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1.
Eur J Med Chem ; 194: 112265, 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32240904

RESUMO

A novel series of O-carbamoyl ferulamide derivatives were designed by multitarget-directed ligands (MTDLs) strategy, the derivatives were synthesized and evaluated to treat Alzheimer's disease (AD). In vitro biological evaluation demonstrated that compound 4f was the best pseudo-irreversible hBChE (human butyrylcholinesterase) inhibitor with an IC50 value of 0.97 µM 4f was a potent selective MAO-B (monoamine oxidase-B) inhibitor (IC50 = 5.3 µM), and could inhibit (58.2%) and disaggregate (43.3%) self-mediated Aß aggregation. 4f also could reduce the levels of pathological tau and APP clearance, and displayed a wide safe range hepatotoxicity on LO2 cells. The in vivo studies revealed that 4f exhibited fascinating dyskinesia recovery rate and response efficiency on AlCl3-mediated zebrafish, and demonstrated significant protective effect on vascular injury caused by Aß1-40. PET-CT imaging demonstrated that [11C]4f exhibited high BBB penetration (especially could reach to hippocampus and striatum of brain) and had a fast brain uptake after intravenous bolus injection. Furthermore, compound 4f could improve scopolamine-induced cognitive impairment. Further, the metabolism in vitro of 4f was also investigated, and presented 3 metabolites in rat liver microsome metabolism, 4 metabolites in human liver microsome, and 4 metabolites in rat intestinal flora, providing previous data for the preclinical study. Therefore, these results implied that compound 4f was an advanced multi-function agent and deserved further preclinical study against mild-to-serve Alzheimer's disease.

2.
Chem Commun (Camb) ; 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32226976

RESUMO

A mixture of pathways including the use of catalyst was proposed for a dirhodium-mediated triazole activation-cycloaddition. This proposal was supported by the results of density functional theory (DFT) calculations, and was indicated to involve a non-catalyzed cleavage of the triazole N-N bond followed by a dirhodium-assisted denitrogenation. Electron-deficient carboxylates were found to be favourable for the rate-determining denitrogenation step.

3.
Org Lett ; 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32216288

RESUMO

Highly regio- and enantioselective hydrogenation of conjugated α-substituted dienoic acids was realized for the first time using Trifer-Rh complex, providing a straightforward method for the synthesis of chiral α-substituted γ,δ-unsaturated acids. DFT calculations revealed N+H-O hydrogen bonding interaction is formed to stabilize the transition state and the coordination of 4,5-double bond to Rh(III) center would facilitate the reductive elimination process. This hydrogenation provided a gram-scale synthesis of the precursor of sacubitril.

4.
Org Lett ; 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32129634

RESUMO

A kinetically controlled radical addition/elimination reaction generating fluorinated allenes was developed. This strategy offers a route to a facile synthesis of diverse trifluoromethyl, difluoromethylene, and perfluoroalkyl functionalized allenes from readily available fluoroalkyl halides and alkynyl aziridines under visible-light irradiation. Density functional theory calculation of this radical clock type of reaction revealed a kinetically controlled C-N bond cleavage overcoming the alternative thermodynamically controlled C-C bond cleavage process.

5.
Biomed Res Int ; 2020: 1921609, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149084

RESUMO

Reprogrammed glucose and glutamine metabolism are essential for tumor initiation and development. As a branch of glucose and metabolism, the hexosamine biosynthesis pathway (HBP) generates uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) and contributes to the O-GlcNAcylation process. However, the spectrum of HBP-dependent tumors and the mechanisms by which the HBP promotes tumor aggressiveness remain areas of active investigation. In this study, we analyzed the activity of the HBP and its prognostic value across 33 types of human cancers. Increased HBP activity was observed in pancreatic ductal adenocarcinoma (PDAC), and higher HBP activity predicted a poor prognosis in PDAC patients. Genetic silencing or pharmacological inhibition of the first and rate-limiting enzyme of the HBP, glutamine:fructose-6-phosphate amidotransferase 1 (GFAT1), inhibited PDAC cell proliferation, invasive capacity, and triggered cell apoptosis. Notably, these effects can be restored by addition of UDP-GlcNAc. Moreover, similar antitumor effects were noticed by pharmacological inhibition of GFAT1 with 6-diazo-5-oxo-l-norleucine (DON) or Azaserine. PDAC is maintained by oncogenic Wnt/ß-catenin transcriptional activity. Our data showed that GFAT1 can regulate ß-catenin expression via modulation of the O-GlcNAcylation process. TOP/FOP-Flash and real-time qPCR analysis showed that GFAT1 knockdown inhibited ß-catenin activity and the transcription of its downstream target genes CCND1 and MYC. Ectopic expression of a stabilized form of ß-catenin restored the suppressive roles of GFAT1 knockdown on PDAC cell proliferation and invasion. Collectively, our findings indicate that higher GFAT1/HBP/O-GlcNAcylation exhibits tumor-promoting roles by maintaining ß-catenin activity in PDAC.

