (RKIP) expression and related signaling molecules in gastric cardia adenocarcinoma. Cancerous and precancerous tissues were collected from patients with gastric cardia adenocarcinoma and normal tissue was collected from healthy controls. RKIP expression was detected in these tissues and the serum levels of NF-κB p65 and T-lymphocyte subsets were measured. Positive RKIP expression was higher in gastric cardia adenocarcinoma tissues than in precancerous tissues. The serum level of total NF-κB p65 was higher in patients with gastric cardia adenocarcinoma than in healthy controls. Levels of NF-κB p65 did not correlate with positive and negative expression of RKIP, but were higher in patients with lymph node metastasis than in those without it. The cellular immune function of the gastric cardia adenocarcinoma group was lower than in normal controls, particularly in cases with negative RKIP expression. RKIP is downregulated in gastric cardia adenocarcinoma tissues, which is related to the occurrence, progression, invasion, and metastasis of tumors. The possible mechanism for this may be the inhibition of NF-κB activity and cellular immune function, which allows for the escape of tumor cells from immune surveillance.
Assuntos
Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Subpopulações de Linfócitos T/imunologia , Fator de Transcrição RelA/metabolismo , Adenocarcinoma/sangue , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Progressão da Doença , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Imunofenotipagem , Metástase Linfática , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fenótipo , Proteína de Ligação a Fosfatidiletanolamina/genética , Neoplasias Gástricas/sangue , Neoplasias Gástricas/patologia , Subpopulações de Linfócitos T/metabolismo , Fator de Transcrição RelA/sangueRESUMO
BACKGROUND: Preclinical and epidemiologic studies suggest that garlic intake is inversely associated with the progression of cancer and cardiovascular disease. OBJECTIVE: We designed a study to probe the mechanisms of garlic action in humans. METHODS: We conducted a randomized crossover feeding trial in which 17 volunteers consumed a garlic-containing meal (100 g white bread, 15 g butter, and 5 g raw, crushed garlic) or a garlic-free control meal (100 g white bread and 15 g butter) after 10 d of consuming a controlled, garlic-free diet. Blood was collected before and 3 h after test meal consumption for gene expression analysis in whole blood. Illumina BeadArray was used to screen for genes of interest, followed by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) on selected genes. To augment human study findings, Mono Mac 6 cells were treated with a purified garlic extract (0.5 µL/mL), and mRNA was measured by qRT-PCR at 0, 3, 6, and 24 h. RESULTS: The following 7 genes were found to be upregulated by garlic intake: aryl hydrocarbon receptor (AHR), aryl hydrocarbon receptor nuclear translocator (ARNT), hypoxia-inducible factor 1α (HIF1A), proto-oncogene c-Jun (JUN), nuclear factor of activated T cells (NFAT) activating protein with immunoreceptor tyrosine-based activation motif 1 (NFAM1), oncostatin M (OSM), and V-rel avian reticuloendotheliosis viral oncogene homolog (REL). Fold-increases in mRNA transcripts ranged from 1.6 (HIF1A) to 3.0 (NFAM1) (P < 0.05). The mRNA levels of 5 of the 7 genes that were upregulated in the human trial were also upregulated in cell culture at 3 and 6 h: AHR, HIF1A, JUN, OSM, and REL. Fold-increases in mRNA transcripts in cell culture ranged from 1.7 (HIF1A) to 12.1 (JUN) (P < 0.01). OSM protein was measured by ELISA and was significantly higher than the control at 3, 6, and 24 h (24 h: 19.5 ± 1.4 and 74.8 ± 1.4 pg/mL for control and garlic, respectively). OSM is a pleiotropic cytokine that inhibits several tumor cell lines in culture. CONCLUSION: These data indicate that the bioactivity of garlic is multifaceted and includes activation of genes related to immunity, apoptosis, and xenobiotic metabolism in humans and Mono Mac 6 cells. This trial is registered at clinicaltrials.gov as NCT01293591.
