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1.
Nature ; 597(7874): 64-69, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34280952

RESUMEN

Synthetic chemistry is built around the formation of carbon-carbon bonds. However, the development of methods for selective carbon-carbon bond cleavage is a largely unmet challenge1-6. Such methods will have promising applications in synthesis, coal liquefaction, petroleum cracking, polymer degradation and biomass conversion. For example, aromatic rings are ubiquitous skeletal features in inert chemical feedstocks, but are inert to many reaction conditions owing to their aromaticity and low polarity. Over the past century, only a few methods under harsh conditions have achieved direct arene-ring modifications involving the cleavage of inert aromatic carbon-carbon bonds7,8, and arene-ring-cleavage reactions using stoichiometric transition-metal complexes or enzymes in bacteria are still limited9-11. Here we report a copper-catalysed selective arene-ring-opening reaction strategy. Our aerobic oxidative copper catalyst converts anilines, arylboronic acids, aryl azides, aryl halides, aryl triflates, aryl trimethylsiloxanes, aryl hydroxamic acids and aryl diazonium salts into alkenyl nitriles through selective carbon-carbon bond cleavage of arene rings. This chemistry was applied to the modification of polycyclic aromatics and the preparation of industrially important hexamethylenediamine and adipic acid derivatives. Several examples of the late-stage modification of complex molecules and fused ring compounds further support the potential broad utility of this methodology.

2.
Plant J ; 117(4): 1264-1280, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37964640

RESUMEN

Rosa roxburghii and Rosa sterilis, two species belonging to the Rosaceae family, are widespread in the southwest of China. These species have gained recognition for their remarkable abundance of ascorbate in their fresh fruits, making them an ideal vitamin C resource. In this study, we generated two high-quality chromosome-scale genome assemblies for R. roxburghii and R. sterilis, with genome sizes of 504 and 981.2 Mb, respectively. Notably, we present a haplotype-resolved, chromosome-scale assembly for diploid R. sterilis. Our results indicated that R. sterilis originated from the hybridization of R. roxburghii and R. longicuspis. Genome analysis revealed the absence of recent whole-genome duplications in both species and identified a series of duplicated genes that possibly contributing to the accumulation of flavonoids. We identified two genes in the ascorbate synthesis pathway, GGP and GalLDH, that show signs of positive selection, along with high expression levels of GDP-d-mannose 3', 5'-epimerase (GME) and GDP-l-galactose phosphorylase (GGP) during fruit development. Furthermore, through co-expression network analysis, we identified key hub genes (MYB5 and bZIP) that likely regulate genes in the ascorbate synthesis pathway, promoting ascorbate biosynthesis. Additionally, we observed the expansion of terpene synthase genes in these two species and tissue expression patterns, suggesting their involvement in terpenoid biosynthesis. Our research provides valuable insights into genome evolution and the molecular basis of the high concentration of ascorbate in these two Rosa species.


Asunto(s)
Rosa , Rosa/genética , Rosa/metabolismo , Ácido Ascórbico/metabolismo , Genes de Plantas , Cromosomas , Evolución Molecular
3.
Drug Resist Updat ; 73: 101028, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38340425

RESUMEN

AIMS: The overexpression of ABC transporters on cancer cell membranes is one of the most common causes of multidrug resistance (MDR). This study investigates the impact of ABCC1 and ABCG2 on the resistance to talazoparib (BMN-673), a potent poly (ADP-ribose) polymerase (PARP) inhibitor, in ovarian cancer treatment. METHODS: The cell viability test was used to indicate the effect of talazoparib in different cell lines. Computational molecular docking analysis was conducted to simulate the interaction between talazoparib and ABCC1 or ABCG2. The mechanism of talazoparib resistance was investigated by constructing talazoparib-resistant subline A2780/T4 from A2780 through drug selection with gradually increasing talazoparib concentration. RESULTS: Talazoparib cytotoxicity decreased in drug-selected or gene-transfected cell lines overexpressing ABCC1 or ABCG2 but can be restored by ABCC1 or ABCG2 inhibitors. Talazoparib competitively inhibited substrate drug efflux activity of ABCC1 or ABCG2. Upregulated ABCC1 and ABCG2 protein expression on the plasma membrane of A2780/T4 cells enhances resistance to other substrate drugs, which could be overcome by the knockout of either gene. In vivo experiments confirmed the retention of drug-resistant characteristics in tumor xenograft mouse models. CONCLUSIONS: The therapeutic efficacy of talazoparib in cancer may be compromised by its susceptibility to MDR, which is attributed to its interactions with the ABCC1 or ABCG2 transporters. The overexpression of these transporters can potentially diminish the therapeutic impact of talazoparib in cancer treatment.