6.
Cell Res ; 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32203131

RESUMO

Hematopoietic stem cells (HSCs) in adults are believed to be born from hemogenic endothelial cells (HECs) in mid-gestational embryos. Due to the rare and transient nature, the HSC-competent HECs have never been stringently identified and accurately captured, let alone their genuine vascular precursors. Here, we first used high-precision single-cell transcriptomics to unbiasedly examine the relevant EC populations at continuous developmental stages with intervals of 0.5 days from embryonic day (E) 9.5 to E11.0. As a consequence, we transcriptomically identified two molecularly different arterial EC populations and putative HSC-primed HECs, whose number peaked at E10.0 and sharply decreased thereafter, in the dorsal aorta of the aorta-gonad-mesonephros (AGM) region. Combining computational prediction and in vivo functional validation, we precisely captured HSC-competent HECs by the newly constructed Neurl3-EGFP reporter mouse model, and realized the enrichment further by a combination of surface markers (Procr+Kit+CD44+, PK44). Surprisingly, the endothelial-hematopoietic dual potential was rarely but reliably witnessed in the cultures of single HECs. Noteworthy, primitive vascular ECs from E8.0 experienced two-step fate choices to become HSC-primed HECs, namely an initial arterial fate choice followed by a hemogenic fate conversion. This finding resolves several previously observed contradictions. Taken together, comprehensive understanding of endothelial evolutions and molecular programs underlying HSC-primed HEC specification in vivo will facilitate future investigations directing HSC production in vitro.

7.
Food Funct ; 11(3): 2639-2653, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32159193

RESUMO

Hyperoxaluria is well known to cause renal injury and end-stage kidney disease. Previous studies suggested that the renal function of rats with hyperoxaluria was improved after dietary vinegar intake. However, its underlying mechanisms remain largely unknown. The aim of the present study was to examine changes of gut microbiota and blood and urinary metabolites that associate with changes in kidney function to identify mechanisms involved with vinegar induced amelioration of hyperoxaluria-induced kidney injury. Using an ethylene glycol (EG)-induced hyperoxaluria rat model, we evaluated the effects of the vinegar on renal injury. Oral administration of vinegar (2 ml kg-1 day-1) reduced the elevated serum creatinine, BUN, and protected against hyperoxaluria-induced renal injury, renal fibrosis, and inflammation. Gut microbiota analysis of 16S rRNA gene in the hyperoxaluria-induced renal injury rats showed that vinegar treatment altered their microbial composition, especially the recovery of the levels of the Prevotella, Ruminiclostridium, Alistipes and Paenalcaligenes genus, which were significantly increased in the hyperoxaluria-induced renal injury rats. Additionally, liquid chromatography-mass spectrometry (LC-MS)-based metabolome analysis showed that total of 35 serum and 42 urine metabolites were identified to be associated with protective effects of vinegar on hyperoxaluria-induced renal injury rats. Most of these metabolites were involved in thiamine metabolism, glycerol phosphate shuttle, biotin metabolism, phosphatidylcholine biosynthesis and membrane lipid metabolism. Importantly, the effects of vinegar against renal injury were weakened after depletion of gut microbiota by antibiotic treatment. These results suggest that vinegar treatment ameliorates the hyperoxaluria-induced renal injury by improving the gut microbiota and metabolomic profiles.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32011784

RESUMO

Axial-to-central chirality transfer is an important strategy to construct chiral centers, where the axially chiral reagents are mostly limited to atropomerically stable ones. Reported herein is a RhIII -catalyzed enantioselective spiroannulative synthesis of nitrones. The coupling proceeds via C-H arylation to give an atropomerically metastable biaryl, followed by intramolecular dearomative trapping under oxidative conditions with high degree of chirality transfer.

