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Glutathione (GSH) plays a crucial role in several physiological processes, including anti-oxidation and heavy metal detoxification. GSH is produced endogenously in the human body and can also be obtained through diet. The development of fast, highly sensitive, and multi-application fluorescent probes remains a challenging task. In this study, we have designed and synthesized a coumarin-based fluorescent probe (NFRF) for the sensitive and rapid detection of GSH in 100 % aqueous solution. By loading probe NFRF on the filter paper, the real-time visual detection of GSH is achieved in both daylight and fluorescence modes, providing a convenient, economical and rapid on-site detection tool. Probe NFRF could be used for the detection of GSH in real samples, with recoveries rates of 81.74 %-115.12 %. Notably, the probe imaged changes in GSH concentrations in oxidative stress environments and during ferroptosis. This work provides a prospective method for GSH detection in food and complex biological systems.
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Skin psoriasis is defined as receiving external stimulation to activate skin dendritic cells (DCs) which can release interleukin 23 (IL-23) to interlink the innate and adaptive immunity as well as induce T helper 17 (Th17) cell differentiation leading to elevated production of interleukin 17 (IL-17) for keratinocytes over production. This autoimmune loop in psoriasis pathogenesis is influenced by G protein-coupled receptor (GPCR) signalling transduction, and in particular, function of adhesion molecule GPR97 in psoriasis endures to be utterly addressed. In this research, our team allocated GPR97 depletion (GPR97-/-), GPR97 conditional depletion on dendritic cell (DC-cKO), and keratin 14-conditional knockout (K14-cKO) mice models to explore the function of GPR97 which influences keratinocytes and skin immunity. It was found that significantly aggravated psoriasis-like lesion in GPR97-/- mice. In addition, hyperproliferative keratinocytes as well as accumulation of DCs and Th17 cells were detected in imiquimod (IMQ)-induced GPR97-/- mice, which was consistent with the results in DC-cKO and K14-cKO psoriasis model. Additional investigations indicated that beclomethasone dipropionate (BDP), an agonist of GPR97, attenuated the psoriasis-like skin disease and restricted HaCaT cells abnormal proliferation as well as Th17 cells differentiation. Particularly, we found that level of NF-κB p65 was increased in GPR97-/- DCs and BDP could inhibit p65 activation in DCs. Role of GPR97 is indispensable and this adhesion receptor may affect immune cell enrichment and function in skin and alter keratinocytes proliferation as well as differentiation in psoriasis.
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OBJECTIVE: To assess the impact of vertical integration (VI) within County-Level Integrated Health Organisations (CIHOs) on the costs of primary care inpatients. METHODS: This study assessed Xishui, a national pilot county for CIHOs, using inpatient claims data. The treatment group comprised 10,118 inpatients from 5 vertically integrated township health centres (THCs), while the control group consisted of 21,165 inpatients from 19 non-vertically integrated THCs. The periods from July 2020 to December 2021 and January 2022 to December 2022 were defined as pre- and post-policy intervention, respectively. The primary outcome variables were total health expenditures (THS), out-of-pocket (OOP) expenditures, and the proportion of OOP expenditures. Propensity score matching was employed to align inpatient demographics and disease characteristics between the groups, followed by a difference-in-differences analysis to evaluate the outcomes. FINDINGS: VI significantly increased THS (ß = 0.1337, p < 0.01) and OOP expenditures per case (ß = 0.1661, p < 0.001), but the increase in the proportion of OOP expenditures per case was not significant (ß = 0.0029, p > 0.05). For the basic medical insurance for urban and rural residents, THS per case (ß = 0.1343, p < 0.01) and OOP expenditures (ß = 0.1714, p < 0.001) significantly increased. For the basic medical insurance system for employees, THS per case also increased significantly (ß = 0.1238, p < 0.01), but the change in OOP expenditure proportion per case was not significant (ß = 0.1020, p > 0.05). The THS per case led by Xishui County People's Hospital, the leading county medical sub-centre (CMSC), significantly increased (ß = 0.1753, p < 0.01), whereas the increase led by Xishui County Traditional Chinese Medicine Hospital was not significant (ß = 0.0742, p > 0.05). Increases in OOP expenditures per case were significant in CMSCs led by the People's Hospital and the Traditional Chinese Medicine Hospital (ß = 0.1782, p < 0.01 and ß = 0.0757, p < 0.05, respectively). CONCLUSION: VI significantly increased THS and OOP expenditures for primary care inpatients. However, VI could exacerbate economic disparities in disease burden across different insurance categories.
