Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 721
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Nature ; 619(7968): 143-150, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37380764

RESUMEN

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4-7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-ß-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.


Asunto(s)
Metabolismo Energético , Factor 15 de Diferenciación de Crecimiento , Músculo Esquelético , Pérdida de Peso , Animales , Humanos , Ratones , Depresores del Apetito/metabolismo , Depresores del Apetito/farmacología , Depresores del Apetito/uso terapéutico , Restricción Calórica , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Factor 15 de Diferenciación de Crecimiento/metabolismo , Factor 15 de Diferenciación de Crecimiento/farmacología , Factor 15 de Diferenciación de Crecimiento/uso terapéutico , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/terapia , Receptores Adrenérgicos beta/metabolismo , Pérdida de Peso/efectos de los fármacos
2.
Brief Bioinform ; 24(4)2023 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-37328705

RESUMEN

Binding free energy calculation of a ligand to a protein receptor is a fundamental objective in drug discovery. Molecular mechanics/Generalized-Born (Poisson-Boltzmann) surface area (MM/GB(PB)SA) is one of the most popular methods for binding free energy calculations. It is more accurate than most scoring functions and more computationally efficient than alchemical free energy methods. Several open-source tools for performing MM/GB(PB)SA calculations have been developed, but they have limitations and high entry barriers to users. Here, we introduce Uni-GBSA, a user-friendly automatic workflow to perform MM/GB(PB)SA calculations, which can perform topology preparation, structure optimization, binding free energy calculation and parameter scanning for MM/GB(PB)SA calculations. It also offers a batch mode that evaluates thousands of molecules against one protein target in parallel for efficient application in virtual screening. The default parameters are selected after systematic testing on the PDBBind-2011 refined dataset. In our case studies, Uni-GBSA produced a satisfactory correlation with the experimental binding affinities and outperformed AutoDock Vina in molecular enrichment. Uni-GBSA is available as an open-source package at https://github.com/dptech-corp/Uni-GBSA. It can also be accessed for virtual screening from the Hermite web platform at https://hermite.dp.tech. A free Uni-GBSA web server of a lab version is available at https://labs.dp.tech/projects/uni-gbsa/. This increases user-friendliness because the web server frees users from package installations and provides users with validated workflows for input data and parameter settings, cloud computing resources for efficient job completions, a user-friendly interface and professional support and maintenance.


Asunto(s)
Descubrimiento de Drogas , Simulación de Dinámica Molecular , Flujo de Trabajo , Entropía , Ligandos , Internet , Unión Proteica
3.
Am J Respir Cell Mol Biol ; 70(3): 215-225, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38061028

RESUMEN

The function of type 2 immunity and mechanisms underlying the initiation of type 2 immunity after sepsis-induced lung injury remain unclear. Sphingosine-1-phosphate receptor 2 (S1PR2) has been demonstrated to modulate type 2 immunity in the context of asthma and pulmonary fibrosis. Thus, this study aims to investigate the role of type 2 immunity and whether and how S1PR2 regulates type 2 immunity in sepsis. Peripheral type 2 immune responses in patients with sepsis and healthy control subjects were assessed. The impact of S1PR2 on type 2 immunity in patients with sepsis and in a murine model of sepsis was further investigated. The type 2 innate immune responses were significantly increased in the circulation of patients 24 hours after sepsis, which was positively related to clinical complications and negatively correlated with S1PR2 mRNA expression. Animal studies showed that genetic deletion or pharmacological inhibition of S1PR2 induced type 2 innate immunity accumulation in the post-septic lungs. Mechanistically, S1PR2 deficiency promoted macrophage-derived interleukin (IL)-33 increase and the associated type 2 response in the lung. Furthermore, S1PR2-regulated IL-33 from macrophages mitigated lung injury after sepsis in mice. In conclusion, a lack of S1PR2 modulates the type 2 immune response by upregulating IL-33 release from macrophages and alleviates sepsis-induced lung injury. Targeting S1PR2 may have potential therapeutic value for sepsis treatment.


