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1.
Clin Ther ; 42(1): 196-209.e5, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31910997

RESUMO

PURPOSE: Immunoglobulin (Ig) G replacement therapy, administered intravenously (IVIG) or subcutaneously (SCIG), is the standard treatment in patients with primary immunodeficiencies (PID). We aimed to characterize the pharmacokinetic (PK) characteristics of serum IgG following administration of IgPro10 every 3 or 4 weeks in Japanese patients with PID, and compare with PK in non-Japanese patients. A previously developed population PK (PPK) model was validated, and predicted parameters were compared with the results from the clinical study. METHODS: The previously developed PPK model, containing IgG concentration data from 5 non-Japanese studies, was supplemented with data from 3 Japanese studies of IgPro10 or IgPro20 to compare the IgG PK parameters between Japanese and non-Japanese patients. The model was externally validated by simulating IgG concentration-time profiles in Japanese patients to predict serum IgG PK characteristics and to compare them with observed Japanese PK data from Study IgPro10_3004. FINDINGS: The analysis included 4502 serum IgG concentration values (from 34 Japanese and 168 non-Japanese patients). PPK estimates from the current analysis demonstrated a clearance (CL) of 0.139 L/d, central volume (V2) of 4.01 L, inter-compartmental clearance (Q) of 0.30 L/d, and peripheral volume of 3.51 L. These results were consistent with those from the previously published PPK model, with similar bootstrap means and 95% CIs. Goodness-of-fit criteria indicated that the final PPK model was consistent with observed data, with no systemic bias in model prediction. Prediction-corrected visual predictive checks confirmed a good description of data on both SCIG and IVIG. PK parameters were equivalent between Japanese and non-Japanese patients. Body weight was determined to be a significant covariate on both CL and V2. Simulated and observed AUC and maximum and minimum serum IgG concentrations were similar, with 90% CIs overlapping between simulated and observed IgG concentrations in Japanese patients. IMPLICATIONS: PK parameter estimates of serum IgG were similar between Japanese and non-Japanese patients with PID. The PPK model, updated with Japanese data, was consistent with the previously published PPK model and could accurately predict both individual and population serum IgG concentration-time profiles following IgPro10 IV infusions every 3 or 4 weeks. EudraCT identifier: 2016-001631-12.

2.
Trials ; 21(1): 29, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907027

RESUMO

BACKGROUND: Scalp acupuncture has been widely used as treatment for motor dysfunction in children with cerebral palsy in China. Previous studies have failed to provide high-quality evidence to demonstrate the effectiveness of this treatment in children with cerebral palsy. No high-quality randomized controlled trials on scalp acupuncture have been published. The aim of this study is to evaluate the effectiveness of Jiao's scalp acupuncture when combined with routine rehabilitation treatment versus routine rehabilitation treatment alone for motor dysfunction in children with cerebral palsy. METHODS/DESIGN: This is a four-centre randomized controlled trial. One hundred cerebral palsy patients with motor dysfunction were enrolled. Patients will be allocated in a 1:1 ratio into either an acupuncture treatment group or a control group. Cerebral palsy patients in the control group will receive conventional rehabilitation treatment, whereas patients in the acupuncture group will receive a combination of scalp acupuncture and conventional rehabilitation treatment. Thirty-six treatment sessions will be performed over a 12-week period. The Gross Motor Function Measure and the Fine Motor Function Measure Scale will be assessed as the primary outcome measures. The Paediatric Evaluation of Disability Inventory and the Cerebral Palsy Quality of Life Questionnaire for Children will be selected as secondary outcome measures. All assessments will be conducted at baseline, week 4 (treatment 12), week 8 (treatment 24), week 12 (treatment 36) and week 24 (follow-up). DISCUSSION: This is the first trial evaluating the efficacy and safety of scalp acupuncture as a treatment for motor dysfunction in children with cerebral palsy. The results of this trial are expected to provide relevant evidence demonstrating that scalp acupuncture can be used as an effective rehabilitation treatment method for improving motor dysfunction in children with cerebral palsy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03921281. Registered on 19 April 2019.

