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High-throughput sequencing has identified numerous intronic variants in the SCN1A gene in epilepsy patients. Abnormal mRNA splicing caused by these variants can lead to significant phenotypic differences, but the mechanisms of epileptogenicity and phenotypic differences remain unknown. Two variants, c.4853-1 G>C and c.4853-25 T>A, were identified in intron 25 of SCN1A, which were associated with severe Dravet syndrome (DS) and mild focal epilepsy with febrile seizures plus (FEFS+), respectively. The impact of these variants on protein expression, electrophysiological properties of sodium channels and their correlation with epilepsy severity was investigated through plasmid construction and transfection based on the aberrant spliced mRNA. We found that the expression of truncated mutant proteins was significantly reduced on the cell membrane, and retained in the cytoplasmic endoplasmic reticulum. The mutants caused a decrease in current density, voltage sensitivity, and an increased vulnerability of channel, leading to a partial impairment of sodium channel function. Notably, the expression of DS-related mutant protein on the cell membrane was higher compared to that of FEFS+-related mutant, whereas the sodium channel function impairment caused by DS-related mutant was comparatively milder than that caused by FEFS+-related mutant. Our study suggests that differences in protein expression levels and altered electrophysiological properties of sodium channels play important roles in the manifestation of diverse epileptic phenotypes. The presence of intronic splice site variants may result in severe phenotypes due to the dominant-negative effects, whereas non-canonical splice site variants leading to haploinsufficiency could potentially cause milder phenotypes.
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Epilepsias Mioclónicas , Epilepsia , Intrones , Canal de Sodio Activado por Voltaje NAV1.1 , Humanos , Canal de Sodio Activado por Voltaje NAV1.1/genética , Canal de Sodio Activado por Voltaje NAV1.1/metabolismo , Masculino , Epilepsias Mioclónicas/genética , Epilepsias Mioclónicas/metabolismo , Epilepsia/genética , Epilepsia/metabolismo , Fenotipo , Femenino , Empalme del ARN , Mutación , Células HEK293RESUMEN
Statins are well-tolerated and widely available lipid-lowering medications with neuroprotective effects against traumatic brain injury (TBI). However, whether delayed statin therapy starting in the subacute phase promotes recovery after TBI is unknown. Elongation of the very long-chain fatty acid protein 1 (ELOVL1) is involved in astrocyte-mediated neurotoxicity, but its role in TBI and the relationship between ELOVL1 and statins are unclear. We hypothesized that delayed simvastatin treatment promotes neurological functional recovery after TBI by regulating the ELOVL1-mediated production of very long-chain fatty acids (VLCFAs). ICR male mice received daily intragastric administration of 1, 2 or 5mg/kg simvastatin on Days 1-14, 3-14, 5-14, or 7-14 after cryogenic TBI (cTBI). The results showed that simvastatin promoted motor functional recovery in a dose-dependent manner, with a wide therapeutic window of at least 7 days postinjury. Meanwhile, simvastatin inhibited astrocyte and microglial overactivation and glial scar formation, and increased total dendritic length, neuronal complexity and spine density on day 14 after cTBI. The up-regulation of ELOVL1 expression and saturated VLCFAs concentrations in the cortex surrounding the lesion caused by cTBI was inhibited by simvastatin, which was related to the inhibition of the mTOR signaling. Overexpression of ELOVL1 in astrocytes surrounding the lesion using HBAAV2/9-GFAP-m-ELOVL1-3xFlag-EGFP partially attenuated the benefits of simvastatin. These results showed that delayed simvastatin treatment promoted functional recovery and brain tissue repair after TBI through the downregulation of ELOVL1 expression by inhibiting mTOR signaling. Astrocytic ELOVL1 may be a potential target for rehabilitation after TBI.