Asunto(s)
Lesión Pulmonar , Sepsis , Animales , Humanos , Ratones , Interleucina-33 , Macrófagos , Sepsis/complicaciones , Receptores de Esfingosina-1-Fosfato
4.
J Biol Chem ; 299(8): 104968, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37380075

RESUMEN

Ykt6 is one of the most conserved SNARE (N-ethylmaleimide-sensitive factor attachment protein receptor) proteins involved in multiple intracellular membrane trafficking processes. The membrane-anchoring function of Ykt6 has been elucidated to result from its conformational transition from a closed state to an open state. Two ways of regulating the conformational transition were proposed: the C-terminal lipidation and the phosphorylation at the SNARE core. Despite many aspects of common properties, Ykt6 displays differential cellular localizations and functional behaviors in different species, such as yeast, mammals, and worms. The structure-function relationship underlying these differences remains elusive. Here, we combined biochemical characterization, single-molecule FRET measurement, and molecular dynamics simulation to compare the conformational dynamics of yeast and rat Ykt6. Compared to rat Ykt6 (rYkt6), yeast Ykt6 (yYkt6) has more open conformations and could not bind dodecylphosphocholine that inhibits rYkt6 in the closed state. A point mutation T46L/Q57A was shown to be able to convert yYkt6 to a more closed and dodecylphosphocholine-bound state, where Leu46 contributes key hydrophobic interactions for the closed state. We also demonstrated that the phospho-mutation S174D could shift the conformation of rYkt6 to a more open state, but the corresponding mutation S176D in yYkt6 leads to a slightly more closed conformation. These observations shed light on the regulatory mechanism underlying the variations of Ykt6 functions across species.


Asunto(s)
Proteínas SNARE , Saccharomyces cerevisiae , Animales , Ratas , Mamíferos/metabolismo , Proteínas R-SNARE/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas SNARE/genética , Proteínas SNARE/metabolismo
5.
J Am Chem Soc ; 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38838245

RESUMEN

The activity of Ru-based alkaline hydrogen oxidation reaction (HOR) electrocatalysts usually decreases rapidly at potentials higher than 0.1 V (vs a reversible hydrogen electrode (RHE)), which significantly limits the lifetime of fuel cells. It is found that this phenomenon is caused by the overadsorption of the O species due to the overcharging of Ru nanoparticles at high potentials. Here, Mn1Ox(OH)y clusters-modified Ru nanoparticles (Mn1Ox(OH)y@Ru/C) were prepared to promote charge transfer from overcharged Ru nanoparticles to Mn1Ox(OH)y clusters. Mn1Ox(OH)y@Ru/C exhibits high HOR activity and stability over a wide potential range of 0-1.0 V. Moreover, a hydroxide exchange membrane fuel cell with a Mn1Ox(OH)y@Ru/C anode delivers a high peak power density of 1.731 W cm-2, much superior to that of a Pt/C anode. In situ X-ray absorption fine structure (XAFS) analysis and density functional theory (DFT) calculations reveal that Mn in Mn1Ox(OH)y clusters could receive more electrons from overcharged Ru at higher potentials and significantly decrease the overadsorption of the O species on Ru, thus permitting the HOR on Ru to proceed at high potentials. This study provides guidance for the design of alkaline HOR catalysts without activity decay at high potentials.

