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1.
J Phys Chem Lett ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31904982

RESUMO

Insertion of organic spacers into halide perovskite slabs have offered a trade-off between efficiency and stability of perovskite solar cells (PSCs). The layered structure of diammonium-intercalated cesium lead halide perovskites is virtually unexplored, in contrast to several works on monoammonium system. In this report, we find that perovskite with 1,4-butanediammonium (BDA) and cesium cations can only form n = 1 and n = 2 layered isologues defined by the chemical formula of (BDA)Csn-1Pbn(I0.7Br0.3)3n+1, while the n = 3 ~ 4 ones will self-constructed into unique heterostructures comprising separated quantum wells (QWs, n = 1 ~ 2) and 3D (n = ∞) perovskites. We highlight that the 2D/3D heterostructures show structural resemblance to that of bulk-heterojunction in organics, thus improve the charge separation and transport more than surface passivation. Solar cells based on (BDA)Cs3Pb4I9.1Br3.9 (n = 4) absorbing layer delivered a power conversion efficiency (PCE) reaching 9.49% with ideal light and thermal stability.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31907645

RESUMO

PURPOSE: This is the first study to compare the pharmacokinetics of QL1101, a proposed bevacizumab biosimilar, with Avastin® sourced from Roche Diagnostics GmbH. METHODS: In this double-blind, single-dose, parallel-group study, healthy male subjects were randomized 1:1 to receive QL1101 or Avastin® 3 mg/kg intravenously. Pharmacokinetic assessments were conducted for 85 days, with additional safety and immunogenicity assessments until day 90. Primary study endpoints were area under the concentration-time curve (AUC) from time zero to infinity (AUC0-∞), AUC from time zero to the last quantifiable concentration (AUC0-last), and maximum serum concentration (Cmax). Pharmacokinetic equivalence was shown if the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of the C0-max, AUC0-last, and AUC0-∞ were within the predefined bioequivalence margin of 80-125.00%. RESULTS: A total of 82 subjects were randomized to the following groups: 42 to QL1101 and 40 to Avastin®. The 90% CIs of the GMRs of AUC0-∞, AUC0-last, and Cmax of QL1101 and Avastin® were (97.8%, 107.0%), (94.5%, 106.9%), and (94.1%, 107.3%), respectively, which were all within the bioequivalence margin. The incidence of adverse events was 90.5% and 95.0% in the QL1101 and Avastin® groups, respectively. Mean serum concentration-time profiles, secondary pharmacokinetic parameters, and safety and immunogenicity profiles were comparable across the two treatment groups. CONCLUSIONS: The study demonstrated the pharmacokinetic equivalence of QL1101 to Avastin®. QL1101 (3 mg/kg, iv) is safe and tolerable in healthy Chinese subjects. These data support the further clinical evaluation of QL1101 as a bevacizumab biosimilar.

3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(12): 1226-1229, 2019 Dec 10.
Artigo em Chinês | MEDLINE | ID: mdl-31813154

RESUMO

OBJECTIVE: To explore the serological and genotypic characteristics of a pedigree with B(A).06 subtype. METHODS: Serological methods was used to identify the ABO phenotypes. Exons 6 and 7 of the ABO gene and flanking regions were subjected to direct sequencing and TA clonal sequencing in order to determine the genotype of individuals with inconsistent results for forward and reverse serological typing. RESULTS: Among 12 individuals from 4 generations, 5 were identified with a AwB phenotype, along with a c.803C>G mutation in exon 7 of the B allele, which was named as B(A).06. The B(A).06/O.01.01 phenotype may be easily missed due to its weak anti-A antibody in the serum upon initial serological test. CONCLUSION: A B(A).06 subtype family was identified. The serological phenotype of individuals carrying the B(A).06 allele may be affected by the opposite DNA strand.

