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1.
Nature ; 616(7955): 199-206, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36922595

RESUMEN

In oxygenic photosynthetic organisms, light energy is captured by antenna systems and transferred to photosystem II (PSII) and photosystem I (PSI) to drive photosynthesis1,2. The antenna systems of red algae consist of soluble phycobilisomes (PBSs) and transmembrane light-harvesting complexes (LHCs)3. Excitation energy transfer pathways from PBS to photosystems remain unclear owing to the lack of structural information. Here we present in situ structures of PBS-PSII-PSI-LHC megacomplexes from the red alga Porphyridium purpureum at near-atomic resolution using cryogenic electron tomography and in situ single-particle analysis4, providing interaction details between PBS, PSII and PSI. The structures reveal several unidentified and incomplete proteins and their roles in the assembly of the megacomplex, as well as a huge and sophisticated pigment network. This work provides a solid structural basis for unravelling the mechanisms of PBS-PSII-PSI-LHC megacomplex assembly, efficient energy transfer from PBS to the two photosystems, and regulation of energy distribution between PSII and PSI.


Asunto(s)
Complejos de Proteína Captadores de Luz , Complejo de Proteína del Fotosistema I , Complejo de Proteína del Fotosistema II , Ficobilisomas , Porphyridium , Transferencia de Energía , Complejos de Proteína Captadores de Luz/química , Complejos de Proteína Captadores de Luz/metabolismo , Complejos de Proteína Captadores de Luz/ultraestructura , Fotosíntesis , Complejo de Proteína del Fotosistema I/química , Complejo de Proteína del Fotosistema I/metabolismo , Complejo de Proteína del Fotosistema I/ultraestructura , Complejo de Proteína del Fotosistema II/química , Complejo de Proteína del Fotosistema II/metabolismo , Complejo de Proteína del Fotosistema II/ultraestructura , Ficobilisomas/química , Ficobilisomas/metabolismo , Ficobilisomas/ultraestructura , Porphyridium/química , Porphyridium/enzimología , Porphyridium/metabolismo , Porphyridium/ultraestructura , Microscopía por Crioelectrón , Imagen Individual de Molécula
2.
J Gene Med ; 26(1): e3636, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38009760

RESUMEN

BACKGROUND: Abnormal N6-methyladenosine (m6A) modification has become a driving factor in tumour development and progression. The linc00659 is abnormally highly expressed in digestive tract tumours and promotes cancer progression, but there is little research on the mechanism of linc00659 and m6A. METHODS: The expression of linc00659 in colorectal cancer (CRC) tissues and cells was assessed by a quantitative real-time PCR. The proliferative capacity of CRC cells was determined by colony formation, Cell Counting Kit-8 and 5-ethynyl-2 deoxyuridine assays, and the migratory capacity of CRC was determined by wound healing and transwell assays and tube formation. In vivo, a xenograft tumour model was used to detect the effect of linc00659 on tumour growth. The Wnt/ß-catenin signalling pathway and related protein expression levels were measured by western blotting. The binding of linc00659 to insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) was assessed by RNA pull-down and an immunoprecipitation assay. The effect of IGF2BP1 on FZD6 was detected by an RNA stability assay. RESULTS: The expression of linc00659 was abnormally elevated in CRC tissues and cells compared to normal colonic tissues and cells. We confirm that linc00659 promotes the growth of CRC cells both in vivo and in vitro. Mechanistically, linc00659 binds to IGF2BP1 and specifically enhances its activity to stabilize the target gene FZD6. Therefore, linc00659 and IGF2BP1 activate the Wnt/ß-catenin signalling pathway, promoting cell proliferation in CRC. CONCLUSIONS: Our results show that linc00659 and IGF2BP1 cooperate to promote the stability of the target FZD6 mRNA, thereby facilitating CRC progression, which may represent a potential diagnostic, prognostic and therapeutic target for CRC.


Asunto(s)
Adenina , Neoplasias Colorrectales , ARN Largo no Codificante , Vía de Señalización Wnt , Animales , Humanos , Adenina/análogos & derivados , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Receptores Frizzled/genética , Receptores Frizzled/metabolismo , Regulación Neoplásica de la Expresión Génica , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero
3.
Plant Cell ; 33(4): 1286-1302, 2021 05 31.
Artículo en Inglés | MEDLINE | ID: mdl-33793891