6.
Small ; 20(17): e2307780, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38168535

RESUMEN

The development of high-performance, stable and platinum-free electrocatalysts for the hydrogen oxidation reaction (HOR) in alkaline media is crucial for the commercial application of anion exchange membrane fuel cells (AEMFCs). Ruthenium, as an emerging HOR electrocatalyst with a price advantage over platinum, still needs to solve the problems of low intrinsic activity and easy oxidation. Herein, Ru nanoparticles are anchored on the oxygen-vacancy-rich metalloid WO2.9 by interfacial engineering to create abundant and efficient Ru and WO2.9 interfacial active sites for accelerated HOR in alkaline media. Ru/WO2.9/C displays excellent catalytic activity with mass activity (8.29 A mgNM -1) and specific activity (1.32 mA cmNM -2), which are 2.5/3.3 and 21.8/8.3 times that of PtRu/C and Pt/C, respectively. Moreover, Ru/WO2.9/C exhibits excellent CO tolerance and operational stability. Experimental and theoretical studies reveal that the improved charge transfer from Ru to WO2.9 in the metal/metalloid heterostructure significantly tune the electronic structure of Ru sites and optimize the hydrogen binding energy (HBE) of Ru. While, WO2.9 provides abundant hydroxyl adsorption sites. Therefore, the equilibrium adsorption of hydrogen and hydroxyl at the interface of Ru/WO2.9 will be realized, and the oxidation of metal Ru would be avoided, thereby achieving excellent HOR activity and durability.

7.
Small ; : e2403107, 2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-39030942

RESUMEN

Designing robust catalysts for increasing the sluggish kinetics of the urea oxidation reaction (UOR) is challenging. Herein, the regulation of spin states for metal active sites by photoexcitation to facilitate the adsorption of urea and intermediates is demonstrated. Mo-doped nickel sulfide nanoribbon arrays (Mo-Ni3S2@NMF) with excellent light-trapping capacity are successfully prepared. Under AM 1.5G illumination, the activity of the Mo-Ni3S2@NMF exhibits a 50% improvement in the UOR current. Compared with those under dark conditions, Mo-Ni3S2@NMF achieve 10 mA cm-2 at 1.315 VRHE for UOR and 1.32 Vcell for urea electrolysis, which are decreases of 15 and 80 mV, respectively. The electron spin resonance, in situ Fourier transform infrared spectroscopy analysis and density functional theory calculations reveal that illumination led to the formation of Ni3+ active sites in a high-spin state, which strengthens the d-p orbital hybridization of Ni-N, hence facilitating the adsorption of urea. C─N cleavage of the *CONN intermediate is further inhibited, which promotes the oxidation of urea molecules via the active N2 pathway, thereby accelerating the UOR rate.

8.
Small ; : e2401404, 2024 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-38644200

RESUMEN

Developing low-loading platinum-group-metal (PGM) catalysts is one of the key challenges in commercializing anion-exchange-membrane-fuel-cells (AEMFCs), especially for hydrogen oxidation reaction (HOR). Here, ruthenium-iridium nanoparticles being deposited on a Zn-N species-doped carbon carrier (Ru6Ir/Zn-N-C) are synthesized and used as an anodic catalyst for AEMFCs. Ru6Ir/Zn-N-C shows extremely high mass activity (5.87 A mgPGM -1) and exchange current density (0.92 mA cm-2), which is 15.1 and 3.9 times that of commercial Pt/C, respectively. Based on the Ru6Ir/Zn-N-C AEMFCs achieve a peak power density of 1.50 W cm-2, surpassing the state-of-the-art commercial PtRu catalysts and the power ratio of the normalized loading is 14.01 W mgPGM anode -1 or 5.89 W mgPGM -1 after decreasing the anode loading (87.49 µg cm-2) or the total PGM loading (0.111 mg cm-2), satisfying the US Department of Energy's PGM loading target. Moreover, the solvent and solute isotope separation method is used for the first time to reveal the kinetic process of HOR, which shows the reaction is influenced by the adsorption of H2O and OH-. The improvement of the hydrogen bond network connectivity of the electric double layer by adjusting the interfacial H2O structure together with the optimized HBE and OHBE is proposed to be responsible for the high HOR activity of Ru6Ir/Zn-N-C.

