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1.
Acta Pharmacol Sin ; 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937932

RESUMO

IgD-Fc-Ig fusion protein, a new biological agent, is constructed by linking a segment of human IgD-Fc with a segment of human IgG1-Fc, which specifically blocks the IgD-IgDR pathway and selectively inhibits the abnormal proliferation, activation, and differentiation of T cells. In this study we investigated whether IgD-Fc-Ig exerted therapeutic effects in collagen-induced arthritis (CIA) rats. CIA rats were treated with IgD-Fc-Ig (1, 3, and 9 mg/kg) or injected with biological agents etanercept (3 mg/kg) once every 3 days for 40 days. In the PBMCs and spleen lymphocytes of CIA rats, both T and B cells exhibited abnormal proliferation; the percentages of CD3+ total T cells, CD3+CD4+ Th cells, CD3+CD4+CD25+-activated Th cells, Th1(CD4+IFN-γ+), and Th17(CD4+IL-17+) were significantly increased, whereas the Treg (CD4+CD25+Foxp3+) cell percentage was decreased. IgD-Fc-Ig administration dose-dependently decreased the indicators of arthritis; alleviated the histopathology of spleen and joint; reduced serum inflammatory cytokines levels; decreased the percentages of CD3+ total T cells, CD3+CD4+ Th cells, CD3+CD4+CD25+-activated Th cells, Th1 (CD4+IFN-γ+), and Th17(CD4+IL-17+); increased Treg (CD4+CD25+Foxp3+) cell percentage; and down-regulated the expression of key molecules in IgD-IgDR-Lck-NF-κB signaling (p-Lck, p-ZAP70, p-P38, p-NF-κB65). Treatment of normal T cells with IgD (9 µg/mL) in vitro promoted their proliferation. Co-treatment with IgD-Fc-Ig (0.1-10 µg/mL) dose-dependently decreased IgD-stimulated T cell subsets percentages and down-regulated the IgD-IgDR-Lck-NF-κB signaling. In summary, this study demonstrates that IgD-Fc-Ig alleviates CIA and regulates the functions of T cells through inhibiting IgD-IgDR-Lck-NF-κB signaling.

2.
J Gastroenterol Hepatol ; 35(2): 343-352, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31318997

RESUMO

BACKGROUND AND AIM: Diabetes mellitus (DM) is a common complication of idiopathic chronic pancreatitis (ICP), which impairs the quality of life for patients. This study aimed to identify risk factors and develop nomogram for DM in ICP to help early diagnosis. METHODS: Idiopathic chronic pancreatitis patients admitted to our center from January 2000 to December 2013 were included. Cumulative rates of DM were calculated by Kaplan-Meier method. Patients were randomly assigned, in a 2:1 ratio, to the training and validation cohort. Based on training cohort, risk factors for DM were identified through Cox proportional hazards regression model, and nomogram was developed. Internal and external validations were performed based on the training and validation cohort, respectively. RESULTS: Totally, 1633 patients with ICP were finally enrolled. The median follow-up duration was 9.8 years. DM was found in 26.3% (430/1633) of patients after the onset of CP. Adult at onset of ICP, biliary stricture at/before diagnosis of CP, steatorrhea at/before diagnosis of CP, and complex pathologic changes in main pancreatic duct were identified risk factors for DM development. The nomogram achieved good concordance indexes in the training and validation cohorts, respectively, with well-fitted calibration curves. CONCLUSIONS: Risk factors were identified, and nomogram was developed to determine the risk of DM in ICP patients. Patients with one or more of the risk factors including adult at onset of ICP, biliary stricture at/before diagnosis of CP, steatorrhea at/before diagnosis of CP, and complex pathologic changes in main pancreatic duct have higher incidence of DM.