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Ghrelin, a peptide primarily secreted in the stomach, acts via the growth hormone secretagogue receptor (GHSR). It regulates several physiological processes, such as feeding behavior, energy homeostasis, glucose and lipid metabolism, cardiovascular function, bone formation, stress response, and learning. GHSR exhibits significant expression within the central nervous system. However, numerous murine studies indicate that ghrelin is limited in its ability to enter the brain from the bloodstream and is primarily confined to specific regions, such as arcuate nucleus (ARC) and median eminence (ME). Nevertheless, the central ghrelin system plays an essential role in regulating feeding behavior. Furthermore, the role of vagal afferent fibers in regulating the functions of ghrelin remains a major topic of discussion among researchers. In recent times, numerous studies have elucidated the substantial therapeutic potential of ghrelin in most gastrointestinal (GI) diseases. This has led to the development of numerous pharmaceutical agents that target the ghrelin system, some of which are currently under examination in clinical trials. Furthermore, ghrelin is speculated to serve as a promising biomarker for GI tumors, which indicates its potential use in tumor grade and stage evaluation. This review presents a summary of recent findings in research conducted on both animals and humans, highlighting the therapeutic properties of ghrelin system in GI disorders.
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Pyruvate dehydrogenase complex (PDC) is a crucial enzyme that connects glycolysis and the tricarboxylic acid (TCA) cycle pathway. It plays an essential role in regulating glucose metabolism for energy production by catalyzing the oxidative decarboxylation of pyruvate to acetyl coenzyme A. Importantly, the activity of PDC is regulated through post-translational modifications (PTMs), phosphorylation, acetylation, and O-GlcNAcylation. These PTMs have significant effects on PDC activity under both physiological and pathophysiological conditions, making them potential targets for metabolism-related diseases. This review specifically focuses on the PTMs of PDC in cardiovascular diseases (CVDs) such as myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, obesity-related cardiomyopathy, heart failure (HF), and vascular diseases. The findings from this review offer theoretical references for the diagnosis, treatment, and prognosis of CVD.
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Chiral light emission plays a key role in sensing, tomography, quantum communication, among others. Whereas, achieving highly pure, tunable chirality emission across a broad spectrum currently presents significant challenges. Free-electron radiation emerges as a promising solution to surpass these barriers, especially in hard-to-reach regimes. Here, chiral free-electron radiation is presented by exploiting the spin-momentum locking (SML) property of spoof surface plasmons (SSPs). When the phase velocity of free electrons matches that of the SSPs, the SSPs can be excited. By implementing wavenumber compensation through perturbations, the confined SSPs are transformed into free-space free-electron radiation. Owing to the law of angular momentum conservation, this process converts the transverse spin angular momentum of SSPs into the longitudinal spin angular momentum of free-electron radiation during the process, producing pure, tunable, and chiral free-electron radiation across a broad spectrum. This method achieves an optimal degree of circular polarization approaching -1. The innovative methodology can be adapted to SML-enabled guided states or silicon photonics platforms, offering new avenues for achieving chiral emission.
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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by complex pathogenesis mechanisms. Among these, ß-amyloid plaques and hyperphosphorylated Tau protein tangles have been identified as significant contributors to neuronal damage. This study investigates thonningianin A (TA) from Penthorum chinense Pursh (PCP) as a potential inhibitor targeting these pivotal proteins in AD progression. The inhibitory potential of PCP and TA on Aß fibrillization was initially investigated. Subsequently, ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry and biolayer interferometry were employed to determine TA's affinity for both Aß and Tau. The inhibitory effects of TA on the levels and cytotoxicity of AD-related proteins were then assessed. In 3xTg-AD mice, the therapeutic potential of TA was evaluated. Additionally, the molecular interactions between TA and either Aß or Tau were explored using molecular docking. We found that PCP-total ethanol extract and TA significantly inhibited Aß fibrillization. Additionally, TA demonstrated strong affinity to Aß and Tau, reduced levels of amyloid precursor protein and Tau, and alleviated mitochondrial distress in PC-12 cells. In 3xTg-AD mice, TA improved cognition, reduced Aß and Tau pathology, and strengthened neurons. Moreover, molecular analyses revealed efficient binding of TA to Aß and Tau. In conclusion, TA, derived from PCP, shows significant neuroprotection against AD proteins, highlighting its potential as an anti-AD drug candidate.
