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1.
Lancet Oncol ; 20(11): e619-e626, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31674320

RESUMO

As a result of recent, substantial capacity building, a new landscape for cancer drug trials is emerging in China. However, data on the characteristics of cancer drug trials, and how they have changed over time, are scarce. Based on clinical trials published on the China Food and Drug Administration Registration and Information Disclosure Platform for Drug Clinical Studies, we aimed to systematically review changes over time in clinical trials of cancer drugs in mainland China from 2009 to 2018, to provide insight on the effectiveness of the pharmaceutical industry and identify unmet clinical needs of stakeholders. A total of 1493 trials of 751 newly tested cancer drugs were initiated. Increases over time were observed for the annual number of initiated trials, newly tested drugs, and newly added leading clinical trial units, with a sharp increase after 2016. Of the 1385 trials in which cancer types were identified, solid tumours (325 [23%] trials), non-small-cell lung cancer (232 [17%]), and lymphoma (126 [9%]) were the most common. A markedly uneven distribution was also observed in the geography of leading units with the largest number of leading units located in east China (50 [41%]) and the smallest number located in southwest China (4 [3%]). The growth trends we observed illustrate the progress in and increasing capability of cancer drug research and development achieved in mainland China over the decade from 2009. The low number of clinical trials on tumours with epidemiological characteristics unique to the Chinese population and the unbalanced geographical distribution of leading clinical trial units will provide potential targets for policy makers and other stakeholders. Further research efforts should address cancers uniquely relevant to Chinese populations, globally rare cancers, and the balance between equitable drug access, efficiency, and sustainability of cancer drug research and development in mainland China.

2.
Nat Prod Res ; : 1-8, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31674834

RESUMO

Investigation into the chemical diversity of Artemisia argyi led to the discovery of two new (1, 4) and four known (2-3, 5-6) sesquiterpenoids. The new structures were determined via extensive spectroscopic data, including IR, UV, MS, and NMR, and the absolute configurations of these compounds were elucidated by calculated ECD method. All isolates were tested for their inhibitory activity against NO production in RAW 264.7 macrophages, and the isolated sesquiterpenoids exhibited NO production inhibitory activity with IC50 values ranging from 1.91 to 36.52 µM.

3.
J Phys Chem B ; 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31718186

RESUMO

We report a kinetics and mechanistic study on the 1O2 oxidation of 9-methylguanine (9MG) and the cross-linking of the oxidized intermediate 2-amino-9-methyl-9H-purine-6,8-dione (9MOGOX) with Nα-acetyl-lysine-methyl ester (abbreviated as LysNH2) in aqueous solutions of different pH. Experimental measurements include the determination of product branching ratios and reaction kinetics using mass spectrometry and absorption spectroscopy, and the characterization of product structures by employing collision-induced dissociation. Strong pH dependence was revealed for both 9MG oxidation and the addition of nucleophiles (water and LysNH2) at the C5 position of 9MOGOX. The 1O2 oxidation rate constant of 9MG was determined to be 3.6 × 107 M-1·s-1 at pH 10.0 and 0.3 × 107 M-1·s-1 at pH 7.0, both of which were measured in the presence of 15 mM LysNH2. The ωB97XD density functional theory coupled with various basis sets and the SMD implicit solvation model was used to explore the reaction potential energy surfaces for the 1O2 oxidation of 9MG and the formation of C5-water and C5-LysNH2 adducts of 9MOGOX. Computational results have shed light on reaction pathways and product structures for the different ionization states of the reactants. The present work has confirmed that the initial 1O2 addition represents the rate-limiting step for the oxidative transformations of 9MG. All of the downstream steps are exothermic with respect to the starting reactants. The C5-cross-linking of 9MOGOX with LysNH2 significantly suppressed the formation of spiroiminodihydantoin (9MSp) resulting from the C5-water addition. The latter became dominant only at the low concentration (∼1 mM) of LysNH2.

