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1.
Bioorg Med Chem Lett ; 30(16): 127339, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32631540

RESUMO

TGF-ß type I receptor (also known as activin-like kinase 5 or ALK5) plays a critical role in the progression of fibrotic diseases and tumor invasiveness and metastasis, as well. The development of small inhibitors targeting ALK5 has been validated as a potential therapeutic strategy for fibrotic diseases and cancer. Here, we developed various 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) oxy) pyridine-2-yl) amino derivatives as ALK5 inhibitors. The optimization led to identification of potent and selective ALK5 inhibitors 12r. The compound 12r exhibited strong inhibitory activity both in vitro and in vivo, and pharmacokinetics study showed an oral bioavailability of 57.6%. Thus, compound 12r may provide as new therapeutic option as ALK5 TGF-ßR1 inhibitor.

2.
Zhongguo Gu Shang ; 33(6): 564-6, 2020 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-32573164

RESUMO

OBJECTIVE: To evaluate the effects of membrane induced by antibiotic-loaded bone cement in skin grafting for tendon exposed wound healing. METHODS: A total of 10 traumatic patients with tendon exposed wound were admitted to our department between February 2016 and December 2018, including 6 males and 4 females, with a mean age of 34.6 years old (ranged, 19 to 43 years old), and treatment duration ranged from 2 to 6 months. There were 7 cases of traffic accidents, 3 cases of mechanical belt injuries, including 8 cases of lower leg and foot wounds and 2 cases of hand back wounds. These tendons exposed wound were covered by antibiotic-loaded bone cement at the earlier stageto induce the formation of the biomembrane, and then skin grafting were performed on the induced membrane. The survival, appearance, texture, sensation of the skin grafting and healing condition of the wounds were studied. RESULTS: Among the 10 patients, skin graft survived well in 8 patients. Partial skin graft necrosis occurred in 2 patients and cured by dressing. CONCLUSION: Using antibiotic bone cement to seal the wound to form induction membrane followed by skin grafting can effectively repair the tendon exposed wound, which has the characteristics of simple operation and less trauma.

3.
Biol Reprod ; 2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32582940

RESUMO

Fetal growth restriction (FGR) is a condition in which a newborn fails to achieve his or her prospective hereditary growth potential. This condition is associated with high newborn mortality, second only to that associated with premature birth. FGR is associated with maternal, fetal and placental abnormalities. Although the placenta is considered to be an important organ for supplying nutrition for fetal growth, research on FGR is limited, and treatment through the placenta remains challenging, as neither proper uterine intervention nor its pathogenesis have been fully elucidated. Yes-associated protein (YAP), as the effector of the Hippo pathway, is widely known to regulate organ growth and cancer development. Therefore, the correlation of the placenta and YAP was investigated to elucidate the pathogenic mechanism of FGR. Placental samples from humans and mice were collected for histological and biomechanical analysis. After investigating the location and role of YAP in the placenta by immunohistochemistry (IHC), we observed that YAP and cytokeratin 7 (CK7) have corresponding locations in human and mouse placentas. Moreover, phosphorylated YAP (p-YAP) was upregulated in FGR and gradually increased as gestational age increased during pregnancy. Cell function experiments and mRNA-Seq demonstrated impaired YAP activity mediated by extracellular signal-regulated kinase (ERK) inhibition. Established FGR-like mice also recapitulated a number of the features of human FGR. The results of this study may help to elucidate the association of FGR development with YAP and provide an intrauterine target that may be helpful in alleviating placental dysfunction.

5.
Sci Rep ; 10(1): 7801, 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385278

RESUMO

Plant growth caused by ambient temperature is thought to be regulated by a complex transcriptional network. A temperature-sensitive peach (Prunus persica) was used to explore the mechanisms behind shoot internode elongation at elevated temperatures. There was a significantly positive correlation between the length of the terminal internode (TIL) and the maximum temperature three days prior to the measuring day. Four critical growth stages (initial period and initial elongation period at lower temperature, rapid growth period and stable growth period at higher temperature) were selected for comparative RNA-seq analysis. About 6.64G clean bases were obtained for each library, and 88.27% of the data were mapped to the reference genome. Differentially expressed gene (DEG) analysis among the three pairwise comparisons resulted in the detection of several genes related to the shoot elongation in temperature-sensitive peach. HSFAs were up-regulated in response to the elevated temperature, while the up-regulated expression of HSPs might influence hormone signaling pathways. Most of DEGs involved in auxin, abscisic acid and jasmonic acid were up-regulated, while some involved in cytokinin and brassinosteroid were down-regulated. Genes related to ethylene, salicylic acid and circadian rhythm were also differentially expressed. Genes related to aquaporins, expansins, pectinesterases and endoglucanase were up-regulated, which would promote cell elongation. These results lay a foundation for further dissection of the regulatory mechanisms underlying shoot elongation at elevated temperatures.

