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1.
Acta Pharmacol Sin ; 2020 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-32123298

RESUMEN

Schizandrol A (SA) is an bioactive component isolated from the Schisandra chinensis (Turcz.) Baill., which has been used as a remedy to prevent oxidative injury. However, whether the cardioprotective effect of SA is associated with regulating endogenous metabolites remains unclear, thus we performed comprehensive metabolomics profiling in acute myocardial ischemia (AMI) mice following SA treatment. AMI was induced in ICR mice by coronary artery ligation, then SA (6 mg·kg-1·d-1, ip) was administered. SA treatment significantly decreased the infarct size, preserved the cardiac function, and improved the biochemical indicators and cardiac pathological alterations. Moreover, SA (10, 100 M) significantly decreased the apoptotic index in OGD-treated H8c2 cardiomycytes in vitro. By using HPLC-Q-TOF/MS, we conducted metabonomics analysis to screen the significantly changed endogenous metabolites and construct the network in both serum and urine. The results revealed that SA regulated the pathways of glycine, serine and threonine metabolism, lysine biosynthesis, pyrimidine metabolism, arginine and proline metabolism, cysteine and methionine metabolism, valine, leucine and isoleucine biosynthesis under the pathological conditions of AMI. Furthermore, we selected the regulatory enzymes related to heart disease, including ecto-5'-nucleotidase (NT5E), guanidinoacetate N-methyltransferase (GAMT), platelet-derived endothelial cell growth factor (PD-ECGF) and methionine synthase (MTR), for validation. In addition, SA was found to facilitate PI3K/Akt activation and inhibit the expression of NOX2 in AMI mice and OGD-treated H9c2 cells. In conclusion, we have elucidated SA-regulated endogenous metabolic pathways and constructed a regulatory metabolic network map. Furthermore, we have validated the new potential therapeutic targets and underlying molecular mechanisms of SA against AMI, which might provide a reference for its future application in cardiovascular diseases.

2.
Medicine (Baltimore) ; 99(2): e18727, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31914089

RESUMEN

The current study aimed to analyze the clinical characteristics of severe fever with thrombocytopenia syndrome (SFTS) and to explore the risk factors of critical patients. From 2016 to 2018, we collected the hospitalized diagnosed cases with SFTS in Jinan infectious disease hospital of Shandong University and analyzed by the descriptive epidemiological method. According to the prognosis, they were divided into general group and severe group. The epidemiological characteristics, clinical features, and laboratory indexes of these 2 groups of patients were compared and analyzed at the first visit. The risk factors related to the severity of the disease were analyzed by univariate Logistic regression. In total, 189 cases of SFTS were treated during the period and 33 deaths occurred in the severe group, with the fatality rate of 17.46%. The patients' age (χ = 8.864, P < .01), ALT (Z = -2.304, P = .03), AST (Z = -3.361, P < .01), GLU (t = -4.115, P < .01), CK (Z = -3.964, P < .01), CK-MB (Z = -2.225, P = .03), LDH (Z = -3.655, P < .01), α-HBDH (Z = -2.040, P = .04), APTT (t = -3.355, P < .01), BUN (Z = -2.040, P = .04), Cr (Z = -3.071, P = .01), and D-dimer (Z = -2.026, P = .04) in the severe group were higher than that in the normal group, but the blood platelet (PLT) counts were significantly lower (Z = -2.778, P < .01) than that in the normal group. With the neuropsychiatric symptoms (OR = 24.083, 95% CI = 6.064-95.642), skin bleeding point (OR = 30.000, 95% CI = 6.936-129.764), multiple organ dysfunction (OR = 34.048, 95% CI = 7.740-149.782), past medical history (OR = 3.792, 95% CI = 1.284-11.200), and fasting glucose elevation (OR = 1.359, 95% CI = 1.106-1.668) could predict the severity of the SFTS. In summary, the abnormality of the laboratory index, the special clinical manifestations, and the past medical history of SFTS patients were the important basis for judging the patient's serious condition.


Asunto(s)
Fiebre/epidemiología , Fiebre/fisiopatología , Trombocitopenia/epidemiología , Trombocitopenia/fisiopatología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Glucemia , Comorbilidad , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/epidemiología , Recuento de Plaquetas , Pronóstico , Factores de Riesgo , Estaciones del Año , Índice de Severidad de la Enfermedad , Trombocitopenia/mortalidad , Adulto Joven
3.
Biomed Pharmacother ; 124: 109820, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31972362

