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1.
Cell ; 166(3): 716-728, 2016 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-27426949

RESUMEN

Fear behaviors are regulated by adaptive mechanisms that dampen their expression in the absence of danger. By studying circuits and the molecular mechanisms underlying this adaptive response, we show that cholinergic neurons of the medial habenula reduce fear memory expression through GABAB presynaptic excitation. Ablating these neurons or inactivating their GABAB receptors impairs fear extinction in mice, whereas activating the neurons or their axonal GABAB receptors reduces conditioned fear. Although considered exclusively inhibitory, here, GABAB mediates excitation by amplifying presynaptic Ca(2+) entry through Cav2.3 channels and potentiating co-release of glutamate, acetylcholine, and neurokinin B to excite interpeduncular neurons. Activating the receptors for these neurotransmitters or enhancing neurotransmission with a phosphodiesterase inhibitor reduces fear responses of both wild-type and GABAB mutant mice. We identify the role of an extra-amygdalar circuit and presynaptic GABAB receptors in fear control, suggesting that boosting neurotransmission in this pathway might ameliorate some fear disorders.


Asunto(s)
Neuronas Colinérgicas/metabolismo , Miedo/fisiología , Habénula/fisiología , Memoria/fisiología , Receptores de GABA-B/metabolismo , Animales , Calcio/metabolismo , Canales de Calcio/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Vías Nerviosas , Neurotransmisores/metabolismo , Transmisión Sináptica
2.
Nature ; 629(8013): 893-900, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38632402

RESUMEN

The blood-brain barrier (BBB) protects the central nervous system from infections or harmful substances1; its impairment can lead to or exacerbate various diseases of the central nervous system2-4. However, the mechanisms of BBB disruption during infection and inflammatory conditions5,6 remain poorly defined. Here we find that activation of the pore-forming protein GSDMD by the cytosolic lipopolysaccharide (LPS) sensor caspase-11 (refs. 7-9), but not by TLR4-induced cytokines, mediates BBB breakdown in response to circulating LPS or during LPS-induced sepsis. Mice deficient in the LBP-CD14 LPS transfer and internalization pathway10-12 resist BBB disruption. Single-cell RNA-sequencing analysis reveals that brain endothelial cells (bECs), which express high levels of GSDMD, have a prominent response to circulating LPS. LPS acting on bECs primes Casp11 and Cd14 expression and induces GSDMD-mediated plasma membrane permeabilization and pyroptosis in vitro and in mice. Electron microscopy shows that this features ultrastructural changes in the disrupted BBB, including pyroptotic endothelia, abnormal appearance of tight junctions and vasculature detachment from the basement membrane. Comprehensive mouse genetic analyses, combined with a bEC-targeting adeno-associated virus system, establish that GSDMD activation in bECs underlies BBB disruption by LPS. Delivery of active GSDMD into bECs bypasses LPS stimulation and opens the BBB. In CASP4-humanized mice, Gram-negative Klebsiella pneumoniae infection disrupts the BBB; this is blocked by expression of a GSDMD-neutralizing nanobody in bECs. Our findings outline a mechanism for inflammatory BBB breakdown, and suggest potential therapies for diseases of the central nervous system associated with BBB impairment.


Asunto(s)
Barrera Hematoencefálica , Encéfalo , Células Endoteliales , Gasderminas , Inflamación , Animales , Femenino , Humanos , Masculino , Ratones , Membrana Basal/metabolismo , Membrana Basal/ultraestructura , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Barrera Hematoencefálica/ultraestructura , Barrera Hematoencefálica/virología , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/ultraestructura , Caspasas Iniciadoras/metabolismo , Dependovirus , Células Endoteliales/metabolismo , Células Endoteliales/ultraestructura , Gasderminas/antagonistas & inhibidores , Gasderminas/metabolismo , Inflamación/patología , Inflamación/metabolismo , Klebsiella pneumoniae/fisiología , Receptores de Lipopolisacáridos/metabolismo , Lipopolisacáridos/sangre , Lipopolisacáridos/farmacología , Ratones Endogámicos C57BL , Piroptosis , Sepsis/metabolismo , Sepsis/patología , Sepsis/microbiología , Análisis de la Célula Individual , Uniones Estrechas/metabolismo , Uniones Estrechas/ultraestructura
3.
Chem Rev ; 124(9): 5617-5667, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38661498