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To investigate the clinical experience of glomus jugulare paraganglioma by presenting a case of giant glomus jugulare paraganglioma. The clinical data of 1 case of giant glomus jugulare paraganglioma with unilateral anacousia and pulsatile tinnitus admitted to our department was retrospectively analyzed, and the relevant literature was reviewed to summarize the characteristics of the disease. The tumor tissue in the jugular venous foramen region was completely resected, with complete preservation of the facial nerve during the operation. There was no tumor recurrence during the 2-year postoperative follow-up period. With nonspecific clinical symptoms and a high rate of early misdiagnosis The giant glomus jugulare paraganglioma case only manifested as symptoms of unilateral anacousia and pulsatile tinnitus is clinically rare. The intraoperative safe resection of the tumor, maximum preservation of facial nerve function remains the focus of surgery.
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Tumor del Glomo Yugular , Humanos , Tumor del Glomo Yugular/cirugía , Paraganglioma/cirugía , Paraganglioma/diagnóstico , Masculino , Foramina Yugular , Persona de Mediana Edad , Femenino , Adulto , Acúfeno/etiología , Estudios Retrospectivos , Venas YugularesRESUMEN
Diabetes, a multifaceted metabolic disorder, poses a significant global health burden with its increasing prevalence and associated complications, such as diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, and diabetic angiopathy. Recent studies have highlighted the intricate interplay between N6-methyladenosine (m6A) and non-coding RNAs (ncRNAs) in key pathways implicated in these diabetes complications, like cell apoptosis, oxidative stress, and inflammation. Thus, understanding the mechanistic insights into how m6A dysregulation impacts the expression and function of ncRNAs opens new avenues for therapeutic interventions targeting the m6A-ncRNAs axis in diabetes complications. This review explores the regulatory roles of m6A modifications and ncRNAs, and stresses the role of the m6A-ncRNA axis in diabetes complications, providing a therapeutic potential for these diseases.
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Adenosina , Complicaciones de la Diabetes , ARN no Traducido , Humanos , Complicaciones de la Diabetes/metabolismo , Complicaciones de la Diabetes/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , ARN no Traducido/genética , Animales , Estrés OxidativoRESUMEN
The erlin1/erlin2 (E1/E2) complex is an endoplasmic reticulum membrane-located assemblage of the proteins erlin1 and erlin2. Here, we demonstrate direct and selective binding of phosphatidylinositol 3-phosphate (PI(3)P) to recombinant erlins and that disruption or deletion of the E1/E2 complex reduces HeLa cell PI(3)P levels by â¼50 %. This reduction correlated with a decrease in autophagic flux, with no effect on the endocytic pathway, and was not due to reduced VPS34 kinase activity, which is critical for maintaining steady-state PI(3)P levels. Pharmacological inhibition of VPS34 and suppression of PI(3)P levels caused a similar reduction in autophagic flux. Overall, these data indicate that by binding to PI(3)P, the E1/E2 complex plays an important role in maintaining the steady-state levels of PI(3)P and, thus, sustains some key PI(3)P-dependent processes, e.g., autophagy.
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Autofagia , Fosfatos de Fosfatidilinositol , Humanos , Fosfatos de Fosfatidilinositol/metabolismo , Células HeLa , Proteínas de la Membrana/metabolismo , Unión Proteica , Fosfatidilinositol 3-Quinasas Clase III/metabolismo , Retículo Endoplásmico/metabolismoRESUMEN
The cerebellum has historically been primarily associated with the regulation of precise motor functions. However, recent findings suggest that it also plays a pivotal role in the development of advanced cognitive functions, including learning, memory, and emotion regulation. Pathological changes in the cerebellum, whether congenital hereditary or acquired degenerative, can result in a diverse spectrum of disorders, ranging from genetic spinocerebellar ataxias to psychiatric conditions such as autism, and schizophrenia. While studies in animal models have significantly contributed to our understanding of the genetic networks governing cerebellar development, it is important to note that the human cerebellum follows a protracted developmental timeline compared to the neocortex. Consequently, employing animal models to uncover human-specific molecular events in cerebellar development presents significant challenges. The emergence of human induced pluripotent stem cells (hiPSCs) has provided an invaluable tool for creating human-based culture systems, enabling the modeling and analysis of cerebellar physiology and pathology. hiPSCs and their differentiated progenies can be derived from patients with specific disorders or carrying distinct genetic variants. Importantly, they preserve the unique genetic signatures of the individuals from whom they originate, allowing for the elucidation of human-specific molecular and cellular processes involved in cerebellar development and related disorders. This review focuses on the technical advancements in the utilization of hiPSCs for the generation of both 2D cerebellar neuronal cells and 3D cerebellar organoids.