7.
Angew Chem Int Ed Engl ; 59(28): 11374-11378, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32277551

RESUMO

Presented here is a class of novel axially chiral aryl-p-quinones as platform molecules for the preparation of non-C2 symmetric biaryldiols. Two sets of aryl-p-quinone frameworks were synthesized with remarkable enantiocontrol by means of chiral phosphoric acid catalyzed enantioselective arylation of p-quinones by central-to-axial chirality conversion. These aryl-p-quinones were then used to access a wide spectrum of highly functionalized non-C2 symmetric biaryldiols with excellent retention of the enantiopurity.

8.
J Am Chem Soc ; 142(16): 7322-7327, 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32267146

RESUMO

The first copper-catalyzed atroposelective Michael-type addition between azonaphthalenes and arylboronic acids for the construction of biaryl atropisomers was established using a novel BINOL-derived phosphoramidite as a chiral ligand. A broad range of atropisomeric biaryls were obtained with good efficiency, and the practicality of this approach was verified by versatile transformations toward axially chiral ligands, catalysts, and other functional atropisomers. This set of catalytic systems successfully inhibited the routine 1,2-addition and promoted the formation of an aryl-aryl chiral axis. Meanwhile, this strategy bypassed the use of an oxidant as well as the harsh conditions normally necessary for transition-metal-mediated arene C-H coupling with arylboronic acids as an arylation counterpart, offering a straightforward alternative to access optically active biaryls.

9.
Macromol Rapid Commun ; 41(8): e2000043, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32180278

RESUMO

Light-induced, shape-changing polymeric microparticles have many applications. Here, the near-infrared (NIR)-light-triggered sequential recovery and separation of assembled large and small polymer microparticles using cross-linked blends of poly(ethylene-vinyl acetate) and trans-polyisoprene as temperature memory polymers as well as two NaYF4 based up-conversion nanoparticles (UCPs) to provide luminescent and photothermal effects are reported. Under irradiation of NIR light with a low light power density, small particles assembled onto the compressed large one recover first due to the low switching temperature (Tsw ) arising from the temperature-memory effect. The small particles can separate from the underlying large particle in flowing aqueous media. The recovery of the large particle occurs at a high power density. Two UCPs of NaYF4 : 20Yb, 0.2Tm, 5Gd and NaYF4 : 18Yb, 2Er, 5Gd facilitate the detection of small and large microparticles via providing blue and green light emissions, respectively. This work can expand the applications of light-induced shape-changing polymer microparticles in the biomedical field, controlled catalysis, microfluidic devices, and so on.

10.
ACS Chem Biol ; 15(3): 766-773, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32118401

RESUMO

Totopotensamide A (TPM A, 1) is a polyketide-peptide glycoside featuring a nonproteinogenic amino acid 4-chloro-6-methyl-5,7-dihydroxyphenylglycine (ClMeDPG). The biosynthetic gene cluster (BGC) of totopotensamides (tot) was previously activated by manipulating transcription regulators in marine-derived Streptomyces pactum SCSIO 02999. Herein, we report the heterologous expression of the tot BGC in Streptomyces lividans TK64, and the production improvement of TPM A via in-frame deletion of two negative regulators totR5 and totR3. The formation of ClMeDPG was proposed to require six enzymes, including four enzymes TotC1C2C3C4 for 3,5-dihydroxyphenylglycine (DPG) biosynthesis and two modifying enzymes TotH (halogenase) and TotM (methyltransferase). Heterologous expression of the four-gene cassette totC1C2C3C4 led to production of 3,5-dihydroxyphenylglyoxylate (DPGX). The aminotransferase TotC4 was biochemically characterized to convert DPGX to S-DPG. Inactivation of totH led to a mutant accumulated a deschloro derivative TPM H1, and the ΔtotHi/ΔtotMi double mutant afforded two deschloro-desmethyl products TPMs HM1 and HM2. A hydrolysis experiment demonstrated that the DPG moiety in TPM HM2 was S-DPG, consistent with that of the TotC4 enzymatic product. These results confirmed that TotH and TotM were responsible for ClMeDPG biosynthesis. Bioinformatics analysis indicated that both TotH and TotM might act on thiolation domain-tethered substrates. This study provided evidence for deciphering enzymes leading to ClMeDPG in TPM A, and unambiguously determined its absolute configuration as S.