4.
Org Lett ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31794234

RESUMO

Regioselectivity-switchable reactions hold irreplaceable importance in the construction of diversified architectures. In this work, Brønsted base-catalyzed regioselectivity-switchable annulations between alkynyl α-diketones and α-cyanoketones have been achieved for the first time, delivering a series of skeletally thoroughly different dihydrofurofuran and furan derivatives. A range of novel transformations of the products can be realized. The work also demonstrates the unique features of alkynyl α-diketone chemistry, which are in sharp contrast to the current understanding of ynone-related chemistry.

5.
Value Health ; 22(12): 1402-1409, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31806197

RESUMO

OBJECTIVES: To develop a practical solution for modeling diabetes progression and account for the variations in risks of diabetes complications in different regions of the world, which is critical for model-based evaluations on the value of diabetes intervention across populations from different regions globally. METHODS: A literature search was conducted to identify eligible clinical trials to support calibration. The Building, Relating, Assessing, and Validating Outcomes (BRAVO) model was employed to simulate diabetes complications using the baseline characteristics of each clinical trial cohort. We utilized regression methods to estimate regional variations across the United States, Europe, Asia, and other regions (eg, Latin America, Africa) in 6 outcomes: myocardial infarction (MI), congestive heart failure (CHF), stroke, angina, revascularization, and mortality. RESULTS: Regional variations were detected in 4 outcomes. Compared with other regions, individuals from the United States had higher risks of MI (hazard ratio [HR] 1.64; 95% confidence interval [CI]1.41-1.91) and revascularization (HR 3.6; 95% CI 2.94-4.41). Individuals from Europe had a lower risk of stroke (HR 0.61; 95% CI 0.46-0.81), and individuals from other regions outside of the United States, Europe, and Asia had a lower risk of CHF (HR 0.18; 95% CI 0.06-0.58). Finally, the simulated outcomes were regressed on observed outcomes using an ordinary least squares model, with an intercept (0.026), slope (1.005), and R-squared value (0.789) indicating good prediction accuracy. CONCLUSION: Recalibrating the BRAVO model's diabetes risk engine to account for regional differences shows improved prediction accuracy when the model is applied to multi-region populations commonly recruited for clinical trials.

6.
Front Chem ; 7: 770, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824916

RESUMO

Nanocarriers with responsibility and surface functionality of targeting molecules have been widely used to improve therapeutic efficiency. Hence, we report the assembly of pH-responsive and targeted polymer nanoparticles (NPs) composed of poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) as the core and poly(carboxybetaine methacrylate) (PCBMA) as the shell, functionalized with cyclic peptides containing Arginine-Glycine-Aspartic acid-D-Phenylalanine-Lysine (RGD). The resulting polymer NPs (PDPA@PCBMA-RGD NPs) can maintain the pH-responsivity of PDPA (pKa ~6.5) and low-fouling property of PCBMA that significantly resist non-specific interactions with RAW 264.7 and HeLa cells. Meanwhile, PDPA@PCBMA-RGD NPs could specifically target αvß3 integrin-expressed human glioblastoma (U87) cells. The pH-responsiveness and low-fouling properties of PDPA@PCBMA NPs are comparable to PDPA@poly(ethylene glycol) (PDPA@PEG) NPs, which indicates that PCBMA is an alternative to PEG for low-fouling coatings. The advantage of PDPA@PCBMA NPs lies in the presence of carboxyl groups on their surfaces for further modification (e.g., RGD functionalization for cell targeting). The reported polymer NPs represent a new carrier that have the potential for targeted therapeutic delivery.