4.
Medicine (Baltimore) ; 98(48): e18182, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770271

RESUMO

RATIONALE: Rupture of an unscarred uterus after in vitro fertilization-embryo transfer (IVF-ET) in a primiparous woman is rare. Assisted reproductive technology (ART)-induced rupture of an unscarred uterus is usually attributable to increased dizygotic twinning rates. Salpingectomy can result in cornual scarring and increase the risk of uterine rupture as well as the mortality rate in a subsequent ectopic pregnancy. Here, we present the first reported case of a spontaneous, third-trimester, uterine rupture in a primiparous woman after IVF-ET due to a history of bilateral salpingectomy because of bilateral oviduct and ovarian cysts; the patient did not have an ectopic pregnancy or any cornual or other uterine scarring during this pregnancy after IVF-ET. PATIENT CONCERNS: A 24-year-old woman with a history of IVF-ET and bilateral salpingectomy was admitted to our hospital with unexplained acute upper abdominal pain during the third trimester. DIAGNOSIS: The fetal heart rate was abnormal. Abdominal ultrasonography was negative. Computed tomography revealed a small amount of abdominal and pericardial effusion. Laboratory tests revealed increased white blood cells. A diagnosis of pregnancy complicated by acute abdomen was considered. Emergent exploratory laparotomy revealed a uterine rupture at the right fundus adjacent to the right cornual area. INTERVENTIONS: The patient was successfully managed with simultaneous exploratory laparotomy and lower-segment cesarean section. The rupture site was repaired. OUTCOMES: Two live infants were uneventfully delivered. Follow-up assessments of the mother and the female baby on the 42nd postpartum day yielded normal results. The male infant was diagnosed with left hydronephrosis and required an operation. LESSONS: We conclude that the ART-associated increase in dizygotic twinning rates may be a neglected risk factor for spontaneous rupture of the unscarred uterus, especially in patients who have undergone salpingectomy. Uterine rupture should be considered in a patient with multiple pregnancy following IVF-ET who presents with acute abdominal pain and abnormal fetal heart rate. Timely exploratory laparotomy is the key to a good prognosis.

5.
Placenta ; 89: 67-77, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31704631

RESUMO

INTRODUCTION: Idiopathic polyhydramnios (IPH) is an abnormal increase in amniotic fluid volume (AFV). This condition has unknown etiologies and is associated with various adverse pregnancy outcomes including maternal and fetal complication. This study aims to establish a comparative proteome profile for the human amniotic fluid (AF) of IPH and normal pregnancies and identify the responsible mediators and pathways that regulate AFV. METHODS: We first employed coupled isobaric tags for relative and absolute quantitation (iTRAQ) proteomics and bioinformatics analysis to examine the differentially expression proteins (DEPs) in the AF of IPH and normal pregnancies. Second, CUL5, HIP1, FSTL3, and LAMP2 proteins were selected for verification in amnion, chorion, and placental tissues by Western blot analysis. RESULTS: We identified 357 DEPs with 282 upregulated and 75 downregulated. Bioinformatics analysis revealed that cell, cellular process, and binding were the most enriched Gene Ontology terms. Amoebiasis, hematopoietic cell lineage, and NF-kappa B signaling pathway were the top significant pathways. In the verification procedure, FSTL3 protein had a highly significant expression in the amnion, chorion, and placentas of IPH and normal AFV groups (p < 0.05). DISCUSSION: Our results provide new insights into idiopathic polyhydramnios and offer fundamental points for future studies on AFV.

6.
Int Wound J ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31724831

RESUMO

Bacterial infection is a common wound complication that can significantly delay healing. Classical local therapies for infected wounds are expensive and are frequently ineffective. One alternative therapy is photodynamic therapy (PDT). We conducted a systematic review to clarify whether PDT is useful for bacteria-infected wounds in animal models. PubMed and Medline were searched for articles on PDT in infected skin wounds in animals. The language was limited to English. Nineteen articles met the inclusion criteria. The overall study methodological quality was moderate, with a low-moderate risk of bias. The animal models were mice and rats. The wounds were excisional, burn, and abrasion wounds. Wound size ranged from 6 mm in diameter to 1.5 × 1.5 cm2 . Most studies inoculated the wounds with Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus. Eleven and 17 studies showed that the PDT of infected wounds significantly decreased wound size and bacterial counts, respectively. Six, four, and two studies examined the effect of PDT on infected wound-cytokine levels, wound-healing time, and body weight, respectively. Most indicated that PDT had beneficial effects on these variables. PDT accelerated bacteria-infected wound healing in animals by promoting wound closure and killing bacteria.