3.
Gastroenterol Rep (Oxf) ; 7(5): 361-366, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31687156

RESUMO

Background: Surgical management of adult slow-transit constipation (ASTC) can be effective for patients with intractable symptoms. This study aimed to evaluate whether barium-strip examination and selective colectomy improved post-operative outcomes in ASTC patients in comparison with subtotal colectomy. Methods: A retrospective cohort study of 53 cases with refractory ASTC was conducted between June 2008 and June 2014. Patients were evaluated by the barium-strip technique, colonoscopy, defecography and anorectal manometry. Patients in the standard group underwent laparoscopic subtotal colectomy and patients in the laparoscopic selective colectomy (LSC) group underwent LSC at the precise location identified by barium strip. Spontaneous bowel movements, the Wexner Constipation Scale and the Gastrointestinal Quality of Life Index (GIQLI) were assessed post-operatively at 3, 6, 12 and 24 months. Results: A total of 49 patients were included in the analysis. The median follow-up was 37 months (range, 26-60 months). The mean post-operative hospital stay was 12 days and similar between groups (P = 0.071). The length of colon resection, operative time and intra-operative blood loss were reduced in the LSC group (all P < 0.05). No major complications occurred. A similar number of patients (24 in the standard group and 25 in the LSC group) exhibited hypoganglionosis or aganglionosis in the colon-wall muscle layer (P = 0.986). Although there were no significant differences in post-operative spontaneous bowel movements and the Wexner Constipation Scale between the two groups, the mean GIQLI of the LSC group was significantly higher at 3, 6 and 24 months post-operatively (all P < 0.05). Conclusions: LSC based on barium-strip examination is an appropriate modality for treating ASTC.

4.
Cancer Med ; 8(18): 7577-7585, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31657530

RESUMO

BACKGROUND: Estimation of incidence and prognosis of melanomas with brain metastases (MBM) at initial diagnosis based on a large cohort is lacking in current research. This study aims to construct an effective prognostic nomogram for newly diagnosed MBM. MATERIALS AND METHODS: Patients diagnosed with melanomas from Surveillance, Epidemiology, and End Results program between 2010 and 2014 were enrolled in our study. Risk factors predicting brain metastases (BM) were identified using logistic regression analysis. Cox regression analysis was performed to identify prognostic factors of overall survival (OS). Nomogram for estimating 6-, 9-, and 12-month OS was established based on Cox regression analysis. The discriminative ability and calibration of the nomogram were tested using C statistics, calibration plots, and Kaplan-Meier curves. RESULTS: Sixty-two thousand three hundred and sixty-nine melanoma patients were enrolled, including 928 with BM. Sex, marital status, insurance status, subsite, surgery of primary sites, radiation, chemotherapy, bone metastases, liver metastases, and lung metastases were associated with MBM at initial diagnosis. On multivariable Cox regression, the following eight variables were incorporated in the prediction of OS: age, unmarried status, absence of surgery to primary sites or unknown, absence of radiation or unknown, absence of chemotherapy or unknown, with bone metastases, with liver metastases, and with lung metastases. The nomogram showed good predictive ability as indicated by discriminative ability and calibration, with the C statistics of 0.716 (95% CI, 0.695-0.737). CONCLUSIONS: The incidence and prognosis of MBM patients were well estimated in this study based on a large cohort. The nomogram performed well and could be a useful tool to predict prognosis.

5.
Exp Ther Med ; 18(5): 3913-3919, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31641378

RESUMO

The current study aimed to explore the effect of homocysteine (Hcy) on the viability and migration ability of human umbilical vein endothelial cells (HUVECs), as well as to examine the underlying mechanism. The association between the expression level of Hcy and lower extremity deep vein thrombosis (DVT) was detected in clinical samples collected from patients. In addition, the effect of Hcy on the viability and migration ability of HUVECs was detected by cell counting kit-8 and Transwell assays, respectively, while vascular endothelial growth factor (VEGF) expression was measured in order to verify the effect of Hcy on VEGF. The results indicated that the serum Hcy levels in DVT patients were significantly increased. In vitro experiments also confirmed that Hcy was able to significantly inhibit the viability and migration ability of HUVECs, and downregulate the expression of VEGF in these cells. Furthermore, the inhibitory effect of Hcy on HUVEC viability and migration ability was achieved by downregulating the expression of VEGF using small interfering RNA transfection. In conclusion, Hcy inhibited the viability and migration ability of HUVECs by downregulating the expression of VEGF. This may underlie the high incidence of DVT in patients with hyperhomocysteinemia.

