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1.
Chem Commun (Camb) ; 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32211653

RESUMO

Using 2% percent of iron dopants as reaction active sites yields a series of single crystals of 1,10-phenanthroline intercalated NiPS3, via a solution reaction with aniline chloride, not possible by a direct reaction. Experimental magnetic susceptibility measurements demonstrate that 1,10-phenanthroline intercalation suppresses the anti-ferromagnetism ordering at around 150 K in Fe0.02Ni0.98PS3, and gives rise to a ferrimagnetic phase transition at a temperature around 75 K. An intercalation mechanism is proposed for the reaction, and this dopant seeding method provides a new approach for intercalation into layered materials.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32052958

RESUMO

Heterostructures composed of superconductor and ferroelectrics (SC/FE) are very important for manipulating the superconducting property and applications. However, growth of high-quality superconducting iron chalcogenide films is challenging because of their volatility and FE substrate with rough surface and large lattice mismatch. Here, we report a two-step growth approach to get high-quality FeSe0.5Te0.5 (FST) films on FE Pb(Mg1/3Nb2/3)0.7Ti0.3O3 with large lattice mismatch, which show superconductivity at only around 10 nm. Through a systematic study of structural and electric transport properties of samples with different thicknesses, a mechanism to grow high-quality FST is discovered. Moreover, electric-field-induced remarkable change of Tc (superconducting transition temperature) is demonstrated in a 20 nm FST film. This work paves the way to grow high-quality films which contain volatile element and have large lattice mismatch with the substrate. It is also helpful for manipulating the superconducting property in SC/FE heterostructures.

5.
N Engl J Med ; 381(10): 990, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31483980

Assuntos
Artemisininas
6.
Nat Commun ; 10(1): 3206, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324795

RESUMO

Diosgenin is a spiroketal steroidal natural product extracted from plants and used as the single most important precursor for the world steroid hormone industry. The sporadic occurrences of diosgenin in distantly related plants imply possible independent biosynthetic origins. The characteristic 5,6-spiroketal moiety in diosgenin is reminiscent of the spiroketal moiety present in anthelmintic avermectins isolated from actinomycete bacteria. How plants gained the ability to biosynthesize spiroketal natural products is unknown. Here, we report the diosgenin-biosynthetic pathways in himalayan paris (Paris polyphylla), a monocot medicinal plant with hemostatic and antibacterial properties, and fenugreek (Trigonella foenum-graecum), an eudicot culinary herb plant commonly used as a galactagogue. Both plants have independently recruited pairs of cytochromes P450 that catalyze oxidative 5,6-spiroketalization of cholesterol to produce diosgenin, with evolutionary progenitors traced to conserved phytohormone metabolism. This study paves the way for engineering the production of diosgenin and derived analogs in heterologous hosts.


Assuntos
Vias Biossintéticas , Sistema Enzimático do Citocromo P-450/metabolismo , Diosgenina/metabolismo , Furanos/metabolismo , Lipogênese/fisiologia , Compostos de Espiro/metabolismo , Antibacterianos , Colesterol/metabolismo , Citocromos/metabolismo , Galactagogos , Perfilação da Expressão Gênica , Ivermectina/análogos & derivados , Melanthiaceae/química , Metabolômica , Reguladores de Crescimento de Planta/metabolismo , Trigonella
8.
Theranostics ; 8(13): 3504-3516, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30026862