Asunto(s)
Antineoplásicos , Neoplasias Ováricas , Ftalazinas , Humanos , Animales , Femenino , Ratones , Ribosa/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Resistencia a Antineoplásicos/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Proteínas de Neoplasias
4.
Drug Resist Updat ; 73: 101065, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38367548

RESUMEN

AIMS: To investigate the collateral sensitivity (CS) of ABCB1-positive multidrug resistant (MDR) colorectal cancer cells to the survivin inhibitor MX106-4C and the mechanism. METHODS: Biochemical assays (MTT, ATPase, drug accumulation/efflux, Western blot, RT-qPCR, immunofluorescence, flow cytometry) and bioinformatic analyses (mRNA-sequencing, reversed-phase protein array) were performed to investigate the hypersensitivity of ABCB1 overexpressing colorectal cancer cells to MX106-4C and the mechanisms. Synergism assay, long-term selection, and 3D tumor spheroid test were used to evaluate the anti-cancer efficacy of MX106-4C. RESULTS: MX106-4C selectively killed ABCB1-positive colorectal cancer cells, which could be reversed by an ABCB1 inhibitor, knockout of ABCB1, or loss-of-function ABCB1 mutation, indicating an ABCB1 expression and function-dependent mechanism. MX106-4C's selective toxicity was associated with cell cycle arrest and apoptosis through ABCB1-dependent survivin inhibition and activation on caspases-3/7 as well as modulation on p21-CDK4/6-pRb pathway. MX106-4C had good selectivity against ABCB1-positive colorectal cancer cells and retained this in multicellular tumor spheroids. In addition, MX106-4C could exert a synergistic anti-cancer effect with doxorubicin or re-sensitize ABCB1-positive cancer cells to doxorubicin by reducing ABCB1 expression in the cell population via long-term exposure. CONCLUSIONS: MX106-4C selectively kills ABCB1-positive MDR colorectal cancer cells via a novel ABCB1-dependent survivin inhibition mechanism, providing a clue for designing CS compound as an alternative strategy to overcome ABCB1-mediated colorectal cancer MDR.


Asunto(s)
Antineoplásicos , Neoplasias Colorrectales , Humanos , Survivin/genética , Survivin/metabolismo , Survivin/farmacología , Resistencia a Múltiples Medicamentos/genética , Sensibilidad Colateral al uso de Fármacos , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Antineoplásicos/uso terapéutico , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/farmacología
5.
Chemistry ; 30(8): e202303686, 2024 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-38054967

RESUMEN

Chromophores with hybridized local and charge-transfer (HLCT) excited state are promising for the realization of high performance blue organic light-emitting diodes (OLEDs). The rational manipulation of HLCT excited state for efficient emitters remains challenging. Herein, we present three donor-π-acceptor (D-π-A) molecules (mPAN, mPANPH, and mPNAPH) with phenanthro[9,10-d]imidazole (PI) and pyridinyl as donor and π-bridge respectively. Changes in various kinds of polycyclic aromatic derivative acceptors (anthracene, 9-phenylanthracene, and 1-phenylnaphthalene) could manipulate the excited states and optoelectronic properties. Theoretical calculations reveal that the S1 state of mPNAPH exhibits HLCT nature while the other two molecules show local excited (LE) state dominated feature. The photophysical properties also demonstrate this characteristic. Therefore, compared with mPAN and mPANPH, mPNAPH has higher photoluminescence quantum yield (PLQY) whether in solutions or neat films. Ultimately, the non-doped devices based on these emitters show high luminance larger than 35000 cd m-2 , and high maximum external quantum efficiencies (EQEmax s) larger than 5 % with low efficiency roll-off. In particular, the mPNAPH-based device displays an excellent performance of pure blue emission at 456 nm with Commission Internationale de L'Eclairage coordinate of (0.15, 0.16) and EQEmax of 6.13 % that benefited from the HLCT state and high-lying reverse intersystem crossing process.

