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Phytochemical investigation of Gynostemma pentaphyllum led to the purification of five novel dammarane-type triterpene isolates, gypenosides B1 - B5 (1-5). Their structures were determined through comprehensive 1D and 2D NMR spectroscopic analyses and HRESIMS data. Of note, 1-3 are inseparable mixtures of epimers due to their unstable nature, and a total of eight dammarane-type triterpene saponins were identified. Additionally, the protective activities of these new compounds against PC12 cell injury induced by hypoxia were evaluated.
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BACKGROUND: Previous observational studies have shown that the prevalence of gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE) is associated with socioeconomic status. However, due to the methodological limitations of traditional observational studies, it is challenging to definitively establish causality. AIM: To explore the causal relationship between the prevalence of these conditions and socioeconomic status using Mendelian randomization (MR). METHODS: We initially screened single nucleotide polymorphisms (SNPs) to serve as proxies for eight socioeconomic status phenotypes for univariate MR analysis. The inverse variance weighted (IVW) method was used as the primary analytical method to estimate the causal relationship between the eight socioeconomic status phenotypes and the risk of GERD and BE. We then collected combinations of SNPs as composite proxies for the eight socioeconomic phenotypes to perform multivariate MR (MVMR) analyses based on the IVW MVMR model. Furthermore, a two-step MR mediation analysis was used to examine the potential mediation of the associations by body mass index, major depressive disorder (MDD), smoking, alcohol consumption, and sleep duration. RESULTS: The study identified three socioeconomic statuses that had a significant impact on GERD. These included household income [odds ratio (OR): 0.46; 95% confidence interval (95%CI): 0.31-0.70], education attainment (OR: 0.23; 95%CI: 0.18-0.29), and the Townsend Deprivation Index at recruitment (OR: 1.57; 95%CI: 1.04-2.37). These factors were found to independently and predominantly influence the genetic causal effect of GERD. Furthermore, the mediating effect of educational attainment on GERD was found to be mediated by MDD (proportion mediated: 10.83%). Similarly, the effect of educational attainment on BE was mediated by MDD (proportion mediated: 10.58%) and the number of cigarettes smoked per day (proportion mediated: 3.50%). Additionally, the mediating effect of household income on GERD was observed to be mediated by sleep duration (proportion mediated: 9.75%). CONCLUSION: This MR study shed light on the link between socioeconomic status and GERD or BE, providing insights for the prevention of esophageal cancer and precancerous lesions.
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Targeting receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic stratagem for neurodegenerative disorders, particularly Alzheimer's disease (AD). A positron emission tomography (PET) probe enabling brain RIPK1 imaging can provide a powerful tool to unveil the neuropathology associated with RIPK1. Herein, the development of a new PET radioligand, [11C]CNY-10 is reported, which may enable brain RIPK1 imaging. [11C]CNY-10 is radiosynthesized with a high radiochemical yield (41.8%) and molar activity (305 GBq/µmol). [11C]CNY-10 is characterized by PET imaging in rodents and a non-human primate, demonstrating good brain penetration, binding specificity, and a suitable clearance kinetic profile. It is performed autoradiography of [11C]CNY-10 in human AD and healthy control postmortem brain tissues, which shows strong radiosignal in AD brains higher than healthy controls. Subsequently, it is conducted further characterization of RIPK1 in AD using [11C]CNY-10-based PET studies in combination with immunohistochemistry leveraging the 5xFAD mouse model. It is found that AD mice revealed RIPK1 brain signal significantly higher than WT control mice and that RIPK1 is closely related to amyloid plaques in the brain. The studies enable further translational studies of [11C]CNY-10 for AD and potentially other RIPK1-related human studies.