9.
Artigo em Inglês | MEDLINE | ID: mdl-32033145

RESUMO

Benzo[a]pyrene (BaP) is a common environmental disrupting chemical that can cause endocrine disorders in organisms. However, the continued interference effects of BaP on multi-generation fish needs further research. In this study, we performed different periods (G1F1-3, G2F2-3, G3F3) of BaP exposure on marine medaka. We determined the embryo toxicity, and analyzed relative reproductive genes (ERα, cyp19a and vtg1) to predict the sexual differentiation of marine medaka. The results showed that high concentrations of BaP (200 µg·L-1) significantly delayed the hatching time of embryos. Moreover, medium/high concentrations of BaP (20 and 200 µg·L-1) prolonged the sexual maturity time of marine medaka. The relative gene expression of ERα, cyp19a and vtg1 were measured at 5 dpf of embryos. We found that BaP had significantly inhibited the expression of the genes related to female fish development. Consequently, there were more males in the offspring sex ratio at BaP exposure. Overall, BaP can cause embryonic toxicity and abnormal sexual differentiation, while the expression of related reproductive genes can effectively indicate the sex ratio.

10.
Nat Commun ; 11(1): 792, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034155

RESUMO

Acyclic contiguous stereocenters are frequently seen in biologically active natural and synthetic molecules. Although various synthetic methods have been reported, predictable and unified approaches to all possible stereoisomers are rare, particularly for those containing non-reactive hydrocarbon substituents. Herein, a ß-boronyl group is employed as a readily accessible handle for predictable α-functionalization of enolates with either syn or anti selectivity depending on reaction conditions. Contiguous tertiary-tertiary and tertiary-quaternary stereocenters are thus accessed in generally good yields and diastereoselectivity. Based on experimental and computational studies, mechanism for syn selective alkylation is proposed, and Bpin (pinacolatoboronyl) behaves as a smaller group than most carbon-centered groups. The synthetic utility of this methodology is demonstrated by preparation of several key intermediates for bioactive molecules.

11.
World Neurosurg ; 137: 218-225, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32059963

RESUMO

BACKGROUND: This report presents the third case of trochlear schwannoma arising from the pineal region and the first case to be resected using a paramedian infratentorial supracerebellar approach. Schwannomas of cranial nerves have traditionally been thought to arise from the transitional point where the axonal envelopment switches from glial cells to Schwann cells; however, recent temporal bone histopathologic evidence from vestibular schwannomas challenges this view. Of the 38 cases of pathology-confirmed trochlear schwannoma in the literature, there are only 2 cases arising from the pineal region, where the nerve sheath transition zone is located. Here, we discuss an unusual case of trochlear schwannoma arising from this transition zone. CASE DESCRIPTION: A 65-year-old man was admitted to our institute after a traffic accident. He complained of headache and dizziness, and a computed tomography scan revealed an isodense mass in the pineal region with obstructive hydrocephalus. Magnetic resonance imaging with contrast showed an enhancing mass in the pineal region. The tumor was subtotally resected using a paramedian infratentorial supracerebellar approach, and pathology confirmed the diagnosis of trochlear schwannoma. CONCLUSIONS: Trochlear schwannoma should be considered when a mass is identified in the pineal region. This diagnosis should still be entertained for mass lesions along the free tentorial edge because the tumor may arise distant from the glial-Schwann transition zone located by the dorsal midbrain. We propose a treatment algorithm for this rare tumor that seeks to maximize functional outcome.

12.
Org Lett ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32011898

RESUMO

A three-layer chirality relay model is proposed for Rh(I)-mediated enantioselective siletane activation. A chiral ligand in the back layer controls the position of the alkyne-coordinated metal center in the middle layer, which then provides a chiral environment for the incoming substrate at the front layer. A two-dimensional contour map analysis further clarified this model.

13.
Artigo em Inglês | MEDLINE | ID: mdl-32014392

RESUMO

OBJECTIVES: To systematically investigate chromosomal abnormalities and copy number variants (CNVs) in fetuses with different types of ventriculomegaly (VM) by karyotyping and/or chromosomal microarray analysis (CMA). METHODS: This retrospective study included 312 fetuses diagnosed with VM. Amniotic fluid and umbilical blood samples were collected by amniocentesis and cordocentesis, respectively, and subjected to karyotyping and/or CMA. Subgroup analysis by VM type, including mild VM (MVM) and severe VM (SVM), unilateral and bilateral VM, isolated VM (IVM), and non-isolated VM (NIVM), was performed. RESULTS: The detection rate of chromosomal abnormalities was 12.1% (34/281) by karyotyping and 20.6% when CMA was additionally performed (P < 0.05). Abnormalities were identified by CMA in 17.4% (38/218) of fetuses and pathogenic CNVs in 5.0% (11/218). Notably, CMA detected CNVs in 10.6% (23/218) of fetuses with normal karyotypes. The incidence of chromosomal abnormalities by karyotyping was higher in bilateral than in unilateral VM (20.5% versus 6.5%), whereas the incidence detected by CMA was higher in NIVM than in IVM (21.4% versus 10.3%; both P < 0.05). In NIVM, CMA provided an additional detection rate of 11.4% (16/140) and a detection rate of 10.0% for pathogenic CNVs and aneuploidies. Central nervous system (CNS) abnormalities were the most common other ultrasonic abnormalities. CONCLUSIONS: CMA is highly recommended for prenatal diagnosis of fetal VM together with karyotyping, especially in fetuses with bilateral VM and NIVM with abnormal CNS findings. Further study is necessary to explore the relationships between genotypes and phenotypes to facilitate prenatal diagnosis of fetal VM.