RESUMEN

The quest to identify precious metal free hydrogen evolution reaction catalysts has received unprecedented attention in the past decade. In this Review, we focus our attention to recent developments in precious metal free hydrogen evolution reactions in acidic and alkaline electrolyte owing to their relevance to commercial and near-commercial low-temperature electrolyzers. We provide a detailed review and critical analysis of catalyst activity and stability performance measurements and metrics commonly deployed in the literature, as well as review best practices for experimental measurements (both in half-cell three-electrode configurations and in two-electrode device testing). In particular, we discuss the transition from laboratory-scale hydrogen evolution reaction (HER) catalyst measurements to those in single cells, which is a critical aspect crucial for scaling up from laboratory to industrial settings but often overlooked. Furthermore, we review the numerous catalyst design strategies deployed across the precious metal free HER literature. Subsequently, we showcase some of the most commonly investigated families of precious metal free HER catalysts; molybdenum disulfide-based, transition metal phosphides, and transition metal carbides for acidic electrolyte; nickel molybdenum and transition metal phosphides for alkaline. This includes a comprehensive analysis comparing the HER activity between several families of materials highlighting the recent stagnation with regards to enhancing the intrinsic activity of precious metal free hydrogen evolution reaction catalysts. Finally, we summarize future directions and provide recommendations for the field in this area of electrocatalysis.

4.
Mol Cell ; 69(2): 279-291.e5, 2018 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-29351847

RESUMEN

Sustained energy starvation leads to activation of AMP-activated protein kinase (AMPK), which coordinates energy status with numerous cellular processes including metabolism, protein synthesis, and autophagy. Here, we report that AMPK phosphorylates the histone methyltransferase EZH2 at T311 to disrupt the interaction between EZH2 and SUZ12, another core component of the polycomb repressive complex 2 (PRC2), leading to attenuated PRC2-dependent methylation of histone H3 at Lys27. As such, PRC2 target genes, many of which are known tumor suppressors, were upregulated upon T311-EZH2 phosphorylation, which suppressed tumor cell growth both in cell culture and mouse xenografts. Pathologically, immunohistochemical analyses uncovered a positive correlation between AMPK activity and pT311-EZH2, and higher pT311-EZH2 correlates with better survival in both ovarian and breast cancer patients. Our finding suggests that AMPK agonists might be promising sensitizers for EZH2-targeting cancer therapies.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Animales , Carcinogénesis/genética , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Metilación de ADN , Proteínas de Unión al ADN/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/fisiología , Epigénesis Genética , Femenino , Histonas/metabolismo , Humanos , Ratones , Proteínas de Neoplasias , Proteínas Nucleares/metabolismo , Oncogenes , Neoplasias Ováricas/metabolismo , Fosforilación , Complejo Represivo Polycomb 2/metabolismo , Complejo Represivo Polycomb 2/fisiología , Factores de Transcripción , Regulación hacia Arriba
5.
Mol Cell ; 71(4): 606-620.e7, 2018 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-30118680

RESUMEN

Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin's role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.


Asunto(s)
Antineoplásicos/farmacología , Antígeno B7-H1/genética , Antígeno CTLA-4/genética , Regulación Neoplásica de la Expresión Génica , Hipoglucemiantes/farmacología , Metformina/farmacología , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/inmunología , Animales , Antígeno B7-H1/inmunología , Antígeno CTLA-4/inmunología , Línea Celular Tumoral , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Degradación Asociada con el Retículo Endoplásmico , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Femenino , Glicosilación , Humanos , Glándulas Mamarias Humanas/citología , Glándulas Mamarias Humanas/efectos de los fármacos , Glándulas Mamarias Humanas/inmunología , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones , Ratones Endogámicos NOD , Fosforilación , Serina/metabolismo , Linfocitos T Citotóxicos/citología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología
6.
PLoS Genet ; 19(11): e1011031, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37956204