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Enfermedad de Alzheimer , Encéfalo , Tomografía de Emisión de Positrones , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Animales , Tomografía de Emisión de Positrones/métodos , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Ratones , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Humanos , Modelos Animales de Enfermedad , Radiofármacos/metabolismo , Radiofármacos/farmacocinética , Masculino , Ratas , Femenino , Autorradiografía/métodos , Radioisótopos de Carbono/metabolismoRESUMEN
Sigma-1 receptor (σ1R) is an intracellular protein implicated in a spectrum of neurodegenerative conditions, notably Alzheimer's disease (AD). Positron emission tomography (PET) imaging of brain σ1R could provide a powerful tool for better understanding the underlying pathomechanism of σ1R in AD. In this study, we successfully developed a 18F-labeled σ1R radiotracer [18F]CNY-05 via an innovative ruthenium (Ru)-mediated 18F-deoxyfluorination method. [18F]CNY-05 exhibited preferable brain uptake, high specific binding, and slightly reversible pharmacokinetics within the PET scanning time window. PET imaging of [18F]CNY-05 in nonhuman primates (NHP) indicated brain permeability, metabolic stability, and safety. Moreover, autoradiography and PET studies of [18F]CNY-05 in the AD mouse model found a significantly decreased brain uptake compared to that in wild-type mice. Collectively, we have provided a novel 18F-radiolabeled σ1R PET probe, which enables visualizing brain σ1R in health and neurological diseases.
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Enfermedad de Alzheimer , Encéfalo , Radioisótopos de Flúor , Tomografía de Emisión de Positrones , Radiofármacos , Receptores sigma , Receptor Sigma-1 , Receptores sigma/metabolismo , Animales , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Radioisótopos de Flúor/química , Tomografía de Emisión de Positrones/métodos , Ratones , Radiofármacos/química , Radiofármacos/farmacocinética , Radiofármacos/síntesis química , Masculino , Imagen Molecular/métodos , Halogenación , Distribución Tisular , HumanosRESUMEN
Elastin expression in the conjoint facial sheath (CFS) of patients of different ages with severe ptosis has been extensively studied, but its expression in the CFS of pediatric patients with severe ptosis with different muscle strengths remains poorly understood. The aim of the present study was to investigate the expression of elastin in the CFS and levator palpebrae superioris muscle (LM) of children with severe congenital ptosis with different LM strengths. In total, 20 pediatric patients with unilateral severe congenital ptosis (20 eyes) were included, who underwent CFS + LM complex suspension surgery from June 2020 to February 2022. Among these patients, the LM strength was 0-1 mm in 10 patients and 2-3 mm in the other 10 patients. Excess CFS and LM tissue samples were obtained from the patients during surgery, before the protein expression levels of elastin in the specimens were measured by western blotting. During the 6-month postoperative follow-up period, the good correction rate, the degree of incomplete eyelid closure and the incidence of complications were observed. Western blotting results showed that, compared with that in the 0-1 mm group, elastin expression was not significantly different in the CFS, whereas it was significantly increased (P=0.021) in the LM of the 2-3 mm group. In addition, elastin expression in the CFS was markedly higher compared with that in the LM in both groups (in the 0-1 mm group, P=0.005; in the 2-3 mm group, P=0.009). Additionally, the curative effect evaluation revealed that the good correction rates in the 0-1 and 2-3 mm groups were 90 and 100%, respectively. In total, 3 patients experienced conjunctival prolapse during the follow-up period, including 2 patients in the 0-1 mm group and 1 patient in the 2-3 mm group, but there were no other complications. To conclude, elastin expression in the CFS was found to be higher compared with that in the LM of children with severe congenital ptosis. Although elastin expression in the LM was positively associated with LM strength, its expression in the CFS displayed no clear association with LM function. Therefore, these observations suggested that CFS + LM complex suspension surgery is viable to correct severe congenital ptosis in pediatric patients.