3.
J Ethnopharmacol ; 251: 112554, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31923541

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is tightly associated with inflammation response and oxidative stress. As a folk medicine applied in treatment of diarrhea, Bruguiera gymnorrhiza also possesses anti-inflammatory and anti-oxidative activities, which indicated that B. gymnorrhiza may exert anti-colitis effect. AIM OF THE STUDY: To investigate effect and mechanism of B. gymnorrhiza on experimental UC. MATERIALS AND METHODS: Aqueous extract of B. gymnorrhiza leaves (ABL) was used for investigation in the present study. Murine UC was established through access to 3% dextran sulfate sodium (DSS) for 7 days. Meanwhile, mice accepted treatment with ABL (25, 50, 100 mg/kg) or sulfasalazine (200 mg/kg) once daily. On the last day, disease activity index (DAI) including body weight loss, fecal character and degree of bloody diarrhea was evaluated, colon segments were obtained for length measurement and further analysis and feces were collected for intestinal microbiota analysis. RESULTS: ABL ameliorated DAI scores, colon length shortening and histopathological damage in DSS-induced colitis mice obviously. SOD activity, levels of MDA and GSH altered by colitis were restored remarkably after ABL treatment. ABL inhibited increases in levels of colonic COX-2, iNOS, TNF-α, IL-6, IL-1ß, IL-4, IL-10 and IL-11 in colitis mice. Moreover, ABL prominently suppressed NF-κB p65 and IκB phosphorylation and down-regulated mRNA levels of COX-2, iNOS, TNF-α, IL-6 and IL-1ß elevated by colitis. As shown in microbiota analysis, ABL modulated composition of intestinal microbiota of colitis mice. CONCLUSION: ABL exhibited protective effect against DSS-induced ulcerative colitis through suppressing NF-κB activation and modulating intestinal microbiota.

4.
Ying Yong Sheng Tai Xue Bao ; 30(12): 4333-4343, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31840480

RESUMO

The regulation on carbon acquisition and water loss plays a critical role in plant growth and survival. Stomata are important portals for plants to control the exchanges of carbon and water between leaves and the atmosphere. Therefore, understanding stomatal control mechanisms and modelling stomatal conductivity are indispensable to accurately simulate carbon and water cycling in terrestrial ecosystems. As global climate change is accelerating in recent years, drought events have become more and more frequent and thus profoundly affect the survival, growth and distribution of plants. In order to deeply understand the underlying mechanism of carbon-water coupling of plants and predict the dynamics of plants and communities under global changes, it is crucial to explore responses of stomatal regulation of plants to drought stress. In this review, we synthesized recent research progress on mechanisms and modeling of plant stomatal regulation under drought stress. First, this review described the active and passive regulation of plant stomatal control in response to drought stress, and discussed the evolution of plant stomatal regulation, including the passive hydraulic regulation of ferns and lycophytes, the active regulation of angiosperms, and the dual-control mechanism of gymnosperms that was proposed as an important transitional type during evolution from ferns to angiosperms. Then, we analyzed the relationship between stomatal and hydraulic regulations, and discussed the debates on the decoupling of plant water potential from stomatal conductivity. The application of stomatal-conductivity optimization models was introduced based on the water use efficiency hypothesis and the maximum carbon gain hypothesis. The model based on the latter had a greater potential of prediction and practical application. Finally, we proposed two issues that should be urgently addressed: 1) to scale up the research of plant stomatal regulation from leaf or individual to ecosystem or even larger scales so as to improve the mechanistic models of carbon and water cycling in terrestrial ecosystems; and 2) to quantify the hydroactive feedback processes of plant stomatal regulation so as to modify current hydraulics models of plant stomatal function.