7.
Drug Des Devel Ther ; 13: 4135-4144, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827320

RESUMO

Purpose: To assess the pharmacokinetics and safety of pure S-ketamine (esketamine) in Chinese patients undergoing painless gastroscopy and evaluate the potential advantage of esketamine in clinical treatment compared with racemate ketamine hydrochloride injection. Patients and methods: A randomized, open-label, parallel-controlled, Phase I study was performed with 32 patients undergoing painless gastroscopy. Patients received a single dose of esketamine (0.5 mg/kg) or racemic ketamine (1 mg/kg, esketamine:R-ketamine=1:1), injected in 10 s. Blood samples were collected for pharmacokinetic analysis. The concentrations of esketamine, R-ketamine, S-norketamine, and R-norketamine were measured with a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Results: After administering a single dose of esketamine and racemate ketamine, the pharmacokinetics parameters of esketamine and S-norketamine are both similar in treatment groups. The clearance of esketamine in two groups was 18.1±3.2 and 18.4±3.4 mL/min•kg, respectively. However, in the ketamine group, esketamine has a larger clearance than R-ketamine (18.4±3.4 mL/min·kg vs 15.8±3.1 mL/min·kg, P<0.001). Further analysis showed that gender did not affect the pharmacokinetics of esketamine and racemate ketamine. Regarding the safety of esketamine and racemate ketamine, no serious adverse events were observed during treatment, and the incidences of adverse events were 75.0% (esketamine) and 87.5% (racemate ketamine). The main adverse reactions were dizziness, agitation, nausea, vomiting, headache, and fatigue. However, compared with racemic ketamine, esketamine offers a shorter recovery time (9 mins vs. 13 mins, P<0.05) and orientation recovery time (11.5 mins vs. 17 mins, P<0.05) after short anesthesia. Conclusion: Esketamine administration as a single dose of 0.5 mg/kg was generally safe and tolerated in patients undergoing painless gastroscopy. In terms of anesthesia, a relatively small dose of esketamine can be used instead of racemate ketamine for routine treatment without consideration of gender differences.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31858916

RESUMO

BACKGROUND: Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia that is characterized by hyperinsulinemia, hypoglycemia, and a high autoantibody titer. About 50% of patients with IAS have taken a medication containing sulfhydryl (-SH) groups. We present a case of IAS that developed after taking clopidogrel, a drug with an active metabolite that contains an SH-group. CASE REPORT: IAS was suspected in a 63-year-old Chinese man because of high concentrations of insulin and C-peptide during hypoglycemic episodes, and positivity for anti-insulin autoantibody (IAA). During his first episode of hypoglycemia, no trigger medication was identified and prednisone therapy was effective. However, imaging examination revealed a colonic carcinoma and the patient was discharged to undergo surgery. He had no episodes of hypoglycemia for 10 weeks after discontinuation of the prednisone, but then hypoglycemia recurred. Review of his medication revealed that he had taken a 10-day course of clopidogrel just before the recurrence. Therefore, a specialized multidisciplinary team consisting of endocrinologists, dieticians, and clinical pharmacists took charge of his management. Prednisone therapy was restarted and tapered off over 16 weeks. The patient also consumed small, frequent, low-carbohydrate meals and was instructed to avoid trigger medications. No further episodes of hypoglycemia were detected. His insulin and C-peptide concentrations and his anti-IAA index normalized during the follow-up period. CONCLUSION: SH-group-containing drugs might induce or exacerbate hypoglycemia in patients with a history of IAS. Furthermore, patients with IAS can benefit from multidisciplinary team management. We suggest herein an evaluation process for patients suspected of IAS.

9.
Mar Drugs ; 18(1)2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31861309

RESUMO

Holothurian glycosaminoglycan isolated from Apostichopus japonicus (named AHG) can suppress hepatic glucose production in insulin resistant hepatocytes, but its effects on glucose metabolism in vivo are unknown. The present study was conducted to investigate the effects of AHG on hyperglycemia in the liver of insulin resistant mice induced by a high-fat diet (HFD) for 12 weeks. The results demonstrated that AHG supplementation apparently reduced body weight, blood glucose level, and serum insulin content in a dose-dependent manner in HFD-fed mice. The protein levels and gene expression of gluconeogenesis rate-limiting enzymes G6Pase and PEPCK were remarkedly suppressed in the insulin resistant liver. In addition, although the total expression of IRS1, Akt, and AMPK in the insulin resistant liver was not affected by AHG supplementation, the phosphorylation of IRS1, Akt, and AMPK were clearly elevated by AHG treatment. These results suggest that AHG could be a promising natural marine product for the development of an antihyperglycemic agent.