RESUMEN

PIWI proteins and their associated piRNAs act to silence transposons and promote gametogenesis. Murine PIWI proteins MIWI, MILI, and MIWI2 have multiple arginine and glycine (RG)-rich motifs at their N-terminal domains. Despite being known as docking sites for the TDRD family proteins, the in vivo regulatory roles for these RG motifs in directing PIWI in piRNA biogenesis and spermatogenesis remain elusive. To investigate the functional significance of RG motifs in mammalian PIWI proteins in vivo, we genetically engineered an arginine to lysine (RK) point mutation of a conserved N-terminal RG motif in MIWI in mice. We show that this tiny MIWI RG motif is indispensable for piRNA biogenesis and male fertility. The RK mutation in the RG motif disrupts MIWI-TDRKH interaction and impairs enrichment of MIWI to the intermitochondrial cement (IMC) for efficient piRNA production. Despite significant overall piRNA level reduction, piRNA trimming and maturation are not affected by the RK mutation. Consequently, MiwiRK mutant mice show chromatoid body malformation, spermatogenic arrest, and male sterility. Surprisingly, LINE1 transposons are effectively silenced in MiwiRK mutant mice, indicating a LINE1-independent cause of germ cell arrest distinctive from Miwi knockout mice. These findings reveal a crucial function of the RG motif in directing PIWI proteins to engage in efficient piRNA production critical for germ cell progression and highlight the functional importance of the PIWI N-terminal motifs in regulating male fertility.


Asunto(s)
ARN de Interacción con Piwi , Testículo , Masculino , Ratones , Animales , Testículo/metabolismo , ARN Interferente Pequeño/metabolismo , Espermatogénesis/genética , Proteínas/metabolismo , Ratones Noqueados , Arginina/metabolismo , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Mamíferos/genética
7.
Exp Cell Res ; 442(2): 114227, 2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-39209142

RESUMEN

Severe conjunctival damage can lead to extensive ocular cicatrisation, fornix shortening, and even ocular surface failure, resulting in significant vision impairment. Conjunctival reconstruction is the primary therapeutic strategy for these clinical conjunctival diseases. However, there have been limited studies on induced differentiation of conjunctival epithelial cells derived from stem cells. In this study, we established a chemical defined differentiation protocol from human embryonic stem cells (hESCs) into conjunctival epithelial cells. hES cell line H1 was used for differentiation, and RT-qPCR, immunofluorescence staining, Periodic-acid-Schiff staining (PAS), and transcriptome analysis were employed to identify the differentiated cells. Here, to imitate the development of the vertebrate conjunctiva, hESCs were induced using a three-step process involving first chetomin was used to induce ocular surface ectoderm, then nicotinamide was used to induce ocular surface epithelial progenitor cells, and finally epidermal growth factor, keratinocyte growth factor and other factors were used to differentiate mature conjunctival epithelial cells. hESC-derived conjunctival epithelial cells expressed mature conjunctival epithelial lineage markers (including PAX6, P63, K13). The presence of goblet cells was confirmed by positive PAS. Transcriptome analysis revealed that hESC-derived conjunctival epithelial cells possessed a more naïve phenotype, and exhibited greater proliferation capacity compared to mature human conjunctival epithelial cells, suggesting their potential as alternative seed cells for conjunctival reconstruction.

8.
BMC Biol ; 22(1): 190, 2024 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-39218865

RESUMEN

BACKGROUND: Hemiptera is the fifth species-rich order of insects and the most species-rich order of hemimetabolous insects, including numerous insect species that are of agricultural or medical significance. Despite much effort and recent advance in inferring the Hemiptera phylogeny, some high-level relationships among superfamilies remain controversial. RESULTS: We sequenced the genomes of 64 hemipteran species from 15 superfamilies and the transcriptomes of two additional scale insect species, integrating them with existing genomic and transcriptomic data to conduct a comprehensive phylogenetic analysis of Hemiptera. Our datasets comprise an average of 1625 nuclear loci of 315 species across 27 superfamilies of Hemiptera. Our analyses supported Cicadoidea and Cercopoidea as sister groups, with Membracoidea typically positioned as the sister to Cicadoidea + Cercopoidea. In most analyses, Aleyrodoidea was recovered as the sister group of all other Sternorrhyncha. A sister-group relationship was supported between Coccoidea and Aphidoidea + Phylloxeroidea. These relationships were further supported by four-cluster likelihood mapping analyses across diverse datasets. Our ancestral state reconstruction indicates phytophagy as the primary feeding strategy for Hemiptera as a whole. However, predation likely represents an ancestral state for Heteroptera, with several phytophagous lineages having evolved from predatory ancestors. Certain lineages, like Lygaeoidea, have undergone a reversal transition from phytophagy to predation. Our divergence time estimation placed the diversification of hemipterans to be between 60 and 150 million years ago. CONCLUSIONS: By expanding phylogenomic taxon sampling, we clarified the superfamily relationships within the infraorder Cicadomorpha. Our phylogenetic analyses supported the sister-group relationship between the superfamilies Cicadoidea and Cercopoidea, and the superfamily Membracoidea as the sister to Cicadoidea + Cercopoidea. Our divergence time estimation supported the close association of hemipteran diversification with the evolutionary success and adaptive radiation of angiosperms during the Cretaceous period.