7.
J Nat Prod ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31742403

RESUMO

Melongenaterpenes A-L (1-12), 12 new sesquiterpenoids with rare spiro[4.5]decane skeletons, were isolated from the roots of Solanum melongena. Their 2D structures and relative configurations were determined based on NMR and HRESIMS data. The absolute configuration of melongenaterpene A (1) was defined by X-ray crystallographic analysis. The absolute configurations of the remaining compounds were determined by comparison of their NMR data with 1 and consideration of the biosynthetic pathway. This is the first report of the crystal structure of a vetispirane-type sesquiterpenoid. None of the compounds exhibited cytotoxic activity against the three human cancer cell lines HepG2, HeLa, and MCF-7.

8.
Nat Genet ; 51(11): 1574-1579, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31676865

RESUMO

Venous thromboembolism is a significant cause of mortality1, yet its genetic determinants are incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank, with testing of approximately 13 million DNA sequence variants for association with venous thromboembolism (26,066 cases and 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 venous thromboembolism cases and 167,295 controls. We identified 22 previously unknown loci, bringing the total number of venous thromboembolism-associated loci to 33, and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for venous thromboembolism that identifies 5% of the population at an equivalent incident venous thromboembolism risk to carriers of the established factor V Leiden p.R506Q and prothrombin G20210A mutations. Our data provide mechanistic insights into the genetic epidemiology of venous thromboembolism and suggest a greater overlap among venous and arterial cardiovascular disease than previously thought.

9.
J Ethnopharmacol ; : 112380, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31707048

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Yueju-Ganmaidazao Decoction (YG) is a multiherbal medicine prescribed for treatment of mood disorder, consisting of two classical traditional Chinese herbal medicine Yueju and Ganmaidazao. Yueju and Ganmaidazao both are used for depression treatment. The combined decoction of Yueju and Ganmaidazao is prescribed to achieve optimal clinical outcomes by dealing with different symptoms of depression. Recent studies indicated ethanol extract of Yueju was capable to confer rapid antidepressant-like response. The antidepressant activity of YG decoction with fast-onset feature remains to be investigated. AIM OF THE STUDY: Rapid and safe antidepressant treatment is urgently needed. This study aimed to assess the rapid antidepressant-like activity of YG and the underlying mechanism, focusing on NMDA/NO/cGMP signaling. MATERIALS AND METHODS: The optimal doses for immediate and persistent antidepressant-like response were first screened using tail suspension test (TST) and forced swimming test (FST) post a single administration of YG. The rapid action was further confirmed by using the chronic mild stress (CMS) and learned helplessness (LH) paradigms. The expressions of NMDA receptor subunits were evaluated post stress and YG. The contributions of NMDA, NO, and cGMP signaling to the antidepressant effect of YG were investigated systematically using pharmacological interventions. RESULTS: The optimal dose for immediate and persistent antidepressant potential, evidenced with reduced immobility times in TST or FST from 30 min to 7 days, was determined. The rapid antidepressant-like effect was confirmed in CMS and LH paradigms, including instant normalization of sucrose preference behavior. The expression of NMDA subunit NR1 in the hippocampus was reduced from 30 min to 5 days post YG. In animals subjected to CMS and LH, hippocampal NR1 expression increased, reversed by YG. YG's antidepressant-like effect was blunted by pretreatment with the agonists along the signalings including NMDA (75 mg/kg), L-arginine (750 mg/kg) and sildenafil (5 mg/kg) in TST or FST. Conversely, administration of subeffective dose of individual antagonists, including MK-801 (0.05 mg/kg), 7-nitroindazole (30 mg/kg), methylene blue (10 mg/kg), in combination with a subeffective dose of YG, elicited antidepressant effects. CONCLUSION: YG conferred rapid antidepressant-like effects, and the antidepressant response was essentially dependent on suppression of NMDA/NO/cGMP signaling.