10.
Oncogenesis ; 8(12): 75, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31857572

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

11.
Chin Med ; 14: 49, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31719838

RESUMO

Background: Lycium barbarum (wolfberry) has been widely cultivated in China, particularly in northwest regions. However, the fruit size and taste of L. barbarum from different habitats are quite different. Traditionally, only the fruit of L. barbarum produced in Ningxia province is recorded as an authentic herb, although the detailed mechanism responsible for this remains obscure. Polysaccharides are considered major active ingredients in L. barbarum which is crucial for its quality evaluation. Methods: In this study, we assessed the yield, monosaccharide composition, molecular weight, and conformation of L. barbarum polysaccharides (LBPs) collected from different regions of China. The antioxidant and immune activities of LBPs were also determined as its quality indicator. Results: Our results showed that the similarity values of monosaccharide composition were larger than 0.926, and the Mw of the two fractions (peaks 1-2) in LBPs were ranging from 1.36 × 106 to 2.01 × 106 (peak 1), and 6.85 × 104 to 10.30 × 104 (peak 2) which indicated that the structure of LBPs were similar. In addition, results showed that there was no significant difference in antioxidant and immune activities of nine LBPs from different regions. However, the yield of LBPs from Qinghai Province (low atmospheric temperature, high altitude) was significantly lower (p < 0.05) than those collected from Xinjiang and Ningxia province. Conclusions: These data suggested that the L. barbarum produced in Ningxia and Xinjiang maybe more suitable as materials for medicines and functional foods. This study also provides a reference for improving the quality control standard of LBPs.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31781028

RESUMO

Recent studies showed that in patients with type 2 diabetes mellitus (T2DM), Sodium-dependent glucose transporters 2 inhibitor (SGLT2I) may cause potential adverse effects on the skeleton such as increasing the risk of fracture. This risk is possibly mediated by effects induced by all SGLT2I class drugs, but whether Dapagliflozin aggravates osteoporosis in patients with T2DM remains controversial. Therefore, we designed this study to explore how Dapagliflozin affects the metabolism and the quality of bone in T2DM animal models. The effect of Dapagliflozin on the skeleton was evaluated on male ZDF (Zucker Diabetic Fatty) rats-a rat model of diet induced spontaneous T2DM. Dapagliflozin was administrated via gavage at the dosage of 10 mg/kg/day. Bone tissue mineral density and the microarchitecture of tibiae were measured with micro-CT and biomechanics characteristic of the femora were tested using a three-point bending test. Serum bone biomarkers and other metabolic parameters were also tested via ELISA or other assays. Our results found that diabetic rats demonstrated symptoms of osteoporosis and Dapagliflozin could help to alleviate these defections caused by diabetes. Compared to the negative controls, the serum CT (calcitonin) level in ZDF rats as well as the uric calcium and phosphate levels were elevated, and these symptoms were alleviated by Dapagliflozin. Tibiae of Dapagliflozin treated rats demonstrated decreased cortical tissue mineral density while trabecular tissue mineral density and mean bone mineral density received a rise when compared to the matched controls. ZDF rats also showed defections in femora stiffness which could be relieved by Dapagliflozin administration. The mechanism of Dapagliflozin affecting bone quality is possibly connected to the suppression of serum calcitonin and excretion of calcium via urine rose by hyperglycemia. In conclusion, Dapagliflozin can prevent osteoporosis in ZDF rats by alleviating hypercalciuria.

