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BACKGROUND: Gastroesophageal reflux disease (GERD) refers to a clinical condition characterized by gastric content reflux into the esophagus, causing symptoms like acid regurgitation and heartburn. While patient education is essential for GERD treatment, traditional educational models often struggle to effectively improve treatment outcomes. METHODS: Between January 2021 and April 2022, we enrolled 257 patients and assessed their GERD knowledge. The patients were randomly assigned to either the WeChat group (60 participants) for health education via WeChat platform or the control group (60 participants) for conventional education only. GERD-Q scores were collected at 1, 3, and 6 months post-intervention, with compliance and satisfaction assessed at the study's conclusion. RESULTS: The overall awareness rate of GERD among patients was approximately 22.3 %. The WeChat group showed better compliance than the control group in terms of adhering to a proper diet, taking medication on time, and engaging in moderate exercise (P < 0.05 for all). Furthermore, the WeChat group demonstrated significantly higher treatment effectiveness and satisfaction than the control group (P < 0.05 for all). CONCLUSION: Patients have a relatively low level of knowledge regarding GERD. WeChat has the potential to facilitate lifestyle changes and improve compliance, treatment effectiveness, and treatment satisfaction among patients with gastroesophageal reflux disease.
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Highly sensitive detection of low-frequency EGFR-L858R mutation is particularly important in guiding targeted therapy of nonsmall-cell lung carcinoma (NSCLC). To this end, a ligase chain reaction (LCR)-based electrochemical biosensor (e-LCR) with an inverted sandwich-type architecture was provided by combining a cooperation of lambda exonuclease-RecJf exonuclease (λ-RecJf exo). In this work, by designing a knife-like DNA substrate (an overhang ssDNA part referred to the "knife arm") and introducing the λ-RecJf exo, the unreacted DNA probes in the LCR were specially degraded while only the ligated products were preserved, after which the ligated knife-like DNA products were hybridized with capture probes on the gold electrode surface through the "knife arms", forming the inverted sandwich-type DNA structure and bringing the methylene blue-label close to the electrode surface to engender the electrical signal. Finally, the sensitivity of the e-LCR could be improved by 3 orders of magnitude with the help of the λ-RecJf exo, and due to the mutation recognizing in the ligation site of the employed ligase, this method could detect EGFR-L858R mutation down to 0.01%, along with a linear range of 1 fM-10 pM and a limit detection of 0.8 fM. Further, the developed method could distinguish between L858R positive and negative mutations in cultured cell samples, tumor tissue samples, and plasma samples, whose accuracy was verified by the droplet digital PCR, holding a huge potential in liquid biopsy for precisely guiding individualized-treatment of NSCLC patients with advantages of high sensitivity, low cost, and adaptability to point-of-care testing.
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Carcinoma de Pulmón de Células no Pequeñas , Técnicas Electroquímicas , Receptores ErbB , Exodesoxirribonucleasas , Neoplasias Pulmonares , Mutación , Receptores ErbB/genética , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Exodesoxirribonucleasas/química , Exodesoxirribonucleasas/metabolismo , Exodesoxirribonucleasas/genética , Técnicas Biosensibles , Reacción en Cadena de la Ligasa , Límite de Detección , Proteínas ViralesRESUMEN
Centella asiatica (L.) Urban is a medical plant rich in triterpenoids, frequently used in Asia to treat skin conditions such as acne. To search for anti-photoaging agents, 16 known triterpenoids and five undescribed triterpenoids, including three ursane, one oleanane and one nor-ursane were isolated from the whole herb of C. asiatica. The structures and relative stereochemistry of these compounds were elucidated by detailed NMR spectra and HRESIMS. Compounds 1 and 2 were isomers of ursane-type and oleane-type triterpenes with rare aldehyde groups on C-23. Compound 4 was a unique example of a nor-ursane type triterpenoid. The Ultraviolet B (UVB) induced HaCaT cell damage model was used to measure the in vitro anti-photoaging activity of all 21 compounds. Twenty compounds significantly increased HaCaT viability and inhibited lactate dehydrogenase (LDH) release after UVB exposure. These findings highlight the protective effects of C. asiatica-derived triterpenoids against UVB damage and indicate their potential as natural agents that can protect the skin against photoaging.
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Centella , Triterpenos , Rayos Ultravioleta , Triterpenos/farmacología , Triterpenos/química , Triterpenos/aislamiento & purificación , Centella/química , Humanos , Supervivencia Celular/efectos de los fármacos , Estructura Molecular , Envejecimiento de la Piel/efectos de los fármacos , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , L-Lactato Deshidrogenasa/metabolismo , Células HaCaTRESUMEN
The microplastics in aquatic ecosystems pose a serious threat to ecological security and environmental health, which have received widespread attention. To reveal the response of a water-Vallisneria natans-sediment system to microplastics exposure, the V. natans was exposed to polyethylene microplastics ï¼PE-MPsï¼ with different mass fractions ï¼1%-5%, sediment wet mass fractionï¼, and the effects of PE-MPs on the physiochemical indicators of water quality, morphological characteristics of submerged plants, physiological characters, antioxidant system, and microbial community structure in sediments were studied respectively. The results showed that the physiochemical properties of the water body were not significantly changed in the PE-MPs treatment group, whereas the plant height, oxidative stress index, and antioxidant system were significantly inhibited. For the plant height, the 1% PE-MPs treatment group height was only 47.44% of that in the control group. Chlorophyll a content was 81.04% of that in the control group, and the activities of catalase ï¼CATï¼, malondialdehyde ï¼MDAï¼, and peroxidase ï¼PODï¼ increased by 233.70%, 117.82%, and 61.62%, respectively. Different mass fractions of PE-MPs had a certain impact on microbial community structure in sediments. The above results are helpful to improve the evaluation system of PE-MPs ecological risk in the water-submerged plant-sediment system.
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Sedimentos Geológicos , Microplásticos , Polietileno , Contaminantes Químicos del Agua , Contaminantes Químicos del Agua/análisis , Microplásticos/toxicidad , Sedimentos Geológicos/química , Hydrocharitaceae/crecimiento & desarrollo , Hydrocharitaceae/efectos de los fármacos , Ecosistema , Monitoreo del AmbienteRESUMEN
Tea drinking impacts aging and aging-related diseases. However, knowledge of anti-aging molecules other than the major catechins in complex tea extracts remains limited. Here we used Caenorhabditis elegans to analyze the longevity effects of tea extracts and constituents comprehensively. We found that the hot water extract of green tea prolonged lifespan and heathspan. Further, the MeOH fraction prolonged lifespan significantly longer than other fractions. Correlation analysis between mass spectroscopic data and anti-aging activity suggests that ester-type catechins (ETCs) are the major anti-aging components, including 4 common ETCs, 6 phenylpropanoid-substituted ester-type catechins (PSECs), 5 cinnamoylated catechins (CCs), 7 ester-type flavoalkaloids (ETFs), and 4 cinnamoylated flavoalkaloids (CFs). CFs (200 µM) are the strongest anti-aging ETCs (with the longest 73% lifespan extension). Green tea hot water extracts and ETCs improved healthspan by enhancing stress resistance and reducing ROS accumulation. The mechanistic study suggests that they work by multiple pathways. Moreover, ETCs modulated gut microbial homeostasis, increased the content of short-chain fatty acids, and reduced fat content. Altogether, our study provides new evidence for the anti-aging benefits of green tea and insights into a deep understanding of the chemical truth and multi-target mechanism.
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Envejecimiento , Caenorhabditis elegans , Camellia sinensis , Catequina , Extractos Vegetales , Té , Animales , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Té/química , Camellia sinensis/química , Catequina/farmacología , Catequina/química , Envejecimiento/efectos de los fármacos , Longevidad/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Background: Alzheimer's disease (AD) is a neurodegenerative disorder caused by a complex interplay of various factors. However, a satisfactory cure for AD remains elusive. Pharmacological interventions based on drug targets are considered the most cost-effective therapeutic strategy. Therefore, it is paramount to search potential drug targets and drugs for AD. Objective: We aimed to provide novel targets and drugs for the treatment of AD employing transcriptomic data of AD and normal control brain tissues from a new perspective. Methods: Our study combined the use of a multi-layer perceptron (MLP) with differential expression analysis, variance assessment and molecular docking to screen targets and drugs for AD. Results: We identified the seven differentially expressed genes (DEGs) with the most significant variation (ANKRD39, CPLX1, FABP3, GABBR2, GNG3, PPM1E, and WDR49) in transcriptomic data from AD brain. A newly built MLP was used to confirm the association between the seven DEGs and AD, establishing these DEGs as potential drug targets. Drug databases and molecular docking results indicated that arbaclofen, baclofen, clozapine, arbaclofen placarbil, BML-259, BRD-K72883421, and YC-1 had high affinity for GABBR2, and FABP3 bound with oleic, palmitic, and stearic acids. Arbaclofen and YC-1 activated GABAB receptor through PI3K/AKT and PKA/CREB pathways, respectively, thereby promoting neuronal anti-apoptotic effect and inhibiting p-tau and Aß formation. Conclusions: This study provided a new strategy for the identification of targets and drugs for the treatment of AD using deep learning. Seven therapeutic targets and ten drugs were selected by using this method, providing new insight for AD treatment.
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Enfermedad de Alzheimer , Aprendizaje Profundo , Simulación del Acoplamiento Molecular , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Humanos , Transcriptoma , Encéfalo/metabolismo , Encéfalo/efectos de los fármacosRESUMEN
Metal-free, photoredox-catalyzed aromatization-driven deconstructive functionalization of spiro-dihydroquinazolinones with α-CF3 alkenes is presented. The readily available spiro-dihydroquinazolinones reacted efficiently with α-CF3 alkenes during photocatalysis to give the gem-difluoroallylated and the CF3-containing quinazolin-4(3H)-ones in good yields with excellent chemoselectivity. The selectivity depends on the electron effect of substituents in α-CF3 alkenes. A wide range of four-, five-, six-, seven-, eight- and twelve-membered spiro-dihydroquinazolinones were compatible with this transformation. The protocol is also characterized by the mild and redox-neutral reaction conditions, good functional group compatibility and excellent atom economy. Mechanistic studies revealed that the reaction proceeds via a radical pathway.
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BACKGROUND: The purpose of this study was to compare safety and efficacy outcomes between immediate breast reconstruction (IBR) and mastectomy alone in locally advanced breast cancer patients. METHODS: We conducted a comprehensive literature search of PUBMED, EMBASE, and Cochrane databases. The primary outcomes evaluated were overall survival, disease-free survival, and local recurrence. The secondary outcome was the incidence of surgical complications. All data were analyzed using Review Manager 5.3. RESULTS: Sixteen studies, involving 15,364 participants were included in this meta-analysis. Pooled data demonstrated that patients underwent IBR were more likely to experience surgical complications than those underwent mastectomy alone (HR: 3.96, 95%CI [1.07,14.67], p = 0.04). No significant difference was found in overall survival (HR: 0.94, 95%CI [0.73,1.20], p = 0.62), disease-free survival (HR: 1.03, 95%CI [0.83,1.27], p = 0.81), or breast cancer specific survival (HR: 0.93, 95%CI [0.71,1.21], p = 0.57) between IBR group and Non-IBR group. CONCLUSIONS: Our study demonstrates that IBR after mastectomy does not affect the overall survival and disease-free survival of locally advanced breast cancer patients. However, IBR brings with it a nonnegligible higher risk of complications and needs to be fully evaluated and carefully decided.
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Neoplasias de la Mama , Mamoplastia , Mastectomía , Complicaciones Posoperatorias , Humanos , Femenino , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Mastectomía/efectos adversos , Mastectomía/métodos , Mamoplastia/métodos , Mamoplastia/efectos adversos , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Pronóstico , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/etiología , Tasa de SupervivenciaRESUMEN
Anthropogenic reactive nitrogen (N) deposition has increased significantly since the industrial revolution. Northern China has become a global hotspot for N deposition. However, few studies have been conducted to quantify the historical changes of atmospheric N deposition fluxes and source contributions in Northern China. By investigating N contents and δ15N values of mosses at Mount Tai (Northern China) in 1984 and 2021, we reconstructed fluxes and source contributions of wet inorganic N deposition and evaluated their historical changes. Compared with 1984, moss N contents (from 1.7 ± 0.3% to 2.1 ± 0.4%) showed a significant increase in 2021, which was mainly attributed to a significant increase in nitrate N deposition fluxes at Mount Tai. Moss δ15N values (from -5.9 ± 0.9 to -5.2 ± 2.4) showed a slight increase from 1984 to 2021 at Mount Tai. The importance of combustion-related NH3 (including vehicle exhaust, coal combustion, and biomass burning) in 2021 (51.2%) were higher than those in 1984 (43.9%), while the importance of volatilization NH3 sources (including waste and fertilizers) in 2021 (48.8%) were lower than those in 1984 (56.1%). It was fossil-fuel NOx (from vehicle exhaust and coal combustion) (54.1%) rather than non-fossil fuel NOx (from biomass burning and microbial N cycles) (45.9%) dominated NOx emissions in both 1984 and 2021. Our results revealed significant contributions of combustion-related NH3 and fossil-fuel NOx sources emissions to the elevation of N deposition at Mount Tai in Northern China, which are beneficial for mitigating N emissions and conducting ecological benefit assessments in Northern China.
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Contaminantes Atmosféricos , Briófitas , Monitoreo del Ambiente , Nitrógeno , China , Briófitas/química , Monitoreo del Ambiente/métodos , Contaminantes Atmosféricos/análisis , Nitrógeno/análisis , Nitratos/análisisRESUMEN
OBJECT: Amplification of the epidermal growth factor receptor (EGFR) and its active mutant type III (EGFRvIII), frequently occurr in glioblastoma (GBM), contributing to chemotherapy and radiation resistance in GBM. Elucidating the underlying molecular mechanism of temozolomide (TMZ) resistance in EGFRvIII GBM could offer valuable insights for cancer treatment. METHODS: To elucidate the molecular mechanisms underlying EGFRvIII-mediated resistance to TMZ in GBM, we conducted a comprehensive analysis using Gene Expression Omnibus and The cancer genome atlas (TCGA) databases. Initially, we identified common significantly differentially expressed genes (DEGs) and prioritized those correlating significantly with patient prognosis as potential downstream targets of EGFRvIII and candidates for drug resistance. Additionally, we analyzed transcription factor expression changes and their correlation with candidate genes to elucidate transcriptional regulatory mechanisms. Using estimate method and databases such as Tumor IMmune Estimation Resource (TIMER) and CellMarker, we assessed immune cell infiltration in TMZ-resistant GBM and its relationship with candidate gene expression. In this study, we examined the expression differences of candidate genes in GBM cell lines following EGFRvIII intervention and in TMZ-resistant GBM cell lines. This preliminary investigation aimed to verify the regulatory impact of EGFRvIII on candidate targets and its potential involvement in TMZ resistance in GBM. RESULTS: Notably, GTPase Activating Rap/RanGAP Domain Like 3 (GARNL3) emerged as a key DEG associated with TMZ resistance and poor prognosis, with reduced expression correlating with altered immune cell profiles. Transcription factor analysis suggested Epiregulin (EREG) as a putative upstream regulator of GARNL3, linking it to EGFRvIII-mediated TMZ resistance. In vitro experiments confirmed EGFRvIII-mediated downregulation of GARNL3 and decreased TMZ sensitivity in GBM cell lines, further supported by reduced GARNL3 levels in TMZ-resistant GBM cells. CONCLUSION: GARNL3 downregulation in EGFRvIII-positive and TMZ-resistant GBM implicates its role in TMZ resistance, suggesting modulation of EREG/GARNL3 signaling as a potential therapeutic strategy.
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Wide variation in amenability to transformation and regeneration (TR) among many plant species and genotypes presents a challenge to the use of genetic engineering in research and breeding. To help understand the causes of this variation, we performed association mapping and network analysis using a population of 1204 wild trees of Populus trichocarpa (black cottonwood). To enable precise and high-throughput phenotyping of callus and shoot TR, we developed a computer vision system that cross-referenced complementary red, green, and blue (RGB) and fluorescent-hyperspectral images. We performed association mapping using single-marker and combined variant methods, followed by statistical tests for epistasis and integration of published multi-omic datasets to identify likely regulatory hubs. We report 409 candidate genes implicated by associations within 5 kb of coding sequences, and epistasis tests implicated 81 of these candidate genes as regulators of one another. Gene ontology terms related to protein-protein interactions and transcriptional regulation are overrepresented, among others. In addition to auxin and cytokinin pathways long established as critical to TR, our results highlight the importance of stress and wounding pathways. Potential regulatory hubs of signaling within and across these pathways include GROWTH REGULATORY FACTOR 1 (GRF1), PHOSPHATIDYLINOSITOL 4-KINASE ß1 (PI-4Kß1), and OBF-BINDING PROTEIN 1 (OBP1).
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Estudio de Asociación del Genoma Completo , Reguladores del Crecimiento de las Plantas , Populus , Populus/genética , Reguladores del Crecimiento de las Plantas/metabolismo , Redes Reguladoras de Genes , Epistasis Genética , Genes de Plantas , Regulación de la Expresión Génica de las Plantas , Fenotipo , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Ovarian cancer is one of the most common malignant tumors in female reproductive system in the world, and the choice of its treatment is very important for the survival rate and prognosis of patients. Traditional open surgery is the main treatment for ovarian cancer, but it has the disadvantages of big trauma and slow recovery. With the continuous development of minimally invasive technology, minimally invasive laparoscopic surgery under general anesthesia has been gradually applied to the treatment of ovarian cancer because of its advantages of less trauma and quick recovery. However, the efficacy and safety of minimally invasive laparoscopic surgery under general anesthesia in the treatment of ovarian cancer are still controversial. AIM: To explore the efficacy and safety of general anesthesia minimally invasive surgery in the treatment of ovarian cancer. METHODS: The clinical data of 90 patients with early ovarian cancer in our hospital were analyzed retrospectively. According to the different surgical treatment methods, patients were divided into study group and control group (45 cases in each group). The study group received minimally invasive laparoscopic surgery under general anesthesia for ovarian cancer, while the control group received traditional open surgery for ovarian cancer. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), clinical efficacy and safety of the two groups were compared. RESULTS: The intraoperative blood loss, length of hospital stay, postoperative gas evacuation time, and postoperative EORTC QLQ-C30 score of the study group were significantly better than those of the control group (P < 0.05). The incidence of postoperative complications in the study group was significantly lower than in the control group (P < 0.05). The two groups had no significant differences in the preoperative adrenocorticotropic hormone (ACTH), androstenedione (AD), cortisol (Cor), cluster of differentiation 3 positive (CD3+), and cluster of differentiation 4 positive (CD4+) indexes (P > 0.05). In contrast, postoperatively, the study group's ACTH, AD, and Cor indexes were lower, and the CD3+ and CD4+ indexes were higher than those in the control group (P < 0.05). CONCLUSION: Minimally invasive laparoscopic surgery under general anesthesia in patients with early ovarian cancer can significantly improve the efficacy and safety, improve the short-term prognosis and quality of life of patients, and is worth popularizing.
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In pyloric metaplasia, mature gastric chief cells reprogram via an evolutionarily conserved process termed paligenosis to re-enter the cell cycle and become spasmolytic polypeptide-expressing metaplasia (SPEM) cells. Here, we use single-cell RNA sequencing (scRNA-seq) following injury to the murine stomach to analyze mechanisms governing paligenosis at high resolution. Injury causes induced reactive oxygen species (ROS) with coordinated changes in mitochondrial activity and cellular metabolism, requiring the transcriptional mitochondrial regulator Ppargc1a (Pgc1α) and ROS regulator Nf2el2 (Nrf2). Loss of the ROS and mitochondrial control in Ppargc1a-/- mice causes the death of paligenotic cells through ferroptosis. Blocking the cystine transporter SLC7A11(xCT), which is critical in lipid radical detoxification through glutathione peroxidase 4 (GPX4), also increases ferroptosis. Finally, we show that PGC1α-mediated ROS and mitochondrial changes also underlie the paligenosis of pancreatic acinar cells. Altogether, the results detail how metabolic and mitochondrial changes are necessary for injury response, regeneration, and metaplasia in the stomach.
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Sistema de Transporte de Aminoácidos y+ , Ferroptosis , Metaplasia , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Especies Reactivas de Oxígeno , Regeneración , Estómago , Animales , Especies Reactivas de Oxígeno/metabolismo , Ratones , Ferroptosis/fisiología , Estómago/patología , Regeneración/fisiología , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Metaplasia/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Mitocondrias/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Mucosa Gástrica/metabolismo , Ratones Endogámicos C57BL , Células Principales Gástricas/metabolismo , Células Acinares/metabolismo , Ratones Noqueados , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Péptidos y Proteínas de Señalización IntercelularRESUMEN
As the backbone of the extracellular matrix (ECM) and the perineuronal nets (PNNs), hyaluronic acid (HA) provides binding sites for proteoglycans and other ECM components. Although the pivotal of HA has been recognized in Alzheimer's disease (AD), few studies have addressed the relationship between AD pathology and HA synthases (HASs). Here, HASs in different regions of AD brains were screened in transcriptomic database and validated in AßPP/PS1 mice. We found that HAS1 was distributed along the axon and nucleus. Its transcripts were reduced in AD patients and AßPP/PS1 mice. Phosphorylated tau (p-tau) mediates AßPP-induced cytosolic-nuclear translocation of HAS1, and negatively regulated the stability, monoubiquitination, and oligomerization of HAS1, thus reduced the synthesis and release of HA. Furthermore, non-ubiquitinated HAS1 mutant lost its enzyme activity, and translocated from the cytosol into the nucleus, forming nuclear speckles (NS). Unlike the splicing-related NS, less than 1 % of the non-ubiquitinated HAS1 co-localized with SRRM2, proving the regulatory role of HAS1 in gene transcription, indirectly. Thus, differentially expressed genes (DEGs) related to both non-ubiquitinated HAS1 mutant and AD were screened using transcriptomic datasets. Thirty-nine DEGs were identified, with 64.1 % (25/39) showing consistent results in both datasets. Together, we unearthed an important function of the AßPP-p-tau-HAS1 axis in microenvironment remodeling and gene transcription during AD progression, involving the ubiquitin-proteasome, lysosome, and NS systems.
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Enfermedad de Alzheimer , Núcleo Celular , Hialuronano Sintasas , Proteínas tau , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Humanos , Proteínas tau/metabolismo , Proteínas tau/genética , Ratones , Hialuronano Sintasas/metabolismo , Hialuronano Sintasas/genética , Núcleo Celular/metabolismo , Núcleo Celular/genética , Transcripción Genética , Fosforilación , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Ratones Transgénicos , UbiquitinaciónRESUMEN
Lung adenocarcinoma (LUAD) is characterized by a high incidence rate and mortality. Recently, POC1 centriolar protein A (POC1A) has emerged as a potential biomarker for various cancers, contributing to cancer onset and development. However, the association between POC1A and LUAD remains unexplored. We extracted The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) data sets to analyse the differential expression of POC1A and its relationship with clinical stage. Additionally, we performed diagnostic receiver operator characteristic (ROC) curve analysis and Kaplan-Meier (KM) survival analysis to assess the diagnostic and prognostic value of POC1A in LUAD. Furthermore, we investigated the correlation between POC1A expression and immune infiltration, tumour mutation burden (TMB), immune checkpoint expression and drug sensitivity. Finally, we verified POC1A expression using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). Cell experiments were conducted to validate the effect of POC1A expression on the proliferation, migration and invasion of lung cancer cells. POC1A exhibited overexpression in most tumour tissues, and its overexpression in LUAD was significantly correlated with late-stage presentation and poor prognosis. The high POC1A expression group showed lower levels of immune infiltration but higher levels of immune checkpoint expression and TMB. Moreover, the high POC1A expression group demonstrated sensitivity to multiple drugs. In vitro experiments confirmed that POC1A knockdown led to decreased proliferation, migration, and invasion of lung cancer cells. Our findings suggest that POC1A may contribute to tumour development by modulating the cell cycle and immune cell infiltration. It also represents a potential therapeutic target and marker for the diagnosis and prognosis of LUAD.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/genética , Ciclo Celular , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , División Celular , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Neoplasias Pulmonares/genética , Regulación hacia Arriba/genéticaRESUMEN
Guiding by LC-MS/MS analysis and the Global Natural Products Social (GNPS) Molecular Networking, three undescribed sesquiterpenoids, stedapgens A-C, and two known analogues were discovered in the barks of Daphne genkwa Sieb. et Zucc. The structures were determined by analysis of their spectroscopic data and quantum-chemical calculations. All the isolated novel compounds were tested for their acetylcholinesterase inhibitory activities with IC50 = 0.754 ± 0.059, 0.696 ± 0.026, and 0.337 ± 0.023 µg/ml. Among them, stedapgen A displayed promising inhibitory activities against AChE, and the binding sites were predicted by molecular docking.
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Proteinopathy, defined as the abnormal accumulation of proteins that eventually leads to cell death, is one of the most significant pathological features of neurodegenerative diseases. Tauopathies, represented by Alzheimer's disease (AD), and synucleinopathies, represented by Parkinson's disease (PD), show similarities in multiple aspects. AD manifests extrapyramidal symptoms while dementia is also a major sign of advanced PD. We and other researchers have sequentially shown the cross-seeding phenomenon of α-synuclein (α-syn) and tau, reinforcing pathologies between synucleinopathies and tauopathies. The highly overlapping clinical and pathological features imply shared pathogenic mechanisms between the two groups of disease. The diagnostic and therapeutic strategies seemingly appropriate for one distinct neurodegenerative disease may also apply to a broader spectrum. Therefore, a clear understanding of the overlaps and divergences between tauopathy and synucleinopathy is critical for unraveling the nature of the complicated associations among neurodegenerative diseases. In this review, we discuss the shared and diverse characteristics of tauopathies and synucleinopathies from aspects of genetic causes, clinical manifestations, pathological progression and potential common therapeutic approaches targeting the pathology, in the aim to provide a timely update for setting the scheme of disease classification and provide novel insights into the therapeutic development for neurodegenerative diseases.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Sinucleinopatías , Tauopatías , Humanos , Sinucleinopatías/genética , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/terapia , Enfermedades Neurodegenerativas/metabolismo , Proteínas tau/metabolismo , Tauopatías/genética , Tauopatías/complicaciones , Tauopatías/metabolismo , Enfermedad de Alzheimer/genéticaRESUMEN
N1-methyladenine (m1A), a modification of transcripts, regulates mRNA structure and translation efficiency. In a recent issue of Nature, Sun et al. reported that m1A in CAG repeat RNA contributes to CAG repeat expansion-induced neurodegeneration in Caenorhabditis elegans and Drosophila through enhancing the ability of endogenous TDP-43 to partition into stress granules mediated by m1A. The study is especially important for revealing the pathological function of m1A in RNA and the pathological mechanisms of CAG repeat expansion-related neurodegenerative diseases.
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Novel N-ethy-2-pyrrolidinone-substituted flavonols, myricetin alkaloids A-C (1-3), quercetin alkaloids A-C (4a, 4b, and 5), and kaempferol alkaloids A and B (6 and 7), were prepared from thermal reaction products of myricetin, quercetin, kaempferolâl-theanine, respectively. We used HPLC-ESI-HRMS/MS to detect 1-7 in 14 cultivars of green tea and found that they were all present in "Shuchazao," "Longjing 43", "Fudingdabai", and "Zhongcha 108" green teas. The structures of 1-4 and 6 were determined by extensive 1D and 2D NMR spectroscopies. These flavonol alkaloids along with their skeletal flavonols were assessed for anti-Alzheimer's disease effect based on molecular docking, acetylcholinesterase inhibition, and the transgenic Caenorhabditis elegans CL4176 model. Compound 7 strongly binds to the protein amyloid ß (Aß1-42) through hydrogen bonds (BE: -9.5 kcal/mol, Ki: 114.3 nM). Compound 3 (100 µM) is the strongest one in significantly extending the mean lifespan (13.4 ± 0.5 d, 43.0% promotion), delaying the Aß1-42-induced paralysis (PT50: 40.7 ± 1.9 h, 17.1% promotion), enhancing the locomotion (140.0% promotion at 48 h), and alleviating glutamic acid (Glu)-induced neurotoxicity (153.5% promotion at 48 h) of CL4176 worms (p < 0.0001).
Asunto(s)
Alcaloides , Enfermedad de Alzheimer , Animales , Té/química , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/farmacología , Caenorhabditis elegans/genética , Quercetina/farmacología , Acetilcolinesterasa , Simulación del Acoplamiento Molecular , Alcaloides/farmacología , Alcaloides/química , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Flavonoles/farmacologíaRESUMEN
Neutral nanomaterials functionalized with PEG or similar molecules have been popularly employed as nanomedicines. Compared to positive counterparts that are capable of harnessing the well-known proton sponge effect to facilitate their escape from lysosomes, it is yet unclear how neutral substances got their entry into the cytosol. In this study, by taking PEGylated, neutral Au nanospheres as an example, we systematically investigated their time-dependent translocation postuptake. Specifically, we harnessed dissipative particle dynamics simulations to uncover how nanospheres bypass lysosomal entrapment, wherein a mechanism termed as "squeezing-out" mode was discovered. We next conducted a comprehensive investigation on how nanomaterials implicate lysosomes in terms of integrity and functionality. By using single-molecule imaging, specific preservation of PEG-terminated with targeting moieties in lysosomes supports the "squeezing-out" mode as the mechanism underlying the lysosomal escape of nanomaterials. All evidence points out that such a process is benign to lysosomes, wherein the escape of nanomaterials proceeds at the expense of targeting moieties loss. Furthermore, we proved that by fine-tuning of the efficacy of nanomaterials escaping from lysosomes, modulation of distinct pathways and metabolic machinery can be achieved readily, thereby offering us a simple and robust tool to implicate cells.