10.
Theranostics ; 9(26): 8138-8154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754386

RESUMO

Thermosensitive liposomes have demonstrated great potential for tumor-specific chemotherapy. Near infrared (NIR) dyes loaded liposomes have also shown improved photothermal effect in cancer theranostics. However, the instability of liposomes often causes premature release of drugs or dyes, impeding their antitumor efficacy. Herein, we fabricated a highly stable thermo-responsive bubble-generating liposomal nanohybrid cerasome with a silicate framework, combined with a NIR dye to achieve NIR light stimulated, tumor-specific, chemo-photothermal synergistic therapy. Methods: In this system, NIR dye of 1,1'-Dioctadecyl-3,3,3',3'- Tetramethylindotricarbocyanine iodide (DiR) with long carbon chains was self-assembled with a cerasome-forming lipid (CFL) to encapsulate ammonium bicarbonate (ABC), which was further used for actively loading doxorubicin (DOX), affording a thermosensitive and photosensitive DOX-DiR@cerasome (ABC). Results: The resulting cerasome could disperse well in different media. Upon NIR light mediated thermal effect, ABC was decomposed to generate CO2 bubbles, resulting in a permeable channel in the cerasome bilayer that significantly enhanced DOX release. After intravenous injection into tumor-bearing mice, DOX-DiR@cerasome (ABC) could be efficiently accumulated at the tumor tissue, as monitored by DiR fluorescence, lasting for more than 5 days. NIR light irradiation was then performed at 36h to locally heat the tumors, resulting in immediate CO2 bubble generation, which could be clearly detected by ultrasound imaging, facilitating the monitoring process of controlled release of the drug. Significant antitumor efficacy could be obtained for the DOX-DiR@cerasome (ABC) + laser group, which was further confirmed by tumor tissue histological analysis.

11.
Med Ultrason ; 21(4): 441-448, 2019 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-31765453

RESUMO

AIM: Studies on the usefulness of speckle tracking echocardiography (STE) in the evaluation of the left ventricle in rats with stress cardiomyopathy (SCM) are limited. Our aim was to investigate whether strain values by STE and cardiac troponin I (cTnI) could predict early myocardial injury in rats with SCM. MATERIAL AND METHODS: SCM was induced in Sprague-Dawley female rats using immobilization (IMO) stress. Biomarkers and echocardiographic parameters were evaluated and compared among groups (group 1 - 30 minutes after IMO stress, group 2 - 24 hours after IMO stress, and control group). We defined myocardial injury as a left ventricular ejection fraction <50%. Possible predictors of early myocardial injury were determined by univariate logistic regression, and independent predictors of early myocardial injury were investigated with multivariable logistic regression. RESULTS: A total of 44 rats with a mean weight of 426±33 g were evaluated. Group 1 had the highest plasma epinephrine and norepinephrine levels (p<0.001) and the highest heart rate (p<0.001). In univariate logistic regression, cTnI (OR=2.61 [1.02‒10.25], p=0.043) and global longitudinal strain (GLS) (OR=2.13 [1.12‒6.26], p=0.022) were predictive of early myocardial injury. When GLS and cTnI were included in a multivariate analysis, only GLS remained an independent predictor of early myocardial injury (OR=2.67 [1.14‒14.76], p=0.027). CONCLUSIONS: STE is useful for the quantitative detection of subtle myocardial abnormalities in rats with SCM. GLS may provide a reliable and non-invasive method to predict early myocardial injury.