RESUMO

Many plant-specialized metabolites have remedial properties and provide an endless chemical resource for drug discovery. However, most of these metabolites have promiscuous binding targets in mammalian cells and elicit a series of responses that collectively change the physiology of the cells. To explore the potential of these multi-functional and multi-targeted drugs, it is critical to understand the direct relationships between their key chemical features, the corresponding binding targets and the relevant biological effects, which is a prerequisite for future drug modification and optimization. Methods: We introduced and demonstrated a general workflow, called Comparative Profiling of Analog Targets (CPAT), to connect specific biological effects with defined chemical structures of drugs. Using resveratrol (RSV) as an example, we have synthesized and characterized a series of partial functional analogs of RSV. An analog (named RSVN) that specifically lost the inhibitory effect of RSV in cell migration was identified. The binding targets of RSVN and RSV was profiled and compared. Results: Comparative profiling of the RSV and RSVN binding targets showed that, unlike RSV, RSVN failed to target specific components involved in DNA methylation (histone deacetylase 1 [HDAC1] and DNA methyltransferase 3 alpha [DNMT3a]), suggesting that RSV suppresses cell migration through epigenetic regulation. Indeed, RSV treatment recruited HDAC1 and DNMT3a to the promoter region of the focal adhesion kinase (FAK), a key factor involved in cell adhesion, enhanced the promoter methylation, and thus attenuated the protein expression. The inhibitory effect of RSV in cell migration was diminished once FAK expression was restored. Thus, the mechanism of RSV in inhibiting cell migration could be largely accounted to epigenetically control of FAK expression. Conclusion: Our results showed that even though RSV exhibits promiscuous binding, its inhibitory effect on cell migration can be mechanistically understood. First, the presence of 4'-hydroxystilbene within the RSV structure is essential for this activity. Second, it inhibits cell migration through epigenetically based downregulation of FAK expression. Taken together, we propose that CPAT might also be adapted to delineate the specific function of other natural products (NPs) that exhibit binding promiscuity.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Perfilação da Expressão Gênica , Melanoma/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Resveratrol/farmacologia , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Movimento Celular/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Resveratrol/administração & dosagem , Resveratrol/análogos & derivados , Relação Estrutura-Atividade
9.
J Cell Biol ; 217(6): 2019-2032, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29653997

RESUMO

Misfolded cytosolic proteins are degraded by the ubiquitin proteasome system through quality control (QC) pathways defined by E3 ubiquitin ligases and associated chaperones. Although they work together as a comprehensive system to monitor cytosolic protein folding, their respective contributions remain unclear. To bridge existing gaps, the pathways mediated by the San1 and Ubr1 E3 ligases were studied coordinately. We show that pathways share the same complement of chaperones needed for substrate trafficking, ubiquitination, and degradation. The significance became clear when Ubr1, like San1, was localized primarily to the nucleus. Appending nuclear localization signals to cytosolic substrates revealed that Ydj1 and Sse1 are needed for substrate nuclear import, whereas Ssa1/Ssa2 is needed both outside and inside the nucleus. Sis1 is required to process all substrates inside the nucleus, but its role in trafficking is substrate specific. Together, these data show that using chaperones to traffic misfolded cytosolic proteins into the nucleus extends the nuclear protein QC pathway to include cytosolic clients.


Assuntos
Citosol/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Transporte Ativo do Núcleo Celular , Núcleo Celular/metabolismo , Modelos Biológicos , Mutação/genética , Dobramento de Proteína , Transporte Proteico , Proteínas de Saccharomyces cerevisiae/química
10.
J Cell Sci ; 131(3)2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29439157

RESUMO

The unfolded protein response (UPR) is classically viewed as a stress response pathway to maintain protein homeostasis at the endoplasmic reticulum (ER). However, it has recently emerged that the UPR can be directly activated by lipid perturbation, independently of misfolded proteins. Comprising primarily phospholipids, sphingolipids and sterols, individual membranes can contain hundreds of distinct lipids. Even with such complexity, lipid distribution in a cell is tightly regulated by mechanisms that remain incompletely understood. It is therefore unsurprising that lipid dysregulation can be a key factor in disease development. Recent advances in analysis of lipids and their regulators have revealed remarkable mechanisms and connections to other cellular pathways including the UPR. In this Review, we summarize the current understanding in UPR transducers functioning as lipid sensors and the interplay between lipid metabolism and ER homeostasis in the context of metabolic diseases. We attempt to provide a framework consisting of a few key principles to integrate the different lines of evidence and explain this rather complicated mechanism.