9.
J Transl Med ; 22(1): 449, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38741129

RESUMEN

Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the impact of TP deficiency on lysosomes remains unclear, which are important for mitochondrial quality control and nucleic acid metabolism. Muscle biopsy tissue and skin fibroblasts from MNGIE patients, patients with m.3243 A > G mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and healthy controls (HC) were collected to perform mitochondrial and lysosomal functional analyses. In addition to mtDNA abnormalities, compared to controls distinctively reduced expression of LAMP1 and increased mitochondrial content were detected in the muscle tissue of MNGIE patients. Skin fibroblasts from MNGIE patients showed decreased expression of LAMP2, lowered lysosomal acidity, reduced enzyme activity and impaired protein degradation ability. TYMP knockout or TP inhibition in cells can also induce the similar lysosomal dysfunction. Using lysosome immunoprecipitation (Lyso- IP), increased mitochondrial proteins, decreased vesicular proteins and V-ATPase enzymes, and accumulation of various nucleosides were detected in lysosomes with TP deficiency. Treatment of cells with high concentrations of dThd and dUrd also triggers lysosomal dysfunction and disruption of mitochondrial homeostasis. Therefore, the results provided evidence that TP deficiency leads to nucleoside accumulation in lysosomes and lysosomal dysfunction, revealing the widespread disruption of organelles underlying MNGIE.


Asunto(s)
ADN Mitocondrial , Fibroblastos , Lisosomas , Mitocondrias , Encefalomiopatías Mitocondriales , Nucleósidos , Timidina Fosforilasa , Humanos , Lisosomas/metabolismo , Timidina Fosforilasa/metabolismo , Timidina Fosforilasa/deficiencia , Timidina Fosforilasa/genética , Encefalomiopatías Mitocondriales/metabolismo , Encefalomiopatías Mitocondriales/patología , Encefalomiopatías Mitocondriales/genética , Fibroblastos/metabolismo , Fibroblastos/patología , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Mitocondrias/metabolismo , Nucleósidos/metabolismo , Seudoobstrucción Intestinal/metabolismo , Seudoobstrucción Intestinal/patología , Seudoobstrucción Intestinal/enzimología , Seudoobstrucción Intestinal/genética , Oftalmoplejía/metabolismo , Oftalmoplejía/patología , Oftalmoplejía/congénito , Distrofia Muscular Oculofaríngea/metabolismo , Distrofia Muscular Oculofaríngea/patología , Masculino , Femenino , Piel/patología , Piel/metabolismo , Proteína 2 de la Membrana Asociada a los Lisosomas/metabolismo
10.
Opt Lett ; 49(4): 903-906, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38359212

RESUMEN

Compared with the single-aperture system, the multi-aperture coherent digital combining system has the technical advantage of the effective mitigation of deep fading under strong turbulence, ease of scalability, and potential higher collected optical power. However, the tricky problem of a multi-aperture system is to efficiently combine multiple branch signals with a static skew mismatch and with time-varying characteristics of received power scintillation. In this Letter, a real-valued massive array multiple-input multiple-output (MIMO) adaptive equalizer is proposed for the first time to our knowledge to realize multi-aperture channel equalization and combining, simultaneously. In the proof-of-principle system, the feasibility of the combining technique is verified based on a MIMO 4 × 2 equalizer in a 2.5-GBaud data rate QPSK modulation FPGA-based two-aperture coherent receiver with a dynamic turbulence simulator. The results show that no reduction in combining efficiency is observed under static turbulence conditions at the hard-decision forward error correction (HD-FEC) limit of 3.8 × 0-3, and combining efficiencies of 95% and 88% are obtained for the dynamic moderate and strong turbulence.

