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1.
FASEB J ; 35(5): e21473, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33811703

RESUMO

Pancreatic diseases including diabetes and exocrine insufficiency would benefit from therapies that reverse cellular loss and/or restore cellular mass. The identification of molecular pathways that influence cellular growth is therefore critical for future therapeutic generation. Deoxyhypusine synthase (DHPS) is an enzyme that post-translationally modifies and activates the mRNA translation factor eukaryotic initiation factor 5A (eIF5A). Previous work demonstrated that the inhibition of DHPS impairs zebrafish exocrine pancreas development; however, the link between DHPS, eIF5A, and regulation of pancreatic organogenesis remains unknown. Herein we identified that the conditional deletion of either Dhps or Eif5a in the murine pancreas results in the absence of acinar cells. Because DHPS catalyzes the activation of eIF5A, we evaluated and uncovered a defect in mRNA translation concomitant with defective production of proteins that influence cellular development. Our studies reveal a heretofore unappreciated role for DHPS and eIF5A in the synthesis of proteins required for cellular development and function.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33881294

RESUMO

Electrochromic displays with bistable color states provide a promising means toward transparent human-machine interfaces. However, the need for external power and the weak optical modulation in the visible light region of most electrochromic devices hinder their practical applications in displays. Here we prepare the MoO3-y/WO3-x films based on MoO3-y nanosheets, which show a dark blue color that matches the response of the eye and meets visual comfort standards compared to pure WO3-x film. By introducing the highly transparent Al3+ ion hydrogel layer, a convenient electrochromic device driven by the internal chemical potential has been designed. The device based on the MoO3-y /WO3-x film exhibits a high optical modulation in the whole visible light range and can operate at self-powered mode with fast response speed and excellent cycle stability. Moreover, we develop an ionic writing board based on the MoO3-y/WO3-x film to surmount the fixed display information issue in conventional electrochromic displays. The ionic writing board exhibits excellent visual display quality and realizes arbitrary writing with a self-powered characteristic. This work provides a simple mechanochemical synthesis procedure of MoO3-y nanosheets and an ingenious design of self-powered electrochromic devices, which will enable the development of next-generation high-performance electrochromic displays.

3.
Int J Epidemiol ; 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33748835

RESUMO

BACKGROUND: Epidemiological studies have demonstrated a positive association between chronic lymphocytic leukaemia (CLL) and non-melanoma skin cancer (NMSC). We hypothesized that shared genetic risk factors between CLL and NMSC could contribute to the association observed between these diseases. METHODS: We examined the association between (i) established NMSC susceptibility loci and CLL risk in a meta-analysis including 3100 CLL cases and 7667 controls and (ii) established CLL loci and NMSC risk in a study of 4242 basal cell carcinoma (BCC) cases, 825 squamous cell carcinoma (SCC) cases and 12802 controls. Polygenic risk scores (PRS) for CLL, BCC and SCC were constructed using established loci. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Higher CLL-PRS was associated with increased BCC risk (OR4th-quartile-vs-1st-quartile = 1.13, 95% CI: 1.02-1.24, Ptrend = 0.009), even after removing the shared 6p25.3 locus. No association was observed with BCC-PRS and CLL risk (Ptrend = 0.68). These findings support a contributory role for CLL in BCC risk, but not for BCC in CLL risk. Increased CLL risk was observed with higher SCC-PRS (OR4th-quartile-vs-1st-quartile = 1.22, 95% CI: 1.08-1.38, Ptrend = 1.36 × 10-5), which was driven by shared genetic susceptibility at the 6p25.3 locus. CONCLUSION: These findings highlight the role of pleiotropy regarding the pathogenesis of CLL and NMSC and shows that a single pleiotropic locus, 6p25.3, drives the observed association between genetic susceptibility to SCC and increased CLL risk. The study also provides evidence that genetic susceptibility for CLL increases BCC risk.