Assuntos
Metabolismo dos Lipídeos , Doenças Metabólicas/metabolismo , Resposta a Proteínas não Dobradas , Animais , Retículo Endoplasmático/metabolismo , Humanos , Lipídeos/química , Fluidez de Membrana
11.
Cell ; 171(2): 346-357.e12, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28919078

RESUMO

Newly synthesized proteins engage molecular chaperones that assist folding. Their progress is monitored by quality control systems that target folding errors for degradation. Paradoxically, chaperones that promote folding also direct unfolded polypeptides for degradation. Hence, a mechanism was previously hypothesized that prevents the degradation of actively folding polypeptides. In this study, we show that a conserved endoplasmic reticulum (ER) membrane protein complex, consisting of Slp1 and Emp65 proteins, performs this function in the ER lumen. The complex binds unfolded proteins and protects them from degradation during folding. In its absence, approximately 20%-30% of newly synthesized proteins that could otherwise fold are degraded. Although the Slp1-Emp65 complex hosts a broad range of clients, it is specific for soluble proteins. Taken together, these studies demonstrate the vulnerability of newly translated, actively folding polypeptides and the discovery of a new proteostasis functional class we term "guardian" that protects them from degradation.


Assuntos
Retículo Endoplasmático/metabolismo , Dobramento de Proteína , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animais , Degradação Associada com o Retículo Endoplasmático , Glicosilação , Camundongos , Chaperonas Moleculares/metabolismo , Proteólise , Saccharomyces cerevisiae/citologia , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Transporte Vesicular/química
12.
ACS Cent Sci ; 3(7): 743-750, 2017 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-28776016

RESUMO

The antimalarial artemisinin (ART) possesses anticancer activity, but its underlying mechanism remains largely unclear. Using a chemical proteomics approach with artemisinin-based activity probes, we identified over 300 specific ART targets. This reveals an anticancer mechanism whereby ART promiscuously targets multiple critical biological pathways and leads to cancer cell death. The specific cytotoxicity of ART against colorectal cancer (CRC) cells rather than normal colon epithelial cells is due to the elevated capacity of heme synthesis in the cancer cells. Guided by this mechanism, the specific cytotoxicity of ART toward CRC cells can be dramatically enhanced with the addition of aminolevulinic acid (ALA), a clinically used heme synthesis precursor, to increase heme levels. Importantly, this novel ART/ALA combination therapy proves to be more effective than an ART monotherapy in a mouse xenograft CRC model. Thus, ART can be repurposed and potentiated by exploitation of its mechanism of action and the metabolic features of the CRC cells.

13.
Med Res Rev ; 37(6): 1492-1517, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28643446

RESUMO

Artemisinin and its derivatives (collectively termed as artemisinins) are among the most important and effective antimalarial drugs, with proven safety and efficacy in clinical use. Beyond their antimalarial effects, artemisinins have also been shown to possess selective anticancer properties, demonstrating cytotoxic effects against a wide range of cancer types both in vitro and in vivo. These effects appear to be mediated by artemisinin-induced changes in multiple signaling pathways, interfering simultaneously with multiple hallmarks of cancer. Great strides have been taken to characterize these pathways and to reveal their anticancer mechanisms of action of artemisinin. Moreover, encouraging data have also been obtained from a limited number of clinical trials to support their anticancer property. However, there are several key gaps in knowledge that continue to serve as significant barriers to the repurposing of artemisinins as effective anticancer agents. This review focuses on important and emerging aspects of this field, highlighting breakthroughs in unresolved questions as well as novel techniques and approaches that have been taken in recent studies. We discuss the mechanism of artemisinin activation in cancer, novel and significant findings with regards to artemisinin target proteins and pathways, new understandings in artemisinin-induced cell death mechanisms, as well as the practical issues of repurposing artemisinin. We believe these will be important topics in realizing the potential of artemisinin and its derivatives as safe and potent anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Artemisininas/farmacologia , Neoplasias/tratamento farmacológico , Animais , Humanos , Terapia de Alvo Molecular
14.
Trends Pharmacol Sci ; 38(6): 506-511, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28473165

RESUMO

Artemisinin and its derivatives, in combination with partner drugs, are currently the most effective treatments for malaria parasite infection. Even though artemisinin has been widely used for decades, its mechanism of action had remained controversial until recently. Artemisinin combination therapies (ACTs) have recently been found to be losing efficacy in Southeast Asia. This 'artemisinin resistance', defined by a delayed parasite clearance time, has been associated with several genetic mutations. As with any other drug resistance phenotype, resistance can best be understood based on its mechanism of action. Recently, it was demonstrated that artemisinin attacks multiple parasitic targets, suggesting that mutations in drug targets are unlikely to cause high-level artemisinin resistance. These findings will help us to better understand the mechanisms of artemisinin resistance and suggest protocol modifications that may improve the efficacy of ACTs.