13.
Front Genet ; 10: 1098, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737059

RESUMO

Monocyte chemoattractant protein 1 (MCP1) affects the chemotaxis of monocytes and is a key chemokine closely related to the development of atherosclerosis (AS). Compared with healthy controls, coronary heart disease (CAD) patients show significantly upregulated plasma concentrations and mRNA expression of MCP1 in CD14+ monocytes. However, the specific regulatory mechanism of MCP1 overexpression in AS is still unclear. Our previous research indicated that there was no significant difference in the H3K4 and H3K27 tri-methylation of the MCP1 promoter in CD14+ monocytes from CAD versus non-CAD patients, but the H3 and H4 acetylation of the MCP1 promoter was increased in CD14+ monocytes from CAD patients. We further found that the H3K9 tri-methylation of the MCP1 promoter in CD14+ monocytes from CAD patients was decreased, but the DNA methylation levels did not differ markedly from those in non-CAD patients. Our previous work showed that the level of regulatory factor X1 (RFX1) was markedly reduced in CD14+ monocytes from CAD patients and played an important role in the progression of AS by regulating epigenetic modification. In this study, we investigated whether RFX1 and epigenetic modifications mediated by RFX1 contribute to the overexpression of MCP1 in activated monocytes in CAD patients. We found that the enrichment of RFX1, histone deacetylase 1 (HDAC1), and suppressor of variegation 3-9 homolog 1 (SUV39H1) in the MCP1 gene promoter region were decreased in CD14+ monocytes from CAD patients and in healthy CD14+ monocytes treated with low-density lipoprotein (LDL). Chromatin immunoprecipitation (ChIP) assays identified MCP1 as a target gene of RFX1. Overexpression of RFX1 increased the recruitments of HDAC1 and SUV39H1 and inhibited the expression of MCP1 in CD14+ monocytes. In contrast, knockdown of RFX1 in CD14+ monocytes reduced the recruitments of HDAC1 and SUV39H1 in the MCP1 promoter region, thereby facilitating H3 and H4 acetylation and H3K9 tri-methylation in this region. In conclusion, our results indicated that RFX1 expression deficiency in CD14+ monocytes from CAD patients contributed to MCP1 overexpression via a deficiency of recruitments of HDAC1 and SUV39H1 in the MCP1 promoter, which highlighted the vital role of RFX1 in the pathogenesis of CAD.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31697199

RESUMO

Background: The reported rate of surgical site infection (SSI) in breast surgery is often higher than expected. Using antibiotic prophylaxis to reduce SSI is debatable because of the risk of developing bacteria resistance and the cost burden. In this study, we evaluated the effectiveness of antibiotic prophylaxis in breast surgery and the factors predisposing patients to SSI. Methods: A retrospective-prospective (ambispective) study was conducted in the Department of Breast Surgery, Qilu Hospital, P.R. China. The retrospective antibiotic-using group was composed of patients found to have breast cancer between January 2008 and October 2010. The prospective non-antibiotic-using group was composed of patients identified between November 2010 and November 2013. Pre-operative, peri-operative, and post-operative clinical data were analyzed. Results: The SSI rate of the non-prophylaxis and prophylaxis groups was 1.1% (11/1,022) and 1.2% (12/1,034), respectively. Neoadjuvant chemotherapy was related to SSI in the non-prophylaxis group (p = 0.026). Staphylococcus aureus was the predominant microorganism responsible for SSI, without obvious resistance to a widely used first-generation cephalosporin. Conclusions: Peri-operative antibiotic prophylaxis is of no significant value in preventing SSI in breast cancer surgery. Our results indicated that neoadjuvant chemotherapy might be a risk factor doe SSI, but further research is needed because of the sample size disparity between infected and uninfected groups.

15.
Front Pharmacol ; 10: 1231, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31708774

RESUMO

Background and Objective: Inhibition of thrombosis and platelet aggregation through a thromboxane synthetase inhibitor proved to be an effective and promising treatment for cardiovascular and/or cerebrovascular disease (CCVD) patients. This phase I study evaluated the safety, tolerability, and pharmacokinetics of sodium pyragrel, a novel thromboxane A2 synthetase inhibitor, in healthy volunteers. Methods: A total of 84 healthy Chinese volunteers were enrolled in the study and randomized into one of five dosing regimens of intravenous pyragrel, which were single ascending dose (30 to 300 mg), multiple doses (pyragrel 180 mg once daily on Day 1 and Day 6, twice daily from Day 2 to Day 5), 3×3 Latin square crossover (60, 120, 240 mg), and a continuous dose (360 mg in 24 h), respectively. Plasma concentrations were determined using HPLC-MS/MS. Pharmacokinetics parameters were calculated with non-compartment analysis. Results: The maximum plasma concentrations of pyragrel were essentially reached at the end of the 3 h infusion. The pharmacokinetic process of pyragrel and two main metabolites (BBS and BJS) is linear over the 30-300 mg dose range, with no significant accumulation on multiple doses. The urinary excretion of pyragrel accounted for more than 70% of the total drug amount. Preliminary pharmacodynamic results demonstrated that the production of urinary 11-D-HTXB2 was time- and dose-dependently inhibited by single i.v. dose of pyragrel. Conclusions: Pyragrel was well tolerated after single ascending doses up to 300 mg, multiple doses of 180 mg, and continuous administration of 360 mg within 24 h. No drug-related, serious adverse drug reactions occurred during the five-part study. The most common pyragrel-related adverse events (AEs) were total bilirubin (TB)/direct bilirubin (DB) elevations with a relatively low incidence rate and seemed to be dose independent. Given the acceptable safety and appropriate pharmacokinetic properties of sodium pyragrel proven in this study, continued clinical development is warranted. The study was registered at http://www.chictr.org.cn (ChiCTR-IID-16010159).