6.
Appl Microbiol Biotechnol ; 108(1): 170, 2024 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-38265689

RESUMEN

The deep-sea environment is an extremely difficult habitat for microorganisms to survive in due to its intense hydrostatic pressure. However, the mechanisms by which these organisms adapt to such extreme conditions remain poorly understood. In this study, we investigated the metabolic adaptations of Microbacterium sediminis YLB-01, a cold and stress-tolerant microorganism isolated from deep-sea sediments, in response to high-pressure conditions. YLB-01 cells were cultured at normal atmospheric pressure and 28 ℃ until they reached the stationary growth phase. Subsequently, the cells were exposed to either normal pressure or high pressure (30 MPa) at 4 ℃ for 7 days. Using NMR-based metabolomic and proteomic analyses of YLB-01 cells exposed to high-pressure conditions, we observed significant metabolic changes in several metabolic pathways, including amino acid, carbohydrate, and lipid metabolism. In particular, the high-pressure treatment stimulates cell division and triggers the accumulation of UDP-glucose, a critical factor in cell wall formation. This finding highlights the adaptive strategies used by YLB-01 cells to survive in the challenging high-pressure environments of the deep sea. Specifically, we discovered that YLB-01 cells regulate amino acid metabolism, promote carbohydrate metabolism, enhance cell wall synthesis, and improve cell membrane fluidity in response to high pressure. These adaptive mechanisms play essential roles in supporting the survival and growth of YLB-01 in high-pressure conditions. Our study offers valuable insights into the molecular mechanisms underlying the metabolic adaptation of deep-sea microorganisms to high-pressure environments. KEY POINTS: • NMR-based metabolomic and proteomic analyses were conducted on Microbacterium sediminis YLB-01 to investigate the significant alterations in several metabolic pathways in response to high-pressure treatment. • YLB-01 cells used adaptive strategies (such as regulated amino acid metabolism, promoted carbohydrate metabolism, enhanced cell wall synthesis, and improved cell membrane fluidity) to survive in the challenging high-pressure environment of the deep sea. • High-pressure treatment stimulated cell division and triggered the accumulation of UDP-glucose, a critical factor in cell wall formation, in Microbacterium sediminis YLB-01 cells.


Asunto(s)
Actinomycetales , Proteómica , Aminoácidos , Glucosa , Uridina Difosfato , Microbacterium
7.
Sensors (Basel) ; 24(9)2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38733012

RESUMEN

The purpose of this article is to establish a prediction model of joint movements and realize the prediction of joint movemenst, and the research results are of reference value for the development of the rehabilitation equipment. This will be carried out by analyzing the impact of surface electromyography (sEMG) on ankle movements and using the Hill model as a framework for calculating ankle joint torque. The table and scheme used in the experiments were based on physiological parameters obtained through the model. Data analysis was performed on ankle joint angle signal, movement signal, and sEMG data from nine subjects during dorsiflexion/flexion, varus, and internal/external rotation. The Hill model was employed to determine 16 physiological parameters which were optimized using a genetic algorithm. Three experiments were carried out to identify the optimal model to calculate torque and root mean square error. The optimized model precisely calculated torque and had a root mean square error of under 1.4 in comparison to the measured torque. Ankle movement models predict torque patterns with accuracy, thereby providing a solid theoretical basis for ankle rehabilitation control. The optimized model provides a theoretical foundation for precise ankle torque forecasts, thereby improving the efficacy of rehabilitation robots for the ankle.