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Myokines are a group of cytokines or polypeptides released from skeletal muscle during exercise. Growing evidence suggests that myokines are associated with the development of cardiovascular disease (CVD). Moreover, several myokines in peripheral blood exhibit dynamic changes in different CVD stages. This review summarizes the potential roles of myokines such as myostatin, irisin, brain-derived neurotrophic factor, mitsugumin 53, meteorin-like, and apelin in various CVD, including myocardial infarction, heart failure, atherosclerosis, hypertension, and diabetes. The association of these myokines with biomarkers currently being used in clinical practice is also discussed. Furthermore, the review considers the emerging role of myokines in CVD and addresses the challenges remaining in translating these discoveries into novel clinical biomarkers for CVD.
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Background: To evaluate the methodological quality, report quality, and evidence quality of meta-analysis (MA) and systematic review (SR) on the efficacy of probiotics in the treatment of rheumatoid arthritis (RA). Methods: Databases were used to identify eligible SRs/MAs until February 12, 2024. The methodological quality of the studies was assessed using AMSTAR-2 tool, the quality of the literature reports was scored using PRISMA checklists, and the quality of the evidence was graded using GRADE system. Results: Seven reviews including 21 outcomes were included. Methodological quality of the included reviews was of general low, and the entries with poor scores were 2, 4, and 7. By PRISMA checklists, there were some reporting deficiencies, and quality problems were mainly reflected in the reporting registration and protocol, comprehensive search strategy and additional analysis. GRADE results elevated the quality of evidence to be low or very low overall. Conclusions: Probiotics may have a therapeutic effect on RA, based on the evidence provided by the SRs/MAs in this overview. Nevertheless, there is still a lack of conclusive evidence due to methodological limitations in the included research. To make trustworthy judgments regarding the efficacy of probiotics in the treatment of RA, more large-scale, high-quality randomized controlled trials are still required.
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Artritis Reumatoide , Probióticos , Revisiones Sistemáticas como Asunto , Probióticos/uso terapéutico , Artritis Reumatoide/terapia , Humanos , Resultado del Tratamiento , Metaanálisis como AsuntoRESUMEN
Houttuynia cordata Thunb., also known as Yuxingcao in Chinese, occupies a pivotal role in Asian traditional medicine and cuisine. The aerial parts and underground stems of H. cordata exhibit remarkable chemical diversity, particularly in essential oil. Nevertheless, the mechanisms regulating essential oil biosynthesis in H. cordata remain unclear. In this study, we present a quantitative overview of the proteomes across four tissues (flower, stem, leaf, and underground stem) of H. cordata, achieved through the application of the isobaric tag for relative and absolute quantitation (iTRAQ). Our research findings indicate that certain crucial ribosomal proteins and their interactions may significantly impact the production of essential oils in H. cordata. These results offer novel insights into the roles of ribosomal proteins and their associations in essential oil biosynthesis across various organisms of H. cordata.