11.
Eur J Nucl Med Mol Imaging ; 51(9): 2744-2757, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38587644

RESUMEN

PURPOSE: Radiopharmaceutical therapies targeting fibroblast activation protein (FAP) have shown promising efficacy against many tumor types. But radiopharmaceuticals alone in most cases are insufficient to completely eradicate tumor cells, which can partially be attributed to the protective interplay between tumor cells and cancer-associated fibroblasts (CAFs). The C-X-C chemokine receptor type 4/C-X-C motif chemokine 12 (CXCR4/CXCL12) interaction plays an important role in orchestrating tumor cells and CAFs. We hereby investigated the feasibility and efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2, a FAP-targeting radiopharmaceutical, in combination with AMD3100, a CXCR4 antagonist, in a preclinical murine model of triple-negative breast cancer (TNBC). METHODS: Public database was first interrogated to reveal the correlation between CAFs' scores and the prognosis of TNBC patients, as well as the expression levels of FAP and CXCR4 in normal tissues and tumors. In vitro therapeutic efficacy regarding cell proliferation, migration, and colony formation was assessed in BALB/3T3 fibroblasts and 4T1 murine breast cancer cells. In vivo therapeutic efficacy was longitudinally monitored using serial 18F-FDG, [18F]AlF-NOTA-FAPI-04, and [68Ga]Ga-DOTA-Pentixafor PET/CT scans and validated using tumor sections through immunohistochemical staining of Ki-67, α-SMA, CXCR4, and CXCL12. Intratumoral abundance of myeloid-derived suppressive cells (MDSCs) was analyzed using flow cytometry in accordance with the PET/CT schedules. Treatment toxicity was evaluated by examining major organs including heart, lung, liver, kidney, and spleen. RESULTS: CAFs' scores negatively correlated with the survival of TNBC patients (p < 0.05). The expression of CXCR4 and FAP was both significantly higher in tumors than in normal tissues. The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 significantly suppressed cell proliferation, migration, and colony formation in cell culture, and exhibited synergistic effects in 4T1 tumor models along with a decreased number of MDSCs. PET/CT imaging revealed lowest tumor accumulation of 18F-FDG and [18F]AlF-NOTA-FAPI-04 on day 13 and day 14 after treatment started, both of which gradually increased at later time points. A similar trend was observed in the IHC staining of Ki-67, α-SMA, and CXCL12. CONCLUSION: The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 is a feasible treatment against TNBC with minimal toxicity in main organs.


Asunto(s)
Quimiocina CXCL12 , Receptores CXCR4 , Neoplasias de la Mama Triple Negativas , Receptores CXCR4/metabolismo , Receptores CXCR4/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/diagnóstico por imagen , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/radioterapia , Animales , Ratones , Quimiocina CXCL12/metabolismo , Humanos , Línea Celular Tumoral , Femenino , Ciclamas/farmacología , Ciclamas/uso terapéutico , Lutecio , Bencilaminas/farmacología , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/química , Radiofármacos/uso terapéutico , Radiofármacos/farmacología , Endopeptidasas , Proliferación Celular/efectos de los fármacos , Gelatinasas/metabolismo , Proteínas de la Membrana/metabolismo , Serina Endopeptidasas/metabolismo
12.
Langmuir ; 40(8): 4174-4185, 2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38359328

RESUMEN

Emulsification flooding can effectively enhance crude oil recovery to solve the problem of petroleum shortage. In this work, a modified Janus Nano Calcium carbonate (JNC-12) with a particle size of 30-150 nm was synthesized, and an in situ emulsification nanofluid (ISEN) was prepared with JNC-12 and alkyl polyglycoside (APG). Scanning electron microscope (SEM) showed that the dispersion of JNC-12 in air or APG solution was better than Nano Calcium carbonate (Nano CaCO3). The emulsification properties, interfacial tension, and expansion modulus of ISEN were studied, and the result showed that with the increase in salinity, the emulsification rate decreased, the water yield rate increased, the interfacial tension first decreased and then increased, and the expansion modulus first increased and then decreased. With the increase in temperature, the emulsification rate, emulsion viscosity, and interfacial tension decreased. With the increased oil-water volume, the water yield rate and the emulsion viscosity increased. With increase in the concentration of JNC-12, the water yield rate, the emulsion viscosity, and the interfacial tension decreased but the expansion modulus increased. The emulsion generated by emulsifying ISEN with crude oil was an O/W emulsion, the crude oil viscosity was 4-10 times that of emulsion, and the average particle size of emulsion was 1.107 µm. The addition of ISEN caused the decrease in interfacial tension of oil-water to 0.01-0.1 mN/m. The wettability alteration experiment found that ISEN could change the lipophilic rock to hydrophilic rock. Finally, the core displacement experiments showed that compared with the first water flooding, the oil recovery of the second water flooding after ISEN flooding enhanced by 17.6%. This research has important guiding significance for in situ emulsified nanofluid flooding to enhance oil recovery.