Asunto(s)
Genoma de los Insectos , Hemípteros , Filogenia , Transcriptoma , Animales , Hemípteros/genética , Hemípteros/clasificación , Genómica , Evolución Molecular , Evolución Biológica
9.
Am J Transplant ; 24(9): 1583-1596, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38648890

RESUMEN

The activation of innate immunity following transplantation has been identified as a crucial factor in allograft inflammation and rejection. However, the role of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signaling-mediated innate immunity in the pathogenesis of allograft rejection remains unclear. Utilizing a well-established murine model of corneal transplantation, we demonstrated increased expression of cGAS and STING in rejected-corneal allografts compared with syngeneic (Syn) and normal (Nor) corneas, along with significant activation of the cGAS/STING pathway, as evidenced by the enhanced phosphorylation of TANK-binding kinase 1and interferon regulatory factor 3. Pharmacological and genetic inhibition of cGAS/STING signaling markedly delayed corneal transplantation rejection, resulting in prolonged survival time and reduced inflammatory infiltration. Furthermore, we observed an increase in the formation of neutrophil extracellular traps (NETs) in rejected allografts, and the inhibition of NET formation through targeting peptidylarginine deiminase 4 and DNase I treatment significantly alleviated immune rejection and reduced cGAS/STING signaling activity. Conversely, subconjunctival injection of NETs accelerated corneal transplantation rejection and enhanced the activation of the cGAS/STING pathway. Collectively, these findings demonstrate that NETs contribute to the exacerbation of allograft rejection via cGAS/STING signaling, highlighting the targeting of the NETs/cGAS/STING signaling pathway as a potential strategy for prolonging allograft survival.


Asunto(s)
Trasplante de Córnea , Trampas Extracelulares , Rechazo de Injerto , Nucleotidiltransferasas , Transducción de Señal , Animales , Masculino , Ratones , Aloinjertos , Trampas Extracelulares/metabolismo , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Rechazo de Injerto/metabolismo , Supervivencia de Injerto/inmunología , Inmunidad Innata , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neutrófilos/inmunología , Neutrófilos/metabolismo , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/genética
10.
Anal Chem ; 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-39023238

RESUMEN

The adjustment of the emission wavelengths and cell permeability of the perylene diimides (PDI) for multicolor cell imaging is a great challenge. Herein, based on a bay-region substituent engineering strategy, multicolor perylene diimides (MCPDI) were rationally designed and synthesized by introducing azetidine substituents on the bay region of PDIs. With the fine-tuned electron-donating ability of the azetidine substituents, these MCPDI showed high brightness, orange, red, and near infrared (NIR) fluorescence along with Stokes shifts increasing from 35 to 110 nm. Interestingly, azetidine substituents distorted to the plane of the MCPDI dyes, and the twist angle of monosubstituted MCPDI was larger than that of disubstituted MCPDI, which might efficiently decrease their π-π stacking. Moreover, all of these MCPDI dyes were cell-permeable and selectively stained various organelles for multicolor imaging of multiple organelles in living cells. Two-color imaging of lipid droplets (LDs) and other organelles stained with MCPDI dyes was performed to reveal the interaction between the LDs and other organelles in living cells. Furthermore, a NIR-emitting MCPDI dye with a mitochondria-targeted characteristic was successfully applied for tumor-specific imaging. The facile synthesis, excellent stability, high brightness, tunable fluorescence emission, and Stokes shifts make these MCPDI promising fluorescent probes for biological applications.