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Houttuynia , Aceites Volátiles , Proteómica , Proteínas Ribosómicas , Houttuynia/metabolismo , Houttuynia/química , Aceites Volátiles/metabolismo , Proteínas Ribosómicas/metabolismo , Proteómica/métodos , Proteínas de Plantas/metabolismo , Proteoma/metabolismoRESUMEN
The timely degradation of tapetum, the innermost somatic anther cell layer in flowering plants, is critical for pollen development. Although several genes involved in tapetum development have been characterized, the molecular mechanisms underlying tapetum degeneration remain elusive. Here, we showed that mutation in Abnormal Degraded Tapetum 1 (ADT1) resulted in overaccumulation of Reactive Oxygen Species (ROS) and abnormal anther development, causing earlier tapetum Programmed Cell Death (PCD) and pollen abortion. ADT1 encodes a nuclear membrane localized protein, which is strongly expressed in the developing microspores and tapetal cells during early anther development. Moreover, ADT1 could interact with metallothionein MT2b, which was related to ROS scavenging and cell death regulation. These findings indicate that ADT1 is required for proper timing of tapetum PCD by regulating ROS homeostasis, expanding our understanding of the regulatory network of male reproductive development in rice.
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Regulación de la Expresión Génica de las Plantas , Mutación , Oryza , Proteínas de Plantas , Polen , Especies Reactivas de Oxígeno , Oryza/genética , Oryza/crecimiento & desarrollo , Oryza/metabolismo , Polen/crecimiento & desarrollo , Polen/genética , Especies Reactivas de Oxígeno/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Muerte Celular , Flores/crecimiento & desarrollo , Flores/genética , ApoptosisRESUMEN
The rapid and accurate detection of illegal adulteration of chemical drugs into dietary supplements is a big challenge in the food chemistry field. Detection of compounds without a standard reference is even more difficult; however, this is a common situation. Here in this study, a novel "standard-free detection of adulteration" (SFDA) method was proposed and phosphodiesterase-5 inhibitor derivatives were used as an example to figure out the possibility and reliability of this SFDA method. After analysis by quadrupole coupled time of flight-tandem mass spectrometry detection and multivariable statistics, six common fragment ions were chosen to indicate whether adulteration was present or not, while 20 characteristic fragment ions indicated whether adulteration was by nitrogen-containing heterocycles or by anilines. Furthermore, the quantitative methods were conducted by high-performance liquid chromatography-tandem mass spectrometry. In a word, this strategy allows for a quick determination of dietary supplement adulteration without any need for standard materials, improving the efficacy of food safety testing.
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Suplementos Dietéticos , Contaminación de Medicamentos , Citrato de Sildenafil , Espectrometría de Masas en Tándem , Suplementos Dietéticos/análisis , Citrato de Sildenafil/análisis , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida de Alta Presión/métodos , Reproducibilidad de los Resultados , Límite de Detección , Modelos Lineales , Inhibidores de Fosfodiesterasa 5/análisisRESUMEN
Cardiac lipotoxicity is a prevalent consequence of lipid metabolism disorders occurring in cardiomyocytes, which in turn precipitates the onset of heart failure. Mimetics of brain-derived neurotrophic factor (BDNF), such as 7,8-dihydroxyflavone (DHF) and 7,8,3'-trihydroxyflavone (THF), have demonstrated significant cardioprotective effects. However, it remains unclear whether these mimetics can protect cardiomyocytes against lipotoxicity. The aim of this study was to examine the impact of DHF and THF on the lipotoxic effects induced by palmitic acid (PA), as well as the concurrent mitochondrial dysfunction. H9c2 cells were subjected to treatment with PA alone or in conjunction with DHF or THF. Various factors such as cell viability, lactate dehydrogenase (LDH) release, death ratio, and mitochondrial function including mitochondrial membrane potential (MMP), mitochondrial-derived reactive oxygen species (mito-SOX) production, and mitochondrial respiration were assessed. PA dose-dependently reduced cell viability, which was restored by DHF or THF. Additionally, both DHF and THF decreased LDH content, death ratio, and mito-SOX production, while increasing MMP and regulating mitochondrial oxidative phosphorylation in cardiomyocytes. Moreover, DHF and THF specifically activated Akt signaling. The protective effects of DHF and THF were abolished when an Akt inhibitor was used. In conclusion, BDNF mimetics attenuate PA-induced injury in cardiomyocytes by alleviating mitochondrial impairments through the activation of Akt signaling.