6.
Biomolecules ; 9(10)2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31614786

RESUMO

Plant microRNAs (miRNAs) have recently been reported to be involved in the cross-kingdom regulation of specific cellular and physiological processes in animals. However, little of this phenomenon is known for the communication between host plant and insect herbivore. In this study, the plant-derived miRNAs in the hemolymph of a cruciferous specialist Plutella xylostella were identified by small RNAs sequencing. A total of 39 miRNAs with typical characteristics of plant miRNAs were detected, of which 24 had read counts ≥ 2 in each library. Three plant-derived miRNAs with the highest read counts were validated, and all of them were predicted to target the hemocyanin domains-containing genes of P. xylostella. The luciferase assays in the Drosophila S2 cell demonstrated that miR159a and novel-7703-5p could target BJHSP1 and PPO2 respectively, possibly in an incomplete complementary pairing mode. We further found that treatment with agomir-7703-5p significantly influenced the pupal development and egg-hatching rate when reared on the artificial diet. The developments of both pupae and adults were severely affected upon their transfer to Arabidopsis thaliana, but this might be independent of the cross-kingdom regulation of the three plant-derived miRNAs on their target genes in P. xylostella, based on expression analysis. Taken together, our work reveals that the plant-derived miRNAs could break the barrier of the insect mid-gut to enter the circulatory system, and potentially regulate the development of P. xylostella. Our findings provide new insights into the co-evolution of insect herbivore and host plant, and novel direction for pest control using plant-derived miRNAs.

7.
Chem Res Toxicol ; 32(10): 2006-2015, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31469264

RESUMO

In this study, we synthesized a small molecule fluorescent probe for detecting mono-2-ethylhexyl phthalate (MEHP) named MEHP-AF, which formed by MEHP cross-linked with 5-aminofluorescein (5-AF) through amide bond. MEHP-AF had been purified based on the different physicochemical properties of 5-AF with MEHP. MEHP-AF showed fluorescence characteristics coming from 5-AF and liposoluble property coming from MEHP. After physicochemical characterization, a series of biological studies of its action in cells were carried out. The results indicated that MEHP-AF was a fluorescent probe with strong specificity and high sensitivity. It can visibly track the location of MEHP in HeLa cell or subcellular levels under confocal laser scanning microscopy in situ. This novel fluorescent probe is expected to use for studying its intracellular behavior at the cell level, especially for investigating the interaction between MEHP and cellular molecules.

8.
Curr Med Sci ; 39(4): 670-678, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31347007

RESUMO

Professionalism is crucial in all professions and is particularly important in the medical field. Measuring students' perceptions of professionalism can help to form education targeting the enhancement of professionalism. This study aimed to validate an effective assessment tool for the measurement of medical students' perceptions of medical professionalism in mainland China. The cross-sectional survey was conducted in three medical colleges in Guangdong, China. Of the 2103 eligible medical students, 1976 responded, and 1856 questionnaires were deemed valid. Students from clinical medicine in these three medical colleges were randomly selected by cluster sampling. First, a Simplified Chinese Version questionnaire to measure Student's Perception of Medical Professionalism (SCV-SPMP) was constructed. Second, questionnaires from 1856 students majoring in clinical medicine at three medical colleges were included in the analysis. Third, exploratory factor analysis, Cronbach's alpha, item-subscale correlation, and confirmatory factor analysis were conducted to test the validity and reliability of the SCV-SPMP. Nine items were eliminated following exploratory factor analysis, and four subscales were extracted from the analysis. All internal consistency reliability exceeded the minimum standard. The overall Cronbach's alpha was 0.94, and four subscales' alphas were 0.82 (Accountability and excellence), 0.81 (Duty), 0.89 (Honor and integrity), and 0.85 (Practice habits and respect for others), respectively. The model fit was good. The convergent validity and discriminant validity were acceptable. The modified SCV-SPMP was found to be a valid and reliable tool to capture the main features of Chinese students' perceptions of medical professionalism in four dimensions, and it provides a quantitative method for the measurement of the students' perceptions in mainland China..


