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1.
Dalton Trans ; 51(14): 5426-5433, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35311836

RESUMO

Temperature sensing plays essential roles in both fundamental research and high-tech applications. In this work, three isomorphic hexanuclear lanthanide metal-organic frameworks (Ln-MOFs), Ln(BPDC-xN) (Ln = Eu3+/Tb3+, x = 0, 1, 2) were prepared based on the cluster-based synthesis strategy with three structurally similar dicarboxylate ligands 4,4'-biphenyldicarboxylic acid (H2BPDC-0N), 6-(4-carboxyphenyl)nicotinic acid (H2BPDC-1N), and [2,2'-bipyridine]-5,5'-dicarboxylic acid (H2BPDC-2N) as the organic linkers. The as-synthesized Ln-MOFs were fully characterized using single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), elemental analysis (EA), and Fourier transform infrared spectra (FT-IR). Using a Eu3+/Tb3+ co-doping approach, Eu0.001Tb0.999(BPDC-xN) (x = 0, 1, 2) were identified as potential ratiometric luminescence thermometers. Since there are two suitable distances between the energy donors and acceptors within the framework for efficient energy transfer, all Eu0.001Tb0.999(BPDC-xN) (x = 0, 1, 2) maintain high relative sensitivity over a wide temperature range from 50 K to 300 K.

2.
Int J Biol Macromol ; 202: 68-79, 2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35033528

RESUMO

The current detoxification options of uranium, a toxic radioactive heavy metal, have obvious side effects. Polygonatum kingianum (PK), a natural product with the function of antioxidant, may be effective in detoxification and prevention of uranium-induced nephrotoxicity. Here, we studied the protective effects of PK polysaccharides (PKP) and aqueous extract (PKAE) on uranium-induced toxicity in human kidney (HK-2) cells. First, the physicochemical properties of PKP and PKAE were characterized. Assays on cultured cells demonstrated that pretreatment with PKP and PKAE significantly increased metabolic activity, relieved morphological impairments, and alleviated apoptosis. The impairments caused by uranium exposure were ameliorated (mitochondrial membrane potential and ATP level increased while reactive oxygen species decreased). Molecular mechanistic studies revealed that PKP and PKAE alleviated uranium-induced cytotoxicity by regulating mitochondria-mediated apoptosis and the GSK-3ß/Fyn/Nrf2 pathway. Collectively, our data support the preventive and therapeutic applications of PKP and PKAE for uranium poisoning.


Assuntos
Polygonatum , Urânio , Apoptose , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Rim , Estresse Oxidativo , Polygonatum/química , Polissacarídeos/metabolismo , Polissacarídeos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Urânio/toxicidade
3.
Proc Natl Acad Sci U S A ; 119(5)2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35082149

RESUMO

Reiterative transcription initiation, observed at promoters that contain homopolymeric sequences at the transcription start site, generates RNA products having 5' sequences noncomplementary to the DNA template. Here, using crystallography and cryoelectron microscopy to define structures, protein-DNA photocrosslinking to map positions of RNAP leading and trailing edges relative to DNA, and single-molecule DNA nanomanipulation to assess RNA polymerase (RNAP)-dependent DNA unwinding, we show that RNA extension in reiterative transcription initiation 1) occurs without DNA scrunching; 2) involves a short, 2- to 3-bp, RNA-DNA hybrid; and 3) generates RNA that exits RNAP through the portal by which scrunched nontemplate-strand DNA exits RNAP in standard transcription initiation. The results establish that, whereas RNA extension in standard transcription initiation proceeds through a scrunching mechanism, RNA extension in reiterative transcription initiation proceeds through a slippage mechanism, with slipping of RNA relative to DNA within a short RNA-DNA hybrid, and with extrusion of RNA from RNAP through an alternative RNA exit.


Assuntos
Sítio de Iniciação de Transcrição/fisiologia , Transcrição Genética/genética , DNA/genética , RNA Polimerases Dirigidas por DNA/genética , Regiões Promotoras Genéticas/genética , RNA/genética
4.
J Hazard Mater ; 424(Pt B): 127546, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34879532

RESUMO

Thorium is a radioactive heavy metal and an emerging environmental pollutant. Ecological and human health risks from thorium exposure are growing with the excavation of rare earth metals and implementation of thorium-based nuclear reactors. Thorium poisoning is associated with carcinogenesis, liver impairments, and congenital anomalies. To date, the biomolecular targets that underlie thorium-induced toxicity remain unknown. Here, we used in vitro enzymatic activity assays to comprehensively evaluate the effects of thorium on the mitochondrial respiration process. Thorium was found to inhibit respiratory chain complex IV (cytochrome c oxidase) at sub-micromolar concentrations (IC50 ~ 0.4 µM, 90 µg/L). This is lower than the thorium level limit (246 µg/L) in drinking water specified by the World Health Organization. The inhibitory effects were further verified in mitochondria from human bone and liver cells (thorium mainly deposits in these organs). The inhibition of cytochrome c oxidase can readily rationalize well-documented cellular toxicities of thorium, such as alteration of mitochondrial membrane potential and production of reactive oxygen species. Therefore, cytochrome c oxidase is potentially a key molecular target underlying thorium-induced toxicological effect.