11.
Plant Physiol ; 193(1): 448-465, 2023 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-37217835

RESUMEN

Bud dormancy is crucial for winter survival and is characterized by the inability of the bud meristem to respond to growth-promotive signals before the chilling requirement (CR) is met. However, our understanding of the genetic mechanism regulating CR and bud dormancy remains limited. This study identified PpDAM6 (DORMANCY-ASSOCIATED MADS-box) as a key gene for CR using a genome-wide association study analysis based on structural variations in 345 peach (Prunus persica (L.) Batsch) accessions. The function of PpDAM6 in CR regulation was demonstrated by transiently silencing the gene in peach buds and stably overexpressing the gene in transgenic apple (Malus × domestica) plants. The results showed an evolutionarily conserved function of PpDAM6 in regulating bud dormancy release, followed by vegetative growth and flowering, in peach and apple. The 30-bp deletion in the PpDAM6 promoter was substantially associated with reducing PpDAM6 expression in low-CR accessions. A PCR marker based on the 30-bp indel was developed to distinguish peach plants with non-low and low CR. Modification of the H3K27me3 marker at the PpDAM6 locus showed no apparent change across the dormancy process in low- and non-low- CR cultivars. Additionally, H3K27me3 modification occurred earlier in low-CR cultivars on a genome-wide scale. PpDAM6 could mediate cell-cell communication by inducing the expression of the downstream genes PpNCED1 (9-cis-epoxycarotenoid dioxygenase 1), encoding a key enzyme for ABA biosynthesis, and CALS (CALLOSE SYNTHASE), encoding callose synthase. We shed light on a gene regulatory network formed by PpDAM6-containing complexes that mediate CR underlying dormancy and bud break in peach. A better understanding of the genetic basis for natural variations of CR can help breeders develop cultivars with different CR for growing in different geographical regions.


Asunto(s)
Malus , Prunus persica , Prunus , Prunus persica/genética , Prunus persica/metabolismo , Prunus/genética , Prunus/metabolismo , Histonas/metabolismo , Estudio de Asociación del Genoma Completo , Malus/genética , Regulación de la Expresión Génica de las Plantas , Latencia en las Plantas/genética
12.
Cytokine ; 175: 156444, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38150791

RESUMEN

Head and neck squamous cell carcinoma (HNSCC) is the most common malignancy of the head and neck epidermis. Accumulating long non-coding RNAs (lncRNAs) have been proven to be involved in the occurrence and development of HNSCC. LncRNA long intergenic non-protein coding RNA 491 (LINC00491) has been confirmed to regulate the progression of some cancers. In our study, we aimed to explore the potential biological function of LINC00491 and expound the regulatory mechanism by which LINC00491 affects the progression of HNSCC. RT-qPCR was utilized to analyze the expression of LINC00491 in HNSCC cell lines and the normal cell line. Functionally, we carried out a series of assays to measure cell proliferation, apoptosis, migration and invasion, such as EdU assay, colony formation, wound healing and western blot assays. Also, mechanism assays including RNA pull down and RIP were also implemented to investigate the interaction of LINC00491 and RNAs. As a result, we discovered that LINC00491 was highly expressed in HNSCC cells. In addition, LINC00491 depletion suppressed cell proliferation, migration and EMT process. Furthermore, we discovered that LINC00491 could bind to miR-508-3p. MiR-508-3p overexpression can restrain HNSCC cell growth. Importantly, miR-508-3p can target SATB homeobox 1 (SATB1) in HNSCC cells. Further, Wnt signaling pathway was proved to be activated by LINC00491 through SATB1 in HNSCC cells. In a word, LINC00491 accelerated HNSCC progression through regulating miR-508-3p/SATB1 axis and activating Wnt signaling pathway.