Assuntos
Secas , Gleiquênias , Ecossistema , Folhas de Planta , Estômatos de Plantas , Transpiração Vegetal , Água
5.
Oxid Med Cell Longev ; 2019: 9151067, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583050

RESUMO

Background/Aims: Obesity, which is related to increased oxidative stress in various tissues, is a risk factor for male infertility. Metformin is reported to have an antioxidant effect; however, the precise role of metformin in obesity-induced male infertility remains unknown. The current study is aimed at exploring the effects of metformin and characterizing its underlying mechanism in the fertility of obese males. Methods: An obese male mouse model was generated by feeding mice with a high-fat diet; then, the mice were administered metformin in water for 8 weeks. Reproductive ability, metabolic parameters, and follicle-stimulating hormone (FSH) were assessed by cohabitation, enzymatic methods, and ELISA, respectively. Damage to the integrity of the blood-testis barrier (BTB), which ensures spermatogenesis, was assessed by transmission electron microscopy and immunofluorescence with a biotin tracer. Malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS) were employed for the assessments of oxidative stress. BTB-related proteins were measured by immunoblotting. Nuclear factor κB (NF-κB) was assessed by immunofluorescence. Results: High-fat-diet-fed mice presented evident lipid metabolic disturbances, disrupted BTB integrity, and decreased reproductive function. Metformin alleviated the decrease in male fertility, decreased ectopic lipid deposition in the testis, and increased serum FSH levels. A further mechanistic analysis revealed that metformin ameliorated the high-fat-diet-induced injury to the BTB structure and permeability and restored the disordered BTB-related proteins, which might be associated with an improvement in oxidative stress and a recovery of NF-κB activity in Sertoli cells (SCs). Conclusion: Metformin improves obese male fertility by alleviating oxidative stress-induced BTB damage. These findings provide new insights into the effect of metformin on various diseases and suggest future possibilities in the treatment of male infertility.

6.
Gynecol Endocrinol ; : 1-5, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31452430

RESUMO

The aim of this study is to clarify the possible association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and pre-eclampsia in Hakka pregnant women in southern China. Pre-eclampsia and normal pregnant women were consecutively collected and MTHFR C677T genotypes were determined by the DNA sequencing method. One hundred and thirteen pre-eclampsia patients were CC homozygote (113 of 191, 59.2%), 68 of 191 (35.6%) were CT heterozygote, and 10 of 191 (5.2%) were TT homozygote, with the frequency of the T allele equal to 0.77. This is in comparison with the normal control group where 106 of 202 (52.5%) were CC homozygote, 83 of 202 (41.1%) were CT heterozygote, and 13 of 202 (6.4%) were TT homozygote, with the frequency of the T allele equal to 0.27. No statistically significant differences were observed in genotype or allele frequencies between the pre-eclampsia and normal control for the C677T polymorphism of MTHFR gene (p > .05). The findings of this study suggest that polymorphisms of MTHFR C677T genes were not associated with pre-eclampsia in Hakka pregnant women from southern China, but additional studies are necessary to explore the mechanisms involving it.

7.
J Cell Mol Med ; 23(10): 6859-6871, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31373170

RESUMO

OBJECTIVE: The high-fat diet (HFD)-induced obesity is responsible for the testosterone deficiency (TD). However, the mechanism remains unknown. Mitochondrial homeostasis is proved to be important for maintaining the function of steroidogenic acute regulatory protein (StAR), the first rate-limiting enzyme in testosterone synthesis. As the key regulator of mitochondrial membrane permeability, cyclophilin D (CypD) plays a crucial role in maintaining mitochondrial function. In this study, we sought to elucidate the role of CypD in the expression of StAR affected by HFD. METHODS: To analyse the influence of CypD on StAR in vivo and in vitro, mouse models of HFD, CypD overexpression and CypD knockout (Ppif-/- ) as well as Leydig cells treated with palmitic acid (PA) and CypD overexpression plasmids were examined with an array of metabolic, mitochondrial function and molecular assays. RESULTS: Compared with the normal diet mice, consistent with reduced testosterone in testes, the expressions of StAR in both mRNA and protein levels in HFD mice were down-regulated, while expressions of CypD were up-regulated. High-fat intake impaired mitochondrial function with the decrease in StAR in Leydig cells. Overexpression of CypD inhibited StAR expressions in vivo and in vitro. Compared with C57BL/6 mice with HFD, expressions of StAR were improved in Ppif-/- mice with HFD. CONCLUSIONS: Mitochondrial CypD involved in the inhibitory effect of HFD on StAR expression in testes.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31320915