14.
Cardiovasc Res ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32044971

RESUMO

AIMS: Hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs), a key component of the endosomal sorting complex required for transport (ESCRT), has been implicated in many essential biological processes. However, the physiological role of endogenous Hgs in the vascular system has not previously been explored. Here, we have generated brain endothelial cell (EC) specific Hgs knockout mice to uncover the function of Hgs in EC polarity and cerebrovascular stability. METHODS AND RESULTS: Knockout of Hgs in brain ECs led to impaired endothelial apicobasal polarity and brain vessel collapse in mice. We determined that Hgs is essential for recycling of VE-cadherin to the plasma membrane, since loss of Hgs blocked trafficking of endocytosed VE-cadherin from early endosomes to recycling endosomes, and impaired the motility of recycling endosomes. Supportively, overexpression of the motor kinesin family member 13A (KIF13A) restored endosomal recycling and rescued abrogated polarized trafficking and distribution of VE-cadherin in Hgs knockdown ECs. CONCLUSIONS: These data uncover a novel physiological function of Hgs and support an essential role for the ESCRT machinery in the maintenance of EC polarity and cerebrovascular stability. TRANSLATIONAL PERSPECTIVE: The structural and functional integrity of cerebral vasculature is critical for supporting normal brain function. Mutations of genes that play important roles in blood vessel development cause not only cardiovascular diseases, but also neurological disorders. In this study, we discovered a novel physiological function of Hgs in the maintenance of EC polarity and cerebrovascular stability, demonstrating that endothelial ESCRT machinery has an essential role in maintaining the integrity of cerebral vasculature. This provides insights into the potential pathogenic links between ESCRT dysfunction and cardiovascular diseases, as well as neurodegenerative disorders.

15.
Org Lett ; 22(7): 2517-2521, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32097018

RESUMO

Protecting-group-free total syntheses of natural products norascyronone A and norascyronone B were accomplished in eight steps from the commercially available starting material 1-bromo-4-methoxy-2-methylbenzene. The key step was a Mn/Cu-mediated oxidative cascade annulation reaction that formed the tetracyclic core of the target molecules bearing vicinal bridge-head all-carbon quaternary chiral centers. Our investigation indicated that the C5 stereogenic center of norascyronone C plays a critical role in the proposed biomimetic oxidative reaction for B-ring formation.

16.
Pharm Stat ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31908134

RESUMO

Decision making is a critical component of a new drug development process. Based on results from an early clinical trial such as a proof of concept trial, the sponsor can decide whether to continue, stop, or defer the development of the drug. To simplify and harmonize the decision-making process, decision criteria have been proposed in the literature. One of them is to exam the location of a confidence bar relative to the target value and lower reference value of the treatment effect. In this research, we modify an existing approach by moving some of the "stop" decision to "consider" decision so that the chance of directly terminating the development of a potentially valuable drug can be reduced. As Bayesian analysis has certain flexibilities and can borrow historical information through an inferential prior, we apply the Bayesian analysis to the trial planning and decision making. Via a design prior, we can also calculate the probabilities of various decision outcomes in relationship with the sample size and the other parameters to help the study design. An example and a series of computations are used to illustrate the applications, assess the operating characteristics, and compare the performances of different approaches.