Assuntos
Complexo IV da Cadeia de Transporte de Elétrons , Tório , Transporte de Elétrons , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Humanos , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Tório/metabolismo
5.
Nucleic Acids Res ; 49(18): 10756-10769, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34530448

RESUMO

Spx is a global transcriptional regulator in Gram-positive bacteria and has been inferred to efficiently activate transcription upon oxidative stress by engaging RNA polymerase (RNAP) and promoter DNA. However, the precise mechanism by which it interacts with RNAP and promoter DNA to initiate transcription remains obscure. Here, we report the cryo-EM structure of an intact Spx-dependent transcription activation complex (Spx-TAC) from Bacillus subtilis at 4.2 Å resolution. The structure traps Spx in an active conformation and defines key interactions accounting for Spx-dependent transcription activation. Strikingly, an oxidized Spx monomer engages RNAP by simultaneously interacting with the C-terminal domain of RNAP alpha subunit (αCTD) and σA. The interface between Spx and αCTD is distinct from those previously reported activators, indicating αCTD as a multiple target for the interaction between RNAP and various transcription activators. Notably, Spx specifically wraps the conserved -44 element of promoter DNA, thereby stabilizing Spx-TAC. Besides, Spx interacts extensively with σA through three different interfaces and promotes Spx-dependent transcription activation. Together, our structural and biochemical results provide a novel mechanistic framework for the regulation of bacterial transcription activation and shed new light on the physiological roles of the global Spx-family transcription factors.


Assuntos
Proteínas de Bactérias/química , Transativadores/química , Ativação Transcricional , Bacillus subtilis , Microscopia Crioeletrônica , RNA Polimerases Dirigidas por DNA/química , Modelos Moleculares , Estresse Oxidativo , Regiões Promotoras Genéticas , Fator sigma/química
6.
Anal Chim Acta ; 1157: 338400, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33832594

RESUMO

It is of great significance to develop facile and economical strategies for on-site detection and treatment of toxic metal ions. Stimulus-responsive DNA hydrogel materials have been increasingly used for convenient detection of metal ions due to their advantages such as simplicity, portability, and ease of storage. However, these methods still require encapsulation of signal tags by labeling or embedding. In this paper, a one-step preparation of Pb2+-responsive pure DNA hydrogel material was designed to realize a new label-free strategy for Pb2+ biosensing. The Pb2+-dependent DNAzyme strand and substrate strand were introduced to fabricate the DNA hydrogel. The presence of Pb2+ in the sample activates the enzyme strand in the hydrogel skeleton and triggers the cleavage of the substrate, thereby destroy the hydrogel structure. DNA fragments released by the collapsed hydrogel were readily measured as signal output for quantifying Pb2+ concentrations with a minimum detection limit of 7.7 nM. We successfully eliminated the need for embedding or labeling of signal molecules by using the DNA molecules that construct hydrogels as the signal output. And the newly developed method for label-free detection of Pb2+ based on pure DNA hydrogel is simple, easy readout, and cost-effective. By adjusting the DNAzyme and substrate sequences, label-free analysis of other metal ions can also be achieved. We expect that our strategy can be applied to the field detection of toxic metal ions.


Assuntos
Técnicas Biossensoriais , DNA Catalítico , DNA , Hidrogéis , Íons , Chumbo , Limite de Detecção
7.
Chem Commun (Camb) ; 57(25): 3143-3146, 2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33634810

RESUMO

Three different thermo-responsive fluorescent thermometers were constructed by regulating the triplet energy level of organic ligands in isostructural Eu/Tb mixed MOFs. Among them, a quite unusual and rarely reported temperature-dependent fluorescence behavior was observed in LnBDC-NH2, and Eu0.01Tb0.99NDC is effective in the physiological range with the maximum relative sensitivity of 7.32% °C-1.


