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AIM: Angiogenesis is a key event in the successful healing of pulp injuries, and hypoxia is the main stimulator of pulpal angiogenesis. In this study, we investigated the effect of hypoxia on the proangiogenic potential of human dental pulp stem cells (hDPSCs) and the role of miR-143-5p in the process. METHODOLOGY: Human dental pulp stem cells were isolated, cultured and characterized in vitro. Cobalt chloride (CoCl2) was used to induce hypoxia in hDPSCs. CCK-8 and Transwell assays were used to determine the effect of hypoxia on hDPSCs proliferation and migration. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting (WB) and ELISA were performed to assess the mRNA and protein levels of HIF-1α and angiogenic cytokines in hDPSCs. The effect of hypoxia on hDPSCs proangiogenic potential was measured in vitro using Matrigel tube formation and chick chorioallantoic membrane (CAM) assays. Recombinant lentiviral vectors were constructed to stably overexpress or inhibit miR-143-5p in hDPSCs, and the proangiogenic effects were assessed using qRT-PCR, WB, and tube formation assays. miR-143-5p target genes were identified and verified using bioinformatics prediction tools, dual-luciferase reporter assays and RNA pull-down experiments. Finally, a subcutaneous transplantation model in nude mice was used to determine the effects of hypoxia treatment and miR-143-5p overexpression/inhibition in hDPSCs in dental pulp regeneration. RESULTS: Hypoxia promotes hDPSCs proliferation, migration and proangiogenic potential. The in vivo experiments showed that hypoxia treatment (50 and 100 µM CoCl2) promoted pulp angiogenesis and dentine formation. In contrast to the levels of proangiogenic factors, miR-143-5p levels decreased with increasing CoCl2 concentration. miR-143-5p inhibition significantly promoted proangiogenic potential of hDPSCs, whereas miR-143-5p overexpression inhibited angiogenesis in vitro. Dual-luciferase reporter assay identified retinoic acid receptor-related orphan receptor alpha (RORA) as an miR-143-5p target gene in hDPSCs. RNA pull-down experiments demonstrated that HIF-1α and RORA were pulled down by biotin-labelled miR-143-5p, and the levels of HIF-1α and RORA bound to miR-143-5p in the hypoxia group were lower than those in the normoxia group. Inhibition of miR-143-5p expression in hDPSCs promoted ectopic dental pulp tissue regeneration. CONCLUSIONS: CoCl2-induced hypoxia promotes hDPSCs-driven paracrine angiogenesis and pulp regeneration. The inhibition of miR-143-5p upregulates the proangiogenic potential of hDPSCs under hypoxic conditions by directly targeting HIF-1α and RORA.
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BACKGROUND: Astrocytes are essential for synaptic transmission, and their dysfunction can result in neuropsychiatric disorders such as anxiety and depression. Many studies have shown that global knockout of Melatonin receptor 2 (Mtnr1b) is associated with the development of various mental disorders. AIM: This study aimed to investigate the effects of astrocyte ablation of Mtnr1b on cognitive function and anxiety-like behavior in mice, as well as the potential biological mechanisms. METHODS: A conditional Cre-loxP system allowing deletion of Mtnr1b from astrocytes was developed to investigate the specific role Mtnr1b. Control and Mtnr1b cKOðºððð mice were selected for cognitive function behavioral testing (Morris water maze test, novel object recognition test) and emotion-related behavioral testing (open field, elevated plus maze). After testing, brain tissue was collected and examined by immunofluorescence for the expression of neuronal nuclei (NeuN), glutamate decarboxylase 67 (GAD67), and vesicular glutamate transporter 1 (vGluT1). RNA-seq was performed on hippocampal tissue from control and Mtnr1b cKOðºððð mice to identify differentially expressed genes. Additional confirmation of differential gene expression was performed using real-time quantitative polymerase chain reaction (qRT-PCR). RESULTS: Mtnr1b cKOðºððð mice were not significantly different from control mice in the Morris water maze and novel object recognition tests. Results from the open field and elevated plus maze tests showed that Mtnr1b cKOðºððð mice exhibited significantly more anxiety-like behavior than did controls. Immunofluorescence revealed that the number of mature neurons did not differ significantly between Mtnr1b cKOðºððð mice and controls. The expression of GAD67 in the hippocampal CA1 and CA3 areas of Mtnr1b cKOðºððð mice was significantly lower than in the control group, but no significant difference was detected for vGluT1 expression. RNA-seq and qRT-PCR results showed that Mtnr1b knockout in astrocytes led to a decrease in the levels of gamma-aminobutyric acid sub-type A (GABAA) receptors and Kir2.2. CONCLUSIONS: The astrocyte-specific knockout in Mtnr1b cKOðºððð mice results in anxiety-like behavior, which is caused by down-regulation of gamma-aminobutyric acid-ergic (GABAergic) synaptic function.
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Astrocitos , Trastornos Mentales , Receptor de Melatonina MT2 , Animales , Masculino , Ratones , Ansiedad , Astrocitos/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Trastornos Mentales/metabolismo , Neuronas/metabolismo , Receptor de Melatonina MT2/genéticaRESUMEN
AIM: Epigallocatechin-3-gallate (EGCG) is a major polyphenol in green tea. In this study, we investigated the effects of EGCG on insulin resistance and insulin clearance in non-alcoholic fatty liver disease (NAFLD) mice. METHODS: Mice were fed on a high-fat diet for 24 weeks. During the last 4 weeks, the mice were injected with EGCG (10, 20 and 40 mg·kg(-1)·d(-1), ip). Glucose tolerance, insulin tolerance and insulin clearance were assessed. After the mice were euthanized, blood samples and tissue specimens were collected. Glucose-stimulated insulin secretion was examined in isolated pancreatic islets. The progression of NAFLD was evaluated histologically and by measuring lipid contents. Insulin-degrading enzyme (IDE) protein expression and enzyme activity were detected using Western blot and immunocapture activity assays, respectively. RESULTS: The high-fat diet significantly increased the body weight and induced grade 2 or 3 liver fatty degeneration (steatosis, lobular inflammation and ballooning) accompanied by severe hyperlipidemia, hyperglycemia, hyperinsulinemia and insulin resistance in the model mice. Administration of EGCG dose-dependently ameliorated the hepatic morphology and function, reduced the body weight, and alleviated hyperlipidemia, hyperglycemia, hyperinsulinemia and insulin resistance in NAFLD mice. Furthermore, EGCG dose-dependently enhanced insulin clearance and upregulated IDE protein expression and enzyme activity in the liver of NAFLD mice. CONCLUSION: EGCG dose-dependently improves insulin resistance in NAFLD mice not only by reducing body weight but also through enhancing the insulin clearance by hepatic IDE. The results suggest that IDE be a potential drug target for the treatment of NAFLD.
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Camellia sinensis , Catequina/análogos & derivados , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Hígado/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Biomarcadores/sangre , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Catequina/farmacología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Insulina/sangre , Insulisina/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Fitoterapia , Plantas Medicinales , Factores de TiempoRESUMEN
SIL1, an endoplasmic reticulum (ER)-resident protein, is reported to play a protective role in Alzheimer's disease (AD). However, the effect of SIL1 on amyloid precursor protein (APP) processing remains unclear. In this study, the role of SIL1 in APP processing was explored both in vitro and in vivo. In the in vitro experiment, SIL1 was either overexpressed or knocked down in cells stably expressing the human Swedish mutant APP695. In the in vivo experiment, AAV-SIL1-EGFP or AAV-EGFP was microinjected into APP23/PS45 mice and their wild-type littermates. Western blotting (WB), immunohistochemistry, RNA sequencing (RNA-seq), and behavioral experiments were performed to evaluate the relevant parameters. Results indicated that SIL1 expression decreased in APP23/PS45 mice. Overexpression of SIL1 significantly decreased the protein levels of APP, presenilin-1 (PS1), and C-terminal fragments (CTFs) of APP in vivo and in vitro. Conversely, knockdown of SIL1 increased the protein levels of APP, ß-site APP cleavage enzyme 1 (BACE1), PS1, and CTFs, as well as APP mRNA expression in 2EB2 cells. Furthermore, SIL1 overexpression reduced the number of senile plaques in APP23/PS45 mice. Importantly, Y-maze and Morris Water maze tests demonstrated that SIL1 overexpression improved cognitive impairment in APP23/PS45 mice. These findings indicate that SIL1 improves cognitive impairment in APP23/PS45 mice by inhibiting APP amyloidogenic processing and suggest that SIL1 is a potential therapeutic target for AD by modulating APP processing.
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Precursor de Proteína beta-Amiloide , Disfunción Cognitiva , Ratones Transgénicos , Animales , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Ratones , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/genética , Péptidos beta-Amiloides/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Regulación de la Expresión Génica , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , HumanosRESUMEN
Amyloid ß protein (Aß) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Aß induces apoptosis, and gasdermin-E (GSDME) expression can switch apoptosis to pyroptosis. In this study, we demonstrated that GSDME was highly expressed in the hippocampus of APP23/PS45 mouse models compared to that in age-matched wild-type mice. Aß treatment induced pyroptosis by active caspase-3/GSDME in SH-SY5Y cells. Furthermore, the knockdown of GSDME improved the cognitive impairments of APP23/PS45 mice by alleviating inflammatory response. Our findings reveal that GSDME, as a modulator of Aß and pyroptosis, plays a potential role in Alzheimer's disease pathogenesis and shows that GSDME is a therapeutic target for AD.
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Enfermedad de Alzheimer , Neuroblastoma , Humanos , Ratones , Animales , Piroptosis/fisiología , Gasderminas , Péptidos beta-Amiloides/metabolismo , Caspasa 3/metabolismoRESUMEN
BACKGROUND: Alpha-lipoic acid (ALA) has a neuroprotective effect on neurodegenerative diseases. In the clinic, ALA can improve cognitive impairments in patients with Alzheimer's disease (AD) and other dementias. Animal studies have confirmed the anti-amyloidosis effect of ALA, but its underlying mechanism remains unclear. In particular, the role of ALA in amyloid-ß precursor protein (APP) metabolism has not been fully elucidated. OBJECTIVE: To investigate whether ALA can reduce the amyloidogenic effect of APP in a transgenic mouse model of AD, and to study the mechanism underlying this effect. METHODS: ALA was infused into 2-month-old APP23/PS45 transgenic mice for 4 consecutive months and their cognitive function and AD-like pathology were then evaluated. An ALA drug concentration gradient was applied to 20E2 cells in vitro to evaluate its effect on the expression of APP proteolytic enzymes and metabolites. The mechanism by which ALA affects APP processing was studied using GI254023X, an inhibitor of A Disintegrin and Metalloproteinase 10 (ADAM10), as well as the mitochondrial toxic drug carbonyl cyanide m-chlorophenylhydrazone (CCCP). RESULTS: Administration of ALA ameliorated amyloid plaque neuropathology in the brain tissue of APP23/PS45 mice and reduced learning and memory impairment. ALA also increased the expression of ADAM10 in 20E2 cells and the non-amyloidogenic processing of APP to produce the 83 amino acid C-terminal fragment (C83). In addition to activating autophagy, ALA also significantly promoted mitophagy. BNIP3L-knockdown reduced the mat/pro ratio of ADAM10. By using CCCP, ALA was found to regulate BNIP3L-mediated mitophagy, thereby promoting the α-cleavage of APP. CONCLUSIONS: The enhanced α-secretase cleavage of APP by ADAM10 is the primary mechanism through which ALA ameliorates the cognitive deficits in APP23/PS45 transgenic mice. BNIP3L-mediated mitophagy contributes to the anti-amyloid properties of ALA by facilitating the maturation of ADAM10. This study provides novel experimental evidence for the treatment of AD with ALA.
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Proteína ADAM10 , Secretasas de la Proteína Precursora del Amiloide , Precursor de Proteína beta-Amiloide , Disfunción Cognitiva , Ratones Transgénicos , Mitofagia , Ácido Tióctico , Animales , Ácido Tióctico/farmacología , Mitofagia/efectos de los fármacos , Proteína ADAM10/metabolismo , Ratones , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Modelos Animales de Enfermedad , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Fármacos Neuroprotectores/farmacología , Ratones Endogámicos C57BL , MasculinoRESUMEN
AIMS: Islet cell autoantigen 1 (ICA1) is involved in autoimmune diseases and may affect synaptic plasticity as a neurotransmitter. Databases related to Alzheimer's disease (AD) have shown decreased ICA1 expression in patients with AD. However, the role of ICA1 in AD remains unclear. Here, we report that ICA1 expression is decreased in the brains of patients with AD and an AD mouse model. RESULTS: The ICA1 increased the expression of amyloid precursor protein (APP), disintegrin and metalloprotease 10 (ADAM10), and disintegrin and metalloprotease 17 (ADAM17), but did not affect protein half-life or mRNA levels. Transcriptome sequencing analysis showed that ICA1 regulates the G protein-coupled receptor signaling pathway. The overexpression of ICA1 increased PKCα protein levels and phosphorylation. CONCLUSION: Our results demonstrated that ICA1 shifts APP processing to non-amyloid pathways by regulating the PICK1-PKCα signaling pathway. Thus, this study suggests that ICA1 is a novel target for the treatment of AD.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Proteína Quinasa C-alfa , Transducción de Señal , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Proteína Quinasa C-alfa/metabolismo , Proteína Quinasa C-alfa/genética , Transducción de Señal/fisiología , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Ratones , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Masculino , Ratones Transgénicos , Femenino , Ratones Endogámicos C57BL , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Encéfalo/metabolismo , Proteínas de Ciclo CelularRESUMEN
OBJECTIVE: To investigate the incidence, duration and consequences of persistent submacular fluid after pars plana vitrectomy (PPV) and scleral buckling surgery (SB) in rhegmatogenous retinal detachment, thus to explore the clinical association between persistent SMF and different surgical methods, and simultaneously, to study the effect of persistent submacular fluid on visual outcome. METHODS: It was a retrospective case-series study. Ninety-two qualified eyes including 54 eyes of males and 38 eyes of females with rhegmatogenous retinal detachment which had been performed PPV or SB were recruited. The average age of the patients was (45.8 ± 15.3) years with a age-range from 15 to 76 years. The inclusion criteria was as follows, the macula-off rhegmatogenous retinal detachments without macular hole and obvious proliferative vitreoretinopathy, the retina was completely reattached 1 month after operation and no redetachment was found by ophthalmoscope and B scan till the last follow-up, the minimal follow-up time was 1 year and the submacular fluid must have been dissolved for at least 6 months. All patients underwent thorough ophthalmologic examinations before and after operation, Those patients in whom a persistent submacular fluid was seen on optical coherence tomography (OCT) at 1 month after operation performed follow-up with repeat of the investigations at 3, 6 and 12 months after surgery, If the abnormality resolved, further observations were continued to undertake for 6 months or more till the last follow-up.Rank-sum test, χ²-test and Fisher exact test were applied respectively to analyze for statistical analysis. RESULTS: The incidence of persistent submacular fluid at 1 month after surgery in the PPV and SB group was 13.9% (5/36) and 48.2% (27/56).Six months later however, the figure expressed as percentage was 2.8% (1/36) and 23.2% (18/28) correspondingly. Persistent submacular fluid was more frequent in eyes with inferior breaks (64.3%) than that with superior ones (13.9%), making a significant differences (χ² = 17.38, P < 0.01) . The persistent submacular fluid group showed worse best-corrected visual acuity than no persistent submacular fluid group 6 and 12 months after surgery (t = 2.525, t = 2.254, both P < 0.05). Comparing the visual acuity (VA) between the eyes with or without persistent submacular fluid 6, 12 months after surgery and the latest followed-up among the ever suffered eyes, a statistically significant differences presented in late stages(average VA: 0.47 ± 0.29, 0.30 ± 0.16; 0.44 ± 0.28, 0.27 ± 0.15;0.42 ± 0.22, 0.27 ± 0.19; t = 2.114, 2.207, 2.068; all P < 0.05), though there were no significant differences in the first three months (average VA: 0.70 ± 0.33, 0.63 ± 0.37; 0.50 ± 0.25,0.45 ± 0.22; t = 0.556, 0.601; both P > 0.05). CONCLUSIONS: Persistent submacular fluid presents in both surgical procedures but it is more frequent after buckling surgery than vitrectomy, the selection of patients, the location of retinal breaks and the duration of detachment may be the potential influencing factors. Persistent submacular fluid after retinal detachment surgery is responsible for delayed recovery, and may affect the final visual outcome. The longer it lasts, the more harm may it do.
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Edema Macular/diagnóstico por imagen , Complicaciones Posoperatorias/diagnóstico por imagen , Tomografía de Coherencia Óptica , Adolescente , Adulto , Anciano , Femenino , Humanos , Edema Macular/etiología , Masculino , Persona de Mediana Edad , Radiografía , Desprendimiento de Retina/cirugía , Estudios Retrospectivos , Adulto JovenRESUMEN
INTRODUCTION: While 15 to 20% of cancers are associated with microbial infection, the relationship between oral microorganisms and oral squamous cell carcinoma (OSCC) remains unclear. The location of bacteria in a tumor is closely related to its carcinogenic mechanism. The aim of this study was to analyse bacterial diversity in clinical OSCC tissue samples and tumor distant normal tissues, locate target bacteria, and search for proteins that may interact with target bacteria. MATERIALS AND METHODS: The 16S rDNA method was used to analyse bacterial diversity in clinical OSCC tissue samples and tumor distant normal tissues. Correlations between Fusobacterium abundance and clinicopathological characteristics were analysed using the χ2 test. The position of target bacteria was analysed by fluorescence in situ hybridization (FISH), and the expression of CK, CD31, CD45, CD68, cyclin D1, ß-catenin, E-cadherin, NF-κB, and HIF-1α was analysed by immunohistochemistry (IHC) in OSCC tumor tissues and tumor distant normal tissues. RESULTS: The 16S rDNA results showed that the detected amount of Fusobacterium in OSCC tumor tissues was significantly larger than that in tumor distant normal tissues. High expression of Fusobacterium was significantly correlated with the lifestyle-related oral risk habits, including smoking (p=0.036) and alcohol consumption (p=0.022), but did not correlate with patient sex, age, tumor laterality, tumor size, grade or TNM stage. Fusobacterium nucleatum was enriched in tumor stroma, where CD31+ blood vessels and inflammatory cells (including CD45+ leukocytes and CD68+ macrophages) were densely distributed. Cyclin D1 was mainly expressed in the nucleus of tumor cells. ß-catenin was expressed in the tumor cell membrane and was positively expressed in tumor interstitial vascular endothelial cells. E-cadherin was mainly expressed in tumor cell membranes. NF-κB was positively expressed in the cytoplasm of tumor cells, tumor interstitial cells and myo-fibrocytes. HIF-1α was mainly expressed in the cytoplasm of tumor interstitial cells. HIF-1α was highly expressed where Fusobacterium nucleatum was densely distributed. CONCLUSION: According to our study, the detected amount of Fusobacterium in OSCC tumor tissues was significantly larger than that in tumor distant normal tissues, and Fusobacterium nucleatum might aggravate inflammation and hypoxia by interacting with NF-κB and HIF-1α in OSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello , Neoplasias de la Boca/patología , Fusobacterium nucleatum , beta Catenina , Ciclina D1 , FN-kappa B , Hibridación Fluorescente in Situ , Células Endoteliales/patología , Cadherinas , ADN RibosómicoRESUMEN
BACKGROUND: Down syndrome (DS) is caused by an extra copy of all or part of chromosome 21. The patients with DS develop typical Alzheimer's disease (AD) neuropathology, indicating the role of genes on human chromosome 21 (HSA21) in the pathogenesis of AD. Purkinje cell protein 4 (PCP4), also known as brain-specific protein 19, is a critical gene located on HSA21. However, the role of PCP4 in DS and AD pathogenesis is not clear. OBJECTIVE: To explore the role of PCP4 in amyloid-ß protein precursor (AßPP) processing in AD. METHODS: In this study, we investigated the role of PCP4 in AD progression in vitro and in vivo. In vitro experiments, we overexpressed PCP4 in human Swedish mutant AßPP stable expression or neural cell lines. In vitro experiments, APP23/PS45 double transgenic mice were selected and treated with AAV-PCP4. Multiple topics were detected by western blot, RT-PCR, immunohistochemical and behavioral test. RESULTS: We found that PCP4 expression was altered in AD. PCP4 was overexpressed in APP23/PS45 transgenic mice and PCP4 affected the processing of AßPP. The production of amyloid-ß protein (Aß) was also promoted by PCP4. The upregulation of endogenous AßPP expression and the downregulation of ADAM10 were due to the transcriptional regulation of PCP4. In addition, PCP4 increased Aß deposition and neural plaque formation in the brain, and exuberated learning and memory impairment in transgenic AD model mice. CONCLUSION: Our finding reveals that PCP4 contributes to the pathogenesis of AD by affecting AßPP processing and suggests PCP4 as a novel therapeutic target for AD by targeting Aß pathology.
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Enfermedad de Alzheimer , Síndrome de Down , Humanos , Ratones , Animales , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Ratones Transgénicos , Encéfalo/patología , Síndrome de Down/metabolismo , Modelos Animales de Enfermedad , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Proteínas del Tejido Nervioso/metabolismoRESUMEN
As bio-inspired vision devices, dynamic vision sensors (DVS) are being applied in more and more applications. Unlike normal cameras, pixels in DVS independently respond to the luminance change with asynchronous output spikes. Therefore, removing raindrops and streaks from DVS event videos is a new but challenging task as the conventional deraining methods are no longer applicable. In this article, we propose to perform the deraining process in the width and time (W-T) space. This is motivated by the observation that rain steaks exhibits discontinuity in the width and time directions while background moving objects are usually piecewise smooth along with both directions. The W-T space can fuse the discontinuity in both directions and thus transforms raindrops and streaks to approximately uniform noise that are easy to remove. The non-local means filter is adopted as background object motion has periodic patterns in the W-T space. A repairing method is also designed to restore edge details erased during the deraining process. Experimental results demonstrate that our approach can better remove rain noise than the four existing methods for traditional camera videos. We also study how the event buffer depth and event frame time affect the performance investigate the potential implementation of our approach to classic RGB images. A new real-world database for DVS deraining is also created and shared for public use.
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Neuroinflammation is a leading cause of secondary neuronal injury in neonatal hypoxic-ischemic encephalopathy (HIE). Regulation of neuroinflammation may be beneficial for treatment of HIE and its secondary complications. Gallic acid (GA) has been shown to have anti-inflammatory and antioxidant effects. In this report we found that oxygen-glucose deprivation and/reoxygenation (OGD/R)-induced cell death, and the generation of excessive reactive oxygen species (ROS) and inflammatory cytokines by microglia were inhibited by GA treatment. Furthermore, GA treatment reduced neuroinflammation and neuronal loss, and alleviated motor and cognitive impairments in rats with hypoxic-ischemic brain damage (HIBD). Together, our results reveal that GA is an effective regulator of neuroinflammation and has potential as a pharmaceutical intervention for HIE therapy.
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To design an ensemble learning based prediction model using different breast DCE-MR post-contrast sequence images to distinguish two kinds of breast cancer subtypes (luminal and non-luminal). We retrospectively studied preoperative dynamic contrast enhanced-magnetic resonance imaging and molecular information of 266 breast cancer cases with either luminal subtype (luminal A and luminal B) or non-luminal subtype (human epidermal growth factor receptor 2 and triple negative). Then, multiple bounding boxes covering tumor lesions were acquired from three series of post-contrast DCE-MR sequence images which were determined by radiologists. Afterwards, three baseline convolutional neural networks (CNNs) with same architecture were concurrently trained, followed by preliminary prediction of probabilities from the testing database. Finally, the classification and evaluation of breast subtypes were realized by means of fusing predicted results from three CNNs employed via ensemble learning based on weighted voting. Taking advantage of 5-fold cross validation CV, the average prediction specificity, accuracy, precision and area under the ROC curve on testing dataset for the luminal versus non-luminal are 0.958, 0.852, 0.961, and 0.867, respectively, which empirically demonstrate that our proposed ensemble model has highly reliability and robustness. The breast DCE-MR post-contrast sequence image analysis utilizing the ensemble CNN model based on deep learning could show a valuable and extendible practical application on breast molecular subtype identification.
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Neoplasias de la Mama , Neoplasias de la Mama/diagnóstico por imagen , Femenino , Humanos , Aprendizaje Automático , Imagen por Resonancia Magnética , Redes Neurales de la Computación , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
Increased endogenous hydrogen sulfide (H2S) level by cystathionine ß-synthase (CBS) has been shown to closely relate tumorigenesis. H2S promotes angiogenesis, stimulates bioenergy metabolism and inhibits selective phosphatases. However, the role of CBS and H2S in chronic myeloid leukemia (CML) remains elusive. In this study, we found that CBS and H2S levels were increased in the bone marrow mononuclear cells of pediatric CML patients, as well as in the CML-derived K562 cells and CBS expression levels were correlated with different disease phases. Inhibition of CBS reduced the proliferation of the CML primary bone marrow mononuclear cells and induced growth inhibition, apoptosis, cell cycle arrest, and migration suppression in K562 cells and tumor xenografts. The knockdown of CBS expression by shRNA and inhibiting CBS activity by AOAA decreased the endogenous H2S levels, promoted mitochondrial-related apoptosis and inhibited the NF-κB-mediated gene expression. Our study suggests that inhibition of CBS induces cell apoptosis, as well as limits cell proliferation and migration, a potential target for the treatment of chronic myeloid leukemia.
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Carcinogénesis/genética , Cistationina betasintasa/genética , Sulfuro de Hidrógeno/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Animales , Apoptosis/genética , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Línea Celular Tumoral , Proliferación Celular/genética , Niño , Cistationina betasintasa/antagonistas & inhibidores , Metabolismo Energético/genética , Femenino , Xenoinjertos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Masculino , Ratones , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Neovascularización Patológica/patologíaRESUMEN
Diabetic retinopathy (DR) is one of the most common causes of blindness globally. Proliferative DR (PDR), an advanced stage of DR, is characterized by the formation of fibrotic membranes at the vitreoretinal interface. The proliferation, migration, and secretion of extracellular matrix molecules in retinal pigment epithelial (RPE) cells contribute to the formation of fibrotic membranes in PDR. Gremlin has been reported to be upregulated in response to elevated glucose levels in the retina of diabetic rat and bovine pericytes. However, the role of gremlin in PDR remains unclear. In the present study, the vitreous concentrations of gremlin were significantly higher in the PDR (67.79 ± 33.96) group than in the control (45.31 ± 12.31) group, and high glucose levels induced the expression of gremlin in RPE cells. The elevated expression of extracellular matrix molecules, such as fibronectin and collagen IV, was significantly reduced by gremlin siRNA in human RPE cells under high-glucose conditions. Thus, gremlin may play a vital role in the development of PDR.
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Retinopatía Diabética/metabolismo , Regulación hacia Abajo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Cuerpo Vítreo/metabolismo , Adulto , Anciano , Glucemia , Colágeno Tipo IV/metabolismo , Matriz Extracelular/metabolismo , Femenino , Fibronectinas/metabolismo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Wieacker-Wolff syndrome (WWS) is a congenital X-linked neuromuscular disorder, which was firstly reported in 1985. Zinc finger C4H2-type containing (ZC4H2) gene has been found to be associated with the disease pathogenesis. However, the underlying mechanism remains elusive. METHODS: Whole-exome sequencing was performed to identify the mutations. Expression plasmids were constructed and cell culture and immune-biochemical assays were used to examine the effects of the mutation. RESULTS: We reported a female patient with classical symptoms of WWS and discovered a novel nonsense heterozygous mutation (p.R67X; c.199C>T) in ZC4H2 gene in the patient but not in her parents. The mutation resulted in a 66 amino-acid truncated ZC4H2 protein. The mutation is located in the key helix domain and it altered the subcellular locations of the mutant ZC4H2 protein. X-chromosome inactivation (XCI) pattern analysis revealed that the XCI ratio of the proband was 22:78. CONCLUSION: Female heterozygous carriers with nonsense mutation with a truncated ZC4H2 protein could lead to the pathogenesis of Wieacker-Wolff syndrome and our study provides a potential new target for the disease treatment.
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Apraxias/genética , Codón sin Sentido , Contractura/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Atrofia Muscular/genética , Proteínas Nucleares/genética , Oftalmoplejía/genética , Apraxias/patología , Contractura/patología , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Células HEK293 , Humanos , Lactante , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Atrofia Muscular/patología , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Oftalmoplejía/patología , Dominios Proteicos , Inactivación del Cromosoma XRESUMEN
Subsequently to the publication of the above paper, the authors have realized that the images presented in Fig. 1A were selected erroneously (essentially, the images for group 'AdBMP9 +++' were chosen to represent the group 'AdGFP'). A corrected version of Fig. 1, including the correct data for the experiments depicted in Fig. 1A, is shown opposite. Note that this change does not affect the results or the conclusions reported in this paper, and all the authors agree to this correction. The authors apologize to the Editor and to the readership of the Journal for any inconvenience caused. [the original article was published in International Journal of Oncology 50: 13631371, 2017; DOI: 10.3892/ijo.2017.3910].
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The present study evaluated the performance of biological denitrification in an anoxic sequencing batch biofilm reactor (ASBBR) and its nitrous oxide (N2O) emission. After 90â¯days operation, the effluent chemical oxygen demand and total nitrogen removal efficiencies high of 94.8% and 95.0%, respectively. Both polysaccharides and protein contents were reduced in bound EPS (TB-EPS) and loosely bound EPS (LB-EPS) after biofilm formation. According to typical cycle, N2O release rate was related to the free nitrous acid (FNA) concentration with the maximum value of 3.88⯵g/min and total conversion rate of 1.27%. Two components were identified from EEM-PARAFAC model in soluble microbial products (SMP). Protein-like substances for component 1 changed significantly in denitrification process, whereas humic-like and fulvic acid-like substances for component 2 remained relatively stable. High-throughput sequencing results showed that Lysobacter, Tolumonas and Thauera were the dominant genera, indicating the co-existence of autotrophic and heterotrophic denitrifiers in ASBBR.
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Desnitrificación , Microbiota , Biopelículas , Reactores Biológicos , Nitrógeno , Óxido NitrosoRESUMEN
The pathology of the fibrotic proliferative vitreoretinopathy (PVR) membrane represents an excessive wound healing response characterised by cells' proliferation, migration and secretion of extracellular matrix molecules (ECMs). Retinal pigment epithelial (RPE) cells are a major cellular component of the fibrotic membrane. Endothelin-1 (ET-1) has been reported to be involved in the development of PVR in vivo research. However, little is known about the role of ET-1 in RPE cells in vitro. In the present study, we investigated the role of ET-1 in the proliferation, migration and secretion of ECMs (such as type I collagen and fibronectin) in RPE cells in vitro. Our results illustrated that ET-1 promoted the proliferation, migration and secretion of ECMs through the protein kinase B (Akt) and extracellular signal-regulated kinase (Erk) signaling pathways in RPE cells in vitro. These findings strongly suggested that ET-1 may play a vital role in the development of PVR.
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Movimiento Celular , Proliferación Celular , Endotelina-1/metabolismo , Sistema de Señalización de MAP Quinasas , Epitelio Pigmentado de la Retina/metabolismo , Línea Celular , Colágeno Tipo I/metabolismo , Citocinas/metabolismo , Matriz Extracelular/metabolismo , Fibronectinas , Regulación de la Expresión Génica , Humanos , Epitelio Pigmentado de la Retina/fisiología , Vitreorretinopatía Proliferativa/metabolismoRESUMEN
Osteosarcoma (OS) is the most common malignant bone tumour and is considered to be a disease caused by a dysfunction in differentiation. Bone morphogenetic protein 9 (BMP9) is the most potent osteogenic factor in mesenchymal stem cells, but it cannot induce osteogenic differentiation in OS cells; this might be one of the determinants in the pathogenesis of OS. All-trans retinoic acid (ATRA) can induce osteogenic differentiation of OS cells and potentiate BMP9-induced osteogenesis in preadipocytes. However, the concomitant effect of ATRA and BMP9 in OS cells is unclear; therefore, in the present study, we focused on this topic. The results showed that BMP9 significantly promoted the proliferation of human OS 143B cells and did not induce osteogenic differentiation of cells in vitro (p<0.01). ATRA inhibited proliferation and induced osteogenesis in 143B cells; these effects could be enhanced by BMP9 overexpression (p<0.05). ATRA could significantly increase the level of phosphorylated p38 MAPK (p-p38) in 143B cells, while BMP9 did not have any significant effect. Notably, BMP9 overexpression enhanced the ability of ATRA to increase the levels of p-p38. Both the osteogenic differentiation and the anti-proliferative activity of BMP9 in the presence of ATRA decreased upon treatment with a specific inhibitor of p38 MAPK (SB203580) (p<0.01). This study indicates that the osteogenic differentiation ability of BMP9 in 143B cells can be restored by ATRA, and the combination of BMP9 and ATRA generated a stronger anti-proliferative effect on 143B cells than ATRA alone. This result may be due to the activation of the p38 MAPK pathway.