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Factor Neurotrófico Derivado del Encéfalo , Flavonas , Potencial de la Membrana Mitocondrial , Miocitos Cardíacos , Ácido Palmítico , Proteínas Proto-Oncogénicas c-akt , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ácido Palmítico/toxicidad , Ácido Palmítico/farmacología , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Ratas , Línea Celular , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Flavonas/farmacología , Supervivencia Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Background: Fruits are essential for health, yet their consumption in children is inadequate, with unclear influencing factors. Methods: A cross-sectional study was conducted among students in grades 3-12 in Beijing, China, from September 2020 to June 2021. Fruit consumption in children was surveyed using a self-administered food frequency questionnaire. Additionally, children's food and nutrition literacy and family food environments were assessed using the "Food and Nutrition Literacy Questionnaire for Chinese School-age Children" and the "Family Food Environment Questionnaire for Chinese School-age Children," respectively. Results: Out of 10,000 participating children, 62.5% consumed fruit daily, with a lower frequency among boys (59.3%) compared to girls (65.8%), and among senior students (48.6%) compared to junior (63.6%) and primary students (71.2%). Fruit consumption was positively associated with other healthy foods (vegetables, whole grains, etc.) and negatively with unhealthy foods (sugared soft drinks). Children with higher food and nutrition literacy consumed fruits daily more frequently (82.4% vs. 59.9%, ORs = 2.438, 95%CI: 2.072-2.868). A significant positive correlation was found between children's fruit consumption and a healthy family food environment (66.4% vs. 50.2%, OR = 1.507, 95%CI: 1.363-1.667). Conclusion: The results indicate that individual food and nutrition literacy and family food environment are key positive predictors of children's fruit consumption. Future interventions should focus on educating children and encouraging parents to foster supportive family environments.
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Frutas , Humanos , Femenino , Masculino , Estudios Transversales , Niño , Encuestas y Cuestionarios , Conducta Alimentaria , Beijing , Adolescente , China , Estudiantes/estadística & datos numéricos , Alfabetización en Salud/estadística & datos numéricos , FamiliaRESUMEN
Objective: The study aimed to build and validate a competitive risk nomogram to predict the cumulative incidence of hepatocellular carcinoma (HCC) for patients with hepatitis B virus (HBV)-related cirrhosis. Methods: A total of 1401 HBV-related cirrhosis patients were retrospectively enrolled from January 1, 2011 to December 31, 2014. Application of 20 times imputation dealt with missing data using multiple imputation by chained equations (MICE). The patients were randomly divided into a training set (n = 1017) and a validation set (n = 384) at a ratio of 3:1. A prediction study was carried out using a competing risk model, where the event of interest was HCC and the competing events were death and liver transplantation, and subdistribution hazard ratios (sHRs) with 95% CIs were reported. The multivariate competing risk model was constructed and validated. Results: There was a negligible difference between the original database and the 20 imputed datasets. At the end of follow-up, the median follow-up time was 69.9 months (interquartile range: 43.8-86.6). There were 31.5% (442/1401) of the patients who developed HCC, with a 5-year cumulative incidence of 22.9 (95%CI, 20.8%-25.2%). The univariate and multivariate competing risk regression and construction of the nomogram were performed in 20 imputed training datasets. Age, sex, antiviral therapy history, hepatitis B e antigen, alcohol drinking history, and alpha-fetoprotein levels were included in the nomogram. The area under receiver operating characteristic curve values at 12, 24, 36, 60, and 96 months were 0.68, 0.69, 0.70, 0.68, and 0.80, and the Brier scores were 0.30, 0.25, 0.23, 0.21, and 0.20 in the validation set. According to the cumulative incidence function, the nomogram effectively screened out high-risk HCC patients from low-risk patients in the presence of competing events (Fine-Gray test p < 0.001). Conclusion: The competitive risk nomogram was allowed to be used for predicting HCC risk in individual patients with liver cirrhosis, taking into account both the association between risk factors and HCC and the modifying effect of competition events on this association.