RESUMO

Acute liver injury is a common consequence of taking overdose of acetaminophen (APAP). The aim of this study was to evaluate the antioxidant activity and hepatoprotective effect of a mangrove plant Sonneratia apetala fruit extract (SAFE) on APAP-induced liver injury in mice. Mice were orally pretreated with SAFE (100, 200, and 400 mg/kg) daily for one week. The control and APAP groups were intragastrically administered with distilled water, and NAC group was treated with N-Acetyl-L-cysteine (NAC) before APAP exposure. The results manifested that SAFE significantly improved survival rates, attenuated hepatic histological damage, and decreased the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in serum in APAP-exposed mice. SAFE treatment also increased glutathione (GSH) level and glutathione peroxidase (GSH-Px) activity, enhanced catalase (CAT), and total antioxidant capacity (T-AOC), as well as reducing malondialdehyde (MDA) level in liver. In addition, the formation of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and elevation of myeloperoxidase (MPO) in APAP-exposed mice were inhibited after SAFE treatment. And SAFE also displayed high DPPH radical scavenging activity and reducing power in vitro. The main bioactive components of SAFE such as total phenol, flavonoid, condensed tannin, and carbohydrate were determined. The current study proved that SAFE exerted potential protective effect against APAP-induced acute liver injury, which might be associated with the antioxidant and anti-inflammatory activities of SAFE.

9.
Contraception ; 100(4): 283-287, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31194965

RESUMO

OBJECTIVE: To assess the pharmacokinetics of combined oral contraceptive (COC) components and prevalence of ovulation in HIV-positive women using ritonavir-containing antiretroviral regimens compared to those using regimens previously found not to interact with COCs or not using any antiretrovirals. STUDY DESIGN: We conducted a prospective cohort pharmacokinetic pilot study comparing the pharmacokinetics of levonorgestrel (LNG) and ethinyl estradiol (EE) in HIV-positive women taking ritonavir-containing antiretroviral regimens to those in women using non-ritonavir-containing regimens or no antiretrovirals. Participants received COCs containing LNG/EE 150/30 mcg for 21 days. Beginning day 21, we collected serial blood samples over 72 h. The primary outcome was area under the curve (AUC) of LNG, with secondary outcomes including other LNG pharmacokinetic measures, EE pharmacokinetics and ovulation as measured by serum progesterone. RESULTS: Pharmacokinetic parameters of LNG showed a trend toward increased exposure in women on ritonavir. LNG AUClast increased by 32.6% (312±60.9 vs. 243±82.6 ng/mL*h, p=.033, n=5) in women taking ritonavir compared to the control group (n=10). The Cmax (9.68±1.81 vs. 7.62±2.29 ng/mL) and Cmin (4.97±1.15 vs. 3.70±1.29 ng/mL) were also higher in the ritonavir arm. After excluding the inconsistent users (n=2), CL of LNG was reduced in the ritonavir arm (p=.032). EE pharmacokinetic profiles were not different between groups. The progesterone concentrations were similar in women of both groups, and none were consistent with ovulation during the treatment cycle. CONCLUSION: Women on ritonavir showed an approximately 30% increase in LNG exposure but no difference in EE exposure. IMPLICATIONS: The current data suggest that ritonavir does not have a clinically significant impact on oral contraceptive pharmacokinetics.