Assuntos
Profissionalismo , Estudantes de Medicina , Adulto , China/epidemiologia , Feminino , Humanos , Masculino , Inquéritos e Questionários , Adulto Jovem
9.
J Food Biochem ; 43(7): e12893, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31353730

RESUMO

Vanillic acid (VA), one of the phenolic acids metabolized by anthocyanidins, can modulate vascular reactivity by reducing the superoxide. We investigated that VA alleviated fatty acid-induced oxidative stress and clarified its potential mechanisms in human umbilical vein endothelial cells (HUVECs). Our results showed that VA reduced the production of reactive oxygen species and malondialdehyde levels. It also restored mitochondrial membrane potential and enhanced the activities of antioxidant enzymes. In addition, VA promoted the expression of p-Nrf2 and HO-1 through LKB1/AMPK signaling pathway, as well as the level of SIRT1 and PGC-1α. Moreover, compound C reduced the effect of VA on the enhancement of p-Nrf2 and HO-1. These results indicated that AMPK was an important target molecule of VA in the process of alleviating oxidative stress in HUVECs, providing a new potential evidence for vascular protection of anthocyanin in vitro. PRACTICAL APPLICATIONS: As a phenolic derivative and phase II metabolite of anthocyanins in vivo, VA can be found in various edible plants and fruits. This study revealed that VA improved oxidative stress in endothelial cells stimulated by palmitic acid by activating AMPK and its downstream proteins. VA could be a potential functional material for the protection of diabetic vascular complications.

10.
Zhongguo Zhong Yao Za Zhi ; 44(10): 2118-2123, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31355570

RESUMO

The aim of this paper was to investigate the mechanism and effect of psoralen and isopsoralen in the treatment of lipid accumulation in LO2 cells. Human LO2 cells nonalcoholic fatty liver models were established by using palmitic acid( PA). Then psoralen and isopsoralen were administered for intervention. Intracellular triglyceride( TG) and total cholesterol( TC) content,the cell supernatant alanine aminotransferase( ALT) and aspartate aminotransferase( AST) levels were determined by enzyme method. Cell supernatant proinflammatory cytokines( IL-6,TNF-α) and chemokines( IL-8,MCP-1) were determined by ELISA method. Western blot method was conducted to detect the protein expression of intracellular nuclear factor( NF-κB) p65 phosphorylation( p-p65),nonphosphorylated protein( p65),and transforming factor TGF-ß1. Result showed that as compared with the model group,intracellular TG and TC levels,the cell supernatant ALT and AST levels,proinflammatory cytokines and chemokines were decreased( P < 0. 01,P <0. 05); the p-p65/p65 ratio and TGF-ß1 protein expression were also significantly decreased( P< 0. 01,P< 0. 05) in psoralen intervention group. As compared with the model cells,intracellular TG content had no significant changes,but all the other indexes were reduced( P<0. 01,P<0. 05) in the cells of isopsoralen intervention group. Psoralen exhibited better effect than isopsoralen( P< 0. 01,P<0. 05). It is concluded that psoralen could improve the adipogenesis of LO2 cells induced by PA; both psoralen and isopsoralen are effective in ameliorating LO2 cells injury induced by PA,reducing inflammation via inhibiting the activation of NF-κB and down-regulating the expression of TGF-ß1.


Assuntos
Ficusina/farmacologia , Furocumarinas/farmacologia , Metabolismo dos Lipídeos , NF-kappa B/metabolismo , Linhagem Celular , Humanos , Hepatopatia Gordurosa não Alcoólica
11.
Parasit Vectors ; 12(1): 319, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31238963

RESUMO

BACKGROUND: Bacillus thuringiensis israelensis (Bti) is a widely used mosquitocidal microbial pesticide due to its high toxicity. ATP-binding proteins (ABP) are prevalently detected in insects and are related to reaction against Bti toxins. However, the function of ABP in mosquito biocontrol is little known, especially in Aedes aegypti. Therefore, this study aimed to clarify the function of ABP in Ae. aegypti against Bti toxin. RESULTS: Aedes aegypti ABP (GenBank: XM_001661856.2) was cloned, expressed and purified in this study. Far-western blotting and ELISA were also carried out to confirm the interaction between ABP and Cry11Aa. A bioassay of Cry11Aa was performed both in the presence and absence of ABP, which showed that the mortality of Ae. aegypti is increased with an increase in ABP. CONCLUSIONS: Our results suggest that ABP in Ae. aegypti can modulate the toxicity of Cry11Aa toxin to mosquitoes by binding to Bti toxin. This could not only enrich the mechanism of Bt toxin, but also provide more data for the biocontrol of this transmission vector.