Asunto(s)
Algoritmos , Articulación del Tobillo , Electromiografía , Torque , Humanos , Articulación del Tobillo/fisiología , Electromiografía/métodos , Masculino , Rango del Movimiento Articular/fisiología , Adulto , Movimiento/fisiología , Fenómenos Biomecánicos/fisiología , Adulto Joven
8.
Bioorg Chem ; 135: 106481, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36966672

RESUMEN

Three series of phenylurea indole derivatives were synthesized with potent inhibitory activities on ABCG2 with simple and efficient synthetic routes. Among these compounds, four phenylurea indole derivatives 3c-3f with extended π system were discovered as the most potent ABCG2 inhibitors, while these compounds showed no inhibition on ABCB1. Compounds 3c and 3f were selected for further investigation to explore the mechanisms of action on reversing ABCG2-mediated multidrug resistance (MDR). The results revealed that compounds 3c and 3f increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing cells, but they did not alter the expression level or localization of ABCG2 in cells. In addition, both 3c and 3f significantly stimulated the ATP hydrolysis of ABCG2 transporter indicating that they can be competitive substrates of ABCG2 transporter, and thereby increase the accumulation of mitoxantrone in ABCG2-overexpressing H460/MX20 cells. Both 3c and 3f was docked into the drug-binding site of the human ABCG2 transporter protein (PDB 6FFC) with high affinities. This study showed that extending the π system of phenylurea indole derivatives enhanced their inhibitory activities on ABCG2, which may provide a clue for the further research to discover more potent ABCG2 inhibitors.


Asunto(s)
Antineoplásicos , Humanos , Antineoplásicos/química , Mitoxantrona/farmacología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Resistencia a Antineoplásicos , Compuestos de Fenilurea/farmacología , Línea Celular Tumoral , Indoles/farmacología , Proteínas de Neoplasias/metabolismo
9.
J Enzyme Inhib Med Chem ; 38(1): 2247183, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37642355

RESUMEN

As part of our continuous efforts to discover novel c-Met inhibitors as antitumor agents, four series of thiazole/thiadiazole carboxamide-derived analogues were designed, synthesised, and evaluated for the in vitro activity against c-Met and four human cancer cell lines. After five cycles of optimisation on structure-activity relationship, compound 51am was found to be the most promising inhibitor in both biochemical and cellular assays. Moreover, 51am exhibited potency against several c-Met mutants. Mechanistically, 51am not only induced cell cycle arrest and apoptosis in MKN-45 cells but also inhibited c-Met phosphorylation in the cell and cell-free systems. It also exhibited a good pharmacokinetic profile in BALB/c mice. Furthermore, the binding mode of 51am with both c-Met and VEGFR-2 provided novel insights for the discovery of selective c-Met inhibitors. Taken together, these results indicate that 51am could be an antitumor candidate meriting further development.


Asunto(s)
Neoplasias , Tiadiazoles , Humanos , Animales , Ratones , Tiadiazoles/farmacología , Tiazoles/farmacología , Fosforilación , Anticonvulsivantes , Apoptosis , Ratones Endogámicos BALB C , Neoplasias/tratamiento farmacológico
10.
Acta Biochim Biophys Sin (Shanghai) ; 55(12): 1913-1924, 2023 12 25.
Artículo en Inglés | MEDLINE | ID: mdl-37705348

RESUMEN

Cancer cachexia (CAC) is a debilitating condition that often arises from noncachexia cancer (NCAC), with distinct metabolic characteristics and medical treatments. However, the metabolic changes and underlying molecular mechanisms during cachexia progression remain poorly understood. Understanding the progression of CAC is crucial for developing diagnostic approaches to distinguish between CAC and NCAC stages, facilitating appropriate treatment for cancer patients. In this study, we establish a mouse model of colon CAC and categorize the mice into three groups: CAC, NCAC and normal control (NOR). By performing nuclear magnetic resonance (NMR)-based metabolomic profiling on mouse sera, we elucidate the metabolic properties of these groups. Our findings unveil significant differences in the metabolic profiles among the CAC, NCAC and NOR groups, highlighting significant impairments in energy metabolism and amino acid metabolism during cachexia progression. Additionally, we observe the elevated serum levels of lysine and acetate during the transition from the NCAC to CAC stages. Using multivariate ROC analysis, we identify lysine and acetate as potential biomarkers for distinguishing between CAC and NCAC stages. These biomarkers hold promise for the diagnosis of CAC from noncachexia cancer. Our study provides novel insights into the metabolic mechanisms underlying cachexia progression and offers valuable avenues for the diagnosis and treatment of CAC in clinical settings.