Assuntos
Administração Oral , Linfócitos B/imunologia , Alho , Linfócitos T/imunologia , Translocador Nuclear Receptor Aril Hidrocarboneto/sangue , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/sangue , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem Celular , Estudos Cross-Over , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Proteínas de Membrana/sangue , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Oncostatina M/sangue , Oncostatina M/genética , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-jun/sangue , Proteínas Proto-Oncogênicas c-jun/genética , RNA Mensageiro/sangue , RNA Mensageiro/metabolismo , Receptores de Hidrocarboneto Arílico/sangue , Receptores de Hidrocarboneto Arílico/genética , Fator de Transcrição RelA/sangue , Fator de Transcrição RelA/genética , Regulação para CimaRESUMO
BACKGROUND: The molecular mechanisms linking breast cancer progression and inflammation still remain obscure. The aim of the present study was to investigate the possible association of angiopoeitin like protein 4 (ANGPTL4) and its regulatory factor, hypoxia inducible factor-1 α (HIF-1α), with the inflammatory markers nuclear factor kappa B/p65 (NF-κB /P65) and interleukin-1 beta (IL-1ß) in order to evaluate their role in inflammation associated breast cancer progression. MATERIALS AND METHODS: Angiopoietin-like protein 4 (ANGPTL4) mRNA expressions were evaluated using quantitative real time PCR and its protein expression by immunohistochemistry. DNA binding activity of NF-κB /P65 was evaluated by transcription factor binding immunoassay. Serum levels of ANGPTL4, HIF-1α and IL-1ß were immunoassayed. Tumor clinico-pathological features were investigated. RESULTS: ANGPTL4 mRNA expressions and serum levels were significantly higher in high grade breast carcinoma (1.47±0.31 and 184.98±18.18, respectively) compared to low grade carcinoma (1.21±0.32 and 171.76±7.58, respectively) and controls (0.70±0.02 and 65.34±6.41, respectively), (p<0.05). Also, ANGPTL4 high/moderate protein expression was positively correlated with tumor clinico-pathological features. In addition, serum levels of HIF-1α and IL-1ß as well as NF-κB /P65 DNA binding activity were significantly higher in high grade breast carcinoma (148.54±14.20, 0.79±0.03 and 247.13±44.35 respectively) than their values in low grade carcinoma ( 139.14±5.83, 0.34±0.02 and 184.23±37.75, respectively) and controls (33.95±3.11, 0.11±0.02 and 7.83±0.92, respectively), (p<0.001). CONCLUSION: ANGPTL4 high serum levels and tissue expressions in advanced grade breast cancer, in addition to its positive correlation with tumor clinico-pathological features and HIF-1α could highlight its role as one of the signaling factors involved in breast cancer progression. Moreover, novel correlations were found between ANGPTL4 and the inflammatory markers, IL-1ß and NF-κB/p65, in breast cancer, which may emphasize the utility of these markers as potential tools for understanding interactions for axes of carcinogenesis and inflammation contributed for cancer progression. It is thus hoped that the findings reported here would assist in the development of new breast cancer management strategies that would promote patients' quality of life and ultimately improve clinical outcomes. However, large-scale studies are needed to verify these results.