RESUMEN

Photosystem II (PSII) uses solar energy to oxidize water and delivers electrons for life on Earth. The photochemical reaction center of PSII is known to possess two stationary states. In the open state (PSIIO), the absorption of a single photon triggers electron-transfer steps, which convert PSII into the charge-separated closed state (PSIIC). Here, by using steady-state and time-resolved spectroscopic techniques on Spinacia oleracea and Thermosynechococcus vulcanus preparations, we show that additional illumination gradually transforms PSIIC into a light-adapted charge-separated state (PSIIL). The PSIIC-to-PSIIL transition, observed at all temperatures between 80 and 308 K, is responsible for a large part of the variable chlorophyll-a fluorescence (Fv) and is associated with subtle, dark-reversible reorganizations in the core complexes, protein conformational changes at noncryogenic temperatures, and marked variations in the rates of photochemical and photophysical reactions. The build-up of PSIIL requires a series of light-induced events generating rapidly recombining primary radical pairs, spaced by sufficient waiting times between these events-pointing to the roles of local electric-field transients and dielectric relaxation processes. We show that the maximum fluorescence level, Fm, is associated with PSIIL rather than with PSIIC, and thus the Fv/Fm parameter cannot be equated with the quantum efficiency of PSII photochemistry. Our findings resolve the controversies and explain the peculiar features of chlorophyll-a fluorescence kinetics, a tool to monitor the functional activity and the structural-functional plasticity of PSII in different wild-types and mutant organisms and under stress conditions.


Asunto(s)
Complejo de Proteína del Fotosistema II/química , Complejo de Proteína del Fotosistema II/metabolismo , Spinacia oleracea/química , Clorofila/análogos & derivados , Clorofila/química , Diurona/farmacología , Fluorescencia , Luz , Complejo de Proteína del Fotosistema II/efectos de los fármacos , Conformación Proteica , Espectrometría de Fluorescencia , Espectroscopía Infrarroja por Transformada de Fourier , Temperatura , Thermosynechococcus/química
4.
Proc Natl Acad Sci U S A ; 118(5)2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33495333

RESUMEN

Photosystem II (PSII) is a multisubunit pigment-protein complex and catalyzes light-driven water oxidation, leading to the conversion of light energy into chemical energy and the release of molecular oxygen. Psb27 is a small thylakoid lumen-localized protein known to serve as an assembly factor for the biogenesis and repair of the PSII complex. The exact location and binding fashion of Psb27 in the intermediate PSII remain elusive. Here, we report the structure of a dimeric Psb27-PSII complex purified from a psbV deletion mutant (ΔPsbV) of the cyanobacterium Thermosynechococcus vulcanus, solved by cryo-electron microscopy. Our structure showed that Psb27 is associated with CP43 at the luminal side, with specific interactions formed between Helix 2 and Helix 3 of Psb27 and a loop region between Helix 3 and Helix 4 of CP43 (loop C) as well as the large, lumen-exposed and hydrophilic E-loop of CP43. The binding of Psb27 imposes some conflicts with the N-terminal region of PsbO and also induces some conformational changes in CP43, CP47, and D2. This makes PsbO unable to bind in the Psb27-PSII. Conformational changes also occurred in D1, PsbE, PsbF, and PsbZ; this, together with the conformational changes occurred in CP43, CP47, and D2, may prevent the binding of PsbU and induce dissociation of PsbJ. This structural information provides important insights into the regulation mechanism of Psb27 in the biogenesis and repair of PSII.


Asunto(s)
Proteínas Bacterianas/química , Complejo de Proteína del Fotosistema II/química , Multimerización de Proteína , Proteínas Bacterianas/aislamiento & purificación , Modelos Moleculares , Complejo de Proteína del Fotosistema II/aislamiento & purificación , Complejo de Proteína del Fotosistema II/metabolismo , Unión Proteica , Homología Estructural de Proteína , Thermosynechococcus/metabolismo
5.
Molecules ; 29(10)2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38792181

RESUMEN

This study investigates the utilisation of organometallic network frameworks composed of fourth-period transition metals and tetrahydroxyquinone (THQ) in electrocatalytic CO2 reduction. Density functional theory (DFT) calculations were employed in analysing binding energies, as well as the stabilities of metal atoms within the THQ frameworks, for transition metal TM-THQs ranging from Y to Cd. The findings demonstrate how metal atoms could be effectively dispersed and held within the THQ frameworks due to sufficiently high binding energies. Most TM-THQ frameworks exhibited favourable selectivity towards CO2 reduction, except for Tc and Ru, which experienced competition from hydrogen evolution reaction (HER) and required solution environments with pH values greater than 5.716 and 8.819, respectively, to exhibit CO2RR selectivity. Notably, the primary product of Y, Ag, and Cd was HCOOH; Mo produced HCHO; Pd yielded CO; and Zr, Nb, Tc, Ru, and Rh predominantly generated CH4. Among the studied frameworks, Zr-THQ displayed values of 1.212 V and 1.043 V, corresponding to the highest limiting potential and overpotential, respectively, while other metal-organic frameworks displayed relatively low ranges of overpotentials from 0.179 V to 0.949 V. Consequently, it is predicted that the TM-THQ framework constructed using a fourth-period transition metal and tetrahydroxyquinone exhibits robust electrocatalytic reduction of CO2 catalytic activity.