Asunto(s)
Caquexia , Neoplasias del Colon , Humanos , Animales , Ratones , Caquexia/diagnóstico , Caquexia/etiología , Caquexia/metabolismo , Lisina , Metabolómica , Neoplasias del Colon/complicaciones , Neoplasias del Colon/diagnóstico , Biomarcadores , Acetatos
11.
Int J Mol Sci ; 24(17)2023 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-37686153

RESUMEN

Trehalose, a naturally occurring non-toxic disaccharide, has attracted considerable attention for its potential in alleviating oxidative stress in skeletal muscle. In this study, our aim was to elucidate the metabolic mechanisms underlying the protective effects of trehalose against hydrogen peroxide (H2O2)-induced oxidative stress in C2C12 myoblasts. Our results show that both trehalose treatment and pretreatment effectively alleviate the H2O2-induced decrease in cell viability, reduce intracellular reactive oxygen species (ROS), and attenuate lipid peroxidation. Furthermore, using NMR-based metabolomics analysis, we observed that trehalose treatment and pretreatment modulate the metabolic profile of myoblasts, specifically regulating oxidant metabolism and amino acid metabolism, contributing to their protective effects against oxidative stress. Importantly, our results reveal that trehalose treatment and pretreatment upregulate the expression levels of P62 and Nrf2 proteins, thereby activating the Nrf2-NQO1 axis and effectively reducing oxidative stress. These significant findings highlight the potential of trehalose supplementation as a promising and effective strategy for alleviating oxidative stress in skeletal muscle and provide valuable insights into its potential therapeutic applications.


Asunto(s)
Peróxido de Hidrógeno , Trehalosa , Trehalosa/farmacología , Factor 2 Relacionado con NF-E2 , Metabolómica , Estrés Oxidativo , Mioblastos
12.
Molecules ; 28(23)2023 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-38067608

RESUMEN

Volatile organic compounds (VOCs) and flavor characteristics of Rosa roxburghii Tratt. (RR) and Rosa sterilis (RS) were analyzed using headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry (HS-SPME-GC-MS). The flavor network was constructed by combining relative odor activity values (ROAVs), and the signature differential flavor components were screened using orthogonal partial least squares discriminant analysis (OPLS-DA) and random forest (RF). The results showed that 61 VOCs were detected in both RR and RS: 48 in RR, and 26 in RS. There were six key flavor components (ROAVs ≥ 1) in RR, namely nonanal, ethyl butanoate, ethyl hexanoate, (3Z)-3-hexen-1-yl acetate, ethyl caprylate, and styrene, among which ethyl butanoate had the highest contribution, whereas there were eight key flavor components (ROAVs ≥ 1) in RS, namely 2-nonanol, (E)-2-hexenal, nonanal, methyl salicylate, ß-ocimene, caryophyllene, α-ionone, and styrene, among which nonanal contributed the most to RS. The flavor of RR is primarily fruity, sweet, green banana, and waxy, while the flavor of RS is primarily sweet and floral. In addition, OPLS-DA and RF suggested that (E)-2-hexenal, ethyl caprylate, ß-ocimene, and ethyl butanoate could be the signature differential flavor components for distinguishing between RR and RS. In this study, the differences in VOCs between RR and RS were analyzed to provide a basis for further development and utilization.


Asunto(s)
Rosa , Compuestos Orgánicos Volátiles , Cromatografía de Gases y Espectrometría de Masas/métodos , Microextracción en Fase Sólida/métodos , Odorantes/análisis , Compuestos Orgánicos Volátiles/análisis , Estirenos
13.
J Am Chem Soc ; 144(29): 13415-13425, 2022 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-35839515

RESUMEN

The electrophilic halogenation of arenes is perhaps the simplest method to prepare aryl halides, which are important structural motifs in agrochemicals, materials, and pharmaceuticals. However, the nucleophilicity of arenes is weakened by the electron-withdrawing substituents, whose electrophilic halogenation reactions usually require harsh conditions and lead to limited substrate scopes and applications. Therefore, the halogenation of arenes containing electron-withdrawing groups (EWGs) and complex bioactive compounds under mild conditions has been a long-standing challenge. Herein, we describe Brønsted acid-catalyzed halogenation of arenes with electron-withdrawing substituents under mild conditions, providing an efficient protocol for aryl halides. The hydrogen bonding of Brønsted acid with the protic solvent 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) enables this transformation and thus solves this long-standing problem.