RESUMEN

Metoprolol (Met) is widely applied in the treatment of myocardial infarction and coronary heart disease in clinic. However, the metabolic network in vivo affected by Met manipulation is still unclear and it's therapeutic molecular mechanisms were remained to be furthered elucidated except ß1 adrenergic receptor. Myocardial infarction (MI) was induced by permanent CAL for 24 h in ICR mice. Myocardial infarct size, biochemical indicators such as creatine kinase (CK), lactate dehydrogenase (LDH), C-reactive Protein (CRP), tumor necrosis factor-α (TNF-α) and cardiac troponin I(cTn-I), cardiac function and myocardial pathological changes were detected to ensure the improvement of Met on MI. Subsequently, the significantly changed endogenous metabolites and the network in both serum and urine were screened and constructed through metabolomics by using HPLC-Q-TOF/MS. Finally, the potential regulatory enzymes that could be the possible new therapeutic targets of Met were selected and validated by western blotting and immunohistochemistry based on the screened differential metabolites and the enrichment analysis. Met effectively reduced the infarct size of myocardial infarction mice, improved the biochemical indicators, and ameliorated the cardiac function and pathological conditions. Our study further found that Met could regulate the pathways of glycine, serine and threonine metabolism, cysteine and methionine metabolism, purine and pyrimidine metabolism under the pathological conditions of MI. Moreover, several regulatory enzymes involved GATM, CSE and NT5E were demonstrated to be regulated by Met. This study constructed the regulatory metabolic network map of Met, elucidated the endogenous metabolic pathway regulated by Met, and validated the new potential therapeutic targets of Met in MI, which might provide a further reference for the clinical application of Met.

4.
Biosci Rep ; 39(9)2019 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-31519769

RESUMEN

The present study was to identify the drug resistance, resistance mechanism and the extended-spectrum ß-lactamase (ESBLs) genotypes of Shigella flexneri (S. flexneri) in Jinan. Susceptibility tests were performed by MIC-determination. The genotypes of ß-lactamase were identified using PCR and DNA sequencing. The resistance transfer ability of the ESBL-producing strains was examined by conjugation tests. A total of 105 S. flexneri isolates were collected, and 34 (32.4%) were ESBL-producing isolates. All ESBL-producing isolates were susceptible to cefoxitin and imipenem, and 35.3% isolates were resistant to ciprofloxacin. ESBL-producing isolates showed high level resistant to ampicillin (100%), cefotaxime (100%), tetracycline (100%), chloramphenicol (100%), trimethoprim/sulfamethoxazole (100%), ceftazidime (73.5%) and cefepime (73.5%). Three types of ß-lactamase genes (blaTEM, blaOXA and blaCTX-M) were identified in all ESBL-producing isolates, and the genotypes were confirmed as blaTEM-1 (23/34), blaOXA-30 (34/34), blaCTX-M-14 (9/34) and blaCTX-M-15 (25/34) by sequencing. In conclusion, the Shigella strains isolated in Jinan are cross-resistant and multi-drug resistant. The main genotypes of ESBLs are CTX-M-14 and CTX-M-15.

5.
Mol Med Rep ; 17(6): 8228-8236, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29693161

RESUMEN

The aim of the present study was to investigate the correlation between the multi­drug resistance of Shigella flexneri and the drug­resistant gene cassette carried by integrons; in the meanwhile, to detect the associations between drug­resistance and gene mutations of the active efflux pump acrAB­tolC gene and its regulatory genes, including marOR, acrR and soxS. A total of 158 isolates were isolated from the stool samples of 1,026 children with diarrhoea aged 14 years old between May 2012 and October 2015 in Henan. The K­B method was applied for the determination of drug resistance of Shigella flexneri, and polymerase chain reaction amplification was used for class 1, 2 and 3 integrase genes. Enzyme digestion and sequence analysis were performed for the variable regions of positive strains. Based on the drug sensitivity assessment, multi­drug resistant strains that were resistant to five or more antibiotics, and sensitive strains were selected for amplification. Their active efflux pump genes, acrA and acrB, and regulatory genes, marOR, acrR and soxS, were selected for sequencing. The results revealed that 91.1% of the 158 strains were multi­resistant to ampicillin, chloramphenicol, tetracycline and streptomycin, and 69.6% of the strains were multi­resistant to sulfamethoxazole/trimethoprim. The resistance to ceftazidime, ciprofloxacin and levofloxacin was <32.9%. All strains (100%) were sensitive to cefoxitin, cefoperazone/sulbactam and imipenem. The rate of the class 1 integron positivity was 91.9% (144/158). Among these class 1 integron­positive strains, 18 strains exhibited the resistance gene cassette dfrV in the variable region of the strain, four strains exhibited dfrA17­aadA5 in the variable region and 140 strains exhibited blaOXA­30­aadA1 in the variable region. Four strains showed no resistance gene in the variable regions. The rate of class 2 integron positivity was 86.1% (136/158), and all positive strains harboured the dfrA1­sat1­aadA resistance gene cassette in the variable region. The class 3 integrase gene was not detected in these strains. The gene sequencing showed the deletion of base CATT in the 36, 37, 38, 39 site in the marOR gene, which is a regulatory gene of the active efflux pump, AcrAB­TolC. Taken together, the multi­drug resistance of Shigella flexneri was closely associated with gene mutations of class 1 and 2 integrons and the marOR gene.