6.
Molecules ; 29(12)2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38930961

RESUMEN

Metal-organic frameworks have demonstrated great capacity in catalytic CO2 reduction due to their versatile pore structures, diverse active sites, and functionalization capabilities. In this study, a novel electrocatalytic framework for CO2 reduction was designed and implemented using 2D coordination network-type transition metal-hexahydroxytricyclic quinazoline (TM-HHTQ) materials. Density functional theory calculations were carried out to examine the binding energies between the HHTQ substrate and 10 single TM atoms, ranging from Sc to Zn, which revealed a stable distribution of metal atoms on the HHTQ substrate. The majority of the catalysts exhibited high selectivity for CO2 reduction, except for the Mn-HHTQ catalysts, which only exhibited selectivity at pH values above 4.183. Specifically, Ti and Cr primarily produced HCOOH, with corresponding 0.606 V and 0.236 V overpotentials. Vanadium produced CH4 as the main product with an overpotential of 0.675 V, while Fe formed HCHO with an overpotential of 0.342 V. Therefore, V, Cr, Fe, and Ti exhibit promising potential as electrocatalysts for carbon dioxide reduction due to their favorable product selectivity and low overpotential. Cu mainly produces CH3OH as the primary product, with an overpotential of 0.96 V. Zn primarily produces CO with a relatively high overpotential of 1.046 V. In contrast, catalysts such as Sc, Mn, Ni, and Co, among others, produce multiple products simultaneously at the same rate-limiting step and potential threshold.

7.
Photosynth Res ; 152(2): 193-206, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35503495

RESUMEN

Photosystem II (PSII) has a number of hydrogen-bonding networks connecting the manganese cluster with the lumenal bulk solution. The structure of PSII from Thermosynechococcus vulcanus (T. vulcanus) showed that D1-R323, D1-N322, D1-D319 and D1-H304 are involved in one of these hydrogen-bonding networks located in the interfaces between the D1, CP43 and PsbV subunits. In order to investigate the functions of these residues in PSII, we generated seven site-directed mutants D1-R323A, D1-R323E, D1-N322R, D1-D319L, D1-D319R, D1-D319Y and D1-H304D of T. vulcanus and examined the effects of these mutations on the growth and functions of the oxygen-evolving complex. The photoautotrophic growth rates of these mutants were similar to that of the wild type, whereas the oxygen-evolving activities of the mutant cells were decreased differently to 63-91% of that of the wild type at pH 6.5. The mutant cells showed a higher relative activity at higher pH region than the wild type cells, suggesting that higher pH facilitated proton egress in the mutants. In addition, oxygen evolution of thylakoid membranes isolated from these mutants showed an apparent decrease compared to that of the cells. This is due to the loss of PsbU during purification of the thylakoid membranes. Moreover, PsbV was also lost in the PSII core complexes purified from the mutants. Taken together, D1-R323, D1-N322, D1-D319 and D1-H304 are vital for the optimal function of oxygen evolution and functional binding of extrinsic proteins to PSII core, and may be involved in the proton egress pathway mediated by YZ.


Asunto(s)
Cianobacterias , Complejo de Proteína del Fotosistema II , Mutación , Oxígeno , Protones , Thermosynechococcus
8.
Cancer Cell Int ; 22(1): 303, 2022 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-36203193

RESUMEN

Long non-coding RNAs (lncRNAs) have been found to play essential roles in the cell proliferation, fission and differentiation, involving various processes in humans. Recently, there is more and more interest in exploring the relationship between lncRNAs and tumors. Many latest evidences revealed that LINC00467, an oncogenic lncRNA, is highly expressed in lung cancer, gastric cancer, colorectal cancer, hepatocellular carcinoma, breast cancer, glioblastoma, head and neck squamous cell carcinoma, osteosarcoma, and other malignant tumors. Besides, LINC00467 expression was linked with proliferation, migration, invasion and apoptosis via the regulation of target genes and multiple potential pathways. We reviewed the existing data on the expression, downstream targets, molecular mechanisms, functions, relevant signaling pathways, and clinical implications of LINC00467 in various cancers. LINC00467 may serve as a novel biomarker or therapeutic target for the diagnosis and prognosis of various human tumors.