13.
Mol Cell Biochem ; 479(3): 707-732, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37171724

RESUMEN

Peroxisome proliferator-activated receptor-α (PPAR-α) belonging to the nuclear hormone receptor superfamily is a promising target for CVDs which mechanistically improves the production of high-density lipid as well as inhibit vascular smooth muscle cell proliferation. PPAR-α mainly interferes with adenosine monophosphate-activated protein kinase, transforming growth factor-ß-activated kinase, and nuclear factor-κB pathways to protect against cardiac complications. Natural products/extracts could serve as a potential therapeutic strategy in CVDs for targeting PPAR-α with broad safety margins. In recent years, the understanding of naturally derived PPAR-α agonists has considerably improved; however, the information is scattered. In vitro and in vivo studies on acacetin, apigenin, arjunolic acid, astaxanthin, berberine, resveratrol, vaticanol C, hispidulin, ginsenoside Rb3, and genistein showed significant effects in CVDs complications by targeting PPAR-α. With the aim of demonstrating the tremendous chemical variety of natural products targeting PPAR-α in CVDs, this review provides insight into various natural products that can work to prevent CVDs by targeting the PPAR-α receptor along with their detailed mechanism.


Asunto(s)
Productos Biológicos , Enfermedades Cardiovasculares , Humanos , PPAR alfa , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/prevención & control , Receptores Citoplasmáticos y Nucleares , Fitoquímicos/farmacología , Fitoquímicos/uso terapéutico
14.
Physiol Plant ; 176(1): e14195, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38332400

RESUMEN

This review aims to elucidate the intricate effects and mechanisms of terahertz (THz) wave stress on Pinellia ternata, providing valuable insights into plant responses. The primary objective is to highlight the imperative for future research dedicated to comprehending THz wave impacts across plant structures, with a specific focus on the molecular intricacies governing root system structure and function, from shoots to roots. Notably, this review highlights the accelerated plant growth induced by THz waves, especially in conjunction with other environmental stressors, and the subsequent alterations in cellular homeostasis, resulting in the generation of reactive oxygen species (ROS) and an increase in brassinosteroids. Brassinosteroids are explored for their dual role as toxic by-products of stress metabolism and vital signal transduction molecules in plant responses to abiotic stresses. The paper further investigates the spatio-temporal regulation and long-distance transport of phytohormones, including growth hormone, cytokinin, and abscisic acid (ABA), which significantly influence the growth and development of P. ternata under THz wave stress. With a comprehensive review of Reactive oxygen species (ROS) and Brassinosteroid Insensitive (BRI) homeostasis and signalling under THz wave stress, the article elucidates the current understanding of BRI involvement in stress perception, stress signalling, and domestication response regulation. Additionally, it underscores the importance of spatio-temporal regulation and long-distance transport of key plant hormones, such as growth hormone, cytokinin, and ABA, in determining root growth and development under THz wave stress. The study of how plants perceive and respond to environmental stresses holds fundamental biological significance, and enhancing plant stress tolerance is crucial for promoting sustainable agricultural practices and mitigating the environmental burdens associated with low-tolerance crop cultivation.