Asunto(s)
Neoplasias de Cabeza y Cuello , Proteínas de Unión a la Región de Fijación a la Matriz , MicroARNs , ARN Largo no Codificante , Humanos , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Factores de Transcripción/metabolismo , Vía de Señalización Wnt/genética
13.
Artículo en Inglés | MEDLINE | ID: mdl-39287631

RESUMEN

The seminal vesicle contributes to a large extent of the semen volume and composition. Removal of seminal vesicle or lack of seminal vesicle proteins leads to decreased fertility. Seminal plasma proteome revealed that seminal fluid contained a wide diversity of proteins. Many of them are known to modulate sperm capacitation and serve as capacitation inhibitors or decapacitation factors. Despite identifying secretory vesicles from the male reproductive tract, such as epididymosomes or prostasomes, isolation, identification, and characterization of seminal vesicle-derived exosomes are still unknown. This chapter aims to review the current understanding of the function of seminal vesicles on sperm physiology and male reproduction and provide ultracentrifugation-based isolation protocols for the isolation of seminal vesicle exosomes. Moreover, via proteomic analysis and functional categorization, a total of 726 proteins IDs were identified in the purified seminal vesicle exosomes fraction. Preliminary data showed seminal vesicle-derived exosomes inhibited sperm capacitation; however, more studies will be needed to reveal other functional involvements of seminal vesicle-derived exosomes on the sperm physiology and, more importantly, how these exosomes interact with sperm membrane to achieve their biological effects.

14.
Phys Rev Lett ; 132(19): 190801, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38804925

RESUMEN

Fidelity estimation is an important technique for evaluating prepared quantum states in noisy quantum devices. A recent theoretical work proposed a frugal approach called neural quantum fidelity estimation (NQFE) [X. Zhang et al., Phys. Rev. Lett. 127, 130503 (2021).PRLTAO0031-900710.1103/PhysRevLett.127.130503]. While this requires a much smaller number of measurement operators than full quantum state tomography, it uses a weight-based floating measurement strategy that predetermines the top global Pauli operators that contribute the most to the fidelity and uses discrete fidelity intervals as predictions. In this Letter, we develop a measurement-fixed NQFE based on a transformer model which requires less measurement cost and can output continuous estimates of fidelity. Here we further experimentally apply the NQFE in a realistic situation using a nuclear spin quantum processor. We prepare the ground states of local Hamiltonians and arbitrary states and investigate how to estimate their fidelity with reference states, and we compare the fidelity estimation strategy with our and the original NQFE to conventional tomography. It is shown that NQFE can estimate the fidelity with comparable accuracy to the tomography approach. In the future, NQFE will become an important tool for benchmarking quantum states ahead of the advent of well-trusted fault-tolerant quantum computers.

15.
Exp Eye Res ; 245: 109971, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38871165

RESUMEN

PURPOSE: This study aims to reveal the immunopathogenesis of the high-risk corneal transplantation using a comparative proteomic approach. METHODS: The immunological properties of ocular tissues (including corneal grafts, aqueous humour, and iris-ciliary body) were analysed using a high-risk rabbit corneal transplantation model employing a comparative proteomic approach. RESULTS: The corneal grafts revealed a dramatic increase in the immune response both at the early (postoperative day 7) and rejection stages, along with the appearance of transplantation stress-induced cellular senescence in the early stage. The aqueous humour (AH) displayed persistent pathological alterations, indicated by the significant enrichment of complement and coagulation cascades pathway in the early stage and interleukin (IL)-17 signalling pathway in the rejection stage. More surprisingly, the pronounced elevation of immune response was also observed in the iris-ciliary body (I-CB) tissues at the early and rejection stages. The enriched immune-related pathways were associated with antigen processing and presentation, complement and coagulation cascades, and IL-17 signalling pathway. Furthermore, proteomic analysis revealed that the implantation of Cyclosporine A drug delivery system (CsA-DDS) into the anterior chamber obviously mitigated corneal transplantation rejection by inhibiting immunoreaction both in the corneal grafts and I-CB tissues. CONCLUSION: The results highlighted the involvement of intraocular immunity both in the grafts and I-CB tissues during corneal transplantation rejection, further suggesting the anterior chamber as an optimal drug-delivery site for its treatment.