Assuntos
Anti-Infecciosos/farmacologia , Artemisininas/farmacologia , Animais , Antimaláricos/farmacologia , Resistência a Medicamentos , Quimioterapia Combinada , Humanos , Malária/tratamento farmacológico
15.
Nat Rev Mol Cell Biol ; 16(12): 742-52, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26465718

RESUMO

Membrane-bound and soluble proteins of the secretory pathway are commonly glycosylated in the endoplasmic reticulum. These adducts have many biological functions, including, notably, their contribution to the maturation of glycoproteins. N-linked glycans are of oligomeric structure, forming configurations that provide blueprints to precisely instruct the folding of protein substrates and the quality control systems that scrutinize it. O-linked mannoses are simpler in structure and were recently found to have distinct functions in protein quality control that do not require the complex structure of N-linked glycans. Together, recent studies reveal the breadth and sophistication of the roles of these glycan-directed modifications in protein biogenesis.


Assuntos
Retículo Endoplasmático/metabolismo , Glicoproteínas/química , Polissacarídeos/química , Dobramento de Proteína , Processamento de Proteína Pós-Traducional , Animais , Glicosilação , Humanos , Estrutura Terciária de Proteína , Schizosaccharomyces/metabolismo
16.
Semin Cell Dev Biol ; 41: 129-34, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25666261

RESUMO

Nowhere else does the cell employ posttranslational protein modifications as extensively as in the endoplasmic reticulum (ER). In fact, such modifications can comprise the bulk of the mass of a mature protein in some cases. The most common modification is glycosylation, with N-linked glycans being the most commonly studied and best understood. However, the covalent modification of serine and threonine side chains with mannose or O-mannosylation has been gaining interest. Part of the attention comes from the realization that O-mannosylation is a conserved process found in most eukaryotes and defects in O-mannosylation can give rise to human disease. Long known to be important structural modification of some endomembrane system proteins, recent findings reveal that it is a common modification of unfolded proteins. For irreversibly misfolded proteins, O-mannosylation can aid in their disposal through ER or lysosomal pathways. The protein O-mannosylation pathway can also play an instrumental role in monitoring the folding of newly synthesized proteins. Proteins that fail to fold efficiently are O-mannosylated to remove them from harmful futile protein folding cycles and prepare them for disposal. Thus, O-mannosylation joins N-linked glycosylation as a major mechanism involved in the folding and quality control of newly synthesized proteins in the ER.


Assuntos
Retículo Endoplasmático/metabolismo , Manose/metabolismo , Polissacarídeos/metabolismo , Processamento de Proteína Pós-Traducional , Retículo Endoplasmático/enzimologia , Glicosilação , Humanos , Manosiltransferases/metabolismo , Modelos Biológicos , Dobramento de Proteína , Saccharomyces cerevisiae/metabolismo
17.
Science ; 340(6135): 978-81, 2013 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-23704572

RESUMO

Newly synthesized polypeptides fold and assemble with assistance from protein chaperones. Full maturation can take multiple attempts, exchanging chaperones at each round. Improperly folded molecules must exit folding cycles and be degraded. In the endoplasmic reticulum (ER), prolonged substrate cycling is detrimental because it expends chaperone and energy resources and increases toxic reactive oxygen species. In budding yeast, we found that unfolded protein O-mannosylation terminated failed folding attempts through the Pmt1/Pmt2 complex. O-mannosylation incapacitated target molecule folding and removed them from folding cycles by reducing engagement with the Kar2 chaperone. In an in vitro protein refolding assay, the modification intrinsically and irreversibly disabled the folding potential of the substrate. Thus, protein folding termination can involve a covalent glycosylation event.


Assuntos
Retículo Endoplasmático/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Manose/metabolismo , Dobramento de Proteína , Saccharomyces cerevisiae/metabolismo , Resposta a Proteínas não Dobradas , Glicosilação , Proteínas de Fluorescência Verde/metabolismo , Manosiltransferases/genética , Manosiltransferases/metabolismo
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