Asunto(s)
Brasinoesteroides , Pinellia , Brasinoesteroides/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Pinellia/metabolismo , Reguladores del Crecimiento de las Plantas/metabolismo , Ácido Abscísico/metabolismo , Estrés Fisiológico , Citocininas/metabolismo , Plantas/metabolismo , Hormona del Crecimiento/metabolismo , Hormona del Crecimiento/farmacología
15.
J Nat Prod ; 87(2): 415-423, 2024 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-38291771

RESUMEN

Pyrrole-containing natural products form a large group of structurally diverse compounds that occur in both terrestrial and marine organisms. In the present study the formation of trideuteromethylated artifacts of pyrrole-containing natural products was investigated, focusing on the discorhabdins. Three deuterated discorhabdins, 1, 3, and 5, were identified to be isolation procedure artifacts caused by the presence of DMSO-d6 during NMR sample preparation and handling. Three additional semisynthetic derivatives, 7-9, were made during the investigation of the mechanism of formation, which was shown to be driven by trideuteromethyl radicals in the presence of water, methanol, TFA, and traces of iron in the deuterated solvent. Generation of trideuteromethylated artifacts was also confirmed for other classes of pyrrole-containing metabolites, namely, makaluvamines, tambjamines, and dibromotryptamines, which had also been dissolved in DMSO-d6 during the structure elucidation process. Semisynthetic discorhabdins were assessed for antiproliferative activity against a panel of human tumor cell lines, and 14-trideuteromethyldiscorhabdin L (3) averaged low micromolar potency.


Asunto(s)
Productos Biológicos , Dimetilsulfóxido , Humanos , Dimetilsulfóxido/química , Pirroles/química , Productos Biológicos/farmacología , Artefactos , Solventes/química
16.
J Nat Prod ; 2024 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-39142023

RESUMEN

A high throughput screen performed to identify catalytic inhibitors of the oncogenic fusion form of cAMP-dependent protein kinase A catalytic subunit alpha (J-PKAcα) found an individual fraction from an organic extract of the marine soft coral Acrozoanthus australiae as active. Bioassay-guided isolation led to the identification of a 2-amino adenine alkaloid acroamine A (1), the first secondary metabolite discovered from this genus and previously reported as a synthetic product. As a naturally occurring protein kinase inhibitor, to unambiguously assign its chemical structure using modern spectroscopic and spectrometric techniques, five N-methylated derivatives acroamines A1-A5 (2-6) were semisynthesized. Three additional brominated congeners A6-A8 (7-9) were also semisynthesized to investigate the structure-activity relationship of the nine compounds as J-PKAcα inhibitors. Compounds 1-9 were tested for J-PKAcα and wild-type PKA inhibitory activities, which were observed exclusively in acroamine A (1) and its brominated analogs (7-9) achieving moderate potency (IC50 2-50 µM) while none of the N-methylated analogs exhibited kinase inhibition.

17.
J Nat Prod ; 87(2): 332-339, 2024 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-38294825

RESUMEN

Neopetrotaurines A-C (1-3), unusual alkaloids possessing two isoquinoline-derived moieties that are linked via a unique taurine bridge, were isolated from a Neopetrosia sp. marine sponge. These new compounds have proton-deficient structural scaffolds that are difficult to unambiguously assign using only conventional 2- and 3-bond 1H-13C and 1H-15N heteronuclear correlation data. Thus, the application of LR-HSQMBC and HMBC NMR experiments optimized to detect 4- and 5-bond long-range 1H-13C heteronuclear correlations facilitated the structure elucidation of these unusual taurine-bridged marine metabolites. Neopetrotaurines A-C (1-3) showed significant inhibition of transcription driven by the oncogenic fusion protein PAX3-FOXO1, which is associated with alveolar rhabdomyosarcoma, and cytotoxic activity against PAX3-FOXO1-positive cell lines.


