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Hypoxia can lead to liver fibrosis and severely limits the efficacy of photodynamic therapy (PDT). Herein, carbon nitride (CN)-based hybrid nanoparticles (NPs) VPSGCNs@TSI for light-driven water splitting were utilized to solve this problem. CNs were doped with selenide glucose (Se-glu) to enhance their red/NIR region absorption. Then, vitamin A-poly(ethylene glycol) (VA-PEG) fragments and aggregation-induced emission (AIE) photosensitizers TSI were introduced into Se-glu-doped CN NPs (VPSGCNs) to construct VPSGCNs@TSI NPs. The introduction of VA-PEG fragments enhanced the targeting of the NPs to activated hepatic stellate cells (HSCs) and reduced their toxicity to ordinary liver cells. VPSGCN units could trigger water splitting to generate O2 under 660 nm laser irradiation, improve the hypoxic environment of the fibrosis site, downregulate HIF-1α expression, and activate HSC ferroptosis via the HIF-1α/SLC7A11 pathway. In addition, generated O2 could also increase the reactive oxygen species (ROS) production of TSI units in a hypoxic environment, thereby completely reversing hypoxia-triggered PDT resistance to enhance the PDT effect. The combination of water-splitting materials and photodynamic materials showed a 1 + 1 > 2 effect in increasing oxygen levels in liver fibrosis, promoting ferroptosis of activated HSCs and reversing PDT resistance caused by hypoxia.
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Ferroptosis , Células Estrelladas Hepáticas , Cirrosis Hepática , Nanopartículas , Fotoquimioterapia , Nanopartículas/química , Animales , Ferroptosis/efectos de los fármacos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Ratones , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Nitrilos/química , Nitrilos/farmacología , Humanos , Hipoxia/tratamiento farmacológico , Hipoxia/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Background and objective: Stent-assisted coil (SAC) embolization is a commonly used endovascular treatment for unruptured intracranial aneurysms (UIAs) but can be associated with symptomatic delayed intracerebral hemorrhage (DICH). Our study aimed to investigate the hemodynamic risk factors contributing to DICH following SAC embolization and to establish a classification for DICH predicated on hemodynamic profiles. Methods: This retrospective study included patients with UIAs located in the internal carotid artery (ICA) treated with SAC embolization at our institution from January 2021 to January 2022. We focused on eight patients who developed postoperative DICH and matched them with sixteen control patients without DICH. Using computational fluid dynamics, we evaluated the hemodynamic changes in distal arteries [terminal ICA, the anterior cerebral artery (ACA), and middle cerebral artery (MCA)] pre-and post-embolization. We distinguished DICH-related arteries from unrelated ones (ACA or MCA) and compared their hemodynamic alterations. An imbalance index, quantifying the differential in flow velocity changes between ACA and MCA post-embolization, was employed to gauge the flow distribution in distal arteries was used to assess distal arterial flow distribution. Results: We identified two types of DICH based on postoperative flow alterations. In type 1, there was a significant lower in the mean velocity increase rate of the DICH-related artery compared to the unrelated artery (-47.25 ± 3.88% vs. 42.85 ± 3.03%; p < 0.001), whereas, in type 2, there was a notable higher (110.58 ± 9.42% vs. 17.60 ± 4.69%; p < 0.001). Both DICH types demonstrated a higher imbalance index than the control group, suggesting an association between altered distal arterial blood flow distribution and DICH occurrence. Conclusion: DICH in SAC-treated UIAs can manifest as either a lower (type 1) or higher (type 2) in the rate of velocity in DICH-related arteries. An imbalance in distal arterial blood flow distribution appears to be a significant factor in DICH development.
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Hypoxia is an important feature, which can upregulate the hypoxia-inducible factor-1α (HIF-1α) expression and promote the activation of hepatic stellate cells (HSCs), leading to liver fibrosis. Currently, effective treatment for liver fibrosis is extremely lacking. Herein, a safe and effective method is established to downregulate the expression of HIF-1α in HSCs via targeted delivery of VA-PEG-modified CNs-based nanosheets-encapsulated (VA-PEG-CN@GQDs) HIF-1α small interfering RNA (HIF-1α-siRNA). Due to the presence of lipase in the liver, the reversible release of siRNA can be promoted to complete the transfection process. Simultaneously, VA-PEG-CN@GQD nanosheets enable trigger the water splitting process to produce O2 under near-infrared (NIR) irradiation, thereby improving the hypoxic environment of the liver fibrosis site and maximizing the downregulation of HIF-1α expression to improve the therapeutic effect, as demonstrated in liver fibrosis mice. Such combination therapy can inhibit the activation of HSCs via HIF-1α-mediated TGF-ß1/Smad pathway, achieving outstanding therapeutic effects in liver fibrosis mice. In conclusion, this study proposes a novel strategy for the treatment of liver fibrosis by regulating the hypoxic environment and the expression of HIF-1α at lesion site.
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Subunidad alfa del Factor 1 Inducible por Hipoxia , Factor de Crecimiento Transformador beta1 , Ratones , Animales , Factor de Crecimiento Transformador beta1/metabolismo , ARN Interferente Pequeño/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Cirrosis Hepática/terapia , HipoxiaRESUMEN
OBJECTIVE: To elucidate the role of transsphenoidal surgery in the treatment of pituitary microprolactinoma. METHODS: The clinical data of 107 prolactinoma cases treated by extra-pseudocapsular transnasal transsphenoidal surgery (ETTS) for different indications in our department since 2011 was retrospectively analyzed. RESULTS: The most common indication was the ineffectiveness of oral medication (41.1%), followed by the personal willingness of the patient (35.5%), and 20.6% of the patients were young women with clear tumor boundaries. The pseudocapsule was not observed in 63 cases (58.9%), incomplete pseudocapsule was observed in 26 cases (24.3%), and complete pseudocapsule in 18 cases (16.8%). A total of 97 patients (90.7%) obtained 1-year post-operation remission. According to the relative location of the adenoma and pituitary gland on the MRI scan, 46 patients were classified into a central type, 59 a lateral type, and 2 a supra-pituitary type. Two patients developed hypogonadism, one patient developed hypocortisolism, and one patient developed post-operative hypothyroidism. Two patients were administrated with hormone replacement treatment, and the treatment was stopped within one week. There was no permanent hypopituitarism. Further investigation demonstrated that the adenoma types could affect the remission rates of hyperprolactinemia and gross total resection rate in microprolactinoma. CONCLUSION: ETTS was an effective treatment for pituitary microprolactinomas. This could be the first choice for patients who presented enclosed adenoma on the MRI and were potentially curable in a preoperative evaluation. Maximal safe removal of the adenoma by ETTS with the aim to increase the sensitivity of the drugs was also recommended for patients with invasive dopamine agonist resistant prolactinomas and patients with difficulty in childbirth.
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Adenoma , Neoplasias Hipofisarias , Prolactinoma , Humanos , Femenino , Prolactinoma/diagnóstico por imagen , Prolactinoma/tratamiento farmacológico , Prolactinoma/cirugía , Neoplasias Hipofisarias/diagnóstico por imagen , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/cirugía , Estudios Retrospectivos , Hipófisis/diagnóstico por imagen , Hipófisis/cirugía , Hipófisis/patología , Adenoma/patología , Adenoma/cirugíaRESUMEN
The latest edition of the WHO classification of the central nervous system was published in 2021. This review summarizes the major revisions to the classification of anterior pituitary tumors. The most important revision involves preferring the terminology of pituitary neuroendocrine tumor (PitNET), even though the terminology of pituitary adenoma (PA) still can be used according to this WHO classification compared to the previous one. Moreover, immunohistochemistry (IHC) examination of pituitary-specific transcription factors (TFs), including PIT1, TPIT, SF-1, GATA2/3, and ERα, is endorsed to determine the tumor cell lineage and to facilitate the classification of PitNET/PA subgroups. However, TF-negative IHC staining indicates PitNET/PA with no distinct cell lineages, which includes unclassified plurihormonal (PH) tumors and null cell (NC) tumors in this edition. The new WHO classification of PitNET/PA has incorporated tremendous advances in the understanding of the cytogenesis and pathogenesis of pituitary tumors. However, due to the shortcomings of the technology used in the diagnosis of PitNET/PA and the limited understanding of the tumorigenesis of PitNET/PA, the application of this new classification system in practice should be further evaluated and validated. Besides providing information for deciding the follow-up plans and adjunctive treatment after surgery, this classification system offers no additional help for neurosurgeons in clinical practice, especially in determining the treatment strategies. Therefore, it is necessary for neurosurgeons to establish a comprehensive pituitary classification system for PitNET/PA that incorporates neuroimaging grading data or direct observation of invasiveness during operation or the predictor of prognosis, as well as pathological diagnosis, thereby distinguishing the invasiveness of the tumor and facilitating neurosurgeons to decide on the treatment strategies and follow-up plans as well as adjunctive treatment after surgery.
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Adenoma , Tumores Neuroendocrinos , Neoplasias Hipofisarias , Humanos , Neoplasias Hipofisarias/diagnóstico , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/patología , Pronóstico , Adenoma/patología , Organización Mundial de la SaludRESUMEN
This study researched the function of long non-coding RNA LINC00365 in lung adenocarcinoma (LAD) progression. LINC00365, miR-429, and KCTD12 expression in the LAD clinical tissues and cells were detcetd by qRT-PCR and Western blot. LINC00365, miR-429, and KCTD12 effects on H1975 cells malignant phenotype were detected by cell counting kit-8 assay, clone formation experiment, Transwell experiment, and glycolysis. Dual luciferase reporter gene assay and RNA pull-down assay were implemented. LINC00365 effect on H1975 cells in vivo growth was detected. LINC00365 was low expressed in the LAD patients and cells, associating with poor outcome. LINC00365 up-regulation attenuated H1975 cells proliferation, migration, invasion, glycolysis and in vivo growth. LINC00365 inhibited KCTD12 expression by sponging miR-429. miR-429 up-regulation and KCTD12 down-regulation partial reversed LINC00365 inhibition on H1975 cells malignant phenotype. Thus, LINC00365 inhibited LAD progression and glycolysis via targeting miR-429/KCTD12 axis. LINC00365 might be a potential candidate for LAD target treatment clinically.
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Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , MicroARNs , ARN Largo no Codificante , Adenocarcinoma/patología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Glucólisis/genética , Humanos , Neoplasias Pulmonares/patología , MicroARNs/genética , MicroARNs/metabolismo , Proteínas/genética , Proteínas/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Drug resistance is a critical factor responsible for the recurrence of non-small cell lung cancer (NSCLC). Previous studies suggest that curcumin acts as a chemosensitizer and radiosensitizer in human malignancies, but the underlying mechanism remains elusive. In the present study, we explored how curcumin regulates the expression of miR-142-5p and sensitizes NSCLC cells to crizotinib. We found that miR-142-5p is significantly downregulated in NSCLC tissue samples and cell lines. Curcumin could increase crizotinib cytotoxicity by epigenetically restoring the expression of miR-142-5p. Furthermore, curcumin treatment suppressed the expression of DNA methylation-related enzymes, including DNMT1, DNMT3A, and DNMT3B, in NSCLC cells. In addition, the upregulation of miR-142-5p expression increased crizotinib cytotoxicity and induced apoptosis in tumor cells in a similar manner to that of curcumin. Strikingly, miR-142-5p overexpression suppressed crizotinib-induced autophagy in A549 and H460 cells. Mechanistically, miR-142-5p inhibited autophagy in lung cancer cells by targeting Ulk1. Overexpression of Ulk1 abrogated the miR-142-5p-induced elevation of crizotinib cytotoxicity in A549 and H460 cells. Collectively, our findings demonstrate that curcumin sensitizes NSCLC cells to crizotinib by inactivating autophagy through the regulation of miR-142-5p and its target Ulk1.
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Carcinoma de Pulmón de Células no Pequeñas , Curcumina , Neoplasias Pulmonares , MicroARNs , Apoptosis/genética , Autofagia/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/genética , Crizotinib/uso terapéutico , Curcumina/farmacología , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
Recent decades have seen a significant increase in invasive fungal infections, resulting in unacceptably high mortality rates. Anidulafungin (AN) is the newest echinocandin and appears to have several advantages over existing antifungals. However, its poor water solubility and burdensome route of administration (i.e., repeated, long-term intravenous infusions) have limited its practical use. The objective of this study was to develop anidulafungin-loaded Human Serum Albumin (HSA) nanoparticles (NP) so as to increase both its solubility and antifungal efficacy. HSA was reduced using SDS and DTT, allowing liberation of free thiols to form the intermolecular disulfide network and nanoassembly. Reduced HSA was then added to MES buffer (0.1 M, pH 4.8) and magnetically stirred at 350 rpm and 25°C with AN (m/m 50:1) for 2 h to form nanoparticles (AN NP). We next performed routine antifungal susceptibility testing of Candida strains (n = 31) using Clinical and Laboratory Standards Institute (CLSI) methodologies. Finally, the in vivo efficacy of both AN and AN NP was investigated in a murine model of invasive infection by one of the most common fungal species-C. albicans. The results indicated that our carrier formulations successfully improved the water solubility of AN and encapsulated AN, with the latter having a particle size of 29 ± 1.5 nm with Polymer dispersity index (PDI) equaling 0.173 ± 0.039. In vitro AN NP testing revealed a stronger effect against Candida species (n = 31), with Minimum Inhibitory Concentration (MIC) values 4- to 32-fold lower than AN alone. In mice infected with Candida and having invasive candidiasis, we found that AN NP prolonged survival time (P < 0.005) and reduced fungal burden in kidneys compared to equivalent concentrations of free drug (P < 0.0001). In conclusion, the anidulafungin nanoparticles developed here have the potential to improve drug administration and therapeutic outcomes for individuals suffering from fungal diseases.
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OBJECTIVES: To study the correlation of fractional anisotropy (FA) on magnetic resonance diffusion tensor imaging with Neonatal Behavioral Neurological Assessment (NBNA) score in preterm infants, and to study the role of FA in evaluating white matter development from the perspective of imaging. METHODS: A prospective study was performed for 98 preterm infants who were admitted to the Neonatal Intensive Care Unit of the Third Affiliated Hospital of Zhengzhou University within 24 hours after birth from October 2016 to January 2020. According to the results of NBNA, they were divided into an abnormal group with 51 infants (NBNA score <37) and a normal group with 47 infants (NBNA score ≥37). The FA values of 10 regions of interest were collected and compared between the two groups. The correlations of FA value and umbilical arterial blood gas pH value with the NBNA score were analyzed. RESULTS: Compared with the normal group, the abnormal group had significantly lower FA value of the posterior limb of the internal capsule and umbilical arterial blood pH (P<0.05). The FA value of the posterior limb of the internal capsule and umbilical arterial blood pH were positively correlated with the NBNA score (r=0.584 and 0.604 respectively, P<0.001), and the FA value of the posterior limb of the internal capsule was positively correlated with umbilical arterial blood pH (r=0.426, P<0.05). CONCLUSIONS: The FA value of the posterior limb of the internal capsule can quantitatively reflect white matter development in preterm infants and is correlated with the NBNA score. The combination of the two indices can help to evaluate white matter development in preterm infants more accurately and objectively. Citation.
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Imagen de Difusión Tensora , Sustancia Blanca , Encéfalo , Imagen de Difusión por Resonancia Magnética , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Estudios Prospectivos , Sustancia Blanca/diagnóstico por imagenRESUMEN
Objective: Pre-eclampsia (PE) can cause brain development delay in infants. This work aims to characterize the pattern differences of brain white matter development in premature infants under PE conditions and those without. Methods: Eighty preterm infants delivered by women with PE were selected as the PE group, and ninety-six preterm infants of the same period born to women without high-risk perinatal factors were used as control. All infants underwent diffusion tensor imaging (DTI) examination. The fractional anisotropy (FA) was measured in five regions of interests (ROIs), including posterior limbs of internal capsule (PLIC), splenium of the corpus callosum (SCC), superior frontal gyrus (SFG), superior parietal lobule (SPL), and superior occipital gyrus (SOG). The relationship between the FA values and postmenstrual age (PMA) was analyzed. Results: After adjusting for the birth weight and gestational ages, in the SCC and PLIC, the PMA and FA values showed a low-to-medium intensity positive correlation in the control group (r = 0.30, p=0.003; r = 0.53, p < 0.0001), while no positive relevance was detected in the PE group (r = 0.08, p=0.47; r = 0.19, p < 0.08). In the PE and control groups, in the SPL and SOG, the PMA and FA values showed a near-consistent positive correlation (r = 0.57, r = 0.55 vs. r = 0.31, r = 0.55; all p < 0.05). In the control group, in SFG, the PMA and FA values had a medium intensity positive correlation (r = 0.47, p < 0.0001), but there was no statistical difference in correlation in PE (r = 0.10, p=0.39). Conclusion: PE may cause lagging brain development in the SCC, PLIC, and SFG during infancy. DTI may be an effective and sensitive detection tool.
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Encéfalo/patología , Imagen de Difusión Tensora/métodos , Retardo del Crecimiento Fetal/diagnóstico , Preeclampsia/fisiopatología , Adulto , Encéfalo/embriología , Estudios de Casos y Controles , Femenino , Retardo del Crecimiento Fetal/etiología , Estudios de Seguimiento , Edad Gestacional , Humanos , Recién Nacido , Recien Nacido Prematuro , Masculino , Embarazo , PronósticoRESUMEN
BACKGROUND: Recent studies show that an increased T217-phosphorylation of tau in plasma could diagnose AD at an early stage with high accuracy and high specificity, while the potential toxic role of tau T217-phosphorylation is not known. OBJECTIVE: To study the potential toxic role of tau T217-phosphorylation. METHODS: We performed stereotactic brain injection, behavioral testing, immunohistochemistry and immunofluorescence, western blotting, Golgi staining, in vitro recombinant tau polymerization, and other measurements. RESULTS: We first constructed tau T217-wild-type (T217), T217-phospho-mimic (T217E), and T217-non-phospho-mimic (T217A) plasmids or their virus vectors on the basis of wild-type tau. We found that expressing tau-T217E induced a significantly increased tau phosphorylation at multiple AD-associated sites with inhibited proteolysis and increased cleavage/fibrillization of tau, while expressing tau-T217A abolished the above changes of tau both in vitro and in vivo. By mutating T217E on tau-P301L, a dominant mutation identified in patients with frontotemporal dementia, we did not observe significant exacerbation of tau-P301L phosphorylation and cognitive impairment although the increased tau cleavage and propagation were shown. CONCLUSION: T217-phosphorylation exacerbates wild-type tau hyperphosphorylation with aggravated tau cleavage/fibrillization and cognitive impairments, while overexpressing T217E on the basis P301L does not exacerbate tau phosphorylation or the P301L-induced cognitive deficits, although it aggravates tau cleavage and propagation.
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Cognición/fisiología , Disfunción Cognitiva/metabolismo , Hipocampo/metabolismo , Aprendizaje por Laberinto/fisiología , Tauopatías/metabolismo , Proteínas tau/metabolismo , Animales , Disfunción Cognitiva/patología , Hipocampo/patología , Humanos , Ratones , Fosforilación , Tauopatías/patologíaRESUMEN
OBJECTIVE: The objective of this study was to investigate clinical neurocognitive performance and microstructural white matter (WM) alterations in infants of mothers with gestational diabetes mellitus (GDM) using diffusion tensor imaging. MATERIALS AND METHODS: Infants (corrected gestational age, 33.42-36.00 weeks) of mothers with GDM (n = 31) and gestational age- and sex-matched unexposed controls (n = 31) accomplished 3-T diffusion tensor imaging scans and neurocognitive tests. Diffusion tensor imaging measures, mainly referring to fractional anisotropy (FA) values, were compared between 2 groups, and within-group analysis of correlation between FA values and neurocognitive testing outcomes in GDM-exposed infants was conducted subsequently. RESULTS: Fractional anisotropy was significantly decreased in the splenium of corpus callosum, posterior limb of internal capsule, thalamus in infants of mothers with GDM when compared with controls (P < 0.05), reflecting microstructural WM abnormalities in the GDM group. Decreased FA was associated with worse neurocognitive performance in the exposed group (P < 0.05). CONCLUSIONS: Individuals of mothers with GDM showed microstructural WM abnormalities in different brain regions, which were significantly related to worse neurocognitive performance. This might reveal that GDM directly insults the brain development of the offspring.
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Encéfalo/fisiopatología , Diabetes Gestacional/epidemiología , Diabetes Gestacional/fisiopatología , Imagen de Difusión Tensora/métodos , Trastornos Neurocognitivos/epidemiología , Trastornos Neurocognitivos/fisiopatología , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/crecimiento & desarrollo , Causalidad , China , Femenino , Humanos , Recién Nacido , Masculino , Pruebas de Estado Mental y Demencia/estadística & datos numéricos , Madres , Trastornos Neurocognitivos/diagnóstico , Embarazo , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/fisiopatologíaRESUMEN
OBJECTIVE: To assess white matter development in preterm infants with bronchopulmonary dysplasia (BPD) using fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values of diffusion tensor imaging (DTI). METHODS: Ninety-six infants with a gestational age of ≤32 weeks and a birth weight of <1â500 g who were admitted to the neonatal intensive care unit within 24 hours after birth from August 2016 to April 2019 and underwent head MRI and DTI before discharge were enrolled. According to the discharge diagnosis, they were divided into BPD group with 48 infants and non-BPD group with 48 infants. The two groups were compared in terms of FA and ADC values of the same regions of interest on DTI image. RESULTS: There were no significant differences in the incidence rates of periventricular/intraventricular hemorrhage, periventricular leukomalacia, and punctate white matter lesions between the two groups (P>0.05). Compared with the non-BPD group, the BPD group had significantly lower FA values and significantly higher ADC values of the posterior limb of the internal capsule, the splenium of the corpus callosum, the occipital white matter, the cerebellum, and the cerebral peduncle (P<0.05). Compared with the non-BPD group, the BPD group had a significantly higher frequency of apnea, a significantly higher proportion of infants with pneumonia or mechanical ventilation, and a significantly longer duration of assisted ventilation (P<0.05). CONCLUSIONS: BPD may has potential adverse effects to white matter development in preterm infants, leading to delayed white matter development. Therefore, it is necessary to pay attention to the neurological function of these infants.
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Displasia Broncopulmonar , Sustancia Blanca , Displasia Broncopulmonar/diagnóstico por imagen , Cuerpo Calloso , Imagen de Difusión Tensora , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Sustancia Blanca/diagnóstico por imagenRESUMEN
BACKGROUND: Increased tau acetylation at K174, K274, K280, and K281 has been observed in the brains of Alzheimer's disease (AD) patients or in transgenic mice, but the role of acetylation in tau propagation is elusive. OBJECTIVE: To study the effect of tau acetylation in entorhinal cortex on tau transmission and learning and memory. METHODS: Stereotactic brain injection, behavioral test, electrophysiological recording, immunohistochemistry, and immunofluorescence were used. RESULTS: We constructed the hyperacetylation mimics of tau (AAV-Tau-4Q), the non-acetylation tau mutant (AAV-Tau-4R), and the wild-type tau (AAV-Tau-WT). By overexpressing these different tau proteins in the entorhinal cortex (EC) of 2-month-old mice, we found that overexpressing Tau-4Q in EC for 3 or 6 months (to 5 or 8 months of age) neither induces tau propagation to dentate gyrus (DG) nor glial activation in DG, nor spatial memory deficit. However, overexpressing Tau-WT and Tau-4Q in EC for 13.5 months (15.5 months of age) at 2 months promoted tau propagation respectively to granulosa and hilus of DG with glial activation, synaptic dysfunction, and memory deficit, while overexpressing Tau-4R abolished tau propagation with improved cellular pathologies and cognitive functions. Furthermore, overexpressing Tau-4Q in unilateral DG of 2-month-old mice for 8 weeks also promoted its contralateral transmission with glial activation, and mice with tau (Tau-WT, Tau-4Q, and Tau-4R) overexpression in DG showed cognitive deficits compared with the empty vector controls. CONCLUSION: Tau acetylation induces a time-dependent propagation from EC to DG, and only hippocampus but not EC tau accumulation induces cognitive deficits.
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Disfunción Cognitiva/metabolismo , Corteza Entorrinal/metabolismo , Hipocampo/metabolismo , Proteínas tau/metabolismo , Acetilación , Animales , Disfunción Cognitiva/genética , Disfunción Cognitiva/patología , Corteza Entorrinal/patología , Hipocampo/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas tau/genéticaRESUMEN
Isotactic polybutylene-1 (iPB) has lots of advantages and is best used as hot water pipe. However, to transform into stable crystal form I, the iPB needs as long as 7 days. In this process, the irreversible damage brings great difficulties to the use of the iPB. The method which convert it directly into crystal I has shortcomings such as being requiring complex operation and being expensive. In this study, an innovative idea was put forward, not paying attention to the crystal transformation of iPB but only focusing on reducing the time it can be applied. In this study, bamboo powder was modified by the silane coupling agent KH570 (KBP) to prepare iPB/KBP composite. The infiltration test and Fourier transform infrared (FTIR) analysis showed that the hydrophilicity of KBP is greatly reduced, which can greatly improve the compatibility of the iPB and KBP. The tensile strength, tensile modulus, flexural strength, and flexural modulus of the composites storage for 3 days is equal to the pure iPB with storage 7 days with the KBP additions of 3%, 3%, 7%, and 5%, respectively. The heat deformation temperature (HDT) of the composite with 3% KBP after 1-day storage reached the value of pure iPB storage for 7 days. This provides more space and possibilities for the industrialization of the iPB. The crystallization behavior of iPB/KBP composites proves that the addition of KBP accelerates the crystallization rate of iPB, but the crystallinity of the iPB/KBP composites is not changed. The SEM photograph of iPB/KBP composites showed that when the KBP addition was low the compatibility between KBP and iPB was good. When the KBP addition was increased the agglomeration of KBP in the iPB was very obvious, which leads to the poor mechanical properties of the composite.
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Intracellular tau accumulation forming neurofibrillary tangles is hallmark pathology of Alzheimer's disease (AD), but how tau accumulation induces synapse impairment is elusive. By overexpressing human full-length wild-type tau (termed hTau) to mimic tau abnormality as seen in the brain of sporadic AD patients, we find that hTau accumulation activates JAK2 to phosphorylate STAT1 (signal transducer and activator of transcription 1) at Tyr701 leading to STAT1 dimerization, nuclear translocation, and its activation. STAT1 activation suppresses expression of N-methyl-D-aspartate receptors (NMDARs) through direct binding to the specific GAS element of GluN1, GluN2A, and GluN2B promoters, while knockdown of STAT1 by AAV-Cre in STAT1flox/flox mice or expressing dominant negative Y701F-STAT1 efficiently rescues hTau-induced suppression of NMDAR expression with amelioration of synaptic functions and memory performance. These findings indicate that hTau accumulation impairs synaptic plasticity through JAK2/STAT1-induced suppression of NMDAR expression, revealing a novel mechanism for hTau-associated synapse and memory deficits.
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Regulación de la Expresión Génica , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Factor de Transcripción STAT1/metabolismo , Proteínas tau/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/psicología , Animales , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Humanos , Janus Quinasa 2/metabolismo , Trastornos de la Memoria/psicología , Ratones , Modelos Biológicos , Plasticidad Neuronal , Fosforilación , Regiones Promotoras Genéticas , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Transporte de Proteínas , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal , Proteínas tau/genéticaRESUMEN
Animal genomes in the Qinghai-Tibetan Plateau provide valuable resources for scientists to understand the molecular mechanism of environmental adaptation. Tibetan fish species play essential roles in the local ecology; however, the genomic information for native fishes was still insufficient. Oxygymnocypris stewartii, belonging to Oxygymnocypris genus, Schizothoracinae subfamily, is a native fish in the Tibetan plateau living within the elevation from roughly 3,000 m to 4,200 m. In this report, PacBio and Illumina sequencing platform were used to generate ~385.3 Gb genomic sequencing data. A genome of about 1,849.2 Mb was obtained with a contig N50 length of 257.1 kb. More than 44.5% of the genome were identified as repetitive elements, and 46,400 protein-coding genes were annotated in the genome. The assembled genome can be used as a reference for future population genetic studies of O. stewartii and will improve our understanding of high altitude adaptation of fishes in the Qinghai-Tibetan Plateau.
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Cyprinidae/genética , Genoma , Animales , Secuenciación de Nucleótidos de Alto Rendimiento , Anotación de Secuencia Molecular , TibetRESUMEN
BACKGROUND: Both type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are common age-associated disorders and T2DM patients show an increased risk to suffer from AD, however, there is currently no marker to identify who in T2DM populations will develop AD. Since glycogen synthase kinase-3ß (GSK-3ß) activity, ApoE genotypes and olfactory function are involved in both T2DM and AD pathogenesis, we investigate whether alterations of these factors can identify cognitive impairment in T2DM patients. METHODS: The cognitive ability was evaluated using Minimum Mental State Examination (MMSE) and Clinical Dementia Rating (CDR), and the mild cognitive impairment (MCI) was diagnosed by Petersen's criteria. GSK-3ß activity in platelet, ApoE genotypes in leucocytes and the olfactory function were detected by Western/dot blotting, the amplification refractory mutation system (ARMS) PCR and the Connecticut Chemosensory Clinical Research Center (CCCRC) test, respectively. The odds ratio (OR) and 95% confidence intervals (95% CI) of the biomarkers for MCI diagnosis were calculated by logistic regression. The diagnostic capability of the biomarkers was evaluated by receiver operating characteristics (ROC) analyses. FINDINGS: We recruited 694 T2DM patients from Jan. 2012 to May. 2015 in 5 hospitals (Wuhan), and 646 of them met the inclusion criteria and were included in this study. 345 patients in 2 hospitals were assigned to the training set, and 301 patients in another 3 hospitals assigned to the validation set. Patients in each set were randomly divided into two groups: T2DM without MCI (termed T2DM-nMCI) or with MCI (termed T2DM-MCI). There were no significant differences for sex, T2DM years, hypertension, hyperlipidemia, coronary disease, complications, insulin treatment, HbA1c, ApoE ε2, ApoE ε3, tGSK3ß and pS9GSK3ß between the two groups. Compared with the T2DM-nMCI group, T2DM-MCI group showed lower MMSE score with older age, ApoE ε4 allele, higher olfactory score and higher rGSK-3ß (ratio of total GSK-3ß to Ser9-phosphorylated GSK-3ß) in the training set and the validation set. The OR values of age, ApoE ε4 gene, olfactory score and rGSK-3ß were 1.09, 2.09, 1.51, 10.08 in the training set, and 1.06, 2.67, 1.47, 7.19 in the validation set, respectively. The diagnostic accuracy of age, ApoE ε4 gene, olfactory score and rGSK-3ß were 0.76, 0.72, 0.66, 0.79 in the training set, and 0.70, 0.68, 0.73, 0.79 in the validation set, respectively. These four combined biomarkers had the area under the curve (AUC) of 82% and 86%, diagnostic accuracy of 83% and 81% in the training set and the validation set, respectively. INTERPRETATION: Aging, activation of peripheral circulating GSK-3ß, expression of ApoE ε4 and increase of olfactory score are diagnostic for the mild cognitive impairment in T2DM patients, and combination of these biomarkers can improve the diagnostic accuracy.
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Enfermedad de Alzheimer/sangre , Apolipoproteína E4/sangre , Disfunción Cognitiva/sangre , Diabetes Mellitus Tipo 2/complicaciones , Glucógeno Sintasa Quinasa 3 beta/sangre , Anciano , Alelos , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/patología , Biomarcadores/sangre , Plaquetas/metabolismo , Estudios de Casos y Controles , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/patología , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
PURPOSE: Endovascular treatment is an attractive approach for the treatment of unruptured vertebral dissecting aneurysms, and includes internal trapping and stent-assisted coil embolization. However, the optimal therapy remains debatable. We reviewed our experience with both endovascular treatment modalities and compared the safety, efficacy, and short-term outcomes for each approach. MATERIALS AND METHODS: We retrospectively reviewed 65 consecutive patients with unruptured vertebral dissecting aneurysms who underwent endovascular treatment between January 2003 and January 2014. 24 patients underwent endovascular internal trapping (group A) while 41 patients underwent stent-assisted coiling (group B). Thirteen patients underwent single stent with coiling while 28 patients underwent double or three stent-assisted coiling. Short-term outcomes were evaluated using the modified Rankin Scale. RESULTS: A favorable clinical outcome was achieved in 58 of 65 patients. Procedure-related complications included ischemic symptoms (n = 6) and recurrence (n = 4). There was no statistical difference in modified Rankin Scale scoring between groups. Group A patients had more ischemia symptoms compared with group B patients (p = 0.043), Group B patients had higher recurrence rates compared with group A patients, but the difference had no statistical significance (p = 1.00). However, recurrence only occurred in patients who underwent stent-assisted coiling alone (p = 0.046). CONCLUSION: Stent-assisted coiling for unruptured vertebral dissecting aneurysms may maintain artery patency. Multilayer disposition of stents with coils may decrease complications and facilitate aneurysm occlusion. Larger, prospective studies are necessary to determine the long-term outcomes of reconstructive therapy.
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Embolización Terapéutica/métodos , Procedimientos Endovasculares/métodos , Stents , Disección de la Arteria Vertebral/terapia , Arteria Vertebral/cirugía , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: Treatment of giant/large internal carotid aneurysm is a challenge for neurologists. Previously, parent artery occlusion was the classic therapy; now the stent-assisted coil embolization has become available in recent years, but the optimal therapy is under debate. The goal of the present study was to compare two endovascular treatment modalities in terms of safety, efficacy and short-term outcomes. METHODS: All the patients were divided into two groups: Group A: patients who underwent parent artery occlusion, and Group B: patients who underwent stent-assisted coil embolization. Follow-up outcomes were evaluated using the modified Rankin Scale (mRS). RESULTS: After 12 months of follow-up, the favorable outcome (mRS: 0-2) had no statistical significance in both groups (p = 1.00). Patients in group A had greater ischemia compared with patients in group B, but the difference did not reach statistical significance (p = 0.421). In group B, patients had a higher rate of partial occlusion (p = 0.255) and recurrence (10% vs. 0%; p = 0.586). CONCLUSIONS: Stent-assisted coiling may not be superior to parent artery occlusion in selected patients after short-term follow-up. Parent artery occlusion is a simple, safe and effective treatment for large/giant internal carotid aneurysms.