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BACKGROUND: In reversed-phase liquid chromatography, the C18 alkyl bonded phase, as the primary stationary phase, is widely used in pharmaceutical and food analysis. The phenyl bonded phase often serves as a complementary choice to the C18 phase to enhance the separation performance of specific categories of compounds. However, both C18 and the currently available phenyl bonded phase chromatography columns show room for further optimization in improving the separation efficiency of specific compound classes, such as dihydroflavonoids. Additionally, the potential role and impact of introducing phosphorus groups into chromatographic stationary phases have not been fully explored, indicating a promising direction for research. RESULTS: In the present work, we prepared a novel phenyl stationary phase by bonding 9-oxa-10-phosphaphenanthrene 10-oxide onto silica gel. The obtained material was characterized by scanning electron microscopy, fourier transforms infrared spectroscopy, and elemental analysis. The results show that 9-oxa-10-phosphaphenanthrene 10-oxide was successfully bonded on the silica surface with a load of 3.90 %. Further chromatographic characterization in high-performance liquid chromatography exhibited high column efficiency (40,792 plates m-1 for the determination of biphenyl) and good stability (RSD of 0.28 %â¼5.38 %). Moreover, we made a detailed study of the column separation mechanism by nuclear magnetic resonance spectroscopy titration experiment. Comparing to commercial phenyl column, the proposed stationary phase showed shorter retention time and higher throughput. In addition, the stationary phase has a strong ability to separate multiple types of compounds, which provides a new strategy for the separation of complex samples, such as active ingredients in traditional Chinese medicine. SIGNIFICANCE: We have developed a novel phenyl column and conducted a comprehensive examination of its chromatographic performance, demonstrating excellent separation capabilities and high efficiency for both nonpolar and moderately polar aromatic compounds. Additionally, we explored the impact of phosphorus-containing groups on the separation performance of chromatographic stationary phases.
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This study aims to investigate the impact of four key factors, namely, temperature, water source, metal ion, and pH, on the stability of molecular chirality of dihydromyricetin (DMY) and proposed effective strategies for configuration protection. The findings reveal that temperatures exceeding 80°C could accelerate the racemization process of DMY, with a significant increase in racemization observed at 100°C. In addition, DMY exhibited heightened stability in ultrapure water as compared to various water sources, including pure water-1, pure water-2, mineral water, and running water. Notably, the presence of Fe2+ displayed an inhibitory effect on the racemization of DMY, whereas Mg2+, Ca2+, and Mn2+ showed a substantial promotional effect. Additionally, acidic conditions (pH < 5.0) were found to be protective for maintaining the stability of DMY, whereas alkaline conditions (pH > 9.0) were observed to be detrimental. Meanwhile, we first identified the presence of another pair of DMY isomers in this work.
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Flavonoles , Flavonoles/farmacología , Flavonoles/química , Concentración de Iones de Hidrógeno , Estereoisomerismo , Agua/química , Temperatura , Isomerismo , Té/químicaRESUMEN
Severe nephrotoxicity and infusion-related side effects pose significant obstacles to the clinical application of Amphotericin B (AmB) in life-threatening systemic fungal infections. In pursuit of a cost-effective and safe formulation, we have introduced multiple phenylboronic acid (PBA) moieties onto a linear dendritic telodendrimer (TD) scaffold, enabling effective AmB conjugation via boronate chemistry through a rapid, high yield, catalysis-free and dialysis-free "Click" drug loading process. Optimized AmB-TD prodrugs self-assemble into monodispersed micelles characterized by small particle sizes and neutral surface charges. AmB prodrugs sustain drug release in circulation, which is accelerated in response to the acidic pH and Reactive Oxygen Species (ROS) in the infection and inflammation. Prodrugs mitigate the AmB aggregation status, reduce cytotoxicity and hemolytic activity compared to Fungizone®, and demonstrate superior antifungal activity to AmBisome®. AmB-PEG5kBA4 has a comparable maximum tolerated dose (MTD) to AmBisome®, while over 20-fold increase than Fungizone®. A single dose of AmB-PEG5kBA4 demonstrates superior efficacy to Fungizone® and AmBisome® in treating systemic fungal infections in both immunocompetent and immunocompromised mice.
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Anfotericina B , Antifúngicos , Fungemia , Profármacos , Animales , Anfotericina B/administración & dosificación , Anfotericina B/farmacología , Anfotericina B/química , Anfotericina B/farmacocinética , Profármacos/administración & dosificación , Profármacos/química , Profármacos/farmacología , Antifúngicos/administración & dosificación , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/uso terapéutico , Humanos , Fungemia/tratamiento farmacológico , Nanopartículas/química , Liberación de Fármacos , Micelas , Ratones , Femenino , Química Clic , Candida albicans/efectos de los fármacos , Polietilenglicoles/química , Polietilenglicoles/administración & dosificaciónRESUMEN
Retroperitoneal Ewing sarcomas (RES) are very rare and mostly described in case reports. The purpose of this study was to retrospectively analyze the clinicopathology, molecular characteristics, biological behavior, and therapeutic information of 13 cases of primary RES with immunohistochemical staining, fluorescence in situ hybridization, RT-PCR and NGS sequencing detection techniques. The thirteen patients included eight males and five females with a mean age of 34 years. Morphologically, the tumors were comprised of small round or epithelial-like cells with vacuolated cytoplasm (6/13,46 %) arranged in diffuse, nested (8/13,62 %) and perivascular (7/13,54 %) patterns. Unusual morphologic patterns, such as meningioma-like swirling structures and sieve-like structures were relatively novel findings. Immunohistochemical studies showed CD99 (12/13; 92 %), CD56 (11/13; 85 %), NKX2.2 (9/13; 69 %), PAX7 (10/11;91 %) and CD117(6/9;67 %) to be positive.12 cases (92 %) demonstrated EWSR1 rearrangement and 3 cases displayed EWSR1::FLI1 fusion by FISH. ERCC4 splice-site variant, a novel pathogenic variant, was discovered for the first time via RNA sequencing. With a median follow-up duration of 14 months (6 to 79 months), 8/13 (62 %) patients died, while 5/13(38 %) survived. Three cases recurred, and five patients developed metastasis to the liver (2 cases), lung (2 cases) and bone (1 case). RES is an aggressive, high-grade tumor, prone to multiple recurrences and metastases, with distinctive morphologic, immunohistochemical, and molecular genetic features. ERCC4 splicing mutation, which is a novel pathogenic variant discovered for the first time, with possible significance for understanding the disease, as well as the development of targeted drugs.
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Proteína Homeobox Nkx-2.2 , Proteína EWS de Unión a ARN , Neoplasias Retroperitoneales , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/metabolismo , Masculino , Femenino , Adulto , Neoplasias Retroperitoneales/genética , Neoplasias Retroperitoneales/patología , Neoplasias Retroperitoneales/diagnóstico , Estudios Retrospectivos , Persona de Mediana Edad , Adulto Joven , Adolescente , Proteína EWS de Unión a ARN/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Hibridación Fluorescente in Situ/métodos , Reordenamiento Génico , Inmunohistoquímica/métodos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Fusión Oncogénica/genética , Niño , Proteínas Nucleares , Proteínas de Homeodominio , Proteínas de Pez CebraRESUMEN
Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder characterized by aberrant amyloid precursor protein (APP) cleavage, pathological aggregations of beta-amyloid (Aß) that make up Aß plaques and hyperphosphorylation of Tau that makes up neurofibrillary tangles (NFTs). Although progress has been made in research on AD, the fundamental causes of this disease have not been fully elucidated. Recent studies have shown that vascular dysfunction especially the loss of pericytes plays a significant role in the onset of AD. Pericytes play a variety of important roles in the nervous system including the regulation of the cerebral blood flow (CBF), the formation and maintenance of the blood-brain barrier (BBB), angiogenesis, and the clearance of toxic substances from the brain. Pericytes participate in the transport of Aß through various receptors, and Aß acts on pericytes to cause them to constrict, detach, and die. The loss of pericytes elevates the levels of Aß1-40 and Aß1-42 by disrupting the integrity of the BBB and reducing the clearance of soluble Aß from the brain interstitial fluid. The aggravated deposition of Aß further exacerbates pericyte dysfunction, forming a vicious cycle. The combined influence of these factors eventually results in the loss of neurons and cognitive decline. Further exploration of the interactions between pericytes and Aß is beneficial for understanding AD and could lead to the identification of new therapeutic targets for the prevention and treatment of AD. In this review, we explore the characterization of pericytes, interactions between pericytes and other cells in the neurovascular unit (NVU), and the physiological functions of pericytes and dysfunctions in AD. This review discusses the interactions between pericytes and Aß, as well as current and further strategies for preventing or treating AD targeting pericytes.