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Coal workers' pneumoconiosis (CWP) is a severe occupational disease resulting from prolonged exposure to coal dust. However, its pathogenesis remains elusive, compounded by a lack of early detection markers and effective treatments. Although the impact of gut microbiota on lung diseases is acknowledged, its specific role in CWP is unclear. This study aims to explore changes in the gut microbiome and metabolome in CWP, while also assessing the correlation between gut microbes and alterations in lung function. Fecal specimens from 43 CWP patients and 48 dust-exposed workers (DEW) were examined using 16S rRNA gene sequencing for microbiota and liquid chromatography-mass spectrometry for metabolite profiling. We observed similar gut microbial α-diversity but significant differences in flora composition (ß-diversity) between patients with CWP and the DEW group. After adjusting for age using multifactorial linear regression analysis (MaAsLin2), the distinct gut microbiome profile in CWP patients revealed an increased presence of pro-inflammatory microorganisms such as Klebsiella and Haemophilus. Furthermore, in CWP patients, alterations in gut microbiota-particularly reduced α-diversity and changes in microbial composition-were significantly correlated with impaired pulmonary function, a relationship not observed in DEW. This underscores the specific impact of gut microbiota on pulmonary health in individuals with CWP. Metabolomic analysis of fecal samples from CWP patients and DEW identified 218 differential metabolites between the two groups, with a predominant increase in metabolites in CWP patients, suggesting enhanced metabolic activity in CWP. Key altered metabolites included various lipids, amino acids, and organic compounds, with silibinin emerging as a potential biomarker. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis linked these metabolites to pathways relevant to the development of pulmonary fibrosis. Additionally, studies on the interaction between microbiota and metabolites showed positive correlations between certain bacteria and increased metabolites in CWP, further elucidating the complex interplay in this disease state. Our findings suggest a potential contributory role of gut microbiota in CWP pathogenesis through metabolic regulation, with implications for diagnostic biomarkers and understanding disease mechanisms, warranting further molecular investigation. IMPORTANCE: The findings have significant implications for the early diagnosis and treatment of coal workers' pneumoconiosis, highlighting the potential of gut microbiota as diagnostic biomarkers. They pave the way for new research into gut microbiota-based therapeutic strategies, potentially focusing on modifying gut microbiota to mitigate disease progression.
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Sample preparation is an inevitable step in the screening workflow for the identification of unknown pollutants in the aquatic environment. However, the possible loss of pollutants during sample preparation has aroused serious concern but remains not effectively resolved. This study shows that high-risk pollutants omitted in solid-phase extraction (SPE) can be identified via in situ thin-film microextraction (TFME) coupled with high-resolution mass spectrometry. It was observed that a total of 541 features showed higher mass spectrometry signal intensity by using in situ TFME in comparison with SPE. Subsequently, 28 compounds were identified from the features with higher intensity by comparing the recorded tandem mass spectra with the online database and validating with standards. Notably, six out of these compounds were completely omitted using SPE, including a dye, drug, and industrial product. It was confirmed that the lower extraction efficiencies of SPE were attributed to the limited sample volumes, the losses of compounds during sample transportation and storage, and the entrapment of compounds in SPE columns. This study demonstrates that in situ TFME should be used as a supplementary technique to SPE for extending the coverage of pollutants in the screening workflows.
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Graph neural networks (GNNs) have demonstrated remarkable success for semisupervised node classification. However, these GNNs are still limited to the conventionally semisupervised framework and cannot fully leverage the potential value of large numbers of unlabeled samples. The pseudolabeling method in semisupervised learning (SSL) is widely recognized because it can clearly leverage unlabeled samples. Nevertheless, the existing pseudolabeling methods usually utilize a fixed threshold for all classes and only use a portion of unlabeled samples (ones with high prediction confidence), which leads to class imbalance and low data utilization. To solve these problems, we propose GNNs with adaptive confidence discrimination (ACDGNN) to fully utilize unlabeled samples for facilitating semisupervised node classification. Specifically, an adaptive confidence discrimination module is designed to divide all unlabeled nodes into two subsets by comparing their confidence scores with the adaptive confidence threshold at each training epoch. Then, different constraint strategies for two subset nodes are employed. Unlabeled nodes with high confidence are used to iteratively expand the label set, while ones with low confidence learn discriminative features by applying contrastive learning. Validated by extensive experiments, the proposed ACDGNN delivers significant accuracy gains over the previous SOTAs: an average improvement of 2.0% on all datasets and 5.7% on the Flickr dataset in particular.