Asunto(s)
Electrones , Halogenación , Ácidos , Catálisis , Enlace de Hidrógeno
14.
Curr Microbiol ; 79(4): 95, 2022 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-35150317

RESUMEN

Microbes living in extreme environments often adopt strategies for survival, however, only a few studies have examined the adaptive mechanism of deep-sea bacteria in in-situ environments. In this study, transcriptomic data of the deep-sea piezotolerant and psychrotolerant actinomycete Microbacterium sediminis YLB-01 under the conditions of NPNT (normal temperature and pressure: 28 °C, 0.1 MPa), HPNT (normal temperature and high pressure: 28 °C, 30 MPa), NPLT (low temperature and atmospheric pressure: 4 °C, 0.1 MPa) and HPLT (low temperature and high pressure: 4 °C, 30 MPa) were examined and compared. Transcriptome results showed that M. sediminis YLB-01 responds to deep-sea low temperature under high-pressure environments by upregulating the ABC transport system, DNA damage repair response, pentose phosphate pathway, amino acid metabolism and fatty acid metabolism, while down-regulating division, oxidative phosphorylation, the TCA cycle, pyruvate metabolism, ion transport and peptidoglycan biosynthesis. Seven key genes specifically expressed under HPLT conditions were screened, and these genes are present in many strains that are tolerant to low temperatures and high pressures. This study provides transcription level insights into the tolerance mechanisms of M. sediminis YLB-01 in a simulated deep-sea in situ environment.


Asunto(s)
Actinomycetales , Transcriptoma , Actinomycetales/genética , Presión Hidrostática , Microbacterium , Temperatura
15.
Drug Resist Updat ; 54: 100743, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33513557

RESUMEN

ATP-binding cassette (ABC) transporters mediate the ATP-driven translocation of structurally and mechanistically distinct substrates against steep concentration gradients. Among the seven human ABC subfamilies namely ABCA-ABCG, ABCC is the largest subfamily with 13 members. In this respect, 9 of the ABCC members are termed "multidrug resistance proteins" (MRPs1-9) due to their ability to mediate cancer multidrug resistance (MDR) by extruding various chemotherapeutic agents or their metabolites from tumor cells. Furthermore, MRPs are also responsible for the ATP-driven efflux of physiologically important organic anions such as leukotriene C4, folic acid, bile acids and cAMP. Thus, MRPs are involved in important regulatory pathways. Blocking the anticancer drug efflux function of MRPs has shown promising results in overcoming cancer MDR. As a result, many novel MRP modulators have been developed in the past decade. In the current review, we summarize the structure, tissue distribution, biological and pharmacological functions as well as clinical insights of MRPs. Furthermore, recent updates in MRP modulators and their therapeutic applications in clinical trials are also discussed.


Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/farmacología , Antineoplásicos/farmacología , Resistencia a Antineoplásicos/fisiología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Transporte Biológico , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos
16.
Chem Soc Rev ; 50(14): 8067-8101, 2021 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-34095935

RESUMEN

Molecular oxygen as a green, non-toxic and inexpensive oxidant has displayed lots of advantages compared with other oxidants towards more selective, sustainable, and environmentally benign organic transformations. The oxygenation reactions which employ molecular oxygen or ambient air as both an oxidant and an oxygen source provide an efficient route to the synthesis of oxygen-containing compounds, and have been demonstrated in practical applications such as pharmaceutical synthesis and late-stage functionalization of complex molecules. This review article introduces the recent advances of radical processes in molecular oxygen-mediated oxygenation reactions. Reaction scopes, limitations and mechanisms are discussed based on reaction types and catalytic systems. Conclusions and perspectives are also given in the end.