12.
Biomed Pharmacother ; 121: 109649, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31733571

RESUMO

BACKGROUND: Nephrolithiasis is a common disease in urology, and its pathogenesis is associated with various factors. Recent studies have shown that reactive oxygen species (ROS) can promote autophagy in the formation of kidney stones and exacerbate kidney injury. Endoplasmic reticulum stress (ERS), a key factor in regulating intracellular environmental homeostasis, is also directly related to ROS production. Therefore, this study aimed to investigate the regulatory effect of superoxide dismutase (SOD) on autophagy-ERS response during the formation of calcium oxalate (CaOx) kidney stones in rats. METHODS: Thirty-two rats were randomly divided into four groups (n = 8): normal control group, stone model group, stone model with atorvastatin group, and stone model with diethyldithiocarbamic acid (DETC) group. Rat models of CaOx kidney stones were established by intragastric administration of 0.75 % ethylene glycol for 4 weeks. Kidney/body weight was used to assess renal enlargement. Renal function was assessed by measuring serum SOD, creatinine (CRE), and blood urea nitrogen (BUN) levels. The expression of autophagy-related proteins LC3B and BECN1 was detected through immunohistochemical staining. Meanwhile, the expression of autophagy-ERS response-related proteins LC3B, BECN1, p62, GRP78, and CHOP was detected using Western blot and RT-PCR. Renal tubular injury markers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (Kim-1) were determined through enzyme-linked immunosorbent assay. The apoptosis of renal tubular cells and the expression of their signature proteins cleaved Caspase-3, Bax and Bcl-2 were detected using Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Western blot assays, respectively. Crystal deposition and histological tissue injury were assessed through Von Kossa staining. RESULTS: Compared with the control group, the stone model group showed higher kidney/body weight ratio; evidently higher expression of autophagy-ERS response- and apoptosis-related proteins LC3B, BECN1, GRP78, CHOP, Bax and cleaved Caspase-3; and lower levels of p62, bcl-2 protein, and SOD. The stone model group also showed higher levels of apoptosis, serum CRE, BUN, NGAL, and Kim-1, as well as considerably greater crystal deposition and renal injury, than the control group. Atorvastatin reduced the levels of autophagy-ERS response, kidney injury, and crystal deposition, but they were increased by DETC. CONCLUSION: Enhanced SOD activity can protect the kidneys by reducing autophagy-ERS response and CaOx kidney stone formation. Atorvastatin may be a new option for the prevention and treatment of nephrolithiasis.

13.
Parasitol Res ; 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31760499

RESUMO

The wide application of pyrethroids has led to the rapid development of insecticide resistance in mosquitoes, leading to a rise in mosquito-borne diseases. We previously identified five differentially expressed lipase family genes upon evaluating the transcriptomes of deltamethrin-resistant and deltamethrin-susceptible strains of Culex pipiens pallens. Herein, the gene expression levels were verified by quantitative real-time PCR, and two lipase family genes, lipase A and pancreatic triacylglycerol lipase A, were chosen for further investigations. Using cell viability assays and Centers for Disease Control and Prevention bottle bioassays, lipase A was found to increase the resistance of mosquitoes against deltamethrin both in vitro and in vivo. Our findings indicate that lipase A is involved in conferring deltamethrin resistance in Cx. pipiens pallens.

14.
Int J Pharm ; : 118829, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31715348

RESUMO

Current work investigates a typical issue in formulating a physically stable solution especially when more than one counter ions exist in the composition. The impact of different counter ions on solubilization of monohydrate esylate salt of a free base GSK-497,[BH+:C2H5SO3-:H2O] (1:1) (pKa value 8.0) was investigated to formulate ready to use small volume injectable solution. The concentration dependent aggregation was also appeared to be responsible for hemolytic nature of the drug, therefore a careful investigation was needed to select appropriate counter ion solution without compromising solubilization and leading into higher order aggregation. The esylate salt's native pH in water was closer to pHmax, thus it was risky to render the solution unbuffered. Generally, it is recommended to formulate at least two pH unit away from pHmax to prevent disproportionation related physical instability. This was achieved by buffering solution away from pHmax, using a lactate counter ion (other than esylate salt of API salt) that did not compromise solubility of the given phase and did not appear to promote higher order of aggregation. The rationale for selecting second counter ion was primarily based on the comparison of esylate salt's solubility product (Ksp), with the Ksp value generated from equilibrium solubility of the free base combined with several different counter ions (chloride, lactate, aspartate, citrate and tartrate) at equimolar molar ratio. This approach suggested that the use of a counter ion with higher Ksp (lactate and aspartate) value did not compromise the solubility of original esylate salt but a higher extent of aggregation was possible if aspartate is used to achieve higher solubility. In contrary, use of a counter ion with lower Ksp (citrate, tartrate, chloride) reduced the solubility hence did not favor higher order of aggregation. Thus, based on Ksp comparison a rationale of selecting second counter ion to buffer the salt solution is discussed in this work and optimal formulation concentration is determined based on drug aggregation threshold in solution.