16.
Front Genet ; 10: 988, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31708963

RESUMO

Follicle development is characterized by the recruitment, growth, selection, and dominance of follicles, and follicle selection determines the lifetime reproductive performance. However, in birds, the molecular mechanisms underlying follicle selection still remain elusive. This study analyzed genome-wide changes in the mRNA and miRNA expression profiles in both the granulosa and theca layers of geese ovarian follicles before selection (4-6- and 8-10-mm follicles) and after selection (F5). The sequencing results showed that a higher number of both differentially expressed (DE) mRNAs and DE miRNAs were identified between 8-10-mm and F5 follicles compared with those between the 4-6- and 8-10-mm follicles, especially in the granulosa layer. Moreover, a Short Time-series Expression Miner analysis identified a large number of DE mRNAs and DE miRNAs that are associated with follicle selection. The functional enrichment analysis showed that DE genes in the granulosa layer during follicle selection were mainly enriched in five pathways related to junctional adhesion and two pathways associated with lipid metabolism. Additionally, an interaction network was constructed to visualize interactions among protein-coding genes, which identified 53 junctional adhesion- and 15 lipid regulation-related protein-coding genes. Then, a co-expression network between mRNAs and miRNAs in relation to junctional adhesion was also visualized and mainly included acy-miR-2954, acy-miR-218, acy-miR-2970, acy-miR-100, acy-miR-1329, acy-miR-199, acy-miR-425, acy-miR-181, and acy-miR-147. Furthermore, miRNA-mRNA interaction pairs related to lipid regulation were constructed including acy-miR-107, acy-miR-138, acy-miR-130, acy-miR-128, and acy-miR-101 during follicular selection. In summary, these data highlight the key roles of junctional adhesion and lipid metabolism during follicular selection and contribute to a better understanding of the mechanisms underlying follicle selection in birds.

17.
Food Funct ; 10(11): 7565-7575, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31687719

RESUMO

The aim of this study was to elucidate the effect and the underlying mechanism of glycosaminoglycan from Apostichopus japonicus (AHG) on hepatic glucose production (HGP) in insulin resistant hepatocytes. Insulin resistance was induced with high glucose (HG) for 24 h in primary hepatocytes. The results showed that AHG exhibited hypoglycemic activity at a relatively low concentration (1 µg mL-1) and revealed non-toxic activity to insulin resistant hepatocytes even at 500 µg mL-1 concentration. The HGP test showed that the treatment of AHG (10 µg mL-1) for 3 h decreased HGP by 25% in insulin resistant hepatocytes. Quantitative PCR and western blot analysis revealed that AHG also ameliorated phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). The data revealed the mechanism of AHG in alleviating HGP via activating the Akt/FoxO1 signaling pathway and suppressing the PKA/CREB signaling pathway in insulin resistant hepatocytes. This finding suggests that AHG could be a potential marine natural product for the treatment of dysregulating glucose homeostasis.