10.
J Cell Mol Med ; 23(5): 3140-3150, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30884106

RESUMO

Emerging epidemiological studies indicate that hypercholesterolaemia is a risk factor for testosterone deficiency. However, the underlying mechanism is unclear. Testicular Leydig cells are the primary source of testosterone in males. To identify the effect and mechanism of cholesterol overload on Leydig cell function, rats were fed with a HC (HC) diet to induce hypercholesterolaemia. During the 16-week feeding period, serum testosterone levels were reduced in a time-dependent manner in rats fed the HC diet. Accordingly, these steroidogenic enzymes within the Leydig cells, including steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage cytochrome P450 (P450scc) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD), were down-regulated. Notably, the HC-fed rats showed evident endoplasmic reticulum (ER) stress in the testis, including a dilated ER as an evident pathological change in the Leydig cell ultrastructure, up-regulated ER stress biomarker (binding immunoglobulin protein) levels and activation of the activating transcription factor 6 (ATF6)-related unfolded protein response pathway. Further analysis showed that when 4-phenyl butyric acid (4-PBA) was used to block ER stress in HC-fed rats for 8 weeks, the testosterone deficiency was significantly alleviated. Our findings suggested that high dietary cholesterol intake affected serum testosterone levels by down-regulating steroidogenic enzymes and that activated ER stress might serve as the underlying mechanism.

11.
Cardiovasc Pathol ; 39: 38-50, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30623879

RESUMO

The traditional classification of congenital aortic arch abnormalities was described by James Stewart and colleagues in 1964. Since that time, advances in diagnostic imaging technology have led to better delineation of the vasculature anatomy and the identification of previously unrecognized and unclassified anomalies. In this manuscript, we review the existing literature and propose a series of modifications to the original Stewart classification of congenital aortic arch abnormalities to incorporate this new knowledge. In brief, we propose the following modifications: (1) In Group I, we further divide subgroup B into left arch atretic and right arch atretic; (2) In Group II, we add three more subgroups, including aberrant right innominate artery, "isolated" right innominate artery (RIA), "isolated" right carotid artery with aberrant right subclavian artery; (3) In Groups I, II, and III, we add a subgroup of absence of both ductus arteriosus; and (4) In Group IV, we add three subgroups, including circumflex retro-esophageal aorta arch, persistent V aortic arch, and anomalous origin of pulmonary artery from ascending aorta.


Assuntos
Aorta Torácica/anormalidades , Cardiopatias Congênitas/classificação , Terminologia como Assunto , Malformações Vasculares/classificação , Aorta Torácica/diagnóstico por imagem , Tomada de Decisão Clínica , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/terapia , Humanos , Valor Preditivo dos Testes , Prognóstico , Malformações Vasculares/diagnóstico por imagem , Malformações Vasculares/terapia
12.
Contraception ; 99(4): 256-263, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30684471

RESUMO

OBJECTIVE: The objective was to evaluate the pharmacokinetics (PKs) of levonorgestrel (LNG)-containing combined oral contraceptives (COCs) in obese women. STUDY DESIGN: We pooled and reanalyzed data from 89 women with different body mass index (BMI) categories from four clinical studies. The LNG and ethinyl estradiol (EE) PKs were analyzed utilizing a zero-order absorption (K0), two-compartment PK model to evaluate key PK parameters in relation to a range of weights, BMI and body surface area (BSA). RESULTS: Increasing of body habitus metrics is correlated with decreasing Cmax (p<.0001) and AUCτ (p<.05) for both LNG and EE, but no correlation was found for Cmin (p≥.17). Increasing weight and BMI were associated with a modest increase (p≤.056) of clearance (CL) and appreciable increases of central volume (V1, p<.05), distribution clearance (CLd, p≤.001) and peripheral volume (V2, p<.0001) for LNG. For EE, increases in CL (p≤.009) were found with greater weight, BMI and BSA. Values of V1, CLd and V2 also increased (p<.0001) in obese subjects. The half-life and steady-state volume were greater among obese women (p<.0001) for both LNG and EE. LNG and EE PK parameters correlated well (p≤.006 for all), indicating that individual subject physiology affected both drugs similarly. CONCLUSIONS: The primary effects of obesity on LNG and EE were a modest increase in CL and a marked increase in distribution parameters. We observed no obesity-related differences in trough LNG and EE concentrations. IMPLICATIONS: This population PK analysis demonstrated reduced systemic exposure to LNG/EE oral contraceptives in obese subjects (Cmax and AUCτ); these particular differences are unlikely to lower contraceptive effectiveness among obese women who are correctly using LNG-containing contraceptives.