4.
Mol Pharm ; 18(4): 1643-1655, 2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33759538

RESUMO

To better promote the application of polymeric mixed micelles (PMMs), a coarse-grained molecular dynamics simulation (CGMD) has been employed to investigate the factors controlling the spatial distribution within the PMMs and predict their drug-loading properties, meanwhile, combined with experimental methods to validate and examine it. In this study, the snapshots obtained from CGMD and the results of proton nuclear magnetic resonance (1H NMR) and transmission electron microscopy (TEM) provide new insights into the distribution principle that the spatial distribution depends on the hydrophobic compatibility of drugs with the regions within PMMs. Docetaxel (DTX) is located within the interior or near the core-corona interface of the HS15 hydrophobic core inside FS/PMMs (PMMs fabricated from a nonionic triblock copolymer (F127)) and a nonionic surfactant (HS15), and therefore, the system with a high HS15 ratio, such as system I, is more suitable for loading DTX. In contrast, the more water-soluble puerarin (PUE) is more likely to be solubilized in the "secondary hydrophobic area," mainly formed by the hydrophobic part of F127 within FS/PMMs. However, when the initial feeding concentration of the drug is increased or the FS mixing ratios are changed, an inappropriate distribution would occur and hence influence the drug-loading stability. Also, this impact was further elucidated by the calculated parameters (solvent-accessible surface area (SASA), the radius of gyration (Rg), and energy landscape), and the analysis of the drug leakage, concluding that inappropriate distribution of the drug would lower the stability of the drug in the PMMs. These results combined together provide new insights into the distribution principle that the spatial distribution of drugs within PMMs depends on the hydrophobic compatibility of drugs with the regions formed by micellar materials. Additionally, in vitro drug release yielded a consistent picture with the above conclusions and provides evidence that both the location of the drug within the systems and the stability of the drug-loading system have a great influence on the drug release behavior. Accordingly, this work demonstrates that we can tune the drug-loading stability and drug release behavior via the drug-PMM interaction and drug location study, and CGMD technology would be a step forward in the search for suitable drug-delivery PMMs.

5.
Zhongguo Zhong Yao Za Zhi ; 46(6): 1311-1331, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33787127

RESUMO

Kudzu plants in the subfamily sphenoideae of Leguminosae are commonly used herbs in China, Japan, Korea, India and Thailand, with a long history of medicinal use. They are recorded in Chinese Pharmacopoeia, Japanese Pharmacopeia, Korea Pharmacopeia, Ayurveda Pharmacopoeia of India and Flora of Thailand. There are 15-20 species of Pueraria in the world, including 7 species and 2 varieties in China. At present, there are 6 species with medicinal value, such as Pueraria lobata and P. thomsonii. The main chemical components of the genus are isoflavones, flavonoids, terpenes, steroids, coumarins, puerarin glycosides and benzopyrans. A total of 240 compounds have been isolated and identified from this genus, and their pharmacological effects mainly include improvement of the cardiovascular system, antioxidant, hypoglycemic, antipyretic, anti-inflammatory, anti-alcoholic and estrogen-like effects. In this study, chemical constituents and pharmacological activities of Pueraria at home and abroad were systematically summarized, in order to provide references for the material basis, quality control and further development of Pueraria genus.


Assuntos
Isoflavonas , Pueraria , China , Isoflavonas/farmacologia , Japão , Raízes de Plantas , República da Coreia , Tailândia
6.
Sci Adv ; 7(11)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33692100

RESUMO

Human eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.

7.
Angew Chem Int Ed Engl ; 60(16): 8889-8895, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33543528

RESUMO

H2 O2 as a well-known efficient oxidant is widely used in the chemical industry mainly because of its homolytic cleavage into . OH (stronger oxidant), but this reaction always competes with O2 generation resulting in H2 O2 waste. Here, we fabricate heterogeneous Fenton-type Fe-based catalysts containing Fe-Nx sites and Fe/Fe3 C nanoparticles as a model to study this competition. Fe-Nx in the low spin state provides the active site for . OH generation. Fe/Fe3 C, in particular Fe3 C, promotes Fe-Nx sites for the homolytic cleavages of H2 O2 into . OH, but Fe/Fe3 C nanoparticles (Fe0 as the main component) with more electrons are prone to the undesired O2 generation. With a catalyst benefiting from finely tuned active sites, 18 % conversion rate for the selective oxidation of methane was achieved with about 96 % selectivity for liquid oxygenates (formic acid selectivity over 90 %). Importantly, O2 generation was suppressed 68 %. This work provides guidance for the efficient utilization of H2 O2 in the chemical industry.

8.
Cell Metab ; 32(6): 1041-1051.e6, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33207244

RESUMO

Diabetes is associated with increased mortality from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Given literature suggesting a potential association between SARS-CoV-2 infection and diabetes induction, we examined pancreatic expression of angiotensin-converting enzyme 2 (ACE2), the key entry factor for SARS-CoV-2 infection. Specifically, we analyzed five public scRNA-seq pancreas datasets and performed fluorescence in situ hybridization, western blotting, and immunolocalization for ACE2 with extensive reagent validation on normal human pancreatic tissues across the lifespan, as well as those from coronavirus disease 2019 (COVID-19) cases. These in silico and ex vivo analyses demonstrated prominent expression of ACE2 in pancreatic ductal epithelium and microvasculature, but we found rare endocrine cell expression at the mRNA level. Pancreata from individuals with COVID-19 demonstrated multiple thrombotic lesions with SARS-CoV-2 nucleocapsid protein expression that was primarily limited to ducts. These results suggest SARS-CoV-2 infection of pancreatic endocrine cells, via ACE2, is an unlikely central pathogenic feature of COVID-19-related diabetes.