9.
Int J Audiol ; 61(10): 876-881, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-34775904

RESUMEN

OBJECTIVE: Few mental health assessment tools are available for people with hearing loss (HL) in China. The Acceptance and Action Questionnaire-Adult Hearing Loss (AAQ-AHL) has been specifically designed to assess psychological inflexibility in adults with HL and may help assess mental health status promptly for targeted psychological interventions. The study aimed to investigate the cross-cultural validity and reliability of the Chinese version of the AAQ-AHL to assess its applicability to teenagers and adults with HL in China. DESIGN: A descriptive and correlational study of a convenience sample of students aged above 12 years. All participants were invited to complete an online questionnaire. STUDY SAMPLES: Participants included 402 students with HL. RESULTS: The Chinese version of the AAQ-AHL was shown to be an excellent, reliable, and valid instrument that can be used to assess psychological inflexibility in teenagers and adults with HL by clinicians working with Mandarin-speaking populations. CONCLUSION: Although the AAQ-AHL showed very good psychometric properties in hearing-impaired students aged above 12 years, further testing is needed to validate the measure across other age groups and validate its feasibility and utility in clinical applications.


Asunto(s)
Sordera , Pérdida Auditiva , Adolescente , Adulto , China , Comparación Transcultural , Pérdida Auditiva/diagnóstico , Humanos , Psicometría , Reproducibilidad de los Resultados , Encuestas y Cuestionarios
10.
Int J Audiol ; : 1-8, 2022 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-36373606

RESUMEN

OBJECTIVE: The current study aims to translate and cross-culturally adapt the Acceptance and Action Questionnaire-Management of Child Hearing Loss (AAQ-MCHL) scale to Chinese caregivers of children with hearing loss (CHL) and verify its psychometric characteristics. DESIGN: This is a cross-sectional design of psychometric validation study. STUDY SAMPLE: In total, 135 caregivers of CHL were invited to participate in the study, and complete data from 125 participants were used to analyse internal consistency, test-retest reliability, content validity, structural validity, criterion validity, and the optimal cut-off score of AAQ-MCHL. RESULTS: Through careful and complete translation and adaptation, the Chinese version of AAQ-MCHL was successfully created. The Chinse version of the AAQ-MCHL had good internal consistency, test-retest reliability, content validity, structural validity, and criterion validity. Our results also showed that poorer speech performance in CHL was a strong predictor of parental psychological inflexibility. CONCLUSIONS: The Chinese version of the AAQ-MCHL could be used as an outcome indicator to evaluate the psychological inflexibility of caregivers of CHL in mainland China, and we suggest that early interventionists should be aware of signs of elevated psychological inflexibility in caregivers of CHL.

11.
Photosynth Res ; 146(1-3): 41-54, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32342261

RESUMEN

PsbV (cytochrome c550) is one of the three extrinsic proteins of photosystem II (PSII) and functions to maintain the stability and activity of the Mn4CaO5 cluster, the catalytic center for water oxidation. PsbV-Y137 is the C-terminal residue of PsbV and is located at the exit of a hydrogen-bond network mediated by the D1-Y161-H190 residue pair. In order to examine the function of PsbV-Y137, four mutants, PsbV-Y137A, PsbV-Y137F, PsbV-Y137G, and PsbV-Y137W, were generated with Thermosynechococcus vulcanus (T. vulcanus). These mutants showed growth rates similar to that of the wild-type strain (WT); however, their oxygen-evolving activities were different. At pH 6.5, the oxygen evolution rates of Y137F and Y137W were almost identical to that of WT, whereas the oxygen evolution rates of the Y137A, Y137G mutants were 64% and 61% of WT, respectively. However, the oxygen evolution in the latter two mutants decreased less at higher pHs, suggesting that higher pHs facilitated oxygen evolution probably by facilitating proton egress in these two mutants. Furthermore, thylakoid membranes isolated from the PsbV-Y137A, PsbV-Y137G mutants exhibited much lower levels of oxygen-evolving activity than that of WT, which was found to be caused by the release of PsbV. In addition, PSII complexes purified from the PsbV-Y137A and PsbV-Y137G mutants lost all of the three extrinsic proteins but instead bind Psb27, an assembly cofactor of PSII. These results demonstrate that the PsbV-Tyr137 residue is required for the stable binding of PsbV to PSII, and the hydrogen-bond network mediated by D1-Y161-H190 is likely to function in proton egress during water oxidation.