Assuntos
Aedes/genética , Bacillus thuringiensis/patogenicidade , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Aedes/microbiologia , Animais , Proteínas de Bactérias/metabolismo , Bioensaio , Clonagem Molecular , Endotoxinas/metabolismo , Proteínas Hemolisinas/metabolismo , Mosquitos Vetores/microbiologia , Controle Biológico de Vetores , Ligação Proteica
12.
Adv Ther ; 36(9): 2463-2474, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31240628

RESUMO

INTRODUCTION: This study aims to investigate the efficacy of incision-free endovenous laser treatment (EVLT) combined with sclerosing foam in treating varicose veins of the lower extremities. METHODS: A total of 140 patients (186 limbs) who underwent laser closure of the great saphenous vein + injection sclerotherapy were included in the present study. Preoperative information, intraoperative conditions, duration of the operation, and length of hospital stay were recorded in detail. During the 6-month follow-up, the closure of the trunk and branches of the great saphenous vein, postoperative pain, the recovery of ulcer and dermatitis, and postoperative complications were traced. RESULTS: All patients were treated with laser closure of the great saphenous vein and lauromacrogol injection. Twenty-six stage C6 limbs (lower extremity with ulcer) healed within 6 months, and the postoperative subjective pain disappeared after 1 month. In six patients, pigmentation in the surgical site did not completely disappear at 6 months after the operation. Saphenous nerve injury was found in five patients within 3 months after the operation, and all healed at 6 months after the operation. CONCLUSION: EVLT combined with sclerosing foam is effective for treating varicose great saphenous veins. TRIAL REGISTRATION: This study was registered at http://www.chictr.org.cn (registration number: ChiCTR1900021409).

13.
Curr Med Sci ; 39(3): 463-471, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31209820

RESUMO

While emergency medical service (EMS) response time (ERT) is a major factor associated with the survival of patients with cardiovascular disease (CVD), relatively few studies have explored the factors associated with ERT. This study aimed to assess the current status of ERT and to identify the factors affecting ERT in patients with CVD in China. Between January 1, 2011 and December 31, 2015, EMS responses to CVD incidents in Guangzhou, China, were examined. The primary outcome was ERT, defined as the time from receipt of an emergency call to the arrival of paramedics on the scene. Factors associated with ERT were evaluated by multivariable logistic regression. A total of 44 383 CVD incidents were analysed. The median ERT was 12.58 min (interquartile range=9.98-15.67). Among the risk factors, distance (OR=13.73, 95% CI=11.76-16.04), level of hospital (OR=1.57, 95% CI=1.40-1.75), and site of the incident (OR=1.53, 95% CI=1.38-1.69) were the top three significant factors affecting the ERT. Our results suggest that greater attention should be given to factors affecting the ERT. It is essential to make continuous efforts to promote the development of effective interventions to reduce the response time.


Assuntos
Doenças Cardiovasculares/diagnóstico , Serviços Médicos de Emergência/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/fisiopatologia , China , Serviços Médicos de Emergência/organização & administração , Feminino , Hospitais , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
14.
Front Pharmacol ; 10: 522, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191298