17.
Int J Med Sci ; 17(1): 13-20, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929734

RESUMO

Diabetes mellitus (DM) is a chronic disease found worldwide. Notably, BKS.Cg- Dock7m +/+ Leprdb/JNarl mice are useful animal models for studying type 2 diabetes mellitus (T2DM). In this study, we investigated casein kinase 2 alpha 1 (CSNK2A1) gene and protein expression in the liver tissues of mice at different ages (4, 16, and 32 weeks) using real-time quantitative polymerase chain reactions, western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay. Our data paved the way for exploring BKS.Cg- Dock7m +/+ Leprdb/JNarl in the mouse model by demonstrating a significant increase in gene and protein expression in T2DM (+Leprdb/+Leprdb) mouse liver when compared to control (+Dock7m/+Dock7m) mouse liver. We also observed that CSNK2A1 protein level in the serum of T2DM patient group was higher than that of the control group, although the data was not statistically significant. Based on our findings, we can now understand the role of CSNK2A1 gene upregulation when encountering T2DM pathologies.

18.
Molecules ; 25(2)2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31936160

RESUMO

: Multidrug resistance (MDR) is a complicated ever-changing problem in cancer treatment, and P-glycoprotein (P-gp), a drug efflux pump, is regarded as the major cause. In the way of developing P-gp inhibitors, natural products such as phenolic acids have gotten a lot of attention recently. The aim of the present study was to investigate the modulating effects and mechanisms of caffeic acid on human P-gp, as well as the attenuating ability on cancer MDR. Calcein-AM, rhodamine123, and doxorubicin were used to analyze the interaction between caffeic acid and P-gp, and the ATPase activity of P-gp was evaluated as well. Resistance reversing effects were revealed by SRB and cell cycle assay. The results indicated that caffeic acid uncompetitively inhibited rhodamine123 efflux and competitively inhibited doxorubicin efflux. In terms of P-gp ATPase activity, caffeic acid exhibited stimulation in both basal and verapamil-stimulated activity. The combination of chemo drugs and caffeic acid resulted in decreased IC50 in ABCB1/Flp-InTM-293 and KB/VIN, indicating that the resistance was reversed. Results of molecular docking suggested that caffeic acid bound to P-gp through GLU74 and TRY117 residues. The present study demonstrated that caffeic acid is a promising candidate for P-gp inhibition and cancer MDR attenuation.

19.
Biochim Biophys Acta Gen Subj ; 1864(4): 129541, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31987956

RESUMO

BACKGROUND: BAX activation is a crucial step for commitment to apoptosis. Several activators, such as BimBH3-based therapeutic peptides and cleaved Bid (cBid) protein, can trigger BAX-mediated apoptosis, but it is unclear whether they proceed through the same pathway. METHODS: Here we utilize PEGylation-based approach, which is shown to efficiently shield individual binding grooves in BAX from activators, to investigate and reveal that the activators take different routes to induce BAX-mediated apoptosis. Various spectroscopic/biochemical tools, including electron spin resonance, circular dichroism, fluorescence recovery after photobleaching, and label-transfer assay, were employed to reveal details in the processes. RESULTS: We observe a key mutant BAX 164-PEG that acts differently in response to cBid and BimBH3 stimuli. While BimBH3 directly interacts with the trigger groove (TG) to induce the conformational changes in BAX that includes the release of α9 from the canonical groove (CG) and oligomerization, cBid engages with CG and works with mitochondrial lipids to fully activate BAX. CONCLUSION: PEGylation-based approach is proven useful to shield individual binding grooves of BAX from apoptotic stimuli. Groove engagement in CG of BAX is required for a full cBid-induced BAX activation. This study has identified differences in the pathways involved during the initiation of BAX activation by full-length cBid protein versus synthetic BimBH3-based peptides. GENERAL SIGNIFICANCE: Our finding is potentially valuable for therapeutic application as the pore-forming activity of 164-PEG is independent from the cBid-mediated apoptotic pathways, but can be administrated by the synthetic short peptides.

20.
Nat Commun ; 11(1): 417, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964876

RESUMO

Cross-coupling reactions have developed into powerful approaches for carbon-carbon bond formation. In this work, a Ni-catalyzed migratory Suzuki-Miyaura cross-coupling featuring high benzylic or allylic selectivity has been developed. With this method, unactivated alkyl electrophiles and aryl or vinyl boronic acids can be efficiently transferred to diarylalkane or allylbenzene derivatives under mild conditions. Importantly, unactivated alkyl chlorides can also be successfully used as the coupling partners. To demonstrate the applicability of this method, we showcase that this strategy can serve as a platform for the synthesis of terminal, partially deuterium-labeled molecules from readily accessible starting materials. Experimental studies suggest that migratory cross-coupling products are generated from Ni(0/II) catalytic cycle. Theoretical calculations indicate that the chain-walking occurs at a neutral nickel complex rather than a cationic one. In addition, the original-site cross-coupling products can be obtained by alternating the ligand, wherein the formation of the products has been rationalized by a radical chain process.

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