13.
J Control Release ; 297: 39-47, 2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30684512

RESUMO

Chemophototherapy (CPT) merges photodynamic therapy with chemotherapy and can substantially enhance drug delivery. Using a singular liposomal formulation for CPT, we describe a semi-mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model to investigate observed antitumor effects. Long-circulating, sterically-stabilized liposomes loaded with doxorubicin (Dox) stably incorporate small amounts of a porphyrin-phospholipid (PoP) photosensitizer in the bilayer. These were administered intravenously to mice bearing low-passage, patient-derived pancreatic cancer xenografts (PDX). Dox PK was described with a two-compartment model and tumor drug disposition kinetics were modeled with first-order influx and efflux rates. Tumor irradiation with 665 nm laser light (200 J/cm2) 1 h after liposome administration increased tumor vascular permeabilization and drug accumulation, which was accounted for in the PK/PD model with increased tumor influx and efflux rates by approximately 12- and 4- fold, respectively. This modeling approach provided an overall 7-fold increase in Dox area under the curve in the tumor, matching experimental data (7.4-fold). A signal transduction model based on nonlinear direct cell killing accounted for observed tumor growth patterns. This PK/PD model adequately describes the CPT anti-PDX tumor response based on enhanced drug delivery at the short drug-light interval used.

14.
Food Chem Toxicol ; 123: 349-362, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30423402

RESUMO

Acetaminophen (APAP) overdose-induced hepatotoxicity is tightly associated with oxidative stress. Tetrahydrocurcumin (THC) and octahydrocurcumin (OHC), the primary and final hydrogenated metabolites of curcumin (CUR), possess stronger antioxidant activity in vitro. The present study was performed to investigate the potential and mechanism of OHC and THC against APAP-induced hepatotoxicity in parallel to CUR. Our results showed that OHC and THC dose-dependently enhanced liver function (ALT and AST levels) and alleviated histopathological deterioration. Besides, OHC and THC significantly restored the hepatic antioxidant status by miring level of MDA and ROS, and elevated levels of GSH, SOD, CAT and T-AOC. In addition, OHC and THC markedly suppressed the activity and expressions of CYP2E1, and bound to the active sites of CYP2E1. Moreover, OHC and THC activated the Keap1-Nrf2 pathway and enormously enhanced the translational activation of Nrf2-targeted gene (GCLC, GCLM, NQO1 and HO-1) against oxidative stress, via inhibiting the expression of Keap1 and blocking the interaction between Keap1 and Nrf2. Particularly, OHC and THC exerted superior hepato-protective and antioxidant activities to CUR. In conclusion, OHC and THC possess favorable hepato-protective effect through restoring antioxidant status, inhibiting CYP2E1 and activating Keap1-Nrf2 pathway, which might represent promising antioxidants for the treatment of APAP-induced hepatotoxicity.


Assuntos
Acetaminofen/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Curcumina/administração & dosagem , Citocromo P-450 CYP2E1/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Substâncias Protetoras/administração & dosagem , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Curcumina/análogos & derivados , Curcumina/química , Curcumina/metabolismo , Citocromo P-450 CYP2E1/genética , Humanos , Hidrogenação , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/química , Substâncias Protetoras/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
IEEE Trans Med Imaging ; 38(1): 180-193, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30040635

RESUMO

Volumetric ultrasound is rapidly emerging as a viable imaging modality for routine prenatal examinations. Biometrics obtained from the volumetric segmentation shed light on the reformation of precise maternal and fetal health monitoring. However, the poor image quality, low contrast, boundary ambiguity, and complex anatomy shapes conspire toward a great lack of efficient tools for the segmentation. It makes 3-D ultrasound difficult to interpret and hinders the widespread of 3-D ultrasound in obstetrics. In this paper, we are looking at the problem of semantic segmentation in prenatal ultrasound volumes. Our contribution is threefold: 1) we propose the first and fully automatic framework to simultaneously segment multiple anatomical structures with intensive clinical interest, including fetus, gestational sac, and placenta, which remains a rarely studied and arduous challenge; 2) we propose a composite architecture for dense labeling, in which a customized 3-D fully convolutional network explores spatial intensity concurrency for initial labeling, while a multi-directional recurrent neural network (RNN) encodes spatial sequentiality to combat boundary ambiguity for significant refinement; and 3) we introduce a hierarchical deep supervision mechanism to boost the information flow within RNN and fit the latent sequence hierarchy in fine scales, and further improve the segmentation results. Extensively verified on in-house large data sets, our method illustrates a superior segmentation performance, decent agreements with expert measurements and high reproducibilities against scanning variations, and thus is promising in advancing the prenatal ultrasound examinations.