Asunto(s)
Complejo de Proteína del Fotosistema II/metabolismo , Enlace de Hidrógeno , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Oxidación-Reducción , Oxígeno/metabolismo , Complejo de Proteína del Fotosistema II/genética , Protones , Thermosynechococcus/genética , Thermosynechococcus/metabolismo , Agua/metabolismo
12.
Photosynth Res ; 146(1-3): 29-40, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32016668

RESUMEN

PsbO-D158 is a highly conserved residue of the PsbO protein in photosystem II (PSII), and participates in one of the hydrogen-bonding networks connecting the manganese cluster with the lumenal surface. In order to examine the role of PsbO-D158, we mutated it to E, N or K in Thermosynechococcus vulcanus and characterized photosynthetic properties of the mutants obtained. The growth rates of these three mutants were similar to that of the wild type, whereas the oxygen-evolving activity of the three mutant cells decreased to 60-64% of the wild type. Fluorescence kinetics showed that the mutations did not affect the electron transfer from QA to QB, but slightly affected the donor side of PSII. Moreover, all of the three mutant cells were more sensitive to high light and became slower to recover from photoinhibition. In the isolated thylakoid membranes from the three mutants, the PsbU subunit was lost and the oxygen-evolving activity was reduced to a lower level compared to that in the respective cells. PSII complexes isolated from these mutants showed no oxygen-evolving activity, which was found to be due to large or complete loss of PsbO, PsbV and PsbU during the process of purification. Moreover, PSII cores purified from the three mutants contained Psb27, an assembly co-factor of PSII. These results suggest that PsbO-D158 is required for the proper binding of the three extrinsic proteins to PSII and plays an important role in maintaining the optimal oxygen-evolving activity, and its mutation caused incomplete assembly of the PSII complex.


Asunto(s)
Fotosíntesis , Complejo de Proteína del Fotosistema II/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Niño , Preescolar , Transporte de Electrón , Fluorescencia , Humanos , Manganeso/metabolismo , Mutación , Oxígeno/metabolismo , Complejo de Proteína del Fotosistema II/genética , Thermosynechococcus/genética , Thermosynechococcus/metabolismo
13.
Physiol Plant ; 166(1): 22-32, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30790299

RESUMEN

Recent chlorophyll-a fluorescence yield measurements, using single-turnover saturating flashes (STSFs), have revealed the involvement of a rate-limiting step in the reactions following the charge separation induced by the first flash. As also shown here, in diuron-inhibited PSII core complexes isolated from Thermosynechococcus vulcanus the fluorescence maximum could only be reached by a train of STSFs. In order to elucidate the origin of the fluorescence yield increments in STSF series, we performed transient absorption measurements at 819 nm, reflecting the photooxidation and re-reduction kinetics of the primary electron donor P680. Upon single flash excitation of the dark-adapted sample, the decay kinetics could be described with lifetimes of 17 ns (∼50%) and 167 ns (∼30%), and a longer-lived component (∼20%). This kinetics are attributed to re-reduction of P680•+ by the donor side of PSII. In contrast, upon second-flash (with Δt between 5 µs and 100 ms) or repetitive excitation, the 819 nm absorption changes decayed with lifetimes of about 2 ns (∼60%) and 10 ns (∼30%), attributed to recombination of the primary radical pair P680•+ Pheo•- , and a small longer-lived component (∼10%). These data confirm that only the first STSF is capable of generating stable charge separation - leading to the reduction of QA ; and thus, the fluorescence yield increments elicited by the consecutive flashes must have a different physical origin. Our double-flash experiments indicate that the rate-limiting steps, detected by chlorophyll-a fluorescence, are not correlated with the turnover of P680.


Asunto(s)
Clorofila A/metabolismo , Cianobacterias/metabolismo , Complejo de Proteína del Fotosistema II/metabolismo , Oxidación-Reducción
14.
AAPS PharmSciTech ; 19(5): 2133-2143, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-29714002

RESUMEN

Combination therapy is one of the important methods to improve therapeutic effect on the treatment of hepatocellular carcinoma (HCC). Sorafenib (SF) is a canonical US Food and Drug Administration-approved multikinase molecule inhibitor against HCC. However, therapeutic benefit with Sorafenib alone was usually unsatisfactory. Ceramide (CE) is an endogenous bioactive sphingolipid, which has a strong potential to suppress various tumors. The combination of SF and CE was hoping to exert maximum synergistic antitumor effect through different tumor-suppressible mechanisms. In this respect, SF and CE co-loaded liposomes (SF/CE-liposomes) were developed to verify synergistic antitumor efficacy. The optimal molar ratio of SF and CE was determined through combination index. SF/CE-liposomes were prepared by thin-film hydration method, which exhibited spherical or ellipsoidal shape. Particle size of SF/CE-liposomes was 174 ± 4 nm with homogeneous distribution. Release profile of SF demonstrated that addition of CE imposed no significant impact on the release of SF. SF/CE-liposomes exhibited acceptable stability in different media and desirable storage stability over 30 days at 4°C. In vitro cellular uptake confirmed that SF/CE-liposomes could be efficiently internalized into HepG2 cells. In vitro cytotoxicity evaluation indicated that SF/CE-liposomes exhibited higher cytotoxicity on HepG2 cells. IC50 value of SF/CE-liposomes was 11.5 ± 0.44 µM, which was significantly lower than that of SF-liposomes (**p < 0.01). Evaluation of in vivo synergistic effect on H22-bearing mice verified that SF/CE-liposomes achieved robust antitumor activity in preventing tumor growth. All results suggested that SF/CE-liposomes might be served as an efficient co-delivery system for improving therapeutic efficacy of HCC.


Asunto(s)
Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Ceramidas/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Animales , Antineoplásicos/metabolismo , Carcinoma Hepatocelular/metabolismo , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Ceramidas/metabolismo , Sinergismo Farmacológico , Femenino , Células Hep G2 , Humanos , Liposomas , Neoplasias Hepáticas/metabolismo , Ratones , Niacinamida/administración & dosificación , Niacinamida/metabolismo , Tamaño de la Partícula , Compuestos de Fenilurea/metabolismo , Sorafenib , Carga Tumoral/efectos de los fármacos , Carga Tumoral/fisiología
15.
Toxicol Appl Pharmacol ; 310: 175-184, 2016 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-27660101

RESUMEN

Lysosomes are important targets for anticancer drug discovery. Our previous study showed that Riccardin D-N (RD-N), a natural macrocylic bisbibenzyl derivative produced by Mannich reaction, induced cell death by accumulating in lysosomes. Experiments were performed on human lung squamous cell carcinoma tissue from left inferior lobar bronchus of patient xenografts and H460 cells. RD-N was administrated for 25days. The specimens of xenografts in Balb/c athymic (nu+/nu+) male mice were removed for immunohistochemistry, subcellular fractionation, enzyme activities and Western blotting analysis. mRFP-GFP-LC3 reporter was used to examine autophagy in H460 cells. Sphingomyelin assay was evaluated by thin-layer chromatography and assay kit. Lysosomal membrane permeabilization (LMP) caused by acid sphingomyelinase (ASM) inhibition and subsequent changes of sphingomyelin (SM) metabolism selectively destabilized the cancer cell lysosomes in RD-N-treated H460 cells in vitro and tumor xenograft model in vivo. The destabilized lysosomes induced the release of cathepsins from the lysosomes into the cytosol and further triggered cell death. These results explain the underlying mechanism of RD-N induced LMP. It can be concluded that a more lysosomotropic derivative was synthesized by introduction of an amine group, which could have more potential applications in cancer therapy.


Asunto(s)
Permeabilidad de la Membrana Celular/efectos de los fármacos , Membranas Intracelulares/efectos de los fármacos , Lisosomas/efectos de los fármacos , Éteres Fenílicos/toxicidad , Esfingomielina Fosfodiesterasa/metabolismo , Esfingomielinas/metabolismo , Estilbenos/toxicidad , Animales , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos
16.
Drug Metab Dispos ; 43(5): 713-24, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25681130

RESUMEN

Guanfu base A (GFA) is a novel heterocyclic antiarrhythmic drug isolated from Aconitum coreanum (Lèvl.) rapaics and is currently in a phase IV clinical trial in China. However, no study has investigated the influence of GFA on cytochrome P450 (P450) drug metabolism. We characterized the potency and specificity of GFA CYP2D inhibition based on dextromethorphan O-demethylation, a CYP2D6 probe substrate of activity in human, mouse, rat, dog, and monkey liver microsomes. In addition, (+)-bufuralol 1'-hydroxylation was used as a CYP2D6 probe for the recombinant form (rCYP2D6), 2D1 (rCYP2D1), and 2D2 (rCYP2D2) activities. Results show that GFA is a potent noncompetitive inhibitor of CYP2D6, with inhibition constant Ki = 1.20 ± 0.33 µM in human liver microsomes (HLMs) and Ki = 0.37 ± 0.16 µM for the human recombinant form (rCYP2D6). GFA is also a potent competitive inhibitor of CYP2D in monkey (Ki = 0.38 ± 0.12 µM) and dog (Ki = 2.4 ± 1.3 µM) microsomes. However, GFA has no inhibitory activity on mouse or rat CYP2Ds. GFA did not exhibit any inhibition activity on human recombinant CYP1A2, 2A6, 2C8, 2C19, 3A4, or 3A5, but showed slight inhibition of 2B6 and 2E1. Preincubation of HLMs and rCYP2D6 resulted in the inactivation of the enzyme, which was attenuated by GFA or quinidine. Beagle dogs treated intravenously with dextromethorphan (2 mg/ml) after pretreatment with GFA injection showed reduced CYP2D metabolic activity, with the Cmax of dextrorphan being one-third that of the saline-treated group and area under the plasma concentration-time curve half that of the saline-treated group. This study suggests that GFA is a specific CYP2D6 inhibitor that might play a role in CYP2D6 medicated drug-drug interaction.