Asunto(s)
Alcaloides , Poríferos , Rabdomiosarcoma Alveolar , Animales , Rabdomiosarcoma Alveolar/metabolismo , Línea Celular , Alcaloides/farmacología , Isoquinolinas/farmacología
18.
J Chem Phys ; 160(24)2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38912672

RESUMEN

The ultrafast proton transfer and the following dynamics for aromatic Schiff bases N,N'-bis(salicylidene)ethylenediamine (salen) and N,N'-bis(salicylidene)-1,4-butylenediamine (salbn) were investigated with experimental and theoretical methods. A dual emission property with a large Stokes shift in salen and salbn indicates that excited state intramolecular proton transfer occurs with photoexcitation. An efficient single proton transfer was confirmed within 200 fs for both molecules. Subsequently, a fast twisted motion of the keto moiety carries cis-keto to a relaxed stable geometry in the S1 state. Following the twisted motion, the phenol ring at keto moiety further rotates to a conical intersection with the ground state and a cis-trans isomerization occurs. The isomerization rate is high, which dominates the competition with the radiative transition, resulting in weak emission intensity. It is confirmed that the length of alkyl chain affects the direction of phenol ring twisting and rotation during the whole subsequent relaxation of excited cis-keto tautomer. Compared with polar solvent acetonitrile, the barrier of isomerization is higher and the hydrogen bond on keto moiety is stronger in nonpolar solvent toluene. It makes fluorescence radiation channels competing with isomerism more likely to occur, contributing to the observed difference of enol/keto emission ratios of salen and salbn in toluene and acetonitrile.

19.
J Chem Phys ; 160(15)2024 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-38619455

RESUMEN

In this work, the ultrafast intramolecular rotation behavior of 1,1,2,3,4,5-hexaphenylsilole has been investigated in several solutions with different viscosities using femtosecond transient absorption spectroscopy combined with density functional theory and time-dependent density functional theory calculations. It is demonstrated that the nonradiative process, which competes with radiative decay, involves two main stages, namely the restricted intramolecular rotation and internal conversion processes. The intramolecular rotation depends on viscosity and presents a significant restriction. The restricted rotational rate is determined to be dozens of picoseconds. The following nonradiative process is strongly dominated by intramolecular rotation. The nonradiative decay rate will decrease with the increase in viscosity, leading to a rise in the radiative probability and photoluminous yield. These results have borne out the mechanism of ultrafast restricted intramolecular rotation of aggregation induced emission and provided a detailed photophysical picture of nonradiative processes.

20.
Lipids Health Dis ; 23(1): 232, 2024 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-39080674

RESUMEN

OBJECTIVE: To investigate how antiretroviral therapy (ART) regimens and body mass index (BMI) interact to affect triglyceride (TG) levels in people living with HIV (PLWH). METHODS: This research involved 451 men living with HIV for cross-sectional analysis, and 132 underwent follow-up assessments in 2021 and 2023. Multivariate logistic regression identified key factors, while covariance regression models assessed interactions between ART regimens and BMI on TG levels. RESULTS: The result of this cross-sectional study indicated that advanced AIDS (acquired immune deficiency syndrome) stage (OR = 2.756, P = 0.003), higher BMI (OR = 1.131, P = 0.003), and waist-hip ratio (WHR, OR = 44.684, P = 0.019) are closely associated with high triglyceride levels. Additionally, regimens containing zidovudine (AZT) (OR = 3.927, P < 0.001) or protease inhibitors/integrase strand transfer inhibitors (PI/INSTI) (OR = 5.167, P < 0.001) were significantly linked to hypertriglyceridemia. Cross-sectional and longitudinal analyses from 2021 to 2023 emphasized that changes in BMI interact with antiretroviral treatment regimens to affect TG levels in PLWH (Pinteraction < 0.05). Especially in the AZT-based drug regimen, the correlation between BMI and TG is more prominent. CONCLUSION: The interaction between ART regimens and BMI influences TG levels in PLWH, indicating that weight management is crucial for reducing the risk of hypertriglyceridemia in this population.


Asunto(s)
Índice de Masa Corporal , Infecciones por VIH , Triglicéridos , Zidovudina , Humanos , Masculino , Triglicéridos/sangre , Estudios Transversales , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/sangre , Estudios Longitudinales , Adulto , Persona de Mediana Edad , Zidovudina/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Relación Cintura-Cadera , Hipertrigliceridemia/sangre , Terapia Antirretroviral Altamente Activa
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA