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BACKGROUND: The disputed phylogenetic position of Aerides flabellata Rolfe ex Downie, due to morphological overlaps with related species, was investigated based on evidence of complete chloroplast (cp) genomes. The structural characterization of complete cp genomes of A. flabellata and A. rosea Lodd. ex Lindl. & Paxton were analyzed and compared with those of six related species in "Vanda-Aerides alliance" to provide genomic information on taxonomy and phylogeny. RESULTS: The cp genomes of A. flabellata and A. rosea exhibited conserved quadripartite structures, 148,145 bp and 147,925 bp in length, with similar GC content (36.7 ~ 36.8%). Gene annotations revealed 110 single-copy genes, 18 duplicated in inverted regions, and ten with introns. Comparative analysis across related species confirmed stable sequence identity and higher variation in single-copy regions. However, there are notable differences in the IR regions between two Aerides Lour. species and the other six related species. The phylogenetic analysis based on CDS from complete cp genomes indicated that Aerides species except A. flabellata formed a monophyletic clade nested in the subtribe Aeridinae, being a sister group to Renanthera Lour., consistent with previous studies. Meanwhile, a separate clade consisted of A. flabellata and six Vanda R. Br. species was formed, as a sister taxon to Holcoglossum Schltr. CONCLUSIONS: This research was the first report on the complete cp genomes of A. flabellata. The results provided insights into understanding of plastome evolution and phylogenetic relationships of Aerides. The phylogenetic analysis based on complete cp genomes showed that A. flabellata should be placed in Vanda rather than in Aerides.
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Genoma del Cloroplasto , Orchidaceae , Filogenia , Orchidaceae/genética , Orchidaceae/clasificación , Composición de Base , Anotación de Secuencia MolecularRESUMEN
Spinal cord injury (SCI), following explosive oxidative stress, causes an abrupt and irreversible pathological deterioration of the central nervous system. Thus, preventing secondary injuries caused by reactive oxygen species (ROS), as well as monitoring and assessing the recovery from SCI are critical for the emergency treatment of SCI. Herein, an emergency treatment strategy is developed for SCI based on the selenium (Se) matrix antioxidant system to effectively inhibit oxidative stress-induced damage and simultaneously real-time evaluate the severity of SCI using a reversible dual-photoacoustic signal (680 and 750 nm). Within the emergency treatment and photoacoustic severity assessment (ETPSA) strategy, the designed Se loaded boron dipyrromethene dye with a double hydroxyl group (Se@BDP-DOH) is simultaneously used as a sensitive reporter group and an excellent antioxidant for effectively eliminating explosive oxidative stress. Se@BDP-DOH is found to promote the recovery of both spinal cord tissue and locomotor function in mice with SCI. Furthermore, ETPSA strategy synergistically enhanced ROS consumption via the caveolin 1 (Cav 1)-related pathways, as confirmed upon treatment with Cav 1 siRNA. Therefore, the ETPSA strategy is a potential tool for improving emergency treatment and photoacoustic assessment of SCI.
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Selenio , Traumatismos de la Médula Espinal , Ratas , Ratones , Animales , Antioxidantes/farmacología , Especies Reactivas de Oxígeno/metabolismo , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/diagnóstico por imagen , Traumatismos de la Médula Espinal/tratamiento farmacológico , Estrés Oxidativo , Tratamiento de UrgenciaRESUMEN
Photocatalytic overall water splitting with two-dimensional materials is a promising strategy to solve the problems of environmental pollution and energy shortage. However, conventional photocatalysts are often limited to a narrow visible photo-absorption range, low catalytic activity, and poor charge separation. Herein, given the intrinsic polarization facilitating the improvement of photogenerated carrier separation, we adopt a polarized g-C3N5 material combining the doping strategy to alleviate the abovementioned problems. Boron (B), as a Lewis acid, has a great chance to improve the capture and catalytic activity of water. By doping B into g-C3N5, the overpotential for the complicated four-electron process of the oxygen reduction reaction is only 0.50 V. Simultaneously, the B doping-induced impurity state effectively reduces the band gap and broadens the photo-absorption range. Moreover, with the increase of B doping concentration, the photo-absorption range and catalytic activity can be gradually improved. Whereas when the concentration exceeds 33.3%, the reduction potential of the conduction band edge will not meet the demand for hydrogen evolution. Therefore, excessive doping is not recommended in experiments. Our work affords not only a promising photocatalyst but also a practical design scheme by combining polarizing materials and the doping strategy for overall water splitting.
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BACKGROUND: Emerging evidence highlighted vascular injury in aggravating radiation-induced brain injury (RIBI), a common complication of radiotherapy. This study aimed to delineate the pathological feature of cerebral small vessel and investigate the functional roles of Notch signaling in RIBI. METHODS: Brain tissue and functional MRI from RIBI patients were collected and analyzed for radiation-induced vasculopathy. A RIBI mouse model was induced by a single dose of 30-Gy cranial irradiation. Vascular morphology, pulsatility, and reactivity to pharmacological interventions, such as nimodipine and 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, were monitored by 2-photon imaging in mice at 6 weeks postirradiation. Western blot, real-time quantitative PCR, immunofluorescence staining, and behavioral tests were performed. The effect of N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester, a Notch inhibitor, was used to investigate the vascular pathogenesis of RIBI mouse model. RESULTS: Morphologically, radiation resulted in vascular malformation featured by focal contractile rings together with general stenosis. Functionally, radiation also led to hypoperfusion, attenuated vascular pulsatility, and decreased dilation to nimodipine and 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid. Mechanically, Notch activation and increased expression of α-SMA protein were found in both surgical specimens of RIBI patients and the irradiated mice. Importantly, Notch inhibition by N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester significantly alleviated cerebral hypoperfusion, vasculopathy, and cognitive deficits in the RIBI mouse model. CONCLUSIONS: Radiation-induced cerebral vasculopathy showed bead-like shape and increased contractile state. Inhibition of Notch signaling by N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester effectively attenuated vasculopathy and relieved cognitive impairment, suggesting Notch signaling as a therapeutic target for the treatment of RIBI.
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Lesiones Encefálicas , Trastornos Cerebrovasculares , Traumatismos por Radiación , Animales , Ratones , Nimodipina , Miocitos del Músculo Liso/patología , Transducción de Señal , Trastornos Cerebrovasculares/complicaciones , Lesiones Encefálicas/patología , Ésteres/metabolismo , Ésteres/farmacología , Receptores Notch/metabolismoRESUMEN
BACKGROUND: Radiation-induced brain injury (RIBI) is the most serious complication of radiotherapy in patients with head and neck tumors, which seriously affects the quality of life. Currently, there is no effective treatment for patients with RIBI, and identifying new treatment that targets the pathological mechanisms of RIBI is urgently needed. METHODS: Immunofluorescence staining, western blotting, quantitative real-time polymerase chain reaction (Q-PCR), co-culture of primary neurons and microglia, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, enzyme-linked immunosorbent assay (ELISA), and CRISPR-Cas9-mediated gene editing techniques were employed to investigate the protective effects and underlying mechanisms of pregabalin that ameliorate microglial activation and neuronal injury in the RIBI mouse model. RESULTS: Our findings showed that pregabalin effectively repressed microglial activation, thereby reducing neuronal damage in the RIBI mouse model. Pregabalin mitigated inflammatory responses by directly inhibiting cytoplasmic translocation of high-mobility group box 1 (HMGB1), a pivotal protein released by irradiated neurons which induced subsequent activation of microglia and inflammatory cytokine expression. Knocking out neuronal HMGB1 or microglial TLR2/TLR4/RAGE by CRISPR/Cas9 technique significantly inhibited radiation-induced NF-κB activation and pro-inflammatory transition of microglia. CONCLUSIONS: Our findings indicate the protective mechanism of pregabalin in mitigating microglial activation and neuronal injury in RIBI. It also provides a therapeutic strategy by targeting HMGB1-TLR2/TLR4/RAGE signaling pathway in the microglia for the treatment of RIBI.
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Lesiones Encefálicas , Proteína HMGB1 , Animales , Lesiones Encefálicas/metabolismo , Citocinas/metabolismo , ADN Nucleotidilexotransferasa/metabolismo , ADN Nucleotidilexotransferasa/farmacología , Proteína HMGB1/metabolismo , Ratones , Microglía/metabolismo , FN-kappa B/metabolismo , Neuronas/metabolismo , Pregabalina/metabolismo , Pregabalina/farmacología , Pregabalina/uso terapéutico , Calidad de Vida , Transducción de Señal , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
The direct C-H trifluoromethylation of arenes via a radical pathway has attracted considerable attention recently. However, a major challenge of C-H trifluoromethylation is the lack of site-selectivity on the phenyl ring especially para-selectivity. Herein we show a new strategy for para-selective C-H trifluoromethylation of benzamide derivatives using iminium activation. The reaction undergoes a radical-type nucleophilic substitution instead of a radical-type electrophilic substitution owing to iminium activation as a result of lowering the LUMO (lowest unoccupied molecular orbital). A wide range of substrates are compatible with this method giving almost exclusive para-trifluoromethylated products.
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Benzamidas , CatálisisRESUMEN
BACKGROUND: Covid-19 became a global pandemic in 2019. Studies have shown that coronavirus can cause neurological symptoms, but clinical studies on its neurological symptoms are limited. In this meta-analysis, we aimed to summarize the various neurological manifestations that occurred in COVID-19 patients and calculate the incidence of various neurological manifestations. At the same time, we further explored the mechanism of nervous system injury and prognosis in COVID-19 patients in combination with their nervous system manifestations. This study provides a reference for early clinical identification of COVID-19 nervous system injury in the future, so as to achieve early treatment and reduce neurological sequelae. METHODS: We systematically searched all published English literature related to the neurological manifestations of COVID-19 from January 1, 2020, to April 30, 2021, in Pubmed, Embase, and Cochrane Library. The keywords used were COVID-19 and terminology related to the nervous system performance. All included studies were selected by two independent reviewers using EndNote and NoteExpress software, any disagreement was resolved by consensus or by a third reviewer, and the selected data were then collected for meta-analysis using a random-effects model. RESULTS: A total of 168 articles (n = 292,693) were included in the study, and the meta-analysis showed that the most common neurological manifestations of COVID-19 were myalgia(33%; 95%CI 0.30-0.37; I2 = 99.17%), smell impairment(33%; 95%CI 0.28-0.38; I2 = 99.40%), taste dysfunction(33%; 95%CI 0.27-0.39; I2 = 99.09%), altered mental status(32%; 95%CI 0.22-0.43; I2 = 99.06%), headache(29%; 95%CI 0.25-0.33; I2 = 99.42%), encephalopathy(26%; 95%CI 0.16-0.38; I2 = 99.31%), alteration of consciousness(13%; 95%CI 0.08-0.19; I2 = 98.10%), stroke(12%; 95%CI 0.08-0.16; I2 = 98.95%), dizziness(10%; 95%CI 0.08-0.13; I2 = 96.45%), vision impairment(6%; 95%CI 0.03-0.09; I2 = 86.82%), intracerebral haemorrhage(5%; 95%CI 0.03-0.09; I2 = 95.60%), seizure(4%; 95%CI 0.02 -0.05; I2 = 98.15%), encephalitis(2%; 95%CI 0.01-0.03; I2 = 90.36%), Guillan-Barré Syndrome (GBS) (1%; 95%CI 0.00-0.03; I2 = 89.48%). CONCLUSIONS: Neurological symptoms are common and varied in Covid-19 infections, and a growing number of reports suggest that the prevalence of neurological symptoms may be increasing. In the future, the role of COVID-19 neurological symptoms in the progression of COVID-19 should be further studied, and its pathogenesis and assessment methods should be explored, to detect and treat early neurological complications of COVID-19 and reduce mortality.
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COVID-19 , Trastornos Mentales , Enfermedades del Sistema Nervioso , Accidente Cerebrovascular , Humanos , SARS-CoV-2RESUMEN
In this present study, a fluorescent probe was developed to detect curcumin, which is derived from the rhizomes of the turmeric. We used a simple and economical way to synthesize boron and nitrogen co-doped carbon dots (BNCDs) by microwave heating. The maximum emission wavelength of the BNCDs was 450 nm at an excitation wavelength of 360 nm. The as-prepared BNCDs were characterized by multiple analytical techniques such as transmission electron microscopy, X-ray photoelectron spectroscopy, X-ray diffraction, and infrared spectroscopy. The synthesized carbon nanoparticles had an average particle diameter of 4.23 nm. The BNCDs exhibited high sensitivity to the detection of curcumin at ambient conditions. The changes of BNCDs fluorescent intensity show a good linear relationship with the curcumin concentrations in the range 0.2-12.5 µM. This proposed method has been successfully applied to detect the curcumin in urine samples with the recoveries of 96.5-105.5%.
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Boro/química , Carbono/química , Curcumina/análisis , Colorantes Fluorescentes/química , Nitrógeno/química , Puntos Cuánticos , Nanopartículas/química , Tamaño de la PartículaRESUMEN
Amyloid beta (Aß) and its aggregation forms in the brain have been suggested as key targets for the therapy of Alzheimer's disease (AD). Therefore, the development of nanocarriers that possess both blood-brain barrier permeability and Aß-targeting ability is of great importance for the intervention of AD. Here we constructed a biomimetic nanocarrier named apolipoprotein E (ApoE)-reconstituted high density lipoprotein nanocarrier (ANC) from recombinant ApoE and synthetic lipids to achieve the above goals. α-Mangostin (α-M), a polyphenolic agent that can inhibit the formation of Aß oligomers and fibrils and accelerate Aß cellular degradation, was used as the model drug. Compared with the control liposome, ANC demonstrated about 54-fold higher cellular uptake in brain endothelial cell line in vitro in an ApoE-dependent manner and much higher brain delivery efficiency in vivo. Confocal microscopy analysis witnessed the penetration of ANC across the brain vessels and its accumulation at the surrounding of Aß aggregates. Following the loading of α-M, the Aß-binding affinity of the nanoformulation (ANC-α-M) was not reduced but even enhanced. The effect of ANC-α-M on facilitating the microglia-mediated uptake and degradation of Aß1-42 was enhanced by 336% and 29-fold when compared with that of the nontreated control and also much higher than that of ANC. Following intravenous administration for 2 to 4 weeks, ANC-α-M exhibited the most efficient efficacy in decreasing amyloid deposition, attenuating microgliosis, and rescuing memory defect in SAMP8 mice, an AD mouse model. Taken together, the findings of this work provided strong evidence that the ApoE-based biomimetic nanocarrier could provide a promising platform for brain drug delivery toward the treatment of AD.
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Péptidos beta-Amiloides/metabolismo , Apolipoproteínas E/química , Apolipoproteínas E/metabolismo , Barrera Hematoencefálica/metabolismo , Lipoproteínas HDL/química , Lipoproteínas HDL/metabolismo , Administración Intravenosa , Enfermedad de Alzheimer/metabolismo , Animales , Apolipoproteínas E/administración & dosificación , Encéfalo/metabolismo , Portadores de Fármacos/química , Composición de Medicamentos , Sistemas de Liberación de Medicamentos/métodos , Lipoproteínas HDL/administración & dosificación , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ratones Transgénicos , Microscopía Confocal , Nanopartículas/química , Xantonas/químicaRESUMEN
Rational design of the physicochemical properties of nanocarriers can optimize their pharmacokinetics, biodistribution, intratumoral penetration and tumor bioavailability. In particular, particle shape is one of the crucial parameters that can impact the circulation time, tumor accumulation and tumor cell internalization of nanocarrier. Biomimetic reconstituted high-density lipoprotein (rHDL), by mimicking the endogenous shape and structure of high-density lipoprotein, has been indicated as a promising tumor-targeting nanoparticulate drug delivery system whereas the effect of shape on tumor-targeting efficiency has not been fully evaluated. Herein, we constructed apolipoprotein E-based biomimetic rHDL in both discoidal form (d-rHDL) and spherical form (s-rHDL), and compared their efficiency in glioblastoma multiforme (GBM)-targeting delivery. s-rHDL showed higher cellular association in GBM cells especially at a high exposure dosage or after a long incubation time. Moreover, it exhibited deeper penetration in 3D GBM spheroids in vitro and higher accumulation at the GBM site in vivo with the GBM-targeting accumulation of s-rHDL increased by 73% when compared with that of d-rHDL at 24 h post-injection. The findings collectively indicated that s-rHDL might serve as a more efficient nanocarrier for glioblastoma-targeting drug delivery.
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Biomimética , Neoplasias Encefálicas/tratamiento farmacológico , Portadores de Fármacos/química , Glioblastoma/tratamiento farmacológico , Lipoproteínas HDL/química , Nanopartículas/química , Animales , Encéfalo/metabolismo , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Glioblastoma/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Tamaño de la Partícula , RatasRESUMEN
We show the synthesis and conformational studies of a series of 7,7-disubstituted-dibenzo[b,d]oxepin-6(7H)-ones that feature biaryl-bridged seven-membered lactones with a quaternary carbon center, in which the larger substituents prefer the axial positions. Further studies on the crystal structures and DFT calculations revealed that the high selectivity observed is attributed to the volume of substituents.
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Mesothelioma, an uncommon yet highly aggressive malignant neoplasm, presents challenges in the effectiveness of current therapeutic approaches. Ferroptosis, a non-apoptotic mechanism of cellular demise, exhibits a substantial association with the progression of diverse cancer forms. It is important to acknowledge that there exists a significant association between ferroptosis and the advancement of various forms of cancer. Nevertheless, the precise role of ferroptosis regulatory factors within the context of mesothelioma remains enigmatic. In our investigation, we initially scrutinized the prognostic significance of 24 ferroptosis regulatory factors in the realm of mesothelioma. Our observations unveiled that heightened expression levels of CARS1, CDKN1A, TFRC, FANCD2, FDFT1, HSPB1, SLC1A5, SLC7A11, coupled with reduced DPP4 expression, were indicative of an unfavorable prognosis. Built upon the nine previously discussed prognostic genes, the ferroptosis prognostic model offers a reliable means to forecast mesothelioma patients' survival with a substantial degree of precision. Furthermore, a notable correlation emerged between these prognostic ferroptosis regulators and parameters such as immune cell infiltration, tumor mutation burden, microsatellite instability, and PD-L1 expression in the context of mesothelioma. Within this cadre of nine ferroptosis regulatory factors with prognostic relevance, FANCD2 exhibited the most pronounced prognostic influence, as elucidated by our analyses. Subsequently, we executed a validation process employing clinical specimens sourced from our institution, thus confirming that heightened FANCD2 expression is a discernible harbinger of an adverse prognosis in the context of mesothelioma. In vitro experiments revealed that knocking down FANCD2 markedly suppressed the proliferation, migration, and ability of mesothelioma cells to attract immune cells. Furthermore, our findings also showed that reducing FANCD2 levels heightened the vulnerability of mesothelioma cells to inducers of ferroptosis. Furthermore, an extensive pan-cancer analysis uncovered a robust association between FANCD2 and the gene expression linked to immune checkpoints, thereby signifying an adverse prognosis across a broad spectrum of cancer types. Additional research is warranted to validate these findings.
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Ferroptosis , Regulación Neoplásica de la Expresión Génica , Mesotelioma , Ferroptosis/genética , Humanos , Pronóstico , Mesotelioma/genética , Mesotelioma/patología , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/genética , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/metabolismo , Línea Celular Tumoral , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Mesotelioma Maligno/genética , Mesotelioma Maligno/patología , Sistema de Transporte de Aminoácidos y+RESUMEN
Nanoparticles (NPs) represent an important advance for delivering diagnostic and therapeutic agents across the blood-brain barrier. However, NP clearance is critical for safety and therapeutic applicability. Here we report on a study of the clearance of model organic and inorganic NPs from the brain. We find that microglial extracellular vesicles (EVs) play a crucial role in the clearance of inorganic and organic NPs from the brain. Inorganic NPs, unlike organic NPs, perturb the biogenesis of microglial EVs through the inhibition of ERK1/2 signalling. This increases the accumulation of inorganic NPs in microglia, hindering their elimination via the paravascular route. We also demonstrate that stimulating the release of microglial EVs by an ERK1/2 activator increased the paravascular glymphatic pathway-mediated brain clearance of inorganic NPs. These findings highlight the modulatory role of microglial EVs on the distinct patterns of the clearance of organic and inorganic NPs from the brain and provide a strategy for modulating the intracerebral fate of NPs.
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Vesículas Extracelulares , Nanopartículas , Microglía , Barrera Hematoencefálica , Encéfalo , Nanopartículas/uso terapéuticoRESUMEN
Both therapeutic hypothermia and neural stem cells (NSCs) transplantation have shown promise in neuroprotection and neural repair after brain injury. However, the effects of therapeutic hypothermia on neuronal differentiation of NSCs are not elucidated. In this study, we aimed to investigate whether mild hypothermia promoted neuronal differentiation in cultured and transplanted human NSCs (hNSCs). A significant increase in neuronal differentiation rate of hNSCs was found when exposed to 35°C, from 33% to 45% in vitro and from 7% to 15% in vivo. Additionally, single-cell RNA sequencing identified upregulation of RNA-binding motif protein 3 (RBM3) in neuroblast at 35°C, which stabilized the SRY-box transcription factor 11 (SOX11) mRNA and increased its protein expression, leading to an increase in neuronal differentiation of hNSCs. In conclusion, our study highlights that mild hypothermia at 35°C enhances hNSCs-induced neurogenesis through the novel RBM3-SOX11 signaling pathway, and provides a potential treatment strategy in brain disorders.
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α-Terpineol, an alcoholic monoterpene with lilac-like aroma, possesses diverse biological activities and has found applications in the food, pharmaceutical, cosmetic, and agricultural industries. Our previous studies indicated that gene PdTP1 was highly expressed in Penicillium digitatum DSM 62840 during the biotransformation of limonene to α-terpineol, while its actual biological functions are not fully understood. Here, PdTP1 was functionally characterized with bioinformatics analysis, subcellular localization, transcriptional activation activity, overexpression, and RNA interference (RNAi) silencing and RNA-seq analysis. Results showed that PdTP1 protein contained a GAL4-like Zn2Cys6 DNA-binding domain and a fungal_trans domain, was located in the nucleus and cell membrane and presented transcriptional activation effect, suggesting that PdTP1 encoded a Zn2Cys6 type transcription factor. Overexpression of PdTP1 in P. digitatum promoted limonene biotransformation and increased α-terpineol production, and opposite results were observed after the silencing of PdTP1. Moreover, transcription factor PdTP1 was found to affect the growth of P. digitatum and participate in ionic stress and oxidative stress responses. RNA-seq data revealed that altering the PdTP1 expression influenced the expression of some genes related to terpene metabolism or biosynthesis, fungal growth, and stress responses. In summary, PdTP1, which encoded a Zn2Cys6 transcription factor, played important roles in improving the production of α-terpineol from limonene and regulating fungal growth and environmental stress responses.
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BACKGROUND: Although abnormal accumulation of amyloid beta (Aß) protein is thought to be the main cause of Alzheimer's disease (AD), emerging evidence suggests a pivotal vascular contribution to AD. Aberrant amyloid ß induces neurovascular dysfunction, leading to changes in the morphology and function of the microvasculature. However, little is known about the underlying mechanisms between Aß deposition and vascular injuries. Recent studies have revealed that pericytes play a substantial role in the vasculopathy of AD. Additional research is imperative to attain a more comprehensive understanding. METHODS: Two-photon microscopy and laser speckle imaging were used to examine cerebrovascular dysfunction. Aß oligomer stereotactic injection model was established to explain the relationship between Aß and vasculopathy. Immunofluorescence staining, western blot, and real-time PCR were applied to detect the morphological and molecular alternations of pericytes. Primary cultured pericytes and bEnd.3 cells were employed to explore the underlying mechanisms. RESULTS: Vasculopathy including BBB damage, hypoperfusion, and low vessel density were found in the cortex of 8 to 10-month-old 5xFAD mice. A similar phenomenon accompanied by pericyte degeneration appeared in an Aß-injected model, suggesting a direct relationship between Aß and vascular dysfunction. Pericytes showed impaired features including low PDGFRß expression and increased pro-inflammatory chemokines secretion under the administration of Aß in vitro, of which supernatant cultured with bEND.3 cells led to significant endothelial dysfunction characterized by TJ protein deficiency. CONCLUSIONS: Our results provide new insights into the pathogenic mechanism underlying Aß-induced vasculopathy. Targeting pericyte therapies are promising to ameliorate vascular dysfunction in AD.
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Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Trastornos Cerebrovasculares , Ratones , Animales , Péptidos beta-Amiloides/metabolismo , Pericitos/patología , Barrera Hematoencefálica/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Enfermedad de Alzheimer/patología , Trastornos Cerebrovasculares/complicacionesRESUMEN
Protein therapeutics are anticipated to offer significant treatment options for central nervous system (CNS) diseases. However, the majority of proteins are unable to traverse the blood-brain barrier (BBB) and reach their CNS target sites. Inspired by the natural environment of active proteins, the cell matrix components hyaluronic acid (HA) and protamine (PRTM) are used to self-assemble with proteins to form a protein-loaded biomimetic core and then incorporated into ApoE3-reconstituted high-density lipoprotein (rHDL) to form a protein-loaded biomimetic nanocarrier (Protein-HA-PRTM-rHDL). This cell matrix-inspired biomimetic nanocarrier facilitates the penetration of protein therapeutics across the BBB and enables their access to intracellular target sites. Specifically, CAT-HA-PRTM-rHDL facilitates rapid intracellular delivery and release of catalase (CAT) via macropinocytosis-activated membrane fusion, resulting in improved spatial learning and memory in traumatic brain injury (TBI) model mice (significantly reduces the latency of TBI mice and doubles the number of crossing platforms), and enhances motor function and prolongs survival in amyotrophic lateral sclerosis (ALS) model mice (extended the median survival of ALS mice by more than 10 days). Collectively, this cell matrix-inspired nanoplatform enables the efficient CNS delivery of protein therapeutics and provides a novel approach for the treatment of CNS diseases.
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Materiales Biomiméticos , Barrera Hematoencefálica , Encéfalo , Catalasa , Portadores de Fármacos , Ácido Hialurónico , Animales , Ratones , Materiales Biomiméticos/química , Portadores de Fármacos/química , Barrera Hematoencefálica/metabolismo , Ácido Hialurónico/química , Catalasa/metabolismo , Catalasa/química , Encéfalo/metabolismo , Nanopartículas/química , Protaminas/química , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/metabolismo , Biomimética/métodosRESUMEN
Burn wounds often bring high risks of delayed healing process and even death. Reactive oxygen species (ROS) play a crucial role in burn wound repair. However, the dynamic process in wound healing requires both the generation of ROS to inhibit bacteria and the subsequent reduction of ROS levels to initiate and promote tissue regeneration, which calls for a more intelligent ROS regulation dressing system. Hence, a dual-layered hydrogel (Dual-Gel) tailored to the process of burn wound repair is designed: the inner layer hydrogel (Gel 2) first responds to bacterial hyaluronidase (Hyal) to deliver aggregation-induced emission photosensitizer functionalized adipose-derived stem cell nanovesicles, which generate ROS upon light irradiation to eliminate bacteria; then the outer layer hydrogel (Gel 1) continuously starts a long-lasting consumption of excess ROS at the wound site to accelerate tissue regeneration. Simultaneously, the stem cell nanovesicles trapped in the burns wound also provide nutrients and mobilize neighboring tissues to thoroughly assist in inflammation regulation, cell proliferation, migration, and angiogenesis. In summary, this study develops an intelligent treatment approach on burn wounds by programmatically regulating ROS and facilitating comprehensive wound tissue repair.
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Quemaduras , Hidrogeles , Especies Reactivas de Oxígeno , Células Madre , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Quemaduras/terapia , Quemaduras/metabolismo , Quemaduras/patología , Animales , Hidrogeles/química , Células Madre/citología , Células Madre/metabolismo , Ratones , Regeneración/efectos de los fármacos , Humanos , Hialuronoglucosaminidasa/metabolismo , Nanoestructuras/química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Proliferación Celular/efectos de los fármacosRESUMEN
OBJECTIVES: This study aimed to observe the color rebound and rebound rates of non-pulp discolored teeth within 1 year after routine internal bleaching to guide clinical practice and prompt prognosis. METHODS: In this work, the efficacy of bleaching was observed in 20 patients. The color of discolored teeth was measured by using a computerized colorimeter before bleaching; immediately after bleaching; and at the 1st, 3rd, 6th, 9th, and 12th months after bleaching. The L*, a*, and b* values of the color of cervical, mesial, and incisal parts of the teeth were obtained, and the color change amounts ΔE*, ΔL*, Δa*, and Δb* were calculated. The overall rebound rate (P*) and the color rebound velocity (V*) were also analyzed over time. RESULTS: In 20 patients following treatment, the average ΔE* of tooth color change was 14.99. After bleaching, the neck and middle of the teeth ΔE* and ΔL* decreased in the 1st, 3rd, 6th, 9th, and 12th months, and the differences were statistically significant. Meanwhile, from the 9th month after bleaching, the rebound speed was lower than that in the 1st month, and the difference was statistically significant. The incisal end of the tooth ΔE* and ΔL* decreased in the 6th, 9th, and 12th months after bleaching, and the differences were statistically significant. No significant difference was found in the rebound speed between time points. However, this rate settled after the 9th month, with an average color rebound rate of 30.11% in 20 patients. CONCLUSIONS: The results indicated that internal bleaching could cause a noticeable color change on pulpless teeth. The color rebound after bleaching was mainly caused by lightness (L*), which gradually decreased with time, and it was slightly related to a* and b*. The color of the teeth after internal bleaching rebounded to a certain extent with time, but the color rebound speed became stable from the 9th month. Clinically, secondary internal bleaching can be considered at this time according to whether the colors of the affected tooth and the adjacent tooth are coordinated and depending on the patient's needs.
Asunto(s)
Blanqueadores Dentales , Blanqueamiento de Dientes , Decoloración de Dientes , Diente no Vital , Diente , Humanos , Blanqueamiento de Dientes/métodos , Diente no Vital/tratamiento farmacológico , Color , Decoloración de Dientes/tratamiento farmacológico , Peróxido de Hidrógeno/uso terapéutico , Blanqueadores Dentales/uso terapéuticoRESUMEN
Objectives: Our purpose was to investigate the influencing factors for mortality in sepsis patients without lactate levels increasing in the early stage. Methods: We conducted a retrospective observational study involving 830 adult sepsis patients admitted to ICU. We calculated time-weighted lactate (LacTW), a dynamic value that incorporates both the magnitude of change and the time interval of such change, to represent lactate levels in the first 24 hours. ROC curve was used to find the cutoff of LacTW for predicting mortality, and the influencing factors for lactate levels and mortality in the low lactate group were further studied. The primary outcome was hospital mortality. Results: Among 830 patients, LacTW > 1.975 mmo/L was found to be the cutoff threshold for predicting mortality (AUC = 0.646, P < 0.001). The following indexes related to organ dysfunction influenced LacTW: acute physiology and chronic health evaluation II (APACHE II) score (P < 0.001), activated partial thromboplastin time (APTT) (P = 0.002), total bilirubin (P = 0.012), creatinine (P = 0.037), with hypotension (P < 0.001), chronic kidney disease (P = 0.013), and required continuous renal replacement therapy (CRRT) (P < 0.001). Of the 394 patients in the low lactate group, age (P = 0.002), malignancy (P < 0.001), lactate dehydrogenase (P = 0.006), required treatment such as mechanical ventilation (P < 0.001), CRRT (P < 0.001), vasoactive drugs (P < 0.001), and glucocorticoid (P < 0.001), and failure to reach the target fluid resuscitation of 30 ml/kg within 6 hours (P = 0.003) were independently associated with hospital mortality. Conclusions: Due to the lower incidence of early organ dysfunction, lactate levels are not increased or delayed in some septic shock patients in the early stage, thus affecting the alertness of clinicians and the timeliness and adequacy of fluid resuscitation, and finally affects the prognosis.