Asunto(s)
Aconitum/química , Alcaloides/farmacología , Antiarrítmicos/farmacología , Inhibidores del Citocromo P-450 CYP2D6/farmacología , Citocromo P-450 CYP2D6/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Isoformas de Proteínas/farmacología , Animales , Dextrometorfano/metabolismo , Dextrorfano/farmacología , Perros , Interacciones Farmacológicas , Femenino , Haplorrinos , Humanos , Masculino , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Quinidina/farmacología , Ratas
17.
ACS Appl Mater Interfaces ; 16(6): 7917-7926, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38263633

RESUMEN

Advanced fabrics with thermal wet management capability as low energy consumption media contribute to personal cooling and drying. Nevertheless, it remains a great challenge to obtain intelligent fabrics with adjustable thermal conductivity (TC) capable of bridging the supply and demand between human body temperature and self-adaptive thermal conduction. Herein, we report hygroscopic-shrinkage nanofiber-based fabrics with excellent moisture sensitivity and significant volume shrinkage, which benefits the construction of high-density thermal conductive pathways by absorbing sweat, with a maximum sweat absorption rate reaching up to 1781%. The TC of the shrunken fabric is significantly increased from the initial 0.102 to 0.731 W·m-1 K-1 with a volume shrinkage rate of 89% due to the synergistic effect of van der Waals force, capillary force, viscous resistance, and gravity. Besides, an enhanced TC of the resulting fabrics facilitates rapid heat transfer to the environments. By capturing the surface temperature variations of the fabric after shrinkage and commercially available cotton/Coolmax, we obtained the fabric that releases the same amount of heat in a shorter period of time (3.3 s). With its exceptional personal thermal and wet management properties, this study paves the way for designing new-generation intelligent fabrics capable of creating more comfortable microclimates.

18.
Nutrients ; 16(11)2024 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-38892543

RESUMEN

Long-chain n-3 polyunsaturated fatty acid (PUFA) supplementation has shown potential benefits in the prevention of coronary heart disease (CHD); however, the impact of omega-3 fatty acid levels on CHD risk remains a subject of debate. Here, we aimed to investigate the association between n-3 PUFA levels and the risk of CHD, with particular reference to the subtypes of n-3 PUFA. METHODS: Prospective studies and retrospective case-control studies analyzing n-3 PUFA levels in CHD, published up to 30 July 2022, were selected. A random effects meta-analysis was used for pooled assessment, with relative risks (RRs) expressed as 95% confidence intervals (CIs) and standardized mean differences expressed as weight mean differences (WMDs). Subgroup and meta-regression analyses were conducted to assess the impact of n-3 PUFA exposure interval on the CHD subtype variables of the study. RESULTS: We included 20 prospective studies (cohort and nested case-control) and 16 retrospective case-control studies, in which n-3 PUFAs were measured. Higher levels of n-3 PUFAs (ALA, EPA, DPA, DHA, EPA + DHA, total n-3 PUFAs) were associated with a reduced risk of CHD, with RRs (95% CI) of 0.89 (0.81, 0.98), 0.83 (0.72, 0.96); 0.80 (0.67,0.95), 0.75 (0.64, 0.87), 0.83 (0.73, 0.95), and 0.80 (0.70, 0.93), respectively, p < 0.05. CHD patients had significantly lower n-3 PUFA levels compared to healthy controls (p < 0.05). In the subgroup analysis, a significant inverse trend was found for both fatal CHD and non-fatal CHD with n-3 PUFA (EPA + DHA) levels. Also, the link between n-3 PUFA levels in erythrocytes with total CHD was generally stronger than other lipid pools. CONCLUSIONS: n-3 PUFAs are significantly related to CHD risk, and these findings support the beneficial effects of n-3 PUFAs on CHD.