Assuntos
Imagem Tridimensional/métodos , Ultrassonografia Pré-Natal/métodos , Algoritmos , Feminino , Feto/diagnóstico por imagem , Humanos , Gravidez
16.
Protein Cell ; 10(8): 566-582, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-29956125

RESUMO

The mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.

17.
Mol Cancer Ther ; 18(3): 592-601, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30587558

RESUMO

Photosensitizers can be integrated with drug delivery vehicles to develop chemophototherapy agents with antitumor synergy between chemo- and photocomponents. Long-circulating doxorubicin (Dox) in porphyrin-phospholipid (PoP) liposomes (LC-Dox-PoP) incorporates a phospholipid-like photosensitizer (2 mole %) in the bilayer of Dox-loaded stealth liposomes. Hematological effects of endotoxin-minimized LC-Dox-PoP were characterized via standardized assays. In vitro interaction with erythrocytes, platelets, and plasma coagulation cascade were generally unremarkable, whereas complement activation was found to be similar to that of commercial Doxil. Blood partitioning suggested that both the Dox and PoP components of LC-Dox-PoP were stably entrapped or incorporated in liposomes. This was further confirmed with pharmacokinetic studies in Fischer rats, which showed the PoP and Dox components of the liposomes both had nearly identical, long circulation half-lives (25-26 hours). In a large orthotopic mammary tumor model in Fischer rats, following intravenous dosing (2 mg/kg Dox), the depth of enhanced Dox delivery in response to 665 nm laser irradiation was over 1 cm. LC-Dox-PoP with laser treatment cured or potently suppressed tumor growth, with greater efficacy observed in tumors 0.8 to 1.2 cm, compared with larger ones. The skin at the treatment site healed within approximately 30 days. Taken together, these data provide insight into nanocharacterization and photo-ablation parameters for a chemophototherapy agent.

18.
Front Pharmacol ; 9: 1181, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386242

RESUMO

Curcumin (CUR), a promising naturally occurring dietary compound, is commonly recognized as the potential anti-inflammatory agent. While the application of CUR was hampered by its low stability and poor systemic bioavailability, it has been suggested that the biological activities of CUR are intimately related to its metabolites. In the current investigation, we aimed to comparatively explore the anti-inflammatory effects of tetrahydrocurcumin (THC), octahydrocurcumin (OHC), and CUR, and to elucidate the underlying action mechanisms on experimental mice models of acute inflammation, i.e., xylene-induced ear edema, acetic acid-induced vascular permeability, and carrageenan-induced paw edema. The results showed that THC and OHC exerted significant and dose-dependent inhibitions on the formation of ear edema induced by xylene and paw edema provoked by carrageenan and inhibited the Evans blue dye leakage in peritoneal cavity elicited by acetic acid. Moreover, THC and OHC treatments were more effective than CUR in selectively inhibiting the expression of cyclooxygenase 2 (COX-2) and suppressing nuclear factor-κB (NF-κB) pathways via transforming growth factor ß activated kinase-1 (TAK1) inactivation in the carrageenan-induced mouse paw edema model.