Assuntos
Európio/química , Limite de Detecção , Estruturas Metalorgânicas/química , Temperatura , Térbio/química , Termometria/instrumentação
8.
Dalton Trans ; 50(5): 1797-1807, 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33464250

RESUMO

Magnesium hydride (MgH2) is considered to be one of the most promising hydrogen storage materials owing to its safety profile, low cost and high hydrogen storage capacity. However, its slow kinetic performance and thermal stability limit the possibility of practical applications. Herein, it is confirmed that the hydrogen storage performance of MgH2 can be effectively improved via doping with a flake Ni nano-catalyst. According to experimental results, a MgH2 + 5 wt% Ni composite begins to dehydrogenate at almost 180 °C and could dehydrogenate 6.7 wt% within 3 min at 300 °C. After complete dehydrogenation, hydrogen can be absorbed below 50 °C, and 4.6 wt% H2 can be absorbed at 125 °C within 20 min at a hydrogen pressure of 3 MPa. In addition, the activation energies of MgH2 hydrogen absorption and dehydrogenation decreased by 28.03 and 71 kJ mol-1, respectively. Cycling stability testing showed that the hydrogen storage capacity decreases significantly in the first few cycles and decreases slightly after 10 cycles. Furthermore, it was found that Mg2Ni/Mg2NiH4 was formed initially during the hydrogen absorption or desorption reaction on the surface of Mg/MgH2, which acted as a "hydrogen pump", accelerating the rates of hydrogen absorption and desorption.

9.
Environ Pollut ; 271: 116377, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33401214

RESUMO

As an emerging pollutant, uranium poses serious concerns to ecological and human health. The kidney has been established as a major deposition site and the most sensitive target organ for uranium poisoning, and the underlying toxicological mechanisms have been associated with oxidative stress and mitochondrial respiration. However, the identities of key molecular targets in uranium-induced toxicity remain elusive. In this study, we comprehensively evaluated the in vitro effects of uranium on ten critical enzymes in the mitochondrial respiration pathway and discovered that respiratory chain complex IV (cytochrome c oxidase) and complex V (ATP synthase) were strongly inhibited. The inhibitory effects were validated with mitochondria from human renal proximal tubule cells-the most affected renal site in uranium poisoning. The IC50 values (around 1 mg/L) are physiologically relevant, as they are comparable to known kidney accumulation levels in uranium poisoning. In addition, these inhibitory effects could explain the well-documented uranium-induced reactive oxygen species generation and mitochondrial alterations. In conclusion, cytochrome c oxidase and ATP synthase are possibly key molecular targets underlying the toxic effects of uranium.


Assuntos
Complexo IV da Cadeia de Transporte de Elétrons , Urânio , Trifosfato de Adenosina/metabolismo , Animais , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Humanos , Mitocôndrias/metabolismo , Estresse Oxidativo , Urânio/metabolismo , Urânio/toxicidade
10.
J Antibiot (Tokyo) ; 72(6): 432-436, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30816347

RESUMO

A concise route to a glycosylated allenic erythronolide was achieved. Key findings include the preparation of a desosamine sulfoxide donor and the use of the donor to glycosylate bulky acceptors. Additionally, the new reagent was used to prepare allene-containing macrocycles and to realize a four-step synthesis of macrolide 6 from bis[allene] 5. The longest linear sequence required to prepare 6 from commercial reagents was 15 steps.


Assuntos
Macrolídeos/síntese química , Glicosilação , Estrutura Molecular
11.
Elife ; 62017 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-29168694

RESUMO

During transcription initiation, RNA polymerase (RNAP) binds to promoter DNA, unwinds promoter DNA to form an RNAP-promoter open complex (RPo) containing a single-stranded 'transcription bubble,' and selects a transcription start site (TSS). TSS selection occurs at different positions within the promoter region, depending on promoter sequence and initiating-substrate concentration. Variability in TSS selection has been proposed to involve DNA 'scrunching' and 'anti-scrunching,' the hallmarks of which are: (i) forward and reverse movement of the RNAP leading edge, but not trailing edge, relative to DNA, and (ii) expansion and contraction of the transcription bubble. Here, using in vitro and in vivo protein-DNA photocrosslinking and single-molecule nanomanipulation, we show bacterial TSS selection exhibits both hallmarks of scrunching and anti-scrunching, and we define energetics of scrunching and anti-scrunching. The results establish the mechanism of TSS selection by bacterial RNAP and suggest a general mechanism for TSS selection by bacterial, archaeal, and eukaryotic RNAP.


Assuntos
Bactérias/genética , RNA Polimerases Dirigidas por DNA/metabolismo , Sítio de Iniciação de Transcrição , Iniciação da Transcrição Genética , Ligação Proteica
12.
Org Lett ; 18(12): 2868-71, 2016 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-27267744

RESUMO

Desmethyl erythronolides have emerged as macrolide targets that may prove effective against resistant bacteria. A five-step sequence to 4,10-didesmethyl (9S)-dihydroerythronolide A (1) from known cyclic bis[allene] 13 is reported. Key structural and mechanistic aspects of the synthesis are discussed along with catalytic allene osmylation. An improved route to 13 is also described.