Asunto(s)
Humor Acuoso , Trasplante de Córnea , Rechazo de Injerto , Proteómica , Animales , Rechazo de Injerto/inmunología , Rechazo de Injerto/metabolismo , Conejos , Humor Acuoso/metabolismo , Modelos Animales de Enfermedad , Iris/inmunología , Cuerpo Ciliar/inmunología , Cuerpo Ciliar/metabolismo , Masculino , Inmunosupresores/uso terapéutico , Córnea/inmunología , Córnea/metabolismo , Córnea/patología , Proteínas del Ojo/metabolismo
16.
Mol Cell Biochem ; 479(1): 63-72, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36988778

RESUMEN

Severe hemorrhage shock and resuscitation (HSR) has been reported to induce myocardial ischemia-reperfusion injury (MIRI), resulting in a poor prognosis. Hirudin, an effective thrombin inhibitor, can offer protection against MIRI. This study aimed to determine if hirudin administration ameliorates HSR-induced MIRI and the underlying mechanism. A rat model of HSR was established by bleeding rats to a mean arterial blood pressure of 30-35 mmHg for 45 min and then resuscitating them with all the shed blood through the left femoral vein. After HSR, 1 mg/kg of hirudin was administrated immediately. At 24 h after HSR, the cardiac injury was assessed using serum CK-MB, cTnT, hematoxylin-eosin (HE) staining, echocardiography, M1-polarized macrophages, and pyroptosis-associated factors, including cleaved caspase-1, Gasdermin D (GSDMD) N-terminal, IL-1ß, and IL-18 were measured by immunofluorescence and western blot assays. Nigericin, a unique agonist, was utilized to evaluate the responsibilities of NLRP3 signaling. Under the HSR condition, rats exhibited a significant increase in myocardial injury score, an elevation of serum cTnT, CK-MB levels, an aggrandization of M1-polarized macrophages, an upregulation of pyroptosis-associated factors, including cleaved caspase-1, GSDMD N-terminal, IL-1ß, and IL-18, but a significant decrease in left ventricular ejection fraction (EF%) and a reduction of left ventricular fractional shortening (FS%), while hirudin administration partially restored the changes. However, the NLRP3 agonist nigericin reversed the cardioprotective effects of hirudin. We determined the cardioprotective effects of hirudin against HSR-induced MIRI. The mechanism may involve the inhibition of NLRP3-induced pyroptosis.


Asunto(s)
Daño por Reperfusión Miocárdica , Choque Hemorrágico , Ratas , Animales , Daño por Reperfusión Miocárdica/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Interleucina-18 , Hirudinas/farmacología , Choque Hemorrágico/metabolismo , Volumen Sistólico , Nigericina/farmacología , Función Ventricular Izquierda , Caspasa 1/metabolismo , Transducción de Señal
17.
J Org Chem ; 89(5): 3383-3389, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38364205

RESUMEN

In this paper, a mild strategy for the oxidative cleavage of carbon-carbon bonds catalyzed by Lewis acid was developed in air condition at room temperature. Under such conditions, the bis-carbonyl compounds 3 were directly afforded from the reaction of D-ribose tosylate 1 and aniline in excellent yields through the oxidative cleavage of the key intermediate iminium-ion A and its tautomer enamine B. A series of N-arylated lactam-type iminosugars 5 were then successfully obtained by removing the isopropylidene group from 3 with the aid of the condensation agent DCC. Additionally, reduction of A and the removal of the isopropylidene group could provide N-arylated iminosugars 4. This strategy enables the oxidative cleavage of carbon-carbon bonds under mild conditions and facilitates the synthesis of the novel iminosugars with potent biological activity.

18.
J Org Chem ; 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39254576

RESUMEN

This study presents the synthesis of novel naphthofurano-iminosugars (4) using 2,3-O-isopropylidene D-ribose tosylate (1a), anilines (2), and 1,4-benzoquinone (3a) as starting materials through key iminium ion/enamine intermediates via [3 + 2] cyclization reactions at room temperature. The reaction has unique regioselectivity and stereoselectivity with moderate to excellent yields. The adaptability of this method has been demonstrated using various substituted anilines, on which both electron-donating and electron-withdrawing groups were well employed in the reactions. Notably, the treatment of the fused multicyclic iminosugar 4 with TFA efficiently leads to an interesting unexpected pyridinium salt (8), possible via four sequential steps: deprotection of the 2,3-O-isopropylidene group, furan ring opening, dehydration condensation of the OH groups, and elimination of water.