11.
Artigo em Inglês | MEDLINE | ID: mdl-32017378

RESUMO

N-arylcarbazole structures are important because of their prevalence in natural products and functional OLED materials. C-H amination of arenes has been widely recognized as the most efficient approach to access these structures. Conventional strategies involving transition-metal catalysts suffer from confined substrate generality and the requirement of exogenous oxidants. Organocatalytic enantioselective C-N chiral axis construction remains elusive. Presented here is the first organocatalytic strategy for the synthesis of novel axially chiral N-arylcarbazole frameworks by the assembly of azonaphthalenes and carbazoles. This reaction accommodates broad substrate scope and gives atropisomeric N-arylcarbazoles in good yields with excellent enantiocontrol. This approach not only offers an alternative to metal-catalyzed C-N cross-coupling, but also brings about opportunities for the exploitation of structurally diverse N-aryl atropisomers and OLED materials.

12.
Sci Rep ; 10(1): 1817, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019948

RESUMO

Mesenchymal stem cells (MSCs) specifically differentiate into cardiomyocytes as a potential way to reverse myocardial injury diseases, and uncovering this differentiation mechanism is immensely important. We have previously shown that histone acetylation/methylation and DNA methylation are involved in MSC differentiation into cardiomyocytes induced by islet-1. These modifications regulate cardiac-specific genes by interacting with each other in the promoter regions of these genes, but the molecular mechanism of these interactions remains unknown. In this study, we found that the key enzymes that regulate GATA4/Nkx2.5 expression are Gcn5/HDAC1, G9A, and DNMT-1. When α-methylene-γ-butyrolactone 3 (MB-3) was used to inhibit Gcn5 expression, we observed that the interactions among these key enzymes in the GATA4/Nkx2.5 promoters were blocked, and MSCs could not be induced into cardiomyocytes. Our results indicated that islet-1 could induce Gcn5 binding to GATA4/Nkx2.5 promoter regions and induce the interactions among Gcn5, HDAC1, G9A and DNMT-1, which upregulated GATA4/Nkx2.5 expression and promoted MSC differentiation into cardiomyocytes.

13.
Org Lett ; 22(3): 1062-1066, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31971807

RESUMO

The heterologous expression of the lobophorin biosynthetic gene cluster from marine-derived Streptomyces pactum SCSIO 02999 has led to the discovery of new analogues that carry d-kijanose (or its variants with a 3-amino or hydroxyl group) at C-9. The identification of intermediates resulting from the inactivation of lobG1 (encoding C-17 kijanosyltransferase) and lobG3 (encoding C-9 digitoxosyltransferase) demonstrates the substrate flexibility of LobG3 to also accept d-kijanose and its variants. Notably, two lobophorins with d-kijanose at C-9 show improved bioactivities.