15.
Biofactors ; 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31758846

RESUMO

Neuroblastoma (NB) is a serious disease with high-risk and poor prognosis in children. Survivors often have serious side effects. Angelica polysaccharide (AP) has been proved to exert antitumor function. Therefore, we explored the mechanism of this function in NB to accelerate the clinical application of AP in NB therapy. SH-SY5Y cells were transfected with miR-205 inhibitor and pretreated by AP. Cell activity, colonies number, and apoptosis were detected via Cell Counting Kit-8 assay, colony formation experiment, and flow cytometry, respectively. Targeting link between miR-205 and zinc finger E-box binding homeobox 1 (ZEB1) was measured via luciferase activity assay. Quantitative reverse transcription polymerase chain reaction and western blot was to examine levels of miR-205 and related factors. We found that AP suppressed cell activity and colony formation, whereas induced apoptosis in SH-SY5Y cells. Besides, AP also suppressed Epithelial-mesenchymal transition process and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) and extracellular signal-regulated kinase (ERK1/2) signal passageways. Additionally, miR-205 was positively regulated by AP. AP played its antitumor functions through up-regulating miR-205. Target of miR-205 was ZEB1. Our study demonstrated that AP played its antitumor role in NB through positively regulation of miR-205, whose target gene was ZEB1.

16.
Zootaxa ; 4614(2): zootaxa.4614.2.7, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31716383

RESUMO

Two new species of the family Xyalidae from the Laizhou Bay of the Bohai Sea, China are described and illustrated herein. Daptonema papillifera sp. nov. is characterized by relatively small body size, L-shaped spicules with a large cephalate proximal end, triangular gubernaculum with a dorsal apophysis, 5-6 conjoint precloacal cuticularized spines and two ventral papillae located at the middle of the tail. Daptonema papillifera sp. nov. is easily distinguished from the other species in this genus by having 5-6 conjoint precloacal cuticularized spines and two ventral caudal papillae. Pseudosteineria anteramphida sp. nov. is characterized by eight groups of long subcephalic setae located posterior to amphideal fovea, curved slender spicules with cephalate proximal end and tapered distal end, tubular gubernaculum without apophysis, precloacal supplements absent, and a short precloacal seta present. In comparison with its most similar congeneric species, P. ventropapillata Tchesunov, 2000 the new species differs in having smaller body, not jointed cephalic setae, absence of precloacal supplements and absence of gubernacular apophysis.


Assuntos
Nematoides , Animais , Baías , Tamanho Corporal , China , Cromadoria
17.
Invest Ophthalmol Vis Sci ; 60(14): 4748-4758, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31731295

RESUMO

Purpose: Lens fibrosis involves aberrant growth, migration, and transforming growth factorß (TGFß)-induced epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs). In this study, we investigated the role of the bromo- and extra-terminal domain (BET) inhibitor in lens fibrotic disorder to identify drug-based therapies. Methods: Rat lens explants, rabbit primary lens epithelial cells (rLECs), human lens explants and human SRA01/04 cells were treated with TGFß2 in the presence or absence of the BET bromodomain inhibitor JQ1 or the MYC inhibitor 10058-F4. Proliferation was determined by MTS assay. Cell migration was measured by wound healing and transwell assays. The expression levels of fibronectin (FN), α-smooth muscle actin (α-SMA), E-cadherin, and phosphorylated downstream Smads were analyzed by Western blot, qRT-PCR, and immunocytochemical experiments. Transcriptome analysis was conducted to explore the molecular mechanism. Results: Blockage of BET bromodomains with JQ1 significantly suppressed rLECs proliferation by inducing G1 cell cycle arrest. Furthermore, JQ1 attenuated TGFß2-dependent upregulation of mesenchymal gene expression and phosphorylation of Smad2/3 during the progression of EMT, whereas E-cadherin expression was preserved. JQ1 repressed MYC expression, which was dose- and time-dependently upregulated by TGFß2. Inhibiting MYC with either the small-molecule inhibitor 10058-F4 or genetic knockdown phenocopied the effects of JQ1 treatment. MYC overexpression partially reversed the JQ1-regulated EMT-related alteration of gene expression. Both JQ1 and 10058-F4 blocked the expression of TGFß receptor II and integrin αv in rLECs and abolished TGFß2-induced opacification and subcapsular plaque formation in rat lens explants. Conclusions: Our results demonstrate the antifibrotic role of JQ1 in maintaining the epithelial characteristics of LECs and blocking TGFß2-induced EMT, possibly by downregulating MYC, thereby providing new avenues for treating lens fibrosis.