18.
Artigo em Inglês | MEDLINE | ID: mdl-31724530

RESUMO

PURPOSE: (R,R)-penehyclidine fumarate (R2PHF) is a highly selective muscarinic receptor antagonist used to suppress glandular secretions before general anesthesia or tracheal intubation and to treat organophosphorus poisoning. This is the first-in-human study to evaluate the safety, tolerability, and pharmacokinetics of R2PHF in healthy subjects. MATERIALS AND METHODS: In this single-center, double-blind, randomized study, 23 subjects received escalation doses of R2PHF (0.0625 mg, 0.25 mg, 0.50 mg, and 1.0 mg), 4 received the parent drug penehyclidine hydrochloride (PHC, 1.0 mg) as a reference, and 4 received a placebo. The pharmacokinetic parameters of R2PHF were determined. Tolerability was assessed based on adverse events and clinical laboratory tests. RESULTS: Single doses of 0.0625 mg, 0.25 mg, and 0.50 mg R2PHF were well-tolerated by healthy subjects. Delirium was set as the termination outcome and appeared in 1 case receiving 1.0 mg. For this reason, the escalation experiment was cut off. The mean half-life (T1/2) ranged from 30.57 to 32.27 hours. CONCLUSION: R2PHF was safe and well-tolerated at doses ranging from 0.0625 to 0.50 mg. A single administration of 0.50 mg was determined to be the maximum tolerated dose of R2PHF. Further pharmacodynamics, safety, and efficacy testing is required to advance R2PHF to the next stage of clinical development and application.
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19.
Animals (Basel) ; 9(10)2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31623192

RESUMO

Anti-Müllerian hormone (AMH) is recognized as a reliable marker of ovarian reserve. However, the regulatory mechanism of goose AMH gene remains poorly understood. In the present study, both the full-length coding sequence (CDS) and promoter sequence of goose AMH have been cloned. Its CDS consisted of 2013 nucleotides encoding 670 amino acids and the amino acid sequence contained two structural domain: AMH-N and transforming growth factor beta (TGF-ß) domain. The obtained promoter sequence spanned from the -2386 bp to its transcription start site (ATG). Core promoter regions and regulatory elements were identified as well as transcription factors were predicted in its promoter sequence. The luciferase activity was the highest spanning from the -331 to -1 bp by constructing deletion promoter reporter vectors. In CHO cells, the luciferase activity significantly increased by co-expression of AMH and GATA binding protein 4 (GATA-4), while that significantly decreased by mutating the binding sites of GATA-4 located in the -778 and -1477 bp. Results from quantitative real-time polymerase chain reaction (qPCR) indicated that levels of AMH mRNA in geese granulosa layers decreased gradually with the increasing follicular diameter. Taken together, it could be concluded that the transcriptional activity of AMH was activated by GATA-4 to inhibit the development of small follicles in goose.

20.
Genes (Basel) ; 10(10)2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31590287

RESUMO

For cancer diagnosis, many DNA methylation markers have been identified. However, few studies have tried to identify DNA methylation markers to diagnose diverse cancer types simultaneously, i.e., pan-cancers. In this study, we tried to identify DNA methylation markers to differentiate cancer samples from the respective normal samples in pan-cancers. We collected whole genome methylation data of 27 cancer types containing 10,140 cancer samples and 3386 normal samples, and divided all samples into five data sets, including one training data set, one validation data set and three test data sets. We applied machine learning to identify DNA methylation markers, and specifically, we constructed diagnostic prediction models by deep learning. We identified two categories of markers: 12 CpG markers and 13 promoter markers. Three of 12 CpG markers and four of 13 promoter markers locate at cancer-related genes. With the CpG markers, our model achieved an average sensitivity and specificity on test data sets as 92.8% and 90.1%, respectively. For promoter markers, the average sensitivity and specificity on test data sets were 89.8% and 81.1%, respectively. Furthermore, in cell-free DNA methylation data of 163 prostate cancer samples, the CpG markers achieved the sensitivity as 100%, and the promoter markers achieved 92%. For both marker types, the specificity of normal whole blood was 100%. To conclude, we identified methylation markers to diagnose pan-cancers, which might be applied to liquid biopsy of cancers.

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