14.
J Matern Fetal Neonatal Med ; 33(7): 1125-1133, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30282494

RESUMO

Introduction: The sufficient invasion and migration of human extravillous trophoblast (EVTs) cells are crucial for placentation. Inadequate invasion of trophoblasts may correlate with the development of preeclampsia. Many studies have suggested that activated Cdc42-associated kinase (ACK1) is associated with tumor metastasis and invasion. This study investigated the ACK1 expression and its function in trophoblasts during placental development.Methods: ACK1 expression in human placentas was determined through immunofluorescence. We investigated the migration/invasion of the immortalized human first-trimester EVT cell line HTR8/SVneo. Hypoxia-reoxygenation (H/R) conditions were applied to mimic preeclampsia model in vitro. Lentiviral vector-based short-hairpin RNA directed against the sequence of ACK1 (ACK1 shRNA) was used to knock down ACK1 expression in HTR8/SVneo cells. Cell apoptosis and proliferation were determined through flow cytometry and cell counting Kit-8 (CCK-8) assays, respectively. The expression of matrix metalloproteinase (MMP) 2/9 and tissue inhibitors of metalloproteinase (TIMP) 1/2 was measured by western blotting.Results: ACK1 localized within trophoblasts of human placental villi, decidual cells in the maternal decidua. ACK1 levels in preeclampsia (PE) placentas were significantly lower than those in controls. ACK1 shRNA significantly inhibited HTR8/SVneo cells migration and invasion but did not affect their apoptosis and proliferation. ACK1 knockdown decreased MMP2/9 and increased TIMP1/2 expression, as well as downregulated the phosphorylation of AKt (p-Akt). In addition, ACK1 and MMP2/9 were downregulated following treatment with LY294002, whereas ACK1 shRNA had no effect on phosphorylation of PI3K(p-PI3K). After exposed in H/R condition, ACK1 expression, MMP2/9 protein, and p-Akt were also significantly decreased.Discussion and conclusions: ACK1 expression is lowered in preeclamptic placentas and promotes trophoblast cell invasion, migration. H/R conditions decrease ACK1 expression and appear to decouple the positive relationship between ACK1 expression and Akt activation.

15.
BMC Genomics ; 20(1): 892, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752682

RESUMO

BACKGROUND: Ubiquitin ligases (E3) are the enzymes in the ubiquitin/26S proteasome pathway responsible for targeting proteins to the degradation pathway and play major roles in multiple biological activities. However, the E3 family and their functions are yet to be identified in the fruit of peach. RESULTS: In this study, genome-wide identification, classification and characterization of the E3 ligase genes within the genome of peach (Prunus persica) was carried out. In total, 765 E3 (PpE3) ligase genes were identified in the peach genome. The PpE3 ligase genes were divided into eight subfamilies according to the presence of known functional domains. The RBX subfamily was not detected in peach. The PpE3 ligase genes were not randomly distributed among the 8 chromosomes, with a greater concentration on the longer chromosomes. The primary mode of gene duplication of the PpE3 ligase genes was dispersed gene duplication (DSD). Four subgroups of the BTB subfamily never characterized before were newly identified in peach, namely BTBAND, BTBBL, BTBP and BTBAN. The expression patterns of the identified E3 ligase genes in two peach varieties that display different types of fruit softening (melting flesh, MF, and stony hard, SH) were analyzed at 4 different stages of ripening using Illumina technology. Among the 765 PpE3 ligase genes, 515 (67.3%) were expressed (FPKM > 1) in the fruit of either MF or SH during fruit ripening. In same-stage comparisons, 231 differentially expressed genes (DEGs) were identified between the two peach cultivars. The number of DEGs in each subfamily varied. Most DEGs were members of the BTB, F-box, U-box and RING subfamilies. PpE3 ligase genes predicted to be involved in ethylene, auxin, or ABA synthesis or signaling and DNA methylation were differentially regulated. Eight PpE3 ligase genes with possible roles in peach flesh texture and fruit ripening were discussed. CONCLUSIONS: The results of this study provide useful information for further understanding the functional roles of the ubiquitin ligase genes in peach. The findings also provide the first clues that E3 ligase genes may function in the regulation of peach ripening.


Assuntos
Frutas/enzimologia , Frutas/genética , Prunus persica/enzimologia , Prunus persica/genética , Ubiquitina-Proteína Ligases/genética , Ácido Abscísico/metabolismo , Cromossomos de Plantas , Etilenos/metabolismo , Frutas/crescimento & desenvolvimento , Duplicação Gênica , Perfilação da Expressão Gênica , Genoma de Planta , Ácidos Indolacéticos/metabolismo , Filogenia , Prunus persica/classificação , Prunus persica/crescimento & desenvolvimento , Ubiquitina-Proteína Ligases/metabolismo
16.
Nat Commun ; 10(1): 4268, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537811

RESUMO

Atropisomeric biaryl motifs are ubiquitous in chiral catalysts and ligands. Numerous efficient strategies have been developed for the synthesis of axially chiral biaryls. In contrast, the asymmetric construction of o-quinone-aryl atropisomers has yet to be realized. Inspired by the rapid progress of the chemistry of biaryls, here we present our initial investigations about the atroposelective construction of axially chiral arylquinones by a bifunctional chiral phosphoric acid-catalyzed asymmetric conjugate addition and central-to-axial chirality conversion. With o-naphthoquinone as both the electrophile and the oxidant, three types of arylation counterparts, namely 2-naphthylamines, 2-naphthols and indoles, are utilized to assemble a series of atropisomeric scaffolds in good yields and excellent enantioselectivities. This approach not only expands the axially chiral library but also offers a route to a class of potential, chiral biomimetic catalysts.