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BACKGROUND AND OBJECTIVES: The aim of this study is to establish dosimetric constraints for the brachial plexus at risk of developing grade ≥ 2 brachial plexopathy in the context of stereotactic body radiation therapy (SBRT). PATIENTS AND METHODS: Individual patient data from 349 patients with 356 apical lung malignancies who underwent SBRT were extracted from 5 articles. The anatomical brachial plexus was delineated following the guidelines provided in the atlases developed by Hall, et al. and Kong, et al.. Patient characteristics, pertinent SBRT dosimetric parameters, and brachial plexopathy grades (according to CTCAE 4.0 or 5.0) were obtained. Normal tissue complication probability (NTCP) models were used to estimate the risk of developing grade ≥ 2 brachial plexopathy through maximum likelihood parameter fitting. RESULTS: The prescription dose/fractionation schedules for SBRT ranged from 27 to 60 Gy in 1 to 8 fractions. During a follow-up period spanning from 6 to 113 months, 22 patients (6.3 %) developed grade ≥2 brachial plexopathy (4.3 % grade 2, 2.0 % grade 3); the median time to symptoms onset after SBRT was 8 months (ranged, 3-54 months). NTCP models estimated a 10 % risk of grade ≥2 brachial plexopathy with an anatomic brachial plexus maximum dose (Dmax) of 20.7 Gy, 34.2 Gy, and 42.7 Gy in one, three, and five fractions, respectively. Similarly, the NTCP model estimates the risks of grade ≥2 brachial plexopathy as 10 % for BED Dmax at 192.3 Gy and EQD2 Dmax at 115.4 Gy with an α/ß ratio of 3, respectively. Symptom persisted after treatment in nearly half of patients diagnosed with grade ≥2 brachial plexopathy (11/22, 50 %). CONCLUSIONS: This study establishes dosimetric constraints ranging from 20.7 to 42.7 Gy across 1-5 fractions, aimed at mitigating the risk of developing grade ≥2 brachial plexopathy following SBRT. These findings provide valuable guidance for future ablative SBRT in apical lung malignancies.
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OBJECTIVE: The authors compared the effect of 2 insertion methods, namely the conventional laryngeal mask airway (LMA) insertion and the index finger-assisted LMA insertion, on the incidence of complications associated with LMA Protector insertion. METHODS: The authors enrolled 300 patients, who underwent painless bronchoscopy. The patients ranged in age between 18 and 75 and were classified as American Society of Anesthesiologists grade I to III. They were randomly divided into 2 groups: a control group of 150 patients and an assisted group comprising 150 patients. LMA was inserted using the conventional and index finger-assisted insertion methods in both groups, respectively. The primary outcome was postoperative complications, such as oral mucosal injury and pharyngeal pain. Secondary outcomes included the success rate of first-time insertion, the incidence rate of inverse folding of LMA tips, oropharyngeal leak pressure (OLP), and other postoperative complications. RESULTS: Compared with the conventional LMA insertion method, index finger-assisted LMA insertion can significantly reduce the incidence rate of oral mucosal injury and pharyngeal pain, with fewer insertion failures. There was a statistically significant difference between the 2 groups in the visual field grading before adjustment for LMA alignment (P<0.0001). The conventional insertion method increased the likelihood of inverse folding of LMA tips. When the conventional insertion method was utilized, there was a significant difference in airway pressure and tidal volume before and after alignment under a fiberoptic bronchoscope (P<0.0001), but no significant difference in visual field grading and respiratory mechanics-related indicators. CONCLUSIONS: Index finger-assisted insertion can significantly reduce the incidence rate of LMA Protector-related complications and inverse folding of LMA tips.
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N6-methyladenosine (m6A) is the most prevalent internal modification of mRNA and plays an important role in regulating plant growth. However, there is still a lack of effective tools to precisely modify m6A sites of individual transcripts in plants. Here, programmable m6A editing tools are developed by combining CRISPR/dCas13(Rx) with the methyltransferase GhMTA (Targeted RNA Methylation Editor, TME) or the demethyltransferase GhALKBH10 (Targeted RNA Demethylation Editor, TDE). These editors enable efficient deposition or removal of m6A modifications at targeted sites of endo-transcripts GhECA1 and GhDi19 within a broad editing window ranging from 0 to 46 nt. TDE editor significantly decreases m6A levels by 24%-76%, while the TME editor increases m6A enrichment, ranging from 1.37- to 2.51-fold. Furthermore, installation and removal of m6A modifications play opposing roles in regulating GhECA1 and GhDi19 mRNA transcripts, which may be attributed to the fact that their m6A sites are located in different regions of the genes. Most importantly, targeting the GhDi19 transcript with TME editor plants results in a significant increase in root length and enhanced drought resistance. Collectively, these m6A editors can be applied to study the function of specific m6A modifications and have the potential for future applications in crop improvement.
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Background: Radiation therapy has become an important treatment for many malignant tumours after surgery and for palliative tumour care. Although modern radiotherapy technology is constantly improving, radiation damage to normal tissues is often difficult to avoid, and radiation-induced skin injury (RSI) is a common complication, manifested as skin erythema, peeling, ulceration, and even bone and deep organ damage, seriously affect the quality of life for patients. Basic research and clinical trials related to RSI have achieved certain results, while no researchers have conducted comprehensive bibliometric studies. Objective: A comprehensive bibliometric analysis of publications on RSI published between 2004 and 2023 was conducted to identify current hotspots and future directions in this area of study. Methods: RSI-related publications published between January 1, 2004, and December 31, 2023, were retrieved from the Web of Science Core Collection (WoSCC) database for analysis using VOSviewer and CiteSpace analytics. Results: A total of 1009 publications on RSI from 2004 to 2023 were included in the WoSCC database. The United States had the highest productivity with 299 papers, accounting for 29.63% of the total production, followed by China with 193 papers (19.13%) and Japan with 111 papers (11.00%). In terms of research institutions and journals, the University of Toronto and Journal of Supportive Care in Cancer published the highest number of papers. Professor Edward Chow published the most articles, while Professor Shuyu Zhang was the most cited. The top ten most-cited papers focused on the pathogenesis, prevention, and management of RSI. Keyword co-occurrence analysis and the top 25 keywords with the strongest citation bursts suggest that current research focuses on the pathogenesis, prevention, and treatment management of RSI. Conclusion: This study conducted a systematic bibliometric analysis of RSI publications from 2004 to 2023; identified the trends in RSI publications, major research countries, major research institutions, major research journals, major research authors, and major research keywords; and revealed the future development direction and research hotspots of this field. This study provides a valuable reference for future RSI research.
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Mitophagy, essential for mitochondrial health, selectively degrades damaged mitochondria. It is intricately linked to the cGAS-STING pathway, which is crucial for innate immunity. This pathway responds to mitochondrial DNA and is associated with cellular stress response. Our review explores the molecular details and regulatory mechanisms of mitophagy and the cGAS-STING pathway. We critically evaluate the literature demonstrating how dysfunctional mitophagy leads to neuroinflammatory conditions, primarily through the accumulation of damaged mitochondria, which activates the cGAS-STING pathway. This activation prompts the production of pro-inflammatory cytokines, exacerbating neuroinflammation. This review emphasizes the interaction between mitophagy and the cGAS-STING pathways. Effective mitophagy may suppress the cGAS-STING pathway, offering protection against neuroinflammation. Conversely, impaired mitophagy may activate the cGAS-STING pathway, leading to chronic neuroinflammation. Additionally, we explored how this interaction influences neurodegenerative disorders, suggesting a common mechanism underlying these diseases. In conclusion, there is a need for additional targeted research to unravel the complexities of mitophagy-cGAS-STING interactions and their role in neurodegeneration. This review highlights potential therapies targeting these pathways, potentially leading to new treatments for neuroinflammatory and neurodegenerative conditions. This synthesis enhances our understanding of the cellular and molecular foundations of neuroinflammation and opens new therapeutic avenues for neurodegenerative disease research.
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PURPOSE: The purpose of this study was to evaluate the effect of UGT1A4 and UGT2B7 polymorphisms on the plasma concentration of lamotrigine in Chinese patients with bipolar disorder. METHODS: A total of 104 patients were included in this study. Steady-state plasma lamotrigine concentrations were determined in each patient after at least 21â days of continuous treatment with a set dose of the drug. Lamotrigine plasma concentrations were ascertained using ultra-performance liquid chromatography. Simultaneously, plasma samples were used for patient genotyping. RESULTS: The age, sex, BMI, daily lamotrigine dose, plasma lamotrigine concentration, and lamotrigine concentration/dose ratio of patients exhibited significant differences, and these were associated with differences in the genotype [ UGT1A4 -142T>G and UGT2B7 -161C>T ( P â <â 0.05)]. Patients with the GG and GT genotypes in UGT1A4 -142T>G had significantly higher lamotrigine concentration/dose values (1.6â ±â 1.1 and 1.7â ±â 0.5â µg/ml per mg/kg) than those with the TT genotype (1.4â ±â 1.1â µg/ml per mg/kg). Likewise, patients with the UGT2B7 -161C>T TT genotype had significantly higher lamotrigine concentration/dose values (1.6â ±â 1.1â µg/ml per mg/kg) than those with the CC genotype (1.3â ±â 1.3â µg/ml per mg/kg). Multiple linear regression analysis showed that sex, lamotrigine dose, UGT1A4 -142T>G, and UGT2B7 -161C>T were the most important factors influencing lamotrigine pharmacokinetics ( P â <â 0.001). CONCLUSION: The study results suggest that the UGT1A4 -142T>G and UGT2B7 -161C>T polymorphisms affect lamotrigine plasma concentrations in patients with bipolar disorder.
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Trastorno Bipolar , Glucuronosiltransferasa , Lamotrigina , Triazinas , Humanos , Lamotrigina/sangre , Lamotrigina/farmacocinética , Lamotrigina/administración & dosificación , Lamotrigina/uso terapéutico , Glucuronosiltransferasa/genética , Masculino , Femenino , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Trastorno Bipolar/sangre , Adulto , Triazinas/farmacocinética , Triazinas/sangre , Triazinas/administración & dosificación , Triazinas/uso terapéutico , Persona de Mediana Edad , Genotipo , Polimorfismo de Nucleótido Simple/genética , Pueblo Asiatico/genéticaRESUMEN
Doxorubicin (DOX) is an anthracycline medication that is commonly used to treat solid tumors. However, DOX has limited clinical efficacy due to known cardiotoxicity. Ferroptosis is involved in DOX-induced cardiotoxicity (DIC). Although mitsugumin-53 (MG53) has cardioprotective effects and is expected to attenuate myocardial ischemic injury, its ability to inhibit DOX-induced ferroptosis has not been extensively studied. This research aims to investigate the pathophysiological impact of MG53 on DOX induced ferroptosis. Here, MG53 levels were evaluated in relation to the extent of ferroptosis by establishing in vivo and in vitro DIC mouse models. Additionally, myocardial specific MG53 overexpressing mice were used to study the effect of MG53 on cardiac function in DIC mice. The study found that the MG53 expression decreased in DOX treated mouse hearts or cardiomyocytes. However, MG53-overexpressing improved cardiac function in the DIC model and effectively reduced myocardial ferroptosis by increasing solute carrier family 7 member 11 (SLC7A11) and Glutathione peroxidase 4 (GPX4) levels, which were decreased by DOX. Mechanistically, MG53 binds to tumor suppressor 53 (p53) to regulate its ubiquitination and degradation. Ferroptosis induced by DOX was prevented by either MG53 overexpression or p53 knockdown in cardiomyocytes. The modulation of the p53/SLC7A11/GPX4 pathway by overexpression of MG53 can alleviate DOX induced ferroptosis. The study indicates that MG53 can provide protection against DIC by increasing p53 ubiquitination. These results highlight the previously unidentified role of MG53 in inhibiting ferroptosis to prevent DIC.
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Sistema de Transporte de Aminoácidos y+ , Cardiotoxicidad , Doxorrubicina , Ferroptosis , Miocitos Cardíacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Proteína p53 Supresora de Tumor , Ferroptosis/efectos de los fármacos , Animales , Doxorrubicina/efectos adversos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Ratones , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Cardiotoxicidad/metabolismo , Cardiotoxicidad/patología , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Humanos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Transducción de Señal/efectos de los fármacos , Masculino , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Proteínas de la MembranaRESUMEN
BACKGROUND: Facial palsy, often resulting from trauma or iatrogenic treatments, leads to significant esthetic and functional impairment. Surgical interventions, such as masseteric-to-facial nerve transfer combined with static suspension, are frequently recommended to restore facial nerve function and symmetry. METHODS: This study examines how Botulinum Toxin A (BoNT-A) treatment on the unaffected side affects facial symmetry and brain connectivity in patients with severe oral commissure droop from facial nerve damage. Patients were divided into two groups: one received BoNT-A injections on the unaffected side, and the other did not. RESULTS: Our findings revealed that BoNT-A treatment not only improved facial symmetry but also induced significant modifications in brain functional network connectivity. These modifications extended beyond the sensorimotor network, involving high-level cognitive processes, and exhibited a significant correlation with the degree of facial asymmetry. CONCLUSIONS: These results provide valuable insights into the mechanisms underlying the positive effects of BoNT-A intervention on motor recovery and brain plasticity in facial palsy patients. Furthermore, the study emphasizes the importance of a multidisciplinary approach to facial palsy rehabilitation. Understanding these intricate interactions between facial symmetry restoration and brain network adaptations may pave the way for more effective treatments and improved quality of life for individuals dealing with facial palsy.