RESUMO

Aim: Bile salt export pump (BSEP) have been confirmed to play an important role for bile acid canalicular export in the treatment of cholestasis. In this study, we investigated the stimulatory effect of emodin on BSEP signaling pathway in cholestasis. Methods: Cell and animal experiments were given different concentrations of emodin. The BSEP upstream molecule farnesoid X receptor was down-regulated by small interfering RNA (siRNA) technology or guggulsterones and up-regulated by lentivirus or GW4064. Real-time PCR and Western blotting was employed to detect the mRNA and protein levels of BSEP in LO2 cell, rat primary hepatocytes and liver tissue. Immunohistochemistry (IHC) was used to examine the expression of BSEP in liver tissues. Rat liver function and pathological changes of liver tissue were performed by biochemical test and hematoxylin and eosin (HE) staining. Results: Emodin could increase the mRNA and protein expression of BSEP and FXR. When down-regulating farnesoid X receptor expression with the siRNA or inhibitor guggulsterones, and up-regulating farnesoid X receptor expression with the lentivirus or agonist GW4064, emodin could increase the mRNA level of BSEP and FXR and the protein level of BSEP, FXR1, and FXR2. Emodin also had a notable effect on rat primary hepatocytes experiment, rat pathological manifestation, BSEP, FXR1, and FXR2 positive staining in liver tissues and the test of liver function. Conclusion: Emodin has a protective effect and a rescue activity on cholestasis via stimulating FXR/BSEP pathways in promoting the canalicular export of accumulated bile.

15.
Acta Pharmacol Sin ; 40(11): 1412-1423, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31000770

RESUMO

Excessive and abnormal vessel growth plays a critical role in the pathogenesis of many diseases, such as cancer. Angiogenesis is one of the hallmarks of cancer growth, invasion, and metastasis. Discovery of novel antiangiogenic agents would provide new insights into the mechanisms of angiogenesis, as well as potential drugs for cancer treatment. In the present study, we investigated the antiangiogenic activity of a series of monocarbonyl analogs of curcumin synthesized previously in our lab. We found that curcumin analog A2 displayed the full potential to be developed as a novel antiangiogenic agent. Curcumin analog A2 at and above 20 µM dramatically inhibited the migration and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro, new microvessels sprouting from the rat aortic rings ex vivo and newly formed microvessels in chicken chorioallantoic membranes (CAMs) and Matrigel plus in vivo. We further demonstrated that curcumin analog A2 exerted its antiangiogenic activity mainly through inducing endothelial cell death via elevating NADH/NADPH oxidase-derived ROS. Curcumin analog A2 at the antiangiogenic concentrations also triggered autophagy in HUVECs, but this process is neither a pre-requisite for toxicity, leading to the cell death nor a protective response against the toxicity of curcumin analog A2. In conclusion, we demonstrate for the first time the potent antiangiogenic activity of the monocarbonyl curcumin analog A2, which could serve as a promising potential therapeutic agent for the prevention and treatment angiogenesis-related diseases, such as cancer.

16.
Neural Regen Res ; 14(5): 841-849, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30688270

RESUMO

Epithelial-specific ETS-1 (ESE1), a member of the ETS transcription factor family, is widely expressed in multiple tissues and performs various functions in inflammation. During neuroinflammation, ESE1 promotes neuronal apoptosis; however, the expression and biological functions of ESE1 remain unclear after cerebral ischemia/reperfusion. We performed in vivo and in vitro experiments to explore the role of ESE1 in cerebral ischemic injury. A modified four vessel occlusion method was used in adult Sprague-Dawley rats. At 6, 12, 24, 48, and 72 hours after model induction, the hippocampus was collected for analysis. Western blot assays and immunohistochemistry showed that the expression of ESE1, phosphorylated p65 and active caspase-3 was significantly up-regulated after ischemia. Double immunofluorescence staining indicated that ESE1 and NeuN were mostly co-located in the hippocampus after ischemia. Furthermore, ESE1 was also co-expressed with active caspase-3. PC12 cells were stimulated with cobalt chloride (CoCl2) to establish a chemical hypoxia model. After ESE1 knockdown by siRNA for 6 hours, cell viability was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assays. The levels of ESE1, phosphorylated p65 and active caspase-3 were also remarkably increased in PC12 cells after CoCl2 stimulation. After ESE1 knockdown, PC12 cell viability was increased after hypoxia. siRNA knockdown of ESE1 decreased the level of p-p65 and active caspase-3 after CoCl2 stimulation. These data reveal that ESE1 levels are elevated in the hippocampus after cerebral ischemia/reperfusion injury. This may play a role in neuronal apoptosis via activation of the nuclear factor-κB pathway.