17.
Org Lett ; 21(15): 6000-6004, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31334666

RESUMO

Structurally novel atropisomeric arylindole frameworks have been successfully constructed through chiral phosphoric acid-catalyzed asymmetric cross-coupling of indoles and quinone derivatives in a precise regioselective manner. This approach features high convergence and functional group tolerance to efficiently deliver diverse heteroaryl atropisomers with excellent enantiocontrol. The dominant formation of axial chirality but not central chirality, as the major unmet challenge for this type of reactions, was conquered by the rational and accurate modulation of the electronic and steric effects on both coupling partners. Preliminary investigation demonstrated the practicality of such axially chiral arylindoles as chiral ligands in asymmetric catalysis.

18.
Chem Asian J ; 14(20): 3572-3576, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31278879

RESUMO

Efficient separation of n-butene (n-C4 H8 ) and iso-butene (iso-C4 H8 ) is of significance for the upgrading of C4 olefins to high-value end products but remains one of the major challenges in hydrocarbon purifications owing to their similar structures. Herein, we report a flexible metal-organic framework, MnINA (INA=isonicotinate), featuring one-dimensional pore channels with periodically large pocket-like cavities connected by narrow bottlenecks, for the first time for efficient n-/iso-C4 H8 separation. MnINA with smaller pore size (4.62 Å) compared with CuINA (4.84 Å), exhibits steep adsorption isotherms and high capacity of 1.79 mmol g-1 for n-C4 H8 (4.46 Å) through strong host-guest interactions via C-H⋅⋅⋅π bonding. The narrow bottlenecks exert barriers for the large molecules of iso-C4 H8 (4.84 Å) within the gate-opening pressure range of 0-0.1 bar. This gives rise to MnINA with excellent separation selectivity of 327.7 for n-/iso-C4 H8 mixture. The adsorption mechanism for n-C4 H8 and the gate-opening effect were investigated by dispersion-corrected density functional (DFT-D) theory, verifying the strong interactions between n-C4 H8 and the frameworks as well as the gate-opening effect derived from the rotation of organic linkers. The breakthrough tests confirmed MnINA and CuINA can be promising candidates for n-/iso-C4 H8 separation.

19.
Angew Chem Int Ed Engl ; 58(38): 13443-13447, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31338946

RESUMO

Axially chiral 2-arylpyrrole frameworks are efficiently accessed through a direct chirality transfer strategy by rapid cyclization of enantioenriched atropisomeric alkenes, which are generated by organocatalytic asymmetric N-alkylation reactions. This approach accommodates a broad scope of substrates with remarkably high chirality transfer efficiency, affording novel atropisomers with a fully substituted pyrrole moiety and high enantiopurities. Given the enantioenriched atropisomeric alkenes, novel heterocyclic 2-arylazepine atropisomers were realized through a rationally designed ene reaction.

20.
Biochem Biophys Res Commun ; 515(1): 24-30, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31122700

RESUMO

Human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) in vitro expansion for long term may undergo epigenetic and genetic alterations that subsequently induce cellular senescence and associated growth inhibition. Increasing evidence implicated that aberrant histone acetylation modulates gene expression responsible for MSCs aging. Whether the dysregulation of p300 and its KAT activity is involved in the aging process of MSCs was still unexplored. In this study, we found a significant decrease of p300 but elevated p53/p21 levels in senescent hUC-MSCs at late-passage. Then we used two different approaches: (i) downregulation of p300 by siRNA and (ii) inhibition of the acetyltransferase(KAT) activity by C646 to determine the role of p300 in regulating MSCs senescence. We showed that inhibition of p300 induce premature senescence and decrease proliferation potential in hUC-MSCs. Moreover, upregulations of p53 and p21 expressions were confirmed in p300 knockdown and C646-treated hUC-MSCs. Taken together, these results suggest that p300 plays an important role in aging process of MSCs associated with activation of p53/p21 signaling pathway.

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