9.
ACS Appl Mater Interfaces ; 12(43): 48526-48532, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33047949

RESUMO

Photocatalytic H2 evolution (PHE) from extremely abundant seawater resources is an ideal way to secure sustainable H2 for humanity, but the saline in seawater easily competitively absorbs the active sites and poisons the catalyst. Herein, a series of low-cost alkali halide (NaI, KI, RbI, CsI, CsBr, and CsCl), analogous to the saline in natural seawater, was selected to modify carbon nitride (MX-CN) through one-step facile pyrolysis with the assistance of water. MX-CN possesses a large amount of negative charges, which could inhibit anion absorption, to some extent, preventing chloride corrosion. Importantly, it can greatly boost the electron transfer between MX-CN and triethanolamine (TEOA) (sacrificial agent) because the alkali cation in seawater can coordinate with TEOA, and easily come in contact with MX-CN through alkali-cation exchange and electrostatic attraction. Benefiting from it, the PHE performance in seawater is 200 times better than that of original CN in deionized water above, and the apparent quantum efficiency of MX-CN (CsI-CN) under 420 nm light irradiation comes to 72% in seawater, the highest value reported for seawater thus far. This work provides a new research direction for engineering the electron transfer pathway between the photocatalyst and sacrificial agent (e.g., pollutant) in natural seawater.

10.
J Am Chem Soc ; 142(43): 18460-18470, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33074671

RESUMO

Organic triplet-triplet annihilation upconversion (TTA-UC) materials have considerable promise in areas as broad as biology, solar energy harvesting, and photocatalysis. However, the development of highly efficient near-infrared (NIR) light activatable TTA-UC systems remains extremely challenging. In this work, we report on a method of systematically tailoring an annihilator to attain such outstanding systems. By chemical modifications of a commonly used perylene annihilator, we constructed a family of perylene derivatives that have simultaneously tailored triplet excited state energy (T1) and singlet excited state energy (S1), two key annihilator factors to determine TTA-UC performance. Via this method, we were able to tune the TTA-UC system from an endothermic type to an exothermic one, thus significantly elevating the upconversion performance of NIR light activatable TTA upconversion systems. In conjunction with the photosensitizer PdTNP (10 µM), the upconversion efficiency using the optimal annihilator (100 µM) identified in this study was measured to be 14.1% under the low-power density of NIR light (100 mW/cm2, 720 nm). Furthermore, using such a low concentration of perylene derivative, we demonstrated that the optimal TTA-UC pair developed in our study can act as a highly effective light wavelength up-shifter to enable NIR light to drive a photoredox catalysis that otherwise requires visible light. We found that such an NIR driven method is highly effective and can even surpass directly visible light driven photoredox catalysis. This method is important for photoredox catalysis as NIR light can penetrate much deeper in colored photoredox catalysis reaction solutions, especially when done in a large-scale manner. Furthermore, this TTA-UC mediated photoredox catalysis reaction is found to be outdoor sunlight operable. Thus, our study provides a solution to enhance NIR activatable organic upconversion and set the stage for a wide array of applications that have previously been limited by the suboptimal efficiency of the existing TTA upconversion materials.

11.
Nat Commun ; 11(1): 4882, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985505

RESUMO

T helper cell differentiation requires lineage-defining transcription factors and factors that have shared expression among multiple subsets. BATF is required for development of multiple Th subsets but functions in a lineage-specific manner. BATF is required for IL-9 production in Th9 cells but in contrast to its function as a pioneer factor in Th17 cells, BATF is neither sufficient nor required for accessibility at the Il9 locus. Here we show that STAT5 is the earliest factor binding and remodeling the Il9 locus to allow BATF binding in both mouse and human Th9 cultures. The ability of STAT5 to mediate accessibility for BATF is observed in other Th lineages and allows acquisition of the IL-9-secreting phenotype. STAT5 and BATF convert Th17 cells into cells that mediate IL-9-dependent effects in allergic airway inflammation and anti-tumor immunity. Thus, BATF requires the STAT5 signal to mediate plasticity at the Il9 locus.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Interleucina-9/imunologia , Fator de Transcrição STAT5/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Diferenciação Celular , Feminino , Humanos , Interleucina-9/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT5/genética , Linfócitos T Auxiliares-Indutores/citologia , Células Th17/imunologia
12.
Org Lett ; 22(15): 5861-5865, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32644806

RESUMO

A gold-catalyzed dearomatization reaction of ß-naphthol derivatives via intramolecular hydroalkylation of alkynes is described. In the presence of 5 mol % Au complex, various spironaphthalenones were obtained from α-tethered alkyne ß-naphthols in good to excellent yields (76-99%) under open-flask conditions.