Assuntos
Angiopoietinas/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-1beta/metabolismo , Fator de Transcrição RelA/metabolismo , Adulto , Proteína 4 Semelhante a Angiopoietina , Angiopoietinas/sangue , Angiopoietinas/genética , Biomarcadores Tumorais/sangue , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Proliferação de Células , Progressão da Doença , Feminino , Seguimentos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Técnicas Imunoenzimáticas , Interleucina-1beta/sangue , Interleucina-1beta/genética , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição RelA/sangue , Fator de Transcrição RelA/genética , Células Tumorais CultivadasRESUMO
BACKGROUND AND OBJECTIVE: Porphyromonas gingivalis (Pg) lipopolysaccharide is associated with the immune response and atherosclerosis. This study aimed to evaluate the effects of micro-amounts of Pg-lipopolysaccharide on rabbit inflammatory immune response and the development of atherosclerosis. MATERIAL AND METHODS: Twenty-four New Zealand white rabbits were randomly divided into four groups (n = 6). Group A was fed a regular diet and normal saline. Group B was supplied with a high-fat diet and normal saline. Group C was treated with a normal diet and Pg-lipopolysaccharide. Group D was given a high-fat diet and Pg-lipopolysaccharide. After 14 wk, the rabbits were killed to determine the changes in pathological indices. RESULTS: The serum lipid levels of groups B and D were significantly higher than that of group A (p < 0.01), and that of group C was higher (p < 0.05). Serum interleukin-6, monocyte chemoattractant protein-1 and tumor necrosis factor-α levels were significantly elevated by individual high-fat diets or Pg-lipopolysaccharide stimulation (p < 0.05). Groups A and C did not undergo evident aortic pathological damages, while foam cells appeared in the other two groups. Real-time polymerase chain reaction detection showed that toll-like receptor-2, interleukin-6, matrix metalloproteinase-9 and monocyte chemoattractant protein-1 were highly expressed in groups B and D (p < 0.05), and toll-like receptor-4, C-reactive protein and tumor necrosis factor-α levels were higher than those of group A (p < 0.05). Western blotting showed that transcription factor NF-κB p65 was expressed more highly in the three experimental groups than in group A (t = 9.26, p < 0.01). CONCLUSION: Micro-amounts of Pg-lipopolysaccharide induced the high expressions of inflammatory factors and mediated the inflammatory response. Pg-lipopolysaccharide elevated the blood lipid level less significantly than the high-fat diet did, but it may promote atherosclerosis.
Assuntos
Aterosclerose/imunologia , Lipopolissacarídeos/imunologia , Porphyromonas gingivalis/imunologia , Animais , Aorta/imunologia , Aorta/patologia , Aterosclerose/sangue , Aterosclerose/microbiologia , Proteína C-Reativa/análise , Quimiocina CCL2/sangue , Dieta Hiperlipídica , Tecido Elástico/imunologia , Tecido Elástico/patologia , Feminino , Células Espumosas/imunologia , Interleucina-6/sangue , Lipídeos/sangue , Masculino , Metaloproteinase 9 da Matriz/sangue , Músculo Liso Vascular/imunologia , Músculo Liso Vascular/patologia , Coelhos , Distribuição Aleatória , Fatores de Tempo , Receptor 2 Toll-Like/sangue , Receptor 4 Toll-Like/sangue , Fator de Transcrição RelA/sangue , Fator de Necrose Tumoral alfa/sangue , Túnica Íntima/imunologia , Túnica Íntima/patologia , Túnica Média/imunologia , Túnica Média/patologiaRESUMO
BACKGROUND: Hepatocellular carcinoma is a complex and heterogeneous tumor with poor prognosis due to frequent intrahepatic spread and extrahepatic metastasis. The molecular mechanisms underlying HCC pathogenesis still remain obscure. OBJECTIVES: We aimed to investigate the abundance and the DNA binding activity of nuclear factor kappa B/p65 subunit in peripheral blood mononuclear cells from patients with HCC and to assess its prognostic significance and association with hypoxia inducible factor one alpha (HIF-1α) in blood. SUBJECTS AND METHODS: This study was carried out on 40 patients classified equally into liver cirrhosis (group I) and HCC (group II), in addition to 20 healthy volunteers (group III). All groups were subjected to measurement of NF-κB /P65 subunit expression levels by real time-PCR, and DNA binding activity was evaluated by transcription factor binding immunoassay. Serum HIF-1α levels were estimated by enzyme-linked immunosorbent assay (ELISA). Significant increase of both the expression level and DNA binding activity of NF-κB /P65 subunit together with serum HIF-1 alpha levels was noted in HCC patients compared to liver cirrhosis and control subjects, with significant positive correlation with parameters for bad prognosis of HCC. In conclusion, NF-κB signaling is activated in HCC and associated with disease prognosis and with high circulating levels of HIF-1 alpha.