Asunto(s)
Enfermedad Coronaria , Ácidos Grasos Omega-3 , Estudios Observacionales como Asunto , Humanos , Ácidos Grasos Omega-3/sangre , Enfermedad Coronaria/sangre , Enfermedad Coronaria/prevención & control , Enfermedad Coronaria/epidemiología , Femenino , Estudios Retrospectivos , Masculino , Estudios de Casos y Controles , Persona de Mediana Edad , Estudios Prospectivos , Suplementos Dietéticos , Anciano , Factores de Riesgo
19.
Pest Manag Sci ; 80(8): 3707-3716, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38460117

RESUMEN

BACKGROUND: Polymeric microcapsules (MCs) have become an important issue and have attracted increasing attention because of their tunable physical and chemical properties. Diverse shell structures can confer multiple properties on MCs. RESULTS: Different polyols (1,4-butanediol and glycerin) and polyamines (triethylenetetramine and isophorondiamine) were selected as crosslinkers to obtain emamectin benzoate (EB)-loaded poly(urethane-urea) MCs (PU-MCs) by interfacial polymerization. The four obtained PU-MCs showed sphericity with different degrees of smoothness on their surfaces, and displayed a uniform size distribution ranging from 500 to 700 nm. Moreover, transmission electron microscopy showed that the shell thickness was roughly uniform, and was greatly influenced by the type and structure of the crosslinker. GI-MCs, prepared using glycerin and isophorondiamine, had the largest shell thickness. GT-MCs, obtained using glycerin and triethylenetetramine, had the highest encapsulation efficiency and drug-loading content, and BT-MCs, obtained using mixtures of 1,4-butanediol and triethylenetetramine, had the fastest release behavior. Thermogravimetric analysis revealed that the greater the degree of shell crosslinking, the higher decomposition temperature and the greater the thermal stability. A BT-MC suspension had the lowest viscosity and contact angle with the best wettability. Bioassay experiments showed that BT-MCs exhibited good insecticidal activity against Plutella xylostella larvae with a half-maximal lethal concentration of 4.19 mg/L. Furthermore, a BT-MC suspension showed good thermal and light stability, with potential applications in minimizing the toxicity of EB through sustained release. CONCLUSION: Various properties of EB-loaded PU-MCs were modulated through simple selection of different polyols and polyamines during fabrication, which might have an important role in constructing the pesticide delivery system and improving pesticide utilization. © 2024 Society of Chemical Industry.


Asunto(s)
Cápsulas , Animales , Poliuretanos/química , Polímeros/química , Mariposas Nocturnas/efectos de los fármacos , Insecticidas/farmacología , Insecticidas/química , Larva/efectos de los fármacos , Larva/crecimiento & desarrollo , Reactivos de Enlaces Cruzados/química , Ivermectina/análogos & derivados , Ivermectina/química , Ivermectina/farmacología
20.
Diagn Interv Radiol ; 29(2): 402-409, 2023 03 29.
Artículo en Inglés | MEDLINE | ID: mdl-36988060

RESUMEN

PURPOSE: Radiomics analysis is a promising image analysis technique. This study aims to extract a radiomics signature from baseline computed tomography (CT) to predict malignant cerebral edema (MCE) in patients with acute anterior circulation infarction after endovascular treatment (EVT). METHODS: In this retrospective study, 111 patients underwent EVT for acute ischemic stroke caused by middle cerebral artery (MCA) and/or internal carotid artery occlusion. The participants were randomly divided into two datasets: the training set (n = 77) and the test set (n = 34). The clinico-radiological profiles of all patients were collected, including cranial non-contrast-enhanced CT, CT angiography, and CT perfusion. The MCA territory on non-contrast-enhanced CT images was segmented, and the radiomics features associated with MCE were analyzed. The clinico-radiological parameters related to MCE were also identified. In addition, a routine visual radiological model based on radiological factors and a combined model comprising radiomics features and clinico-radiological factors were constructed to predict MCE. RESULTS: The areas under the curve (AUCs) of the radiomics signature for predicting MCE were 0.870 (P < 0.001) and 0.837 (P = 0.002) in the training and test sets, respectively. The AUCs of the routine visual radiological model were 0.808 (P < 0.001) and 0.813 (P = 0.005) in the training and test sets, respectively. The AUCs of the model combining the radiomics signature and clinico-radiological factors were 0.924 (P < 0.001) and 0.879 (P = 0.001) in the training and test sets, respectively. CONCLUSION: A CT image-based radiomics signature is a promising tool for predicting MCE in patients with acute anterior circulation infarction after EVT. For clinicians, it may assist in diagnostic decision-making.


Asunto(s)
Edema Encefálico , Accidente Cerebrovascular Isquémico , Radiología , Humanos , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/cirugía , Edema Encefálico/diagnóstico por imagen , Edema Encefálico/etiología , Estudios Retrospectivos , Infarto
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