13.
BMC Bioinformatics ; 21(Suppl 7): 152, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32366259

RESUMO

BACKGROUND: Cervical cancer is the fourth most common tumor in women worldwide, mostly resulting from high-risk human papillomavirus (HR-HPV) with persistent infection. RESULTS: The present discoveries are comprised of the following: (i) A total of 16.64% of the individuals were positive for HR-HPV infection, with 13.04% having a single HR-HPV type and 3.60% having multiple HR-HPV types. (ii) Cluster analysis showed that the infection rate trends of HPV31 and HPV33 in all infections as well as HPV33 and HPV35 in single infections in precancerous stages were very similar. (iii) The single/multiple infection proportions of HR-HPV demonstrated a trend that the multiple infections rates of HR-HPV increased as the disease developed. CONCLUSIONS: The HR-HPV prevalence in outpatients was 16.64%, and the predominant HR-HPV types in the study were HPV52, HPV58 and HPV16. HR-HPV subtypes with common biological properties had similar infection rate trends in precancerous stages. Especially, as the disease development of precancer evolved, defense against HPV infection broke, meanwhile, the potential of more HPV infection increased, which resulted in increase of multiple infections of HPV.


Assuntos
Carcinogênese , Modelos Biológicos , Papillomaviridae , Infecções por Papillomavirus/complicações , Neoplasias do Colo do Útero/etiologia , Transformação Celular Viral , Feminino , Humanos , Infecções por Papillomavirus/epidemiologia , Prevalência , Neoplasias do Colo do Útero/patologia
14.
Sci Rep ; 10(1): 8753, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32472001

RESUMO

The OlympiAD Phase III study (NCT02000622) established the clinical benefits of olaparib tablet monotherapy (300 mg twice daily) over chemotherapy treatment of physician's choice (TPC) in patients with a germline BRCA1/2 mutation (gBRCAm) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who had received ≤2 chemotherapy lines in the metastatic setting. Here, we report pre-specified analyses of data from Asian (China, Japan, Korea and Taiwan) patients in the study. All patients were randomized 2:1 to olaparib tablets (300 mg twice daily) or single-agent chemotherapy TPC (21-day cycles of either capecitabine, eribulin or vinorelbine). The primary endpoint was progression-free survival assessed by blinded independent central review. The prevalence of gBRCAm in the OlympiAD Asian subgroup screened for study recruitment was 13.5%. Patient demographics and disease characteristics of the Asian subgroup (87/302 patients) were generally well balanced between treatment arms. Asian patients in the olaparib arm achieved longer median progression-free survival, assessed by blinded independent central review, versus the chemotherapy TPC arm (5.7 vs 4.2 months; HR = 0.53 [95% CI: 0.29-0.97]), which was consistent with findings in the global OlympiAD study population. Findings on secondary efficacy and safety/tolerability outcome measures in Asian patients were also similar to those observed in the global OlympiAD study population. The OlympiAD study was not powered to detect race-related differences between treatment groups; however, the consistency of our findings with the global OlympiAD study population suggests that previously reported findings are generalizable to Asian patients.

15.
Arch Toxicol ; 94(8): 2691-2705, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32435916

RESUMO

1,2-Dichloropropane (1,2-DCP) is recognized as the causative agent for cholangiocarcinoma among offset color proof-printing workers in Japan. The aim of the present study was to characterize the molecular mechanisms of 1,2-DCP-induced hepatotoxic effects by proteomic analysis. We analyzed quantitatively the differential expression of proteins in the mouse liver and investigated the role of P450 in mediating the effects of 1,2-DCP. Male C57BL/6JJcl mice were exposed to 0, 50, 250, or 1250 ppm 1,2-DCP and treated with either 1-aminobenzotriazole (1-ABT), a nonselective P450 inhibitor, or saline, for 8 h/day for 4 weeks. Two-dimensional difference in gel electrophoresis (2D-DIGE) combined with matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF/TOF/MS) was used to detect and identify proteins affected by the treatment. PANTHER overrepresentation test on the identified proteins was conducted. 2D-DIGE detected 61 spots with significantly different intensity between 0 and 250 ppm 1,2-DCP groups. Among them, 25 spots were identified by MALDI-TOF/TOF/MS. Linear regression analysis showed significant trend with 1,2-DCP level in 17 proteins in mice co-treated with 1-ABT. 1-ABT mitigated the differential expression of these proteins. The gene ontology enrichment analysis showed overrepresentation of proteins functionally related to nickel cation binding, carboxylic ester hydrolase activity, and catalytic activity. The results demonstrated that exposure to 1,2-DCP altered the expression of proteins related with catalytic and carboxylic ester hydrolase activities, and that such effect was mediated by P450 enzymatic activity.