19.
Cell Biol Int ; 48(9): 1378-1391, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38922770

RESUMEN

Oxidative stress plays a pivotal role in the development of diabetic cardiomyopathy (DCM). Previous studies have revealed that inhibition of mitochondrial fission suppressed oxidative stress and alleviated mitochondrial dysfunction and cardiac dysfunction in diabetic mice. However, no research has confirmed whether mitochondria fission accentuates hyperglycemia-induced cardiomyoblast oxidative stress through regulating fatty acid oxidation (FAO). We used H9c2 cardiomyoblasts exposed to high glucose (HG) 33 mM to simulate DCM in vitro. Excessive mitochondrial fission, poor cell viability, and lipid accumulation were observed in hyperglycemia-induced H9c2 cardiomyoblasts. Also, the cells were led to oxidative stress injury, lower adenosine triphosphate (ATP) levels, and apoptosis. Dynamin-related protein 1 (Drp1) short interfering RNA (siRNA) decreased targeted marker expression, inhibited mitochondrial fragmentation and lipid accumulation, suppressed oxidative stress, reduced cardiomyoblast apoptosis, and improved cell viability and ATP levels in HG-exposed H9c2 cardiomyoblasts, but not in carnitine palmitoyltransferase 1 (CPT1) inhibitor etomoxir treatment cells. We also found subcellular localization of CPT1 on the mitochondrial membrane, FAO, and levels of nicotinamide adenine dinucleotide phosphate (NADPH) were suppressed after exposure to HG treatment, whereas Drp1 siRNA normalized mitochondrial CPT1, FAO, and NADPH. However, the blockade of FAO with etomoxir abolished the above effects of Drp1 siRNA in hyperglycemia-induced H9c2 cardiomyoblasts. The preservation of mitochondrial function through the Drp1/CPT1/FAO pathway is the potential mechanism of inhibited mitochondria fission in attenuating oxidative stress injury of hyperglycemia-induced H9c2 cardiomyoblasts.


Asunto(s)
Ácidos Grasos , Hiperglucemia , Dinámicas Mitocondriales , Oxidación-Reducción , Estrés Oxidativo , Animales , Dinámicas Mitocondriales/efectos de los fármacos , Hiperglucemia/metabolismo , Ratas , Línea Celular , Ácidos Grasos/metabolismo , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dinaminas/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Carnitina O-Palmitoiltransferasa/metabolismo , Carnitina O-Palmitoiltransferasa/genética , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Mitocondrias/metabolismo , Mioblastos Cardíacos/metabolismo , Mioblastos Cardíacos/efectos de los fármacos , Glucosa/farmacología , Adenosina Trifosfato/metabolismo
20.
Inorg Chem ; 63(1): 593-601, 2024 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-38103019

RESUMEN

In nature, biological nitrogen fixation is accomplished through the π-back-bonding mechanism of nitrogenase, which poses significant challenges for mimic artificial systems, thanks to the activation barrier associated with the N≡N bond. Consequently, this motivates us to develop efficient and reusable photocatalysts for artificial nitrogen fixation under mild conditions. We employ a charge-assisted self-assembly process toward encapsulating one polyoxometalate (POM) within a dehydrated Zr-based metal-organic framework (d-UiO-66) exhibiting nitrogen photofixation activities, thereby constructing an enzyme-mimicking photocatalyst. The dehydration of d-UiO-66 is favorable for facilitating nitrogen chemisorption and activation via the unpaired d-orbital electron at the [Zr6O6] cluster. The incorporation of POM guests enhanced the charge separation in the composites, thereby facilitating the transfer of photoexcited electrons into the π* antibonding orbital of chemisorbed N2 for efficient nitrogen fixation. Simultaneously, the catalytic efficiency of SiW9Fe3@d-UiO-66 is enhanced by 9.0 times compared to that of d-UiO-66. Moreover, SiW9Fe3@d-UiO-66 exhibits an apparent quantum efficiency (AQE) of 0.254% at 550 nm. The tactics of "working-in-tandem" achieved by POMs and d-UiO-66 are extremely vital for enhancing artificial ammonia synthesis. This study presents a paradigm for the development of an efficient artificial catalyst for nitrogen photofixation, aiming to mimic the process of biological nitrogen fixation.

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