Asunto(s)
Antibacterianos/farmacología , Farmacorresistencia Bacteriana , Regulación Bacteriana de la Expresión Génica , Genes Bacterianos , Mutación , Shigella flexneri/efectos de los fármacos , Shigella flexneri/genética , Adolescente , Niño , Preescolar , Disentería Bacilar/tratamiento farmacológico , Disentería Bacilar/microbiología , Femenino , Humanos , Lactante , Masculino , Pruebas de Sensibilidad Microbiana , Fenotipo
6.
Int J Infect Dis ; 58: 45-51, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28249810

RESUMEN

OBJECTIVES: The aim of this study was to dynamically investigate laboratory parameters and peripheral blood lymphocyte subsets in severe fever with thrombocytopenia syndrome (SFTS) patients at different stages, to evaluate the significance of these changes in the infection process and its influence on prognosis. METHODS: Case-control study was used in the research. Sixty-nine confirmed thrombocytopenia syndrome virus(SFTSV) infected patients were enrolled. They were divided into two groups, recovery group and poor prognosis group, according to the clinical prognosis of the diseases. The laboratory parameters were measured by matched fully-automatic detector. The dynamic lymphocyte subsets of each group were tested by flow cytometry. Independent-group Student's t-test, Bonferroni test and Nemenyi test were used to compare the mean value of every group. RESULTS: The clinical manifestations typically became worse on about the 7th day. Most of them had multi organ dysfunction, and part of them had hemophagocytic lymphohistiocytosis histiocytosis (HLH). The characteristic laboratory findings in the early stage were the drop of platelets (PLT), while the increase of alanine aminotransferase (ALT), aspartate amino transferase (AST), creatine kinase (CK), and lactate dehydrogenase (LDH). SFTSV viral loads reached the highest on Days 7-10 after onset of fever in SFTS patients. CD3+, CD3+CD4+ T cell counts were significantly reduced in poor prognosis group, more so on Days 7-10 after onset of fever. CD3-CD19+ (B cell) counts in SFTS patients were significantly higher than that of healthy controls. 11 days after illness onset, symptoms were improved, accompanied by resolution of laboratory abnormalities. CONCLUSIONS: These results indicated that SFTS had an acute onset and self-limited course. It was a systemic infection. The host immune response caused tissues and organs injury. The improvement of symptoms and laboratory tests was consistent with the elimination of the virus and recover of immune response. Further investigation should be done in order to reveal the mechanisms of SFTSV pathogenesis and guide the clinical treatment.


Asunto(s)
Infecciones por Bunyaviridae/inmunología , Enfermedades Transmisibles Emergentes/inmunología , Subgrupos Linfocitarios , Phlebovirus , Trombocitopenia/virología , Adulto , Anciano , Aspartato Aminotransferasas/metabolismo , Infecciones por Bunyaviridae/sangre , Infecciones por Bunyaviridae/diagnóstico , Linfocitos T CD4-Positivos/inmunología , Estudios de Casos y Controles , Enfermedades Transmisibles Emergentes/sangre , Femenino , Fiebre/virología , Citometría de Flujo , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Phlebovirus/inmunología , Pronóstico , Trombocitopenia/sangre , Carga Viral
7.
Drug Dev Ind Pharm ; 42(12): 1938-1944, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27142812

RESUMEN

CONTEXT: Combination therapies provide a potential solution to address the tumor heterogeneity and drug resistance issues by taking advantage of distinct mechanisms of action of the multiple therapeutics. OBJECTIVE: To design arginine-glycineaspartic acid (RGD) modified lipid-coated nanoparticles (NPs) for the co-delivery of the hydrophobic drugs against hepatocellular carcinoma (HCC). MATERIALS AND METHODS: RGD modified lipid-coated PLGA NPs were developed for the targeted delivery of both sorafenib (SRF) and quercetin (QT) (RGD-SRF-QT NPs). Chemical-physical characteristics and release profiles were evaluated. In vitro cell viability assays were carried out on HCC cells. In vivo antitumor efficacies were evaluated in HCC animal model. RESULTS AND DISCUSSION: The combination of SRF and QT formulations was more effective than the single drug formulations in both NPs and solution groups. RGD-SRF-QT NPs achieved the most significant tumor growth inhibition effect in vitro and in vivo. CONCLUSION: The resulting NPs could provide a promising platform for co-delivery of multiple anticancer drugs for achievement of combinational therapy and could offer potential for enhancing the therapeutic efficacy on HCC.