17.
Arch Microbiol ; 203(6): 3279-3285, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33860341

RESUMEN

A halophilic, Gram-staining-negative, rod-shaped, flagellated and motile bacterium, strain QX-1 T, was isolated from deep-sea sediment at a depth of 3332 m in the southwestern Indian Ocean. Strain QX-1 T growth was observed at 4-50 °C (optimum 37 °C), pH 5.0-11.0 (optimum pH 7.0), 3-25% NaCl (w/v; optimum 7%), and it did not grow without NaCl. A phylogenetic analysis based on the 16S rRNA gene placed strain QX-1 T in the genus Halomonas and most closely related to Halomonas sulfidaeris (97.9%), Halomonas zhaodongensis (97.8%), Halomonas songnenensis (97.6%), Halomonas hydrothermalis (97.4%), Halomonas subterranea (97.3%), Halomonas salicampi (97.1%), and Halomonas arcis (97.0%). DNA-DNA hybridization (< 26.5%) and average nucleotide identity values (< 83.5%) between strain QX-1 T and the related type strains meet the accepted criteria for a new species. The principal fatty acids (> 10%) of strain QX-1 T are C16:0 (25.5%), C17:0 cyclo (14.0%), C19:0 cyclo ω8c (18.7%), and summed feature 8 (C18:1 ω7c and/or C18:1 ω6c, 18.1%). The polar lipids of strain QX-1 T are mainly diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, unidentified phospholipid, unidentified aminophospholipid, and five unidentified lipids. The main respiratory quinone is Q-9. The G + C content of its chromosomal DNA is 54.4 mol%. Its fatty acid profile, respiratory quinones, and G + C content also support the placement of QX-1 T in the genus Halomonas. These phylogenetic, phenotypic, and chemotaxonomic analyses indicate that QX-1 T is a novel species, for which the name Halomonas maris is proposed. The type strain is QX-1 T (= MCCC 1A17875T = KCTC 82198 T = NBRC 114670 T).


Asunto(s)
Sedimentos Geológicos/microbiología , Halomonas/aislamiento & purificación , Composición de Base , ADN Bacteriano/química , Ácidos Grasos/análisis , Halomonas/química , Halomonas/clasificación , Halomonas/genética , Océano Índico , Lípidos/análisis , Filogenia , Tolerancia a la Sal
18.
Bioorg Med Chem ; 52: 116522, 2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-34837819

RESUMEN

Stroke is a major public health problem with an imperative need for a more effective and tolerated therapy. Neuroprotective therapy may be an effective therapeutic intervention for stroke. The morbidity and mortality of stroke-induced secondary brain injury is mainly caused by neuronal apoptosis, which can be executed in a caspase-dependent or apoptosis inducing factor (AIF)-dependent manner. As apoptosis is an energy-dependent process with a relative time delay, abnormal energy metabolism could be a significant and fundamental pathophysiological basis of stroke. To our knowledge, convincible evidences that AMPK inhibition exerts neuroprotection in cerebral ischemia injury via anti-apoptosis remain to be investigated. Accordingly, the aims of this study were to investigate the protective effects of AMPK inhibitor BML-275 on cerebral ischemic/reperfusion (I/R) injury and to elucidate the underlying mechanisms. Cerebral ischemia was induced by transient middle cerebral artery occlusion (tMCAO) in male C57BL/6 mice. The therapeutic effects of BML-275 were evaluated by infarct sizes, neurological scores and the proportion of apoptotic neurons after 24 h of reperfusion. The cell apoptosis markers cyt c and AIF were also evaluated. The results showed that intraperitoneally administration of BML-275 alleviate the cerebral infarction, neurological deficit and neuronal apoptosis induced by MCAO. BML-275 simultaneously induces anti-apoptosis and decreases the expression of cyt c and AIF. This study supports the hypothesis that anti-apoptosis is one of potential neuroprotective strategies for the treatment of stroke.