17.
Bioorg Chem ; 85: 364-372, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30658236

RESUMO

Catechin and epicatechin are flavan-3-ols, with (+)-catechin (C) and (-)-epicatechin (EC) being the most common optical isomers found in nature. In this study, we found that C and EC showed notable inhibitory activity against a-glucosidase (AGH), and that both inhibition activities reversible and competitive. Additionally, we observed that C and EC quenched the intrinsic fluorescence of AGH through a static quenching mechanism, and that the electrostatic force was the predominant driving factor in the binding reaction. Molecular docking studies indicated that the benzene-ring-4'-hydroxyphenyl construct on flavan-3-ol plays an important role in AGH inhibition, and that the inhibition increases along with increased binding of amino acid residues at this site. Furthermore, C and EC inhibited glucose absorption in everted intestine sleeves in vitro and suppressed increases in postprandial blood glucose levels in vivo. Our results suggest that C and EC are useful to protect against hyperglycemia through inhibiting the activity of a-glucosidase.


Assuntos
Catequina/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/farmacologia , alfa-Glucosidases/metabolismo , Animais , Domínio Catalítico , Catequina/metabolismo , Inibidores de Glicosídeo Hidrolases/metabolismo , Hipoglicemiantes/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Simulação de Acoplamento Molecular , Ligação Proteica , Ratos Sprague-Dawley , Saccharomyces cerevisiae/enzimologia , alfa-Glucosidases/química
18.
Acta Pharmacol Sin ; 40(6): 801-813, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30446734

RESUMO

Paeoniflorin-6'-O-benzene sulfonate (CP-25) is a new ester derivative of paeoniflorin with improved lipid solubility and oral bioavailability, as well as better anti-inflammatory activity than its parent compound. In this study we explored whether CP-25 exerted therapeutic effects in collagen-induced arthritis (CIA) mice through regulating B-cell activating factor (BAFF)-BAFF receptors-mediated signaling pathways. CIA mice were given CP-25 or injected with biological agents rituximab or etanercept for 40 days. In CIA mice, we found that T cells and B cells exhibited abnormal proliferation; the percentages of CD19+ total B cells, CD19+CD27+-activated B cells, CD19+BAFFR+ and CD19+TACI+ cells were significantly increased in PBMCs and spleen lymphocytes. CP-25 suppressed the indicators of arthritis, alleviated histopathology, accompanied by reduced BAFF and BAFF receptors expressions, inhibited serum immunoglobulin levels, decreased the B-cell subsets percentages, and prevented the expressions of key molecules in NF-κB signaling. Furthermore, we showed that treatment with CP-25 reduced CD19+TRAF2+ cell expressions stimulated by BAFF and decreased TRAF2 overexpression in HEK293 cells in vitro. Thus, CP-25 restored the abnormal T cells proliferation and B-cell percentages to the normal levels, and normalized the elevated levels of IgA, IgG2a and key proteins in NF-κB signaling. In comparison, rituximab and etanercept displayed stronger anti-inflammatory activities than CP-25; they suppressed the elevated inflammatory indexes to below the normal levels in CIA mice. In summary, our results provide evidence that CP-25 alleviates CIA and regulates the functions of B cells through BAFF-TRAF2-NF-κB signaling. CP-25 would be a soft immunomodulatory drug with anti-inflammatory effect.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Regulação para Baixo/efeitos dos fármacos , Glucosídeos/uso terapêutico , Monoterpenos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Artrite Experimental/induzido quimicamente , Artrite Reumatoide/induzido quimicamente , Fator Ativador de Células B/metabolismo , Linfócitos B/metabolismo , Proliferação de Células/efeitos dos fármacos , Colágeno , Etanercepte/uso terapêutico , Células HEK293 , Humanos , Articulações/patologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos Endogâmicos DBA , Subunidade p50 de NF-kappa B/metabolismo , Rituximab/uso terapêutico , Baço/patologia , Linfócitos T/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo
19.
Nanotechnology ; 30(8): 085101, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30523865

RESUMO

To increase the efficacy of small molecule chemotherapeutic drug (SMCD) and reduce its toxic and side effects, we selected two model drugs doxorubicin (DOX) and chloroquine (CQ). DOX is a SMCD and CQis a chemosensitizer with autophagy inhibition. Poly(lactic-co-glycolic acid) (PLGA) and alpha-tocopherol polyethylene glycol 1000 succinate were chosen as delivery carriers to design and prepare a novel type of drug co-delivery single-nanoparticles by emulsification-solvent volatilisation, named NPDOX+CQ. The physicochemical properties of NPDOX+CQ were characterised. Then A549 cells and A549/Taxol cells were used for the in vitro anti-cancer effect study. At the same time, cellular uptake, intracellular migration and anti-cancer mechanism of nanoparticles were studied. The NPs showed a uniform spherical shape with good dispersibility, and both drugs had good encapsulation efficiency and loading capacity. In all formulations, NPDOX+CQ showed the highest in vitro cytotoxicity. The results showed that NPs could protect drugs from being recognised and excluded by P-glycoprotein (P-gp). Moreover, the results of the mechanistic study demonstrated that NPs were transported by autophagy process after being taken up by the cells. Therefore, during the migration of NPDOX+CQ, CQ could exert its efficacy and block autophagy so that DOX would not be hit by autophagy. Western Blot results showed that NPDOX+CQ had the best inhibition effect of autophagy. It can be concluded that the system can prevent the drug from being recognised and excluded by P-gp, and CQ blocks the process of autophagy so that the DOX is protected and more distributed to the nucleus of multidrug resistance (MDR) cell. The NPDOX+CQ constructed in this study provides a feasible strategy for reversing MDR in tumour cells.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Cloroquina/administração & dosagem , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Neoplasias/tratamento farmacológico , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Cloroquina/farmacocinética , Cloroquina/farmacologia , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Nanopartículas/química , Neoplasias/metabolismo , Polietilenoglicóis/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , alfa-Tocoferol/análogos & derivados
20.
Chin Med J (Engl) ; 131(23): 2800-2807, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30511682

RESUMO

Background: Neural respiratory drive (NRD) using diaphragm electromyography through an invasive transesophageal multi-electrode catheter can be used as a feasible clinical physiological parameter in patients with chronic obstructive pulmonary disease (COPD) to provide useful information on the treatment response. However, it remains unknown whether the surface diaphragm electromyogram (EMGdi) could be used to identify the deterioration of clinical symptoms and to predict the necessity of hospitalization in acute exacerbation of COPD (AECOPD) patients. Methods: COPD patients visiting the outpatient department due to acute exacerbation were enrolled in this study. All patients who were subjected to EMGdi and classical parameters such as spirometry parameters, arterial blood gas analysis, COPD assessment test (CAT) score, and the modified early warning score (MEWS) in outpatient department, would be treated effectively in the outpatient or inpatient settings according to the Global Initiative for Chronic Obstructive Lung Disease guideline. When the acute exacerbation of the patients was managed, all the examination above would be repeated. Results: We compared the relationships of admission-to-discharge changes (Δ) in the normalized value of the EMGdi, including the change of the percentage of maximal EMGdi (ΔEMGdi%max) and the change of the ratio of minute ventilation to the percentage of maximal EMGdi (ΔVE/EMGdi%max) with the changes of classical parameters. There was a significant positive association between ΔEMGdi%max and ΔCAT, ΔPaCO2, and ΔpH. The change (Δ) of EMGdi%max was negatively correlated with ΔPaO2/FiO2in the course of the treatment of AECOPD. Compared with the classical parameters including forced expiratory volume in 1 s, MEWS, PaO2/FiO2, the EMGdi%max (odds ratio 1.143, 95% confidence interval 1.004-1.300) has a higher sensitivity when detecting the early exacerbation and enables to predict the admission of hospital in the whole cohort. Conclusions: The changes of surface EMGdi parameters had a direct correlation with classical measures in the whole cohort of AECOPD. The measurement of NRD by surface EMGdi represents a practical physiological biomarker, which may be helpful in detecting patients who should be hospitalized timely.


Assuntos
Eletromiografia/métodos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Diafragma/fisiopatologia , Volume Expiratório Forçado/fisiologia , Hospitalização , Humanos , Espirometria , Capacidade Vital/fisiologia
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