8.
Zhonghua Er Ke Za Zhi ; 53(10): 765-70, 2015 Oct.
Artículo en Chino | MEDLINE | ID: mdl-26758113

RESUMEN

OBJECTIVE: To investigate the correlation between Shigella flexneri multi-drug resistance and drug resistance gene cassette of integrons. METHOD: All 79 strains of Shigella flexneri were isolated from the feces of children ranged in age from 6 months to 14 years in some hospitals of Jinan, between May 2009 and April 2012.The resistance was detected by Kirby Bauer agar diffusion method, 1, 2 and 3 integron gene was amplified by PCR, the variable region of positive strains treated with enzyme digestion and determined by Series Analysis. RESULT: Among 79 Shigella flexneri strains, the resistance rate was 91% (72/79) to ampicillin, chloramphenicol, tetracycline, streptomycin, 70% (55/79) to sulfamethoxazole/trimethoprim, 30% (24/79), 23% (18/79), 33% (26/79) and 32% (25/79) to cefotaxime, ceftazidime, ciprofloxacin and levofloxacin.All 79 strains were susceptible to cefoxitin, imipenem, cefoperazone/sulbactam. The common drug resistance pattern is ampicillin tetracycline-chloramphenicol-streptomycin, accounted for 91% (72/79); 91% (72/79) strains carried integrons of class 1, 86% (68/79) strains carried integrons of class 2, No intI3 was detected. The resistance to ampicillin, streptomycin, tetracycline, chloramphenicol of atypical class 1 integron positive strains was significantly higher than the negative strains (χ² = 35.96, P<0.01). The sequencing results:dfrV was detected in class 1 integron variable regions of 9 strains, dfrA17-aadA5 in 2 strains, blaOXA-30-aadA1 in 70 strains, 2 strains were not detected resistance gene cassette, all resistance gene cassettes were dfrA1-sat1-aadA1 in class 2 integron variable regions. CONCLUSION: The muti-drug resistance of Shigella flexneri in Jinan was closely associated with integrons.


Asunto(s)
Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/genética , Integrones , Shigella flexneri/efectos de los fármacos , Adolescente , Niño , Preescolar , Disentería Bacilar/microbiología , Heces/microbiología , Humanos , Lactante , Reacción en Cadena de la Polimerasa , Shigella flexneri/genética
9.
Int J Biol Sci ; 6(5): 454-64, 2010 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-20827398

RESUMEN

Peptidylarginine deiminase type 4 (PADI4) converts arginine residues into citrulline. The current study focused on the expression of PADI4 in various subtypes of ovary cancers, and this study investigated the effects of estrogen on PADI4 expression in SKOV-3 cells that originated from ovary tumors. We utilized immunohistochemistry, real-time PCR and western blotting to analyze the expression of PADI4 in the tumor tissues and in the cell line that were cultured with estrodial-17ß. PADI4 was detected in serious cystadenocarcinoma (n=39, positivity=100%), clear cell cancer (n=7, positivity= 100%), mucinous cystadenocarcinoma (n=6, positivity=100%), dysgerminoma (n=6, positivity=100%), squamous cell tumor (n=6, positivity=100%), sibnet-ring cell carcinoma (n=6, positivity=100%), endodermal sinus tumor (n=6, positivity=100%), germ cell tumors (n=6, positivity=100%) and immature teratoma (n=6, positivity=100%). However, PADI4 was either not detected or detected at low levels in granulosa cell tumor (n=6), malignant thecoma (n=6), ovarian cystadenoma (n=5) and normal ovarian tissue (n=11). For serious cystadenocarcinoma, all of the samples with high PADI4 expression belonged to the T1 and T2 stages of pTMN, whereas all of the samples that exhibited weak or moderate PADI4 expression belonged to the T3 and T4 stages. PADI4 was evenly distributed in the cytoplasm of tumor cells of serious cystadenocarcinoma that were classified as being grade II and III by histopathological scoring. However, PADI4 showed granular cellular distribution in the tumor tissues that were isolated from grade I cystadenocarcinoma. In addition, the PADI4 level was positively related with the ages of the patients that presented with serious adenocarcinoma (p=0.029). Real-time PCR and western blot analyses confirmed that PADI4 was expressed at higher levels in ovarian adenocarcinoma (n=8) compared to ovarian cystadenoma (n=5) (p< 0.05). The study also detected an increased level of PADI4 in SKOV-3 cells that were incubated with estrodial-17ß in the range of 10(-12) to 10(-4)M. The results suggest an important role for PADI4 in the tumorigenesis of ovary cancers that are under the regulation of estrogen.


Asunto(s)
Hidrolasas/metabolismo , Neoplasias Ováricas/enzimología , Western Blotting , Línea Celular Tumoral , Estradiol/farmacología , Estradiol/fisiología , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Hidrolasas/genética , Inmunohistoquímica , Reacción en Cadena de la Polimerasa , Desiminasas de la Arginina Proteica , ARN Mensajero/metabolismo
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