19.
Int J Nanomedicine ; 13: 6223-6233, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349246

RESUMO

Background: Functionalizing biomaterial substrates with biological signals shows promise in regulating neural stem cell (NSC) behaviors through mimicking cellular microenvironment. However, diverse methods for immobilizing biological molecules yields promising results but with many problems. Biomimetic apatite is an excellent carrier due to its non-toxicity, good biocompatibility, biodegradability, and favorable affinity to plenty of molecules. Therefore, it may provide a promising alternative in regulating NSC behaviors. Methods: Biomimetic apatite immobilized with the extracellular protein - laminin (LN) was prepared through coprecipitation process in modified Dulbecco's phosphate-buffered saline (DPBS) containing LN. The amount of coprecipitated LN and their release kinetics were examined. The adhesion and proliferation behaviors of NSC on biomimetic apatite immobilized with LN were investigated. Results: The coprecipitation approach provided well retention of LN within biomimetic apatite up to 28 days, and supported the adhesion and proliferation of NSCs without cytotoxicity. For long-term cultivation, NSCs formed neurosphere-like aggregates on non-functionalized biomimetic apatite. A monolayer of proliferated NSCs on biomimetic apatite with coprecipitated LN was observed and even more stable than the positive control of LN coated tissue-culture treated polystyrene (TCP). Conclusion: The simple and reproducible method of coprecipitation suggests that biomimetic apatite is an ideal carrier to functionalize materials with biological molecules for neural-related applications.


Assuntos
Apatitas/química , Apatitas/farmacologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Laminina/química , Laminina/farmacologia , Células-Tronco Neurais/citologia , Animais , Adesão Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Liberação Controlada de Fármacos , Cinética , Camundongos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/ultraestrutura , Espectroscopia Fotoeletrônica
20.
Thyroid ; 2018 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-30244634

RESUMO

BACKGROUND: MiR-146b has been reported to be over-expressed in papillary thyroid cancer (PTC) tissues and showed association with aggressive PTC. MiR-146b-5p has been confirmed to increase cell proliferation by repressing SMAD4, however as the other expression of miR-146b, detailed functional analysis of miR-146b-3p has not been carried out. In this study, we aimed to identify miR-146b-5p and miR-146b-3p differentially expressed in PTC with more aggression, such as lymph node metastasis and further elucidate the contribution and mechanism of miR-146b-3p in the process of PTC metastasis. METHODS: Expression of miR-146b-5p and miR-146b-3p was assessed in formalin-fixed paraffin-embedded (FFPE) tissues samples of PTC patients and the relationship with lymph node metastasis was analyzed.. A variety of PTC cells including BHP10-3 and K1 cells were cultured and miR-146b-5p or miR-146b-3p were over-expressed with microRNA mimics. The cell abilities of migration and invasion were detected by RTCA assay and transwell assay. PTC xenograft models were used to examine the effect of miR-146b-3p on PTC metastasis ability in vivo. Direct downstream target of miR-146b-3p was analyzed by luciferase reporter assay and western blot. The mechanism of miR-146b-3p on cell metastasis was further determined by co-transfected with merlin (the protein product of NF2 gene). RESULTS: MiR-146b-5p and miR-146b-3p expression was significantly higher in thyroid cancer tissues and cell lines compared to normal thyroid tissue and cells. Moreover, expression of miR-146b-5p and miR-146b-3p was further higher in thyroid metastatic nodes than thyroid cancer. After overexpression of miR-146b-5p or miR-146b-3p in BHP10-3, papillary thyroid cancer migration and invasion were increased. Notably, miR-146b-3p increased cell migration and invasion more obviously than miR-146b-5p. Overexpression of miR-146b-3p also significantly promoted PTC tumor metastasis in vivo. Luciferase reporter assay revealed that NF2 was a downstream target of miR-146b-3p in PTC cells as miR-146b-3p bound directly to the 3' untranslated region of NF2, thus reducing protein levels of NF2. Over-expression of merlin reversed the enhanced aggressive effects of miR-146b-3p. CONCLUSIONS: Over-expression of miR-146b-5p and miR-146b-3p was associated with PTC metastasis. MiR-146b-3p could enhance cell invasion and metastasis more obviously than miR-146b-5p through the suppression of gene NF2. These findings suggest a diagnosis and therapeutic benefit in PTC metastasis.

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