Asunto(s)
Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Factor Inductor de la Apoptosis/antagonistas & inhibidores , Isquemia Encefálica/tratamiento farmacológico , Citocromos c/antagonistas & inhibidores , Fármacos Neuroprotectores/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Apoptosis/efectos de los fármacos , Factor Inductor de la Apoptosis/genética , Factor Inductor de la Apoptosis/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Citocromos c/genética , Citocromos c/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad
19.
Curr Microbiol ; 78(4): 1662-1669, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33651187

RESUMEN

A Gram-staining-negative, aerobic, flagellated, motile, rod-shaped, halophilic bacterium QX-2T was isolated from the deep-sea sediment of the Southwest Indian Ocean at a depth of 2699 m. Growth of the QX-2T bacteria was observed at 4-50 °C (optimum 30 °C), pH 5.0-12.0 (optimum pH 6.0) and 0%-30% NaCl (w/v) [optimum 4% (w/v)]. 16S rRNA gene sequencing revealed that strain QX-2T has the closest relationship with Halomonas titanicae DSM 22872T (98.2%). Phylogeny analysis classified the strain QX-2T into the genus Halomonas. The average nucleotide identity and DNA-DNA hybridization values between strain QX-2T and related type strains were lower than the currently accepted new species definition standards. Principal fatty acids (> 10%) determined were C16:0 (12.41%), C12:0-3OH (25.15%), summed feature 3 (C16:1 ω7c and/or C16:1 ω6c, 11.55%) and summed feature 8 (C18:1 ω7c and/or C18:1 ω6c, 16.06%). Identified polar lipids in strain QX-2T were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, unidentified phospholipid, unidentified aminophospholipid and five unidentified lipids (L1-L5). The main respiratory quinone was Q-9. The content of DNA G+C was determined to be 54.34 mol%. The results of phylogenetic analysis, phenotypic analysis and chemotaxonomic studies showed that strain QX-2T represents a novel species within the genus Halomonas, for which the name Halomonas sedimenti sp. nov. is proposed, with the type strain QX-2T (MCCC 1A17876T = KCTC 82199T).


Asunto(s)
Halomonas , Técnicas de Tipificación Bacteriana , Composición de Base , ADN Bacteriano/genética , Ácidos Grasos/análisis , Halomonas/genética , Océano Índico , Fosfolípidos/análisis , Filogenia , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN
20.
BMC Musculoskelet Disord ; 22(1): 379, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33892699

RESUMEN

BACKGROUNDS: Theaim of this study was to assess the efficacy of a modified intrafocal pinningtechnique with three-dimensional (3D) planning to facilitate volar plating in dorsally comminuted intra-articular distal radius fractures. METHODS: Intotal 35 AO/OTA type C2 and C3 fractures were finally included.The 3D digital model of the fracture was reconstructed based on preoperative computedtomographic (CT) images, with the displacement of the comminuted dorsalfragment and the intra-articular fragment analyzed for preoperative planning. During operation, amodified intrafocal pinning technique was applied percutaneously from thedorsal aspect of the radius to reduce the collapsed intra-articular fragmentfollowing volar plating. Adequate reduction was confirmed in all of patientsconsidering radial height, radial inclination and volar tilt in postoperativeradiographs. RESULTS: No significant fracture re-displacement wasobserved in most of the cases during a mean follow-up period of 17.4 months, exceptfor two patients withthe C3 fracture. All of the patients achieved adequate clinicalROMs at 12 months postoperatively, with a mean DASH score of 12.0. Most of the patients achievedan excellent (n = 21) or good (n = 12) Gartland and Werley wrist score. CONCLUSIONS: Ourmodified intrafocal pinning technique with 3D planning contributes to a satisfactoryclinical and radiological outcome in dorsally comminuted intra-articular distalradius fractures fixed with a volar locking plate. TRIALREGISTRATION: Notapplicable because the design of the study is retrospective.


Asunto(s)
Fracturas Conminutas , Fracturas del Radio , Placas Óseas , Fijación Interna de Fracturas , Fracturas Conminutas/diagnóstico por imagen , Fracturas Conminutas/cirugía , Humanos , Fracturas del Radio/diagnóstico por imagen , Fracturas del Radio/cirugía , Rango del Movimiento Articular , Estudios Retrospectivos , Resultado del Tratamiento
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