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Background: Colorectal cancer (CRC) is a major global health challenge with a need for new biomarkers and therapeutic targets. This work aimed to investigate the biological mechanisms and clinical value of Ly1 antibody reactive (LYAR) in CRC. Methods: We analyzed LYAR mRNA expression across multiple public databases, including genotype-tissue expression, gene expression omnibus, Oncomine, and the cancer genome atlas, alongside in-house immunohistochemical data to evaluate LYAR protein expression in CRC and non-CRC colorectal tissues. Gene set enrichment analysis (GSEA) was used to elucidate LYAR's biological functions, and its impact on the tumor immune microenvironment was assessed using CIBERSORT, ESTIMATE, and single-cell RNA sequencing techniques. In addition, LYAR's association with clinicopathological features and patient prognosis was explored, and its influence on drug sensitivity was investigated using the Connectivity Map database. Results: LYAR was significantly upregulated in CRC tissues compared with non-CRC colorectal counterparts, associated with altered immune cell composition and enhanced RNA processing, splicing, and cell cycle regulation. High LYAR expression correlated with poor disease-free and overall survival, underscoring its prognostic value. GSEA revealed LYAR's involvement in critical cellular processes and pathways, including DNA repair, cell cycle, and mTORC1 signaling. Correlation analysis identified genes positively and negatively associated with LYAR, leading to the discovery of temsirolimus and WYE-354, mTOR inhibitors, as potential therapeutic agents for CRC. Furthermore, LYAR expression predicted increased sensitivity to cetuximab in RAS wild-type metastatic CRC, indicating its utility as a biomarker for treatment responsiveness. Conclusions: LYAR's upregulation in CRC highlights its potential as a biomarker for prognosis and therapeutic targeting, offering insights into CRC pathology and suggesting new avenues for treatment optimization.
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Previous studies have revealed that thyroid hormone (TH) levels are associated with the risk of diabetic peripheral neuropathy (DPN) in euthyroid patients with type 2 diabetes mellitus (T2DM). However, the relationship between TH sensitivity, a complementary method for assessing thyroid function, and DPN remains unclear. This study aimed to investigate the correlation between DPN and TH sensitivity in euthyroid patients with T2DM. Exactly 708 euthyroid adults with T2DM were retrospectively enrolled. The FT3/FT4 ratio was used to estimate peripheral TH sensitivity. Central TH sensitivity was assessed using the Thyrotroph T4 Resistance Index (TT4RI), Thyroid-Stimulating Hormone Index (TSHI), Thyroid Feedback Quantile-based Index (TFQI), and Parametric TFQI (PTFQI). DPN was assessed using neurologic symptoms, signs, and nerve conduction velocity tests. The relationship between DPN and TH sensitivity was examined using logistic regression analysis. We observed that an elevated FT3/FT4 ratio was associated with DPN (OR = 1.36, 95%CI: 1.13-1.63, p = 0.0012). For each standard deviation (SD) increase in the TT4RI, TSHI, TFQI, and PTFQI, the OR of DPN was 0.80 (95%CI: 0.68-0.94, p = 0.0078), 0.72 (95%CI: 0.60-0.86, p = 0.0002), 0.69 (95%CI: 0.58-0.83, p < 0.0001), and 0.69 (95%CI: 0.58-0.82, p < 0.0001), respectively. These results suggested that reduced central and peripheral TH sensitivity is associated with a decreased risk of developing DPN.