18.
Toxicol Lett ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31733319

RESUMO

Information on the effects of gibberellic acid (gibberellin A3, GA3) on ovarian follicle development is limited. In our present study, 21-day-old female Wistar rats were exposed to GA3 by gavage (25, 50, and 100 mg/kg body weight, once per day) for eight weeks to evaluate the influence of GA3 on ovarian follicle development. After treatment, significant (P < 0.05) increases (to 40.17% and 44.5%, respectively) in atretic follicle proportions and significant decreases (to 19.49% and 17.86%, respectively) in corpus luteum proportions were observed in the 50 and 100 mg/kg treatment groups compared to the control group. Significant (P < 0.05) increases (to 31.3% and 42.0%, respectively) in follicle apoptosis were observed in the 50 and 100 mg/kg treatment groups by transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. Significantly increased expression of caspase-3, caspase-8, caspase-9 and Fas was observed by real-time PCR and Western blotting. Bisulfite sequencing PCR (BSP) revealed obviously decreased total methylation percentages of the caspase-3 promoter region in the two treatment groups. Real-time quantitative PCR also showed significantly decreased mRNA expression of DNA methyltransferase (Dnmt) 3a and Dnmt3b. Further in vitro studies showed that a DNA methylation inhibitor could enhance the GA3-induced increase in the mRNA expression of caspase-3. Overall, our present study indicates that GA3 administration from weaning until sexual maturity can affect ovarian follicle development by inducing apoptosis and suggests that signaling through the Fas-mediated apoptotic pathway may be an important underlying mechanism of this apoptosis. In addition, GA3-induced aberrant DNA methylation patterns might be partly responsible for upregulation of caspase-3 gene expression.

19.
Artigo em Inglês | MEDLINE | ID: mdl-31717466

RESUMO

In order to restore degraded grasslands, the Chinese central government initiated the Prohibited Grazing Policy (PGP) in areas of severe grassland degradation and ecologically fragile regions which is an important payment for ecosystem services (PES) program. Since the initiation of this policy in the early 2000s, the PGP has significantly influenced participants' lives. Therefore, in order for the policy to be successful, it is necessary to understand what determines participants' satisfaction in the policy. This paper presents an analysis of survey data from Yanchi County using ordered probit regression models to explore the factors influencing PGP satisfaction and life satisfaction. The empirical results suggest that farmers' policy perception, environmental perception, and livelihood strategies of raising sheep had significant effects on PGP satisfaction. Additionally, PGP satisfaction, marital status, environmental satisfaction, self-reported influence of the PGP on income, self-reported income level, and self-reported income and expenditure had significantly positive effects on overall life satisfaction. These results are important for promoting better implementation of such programs as well as enhancing social stability and sustainable development in these regions.

20.
J Dairy Sci ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31733844

RESUMO

This study investigated the antimicrobial susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) isolated from cases of subclinical bovine mastitis in China, as well as resistance mechanisms and virulence genes encoding adhesins and toxins. We determined antimicrobial susceptibility using the disk diffusion method, and analyzed resistance, adhesin, and toxin genes using PCR. We confirmed MRSA in 73 of 498 (14.7%) Staph. aureus isolates recovered from subclinical mastitic milk samples. All isolates were positive for mecA. The MRSA isolates showed high resistance to penicillin (100.0%), gentamicin (100.0%), and tetracycline (98.6%). All MRSA isolates harbored resistance genes blaZ (penicillin), aacA/aphD (gentamicin), and tetM (alone or in combination with tetK, tetracycline). Moreover, all isolates carried the adhesin genes fnbpA, clfA, clfB, cna, sdrE, and map/eap, and most carried sdrC (98.6%), sdrD (95.9%), bbp (94.5%), and ebpS (80.8%). The toxin genes seh, hla, and hld were present in all isolates, and most isolates carried sea (71.2%), seg (84.9%), sei (82.2%), lukE-lukD (97.3%), and hlg (72.6%). These findings of high-level resistance to antimicrobials commonly used in dairy cattle should lead to calls for antibiogram analysis before antimicrobial therapy. The high frequency of adhesin and toxin genes in MRSA indicates their potential virulence in bovine mastitis in China.

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