16.
Australas J Dermatol ; 61(3): e339-e343, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32424840

RESUMO

OBJECTIVES: The study examines the changes in dermoscopic features of actinic keratosis (AK) after photodynamic therapy, and delineates the association between AK dermoscopic and histopathological findings. METHODS: A total of 21 patients (23 lesions) with pathologically confirmed actinic keratosis who received 5-aminolaevulinic acid (ALA) photodynamic therapy (ALA-PDT) were enrolled. The numbers of PDT treatments were: 1, n = 1; 2, n = 2; 3, n = 10; 4, n = 6; 5, n = 2; 6, n = 2). The dermoscopic features before and after the PDT were compared. RESULTS: There were statistically significant decreases in the positive rates of dermoscopic features including scales (P < 0.001), follicular plugs with whitish halo (P = 0.013), and red pseudonetwork (P = 0.022) among patients treated with ALA-PDT. Dermoscopic feature was significantly associated with pathological grade (P < 0.001). Histopathological hyperkeratosis was significantly associated with dermoscopic red pseudonetwork (P = 0.034) and wavy vessel (P = 0.005). Parakeratosis was associated with wavy vessels (P = 0.001). For vascular hyperplasia in dermal papillae, the significant correlates included scales (P = 0.011), follicular plugs with whitish halo (P = 0.011), red pseudonetwork (P < 0.001); coiled vessels (P = 0.003) and rosette sign (P = 0.004). Wavy vessels was the only feature correlating keratosis pilaris (P = 0.003). CONCLUSIONS: The findings of the present study support dermoscopy as having potential to be useful for diagnosing and monitoring of actinic keratosis.

18.
N Engl J Med ; 382(22): 2091-2102, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32343890

RESUMO

BACKGROUND: Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in patients with prostate and other cancers. METHODS: We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2, or ATM; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician's choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review. RESULTS: In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib. CONCLUSIONS: In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone. (Funded by AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).


Assuntos
Antineoplásicos/uso terapêutico , Mutação com Perda de Função , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Androstenos/efeitos adversos , Androstenos/uso terapêutico , Antineoplásicos/efeitos adversos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Genes BRCA1 , Genes BRCA2 , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Feniltioidantoína/efeitos adversos , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia
19.
Org Lett ; 22(8): 3239-3244, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32243186

RESUMO

An efficient and facile formal [4 + 2] cycloaddition reaction was developed to synthesize diverse thiazole-fused dihydropyrans (TFDP) on DNA. Mild reaction conditions, broad substrate scope, and compatibility with subsequent enzymatic ligation demonstrated the utility of this methodology in DNA-encoded library synthesis.

20.
Front Pharmacol ; 11: 345, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32265716

RESUMO

Hypertension is a clinical cardiovascular syndrome characterized by elevated systemic arterial pressure with or without multiple cardiovascular risk factors. Radix Pueraria (RP) has the effects of anti-myocardial ischemia, anti-arrhythmia, vasodilatation, blood pressure reduction, anti-inflammation, and attenuating insulin resistance. Although RP can be effective for the treatment of hypertension, its active compounds, drug targets, and exact molecular mechanism are still unclear. In this study, systems pharmacology was used to analyze the active compounds, drug target genes, and key pathways of RP in the treatment of hypertension. Thirteen active compounds and related information on RP were obtained from the TCMSP database, and 140 overlapping genes related to hypertension and drugs were obtained from the GeneCards and OMIM databases. A PPI network and a traditional Chinese medicine (TCM) comprehensive network (Drug-Compounds-Genes-Disease network) were constructed, and 2,246 GO terms and 157 pathways were obtained by GO enrichment analysis and KEGG pathway enrichment analysis. Some important active compounds and targets were evaluated by in vitro experiments. This study shows that RP probably acts by influencing the proliferation module, apoptosis module, inflammation module, and others when treating hypertension. This study provides novel insights for researchers to systematically explore the mechanism of action of TCM.

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