Assuntos
Alcadienos/química , Antibacterianos/síntese química , Eritromicina/análogos & derivados , Catálise , Eritromicina/síntese química , Estrutura Molecular , Estereoisomerismo
13.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 7): o1547, 2009 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-21582833

RESUMO

THE TITLE COMPOUND [SYSTEMATIC NAME: 11-oxo-2,3-(oxy-dinitrilo)olean-12-en-29-oic acid], C(30)H(42)N(2)O(4), contains a linear array of five six-membered rings and a five-membered heterocyclic ring. The C ring, containing an α,ß-unsaturated ketone, has a slightly distorted half-chair conformation, as does the A ring, with N-C-C angles 125.3 (5), 111.2 (4), 124.9 (5) and 109.2 (5)°, while the other three six-membered rings adopt chair conformations. The enanti-omer has been assigned by reference to unchanging chiral centres in the synthetic procedure. An intramolecular C-H⋯O interaction is present. In the crystal structure, inter-molecular O-H⋯O hydrogen bonds link the mol-ecules.

14.
J Org Chem ; 71(8): 3137-40, 2006 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-16599610

RESUMO

Highly efficient methods for the syntheses of spiroimidazolinones via microwave-assisted three-component one-pot sequential reactions or one-pot domino reactions are described. The efficiency and utility of the methods have been demonstrated by quickly accessing the antihypertensive drug irbesartan (2).

15.
J Org Chem ; 70(25): 10488-93, 2005 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-16323862

RESUMO

[reactions: see text] One-pot total syntheses of the quinazolinobenzodiazepine alkaloids sclerotigenin (1), (+/-)-circumdatin F (2), and (+/-)-asperlicin C (3) via novel microwave-assisted domino reactions were achieved in 55%, 32%, and 20% yields, respectively, from commercially available starting materials. A two-step total synthesis of (+/-)-benzomalvin A (4) was accomplished with an overall yield of 16%. Additionally, analogues of circumdatin E were synthesized via the three-component one-pot sequential reactions promoted by microwave irradiation. Finally, a two-step formal total synthesis of (+/-)-asperlicin E (5) was also realized by using this microwave-assisted protocol.


Assuntos
Alcaloides/síntese química , Benzodiazepinas/síntese química , Micro-Ondas , Quinazolinas/síntese química , Benzodiazepinonas/síntese química , Métodos , Pirimidinonas/síntese química
16.
J Org Chem ; 70(16): 6339-45, 2005 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-16050695

RESUMO

A microwave-promoted three-component one-pot reaction has been developed to provide access to the core pyrazino[2,1-b]quinazoline-3,6-dione (1) scaffold, which is common to several families of alkaloids with significant biological activities. By adapting this synthetic strategy through the use of selected Boc-amino acids and amino acid esters, we have accomplished highly efficient and concise total syntheses of glyantrypine (2), fumiquinazoline F (3), and fiscalin B (5), achieving overall yields of 55, 39, and 20%, respectively.


Assuntos
Indóis/síntese química , Micro-Ondas , Quinazolinas/síntese química , Triptofano/análogos & derivados , Alcaloides/química , Fatores Biológicos/química , Indóis/química , Espectrometria de Massas , Estrutura Molecular , Quinazolinas/química , Triptofano/síntese química , Triptofano/química
17.
J Org Chem ; 70(6): 2332-4, 2005 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-15760224

RESUMO

[reaction: see text] The microwave-promoted Suzuki coupling reaction of aryl chlorides with boronic acids performed in an aqueous media was studied using the air- and moisture-stable catalyst POPd2 (dihydrogen di-mu-chlorodichlorobis(di-tert-butylphosphinito-kappaP)dipalladate (2-)). This catalyst system under microwave conditions (150 degrees C, 15 min) provided coupled products with yields ranging from 64% to 99%. This method tolerated a variety of substituents and sterically hindered substrates.


Assuntos
Compostos de Bifenilo/síntese química , Hidrocarbonetos Clorados/química , Micro-Ondas , Ácidos Borônicos/química , Estrutura Molecular , Compostos Organometálicos/química , Platina/química , Água/química
18.
Mol Divers ; 9(1-3): 81-9, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15789555

RESUMO

A series of diverse indole-based chemotypes were synthesized from beta-tetrahydrocarboline (beta-THC) scaffolds prepared from commercially and readily available tryptamines and alpha-ketoesters. Diversity can be generated within these chemotypes through the following strategies: (a) appendage of substituents to the beta-THC scaffold, prepared in situ or as a template, through further elaboration and (b) skeletal modifications to the beta-THC scaffold via ring forming or ring breaking reactions. The strategies described here are amenable to high throughput solution-phase parallel synthesis, providing access to novel indole-based screening libraries for drug discovery.


Assuntos
Alcaloides Indólicos/química , Carbolinas/química , Desenho de Fármacos , Indicadores e Reagentes , Conformação Molecular , Estrutura Molecular
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