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Ziziphi Spinosae Semen refers to the dried seed of Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou. The seed is composed of a reddish brown coat and a yellow kernel. A comparative study was conducted to investigate differences in the chemical composition and their relative contents between the seed coat and kernel of Ziziphi Spinosae Semen. First, the chemical compounds found in the seed coat and kernel were characterized and identified using ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). The analytical results tentatively identified 57 chemical compounds based on reference-compound comparison, literature retrieval, and chemical-database (e. g., MassBank) searches; these compounds included 14 triterpenes, 23 flavonoids, 7 alkaloids, 6 carboxylic acids, and 7 other types of compounds. The mass error of the identified compounds was within the mass deviation range of 5×10-6 (5 ppm). Next, two methods of multivariate statistical analysis, namely, principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA), were used to compare the differential compounds between the two seed parts. A total of 17 differential compounds were screened out via OPLS-DA based on a variable importance in projection (VIP) value of >5. The results revealed that betulinic acid, betulonic acid, alphitolic acid, and jujuboside â mainly existed in the seed coat whereas the 13 other compounds, such as spinosin, jujuboside A, and 6â´-feruloylspinosin, mainly existed in the seed kernel. Therefore, these 17 differential compounds can be used to distinguish between the two seed parts. Finally, a semiquantitative method was established using UPLC and a charged aerosol detector (CAD) with inverse gradient compensation in the mobile phase. Six representative compounds with different types were selected to examine the CAD response consistency: magnoflorine (alkaloid), spinosin (flavone), 6â´-feruloylspinosin (flavone), jujuboside A (triterpenoid saponin), jujuboside B (triterpenoid saponin), and betulinic acid (triterpenoid acid). The results showed that the relative standard deviation (RSD) of the average response factors at different levels of these six compounds was 7.04% and that their response intensities were similar. Moreover, each compound in the fingerprint demonstrated good response consistency, and the peak areas obtained directly reflected the contents of each compound. Based on the semiquantitative fingerprints obtained, betulinic acid and oleic acid were considered the main components of the seed coat. The betulinic acid content in the seed coat was approximately 7 times higher than that in the seed kernel. Spinosin, jujuboside A, linoleic acid, betulinic acid, and oleic acid were the main components of the seed kernel. The spinosin content in the seed kernel was 18 times higher than that in the seed coat. In addition, the jujuboside A content in the seed kernel was 24 times higher than that in the seed coat. The proposed method can accurately determine the main components and compare the relative contents of these components in different seed parts. In summary, this study identified the differences in chemical components between the seed coat and kernel of Ziziphi Spinosae Semen and clarified the main components and their relative contents in these parts. The findings can not only provide a basis for the identification of chemical compounds and quality research on different parts of Ziziphi Spinosae Semen but also promote the development and utilization of this traditional Chinese medicine.
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Alcaloides , Medicamentos Herbarios Chinos , Flavonas , Saponinas , Triterpenos , Ziziphus , Medicamentos Herbarios Chinos/química , Ácido Betulínico , Saponinas/química , Ácidos Oléicos , Cromatografía Líquida de Alta Presión , Ziziphus/química , SemillasRESUMEN
Introduction: Sirtuins (SIRTs) comprise a group of histone deacetylase enzymes crucial for regulating metabolic pathways and contributing significantly to various disease mechanisms. Sirtuin 1 (SIRT1), among the seven known mammalian homologs, is extensively investigated and understood, playing a key role in neurodegenerative disorders and cancer. This study focuses on potential as a therapeutic target for conditions such as Parkinson's disease (PD), Huntington's disease (HD), and Alzheimer's disease (AD). Methods: Utilizing positron emission tomography (PET) as a noninvasive molecular imaging modality, we aimed to expedite the validation of a promising sirtuin 1 inhibitor for clinical trials. However, the absence of a validated sirtuin 1 PET radiotracer impedes clinical translation. We present the development of [11C]1, and 11C-labeled benzoxazine-based derivative, as a lead imaging probe. The radiosynthesis of [11C]1 resulted in a radiochemical yield of 31 ± 4%. Results: Baseline studies demonstrated that [11C]1 exhibited excellent blood-brain barrier (BBB) penetration capability, with uniform accumulation throughout various brain regions. Self-blocking studies revealed that introducing an unlabeled compound 1, effectively blocking sirtuin 1, led to a substantial reduction in whole-brain uptake, emphasizing the in vivo specificity of [11C]1 for sirtuin 1. Discussion: The development of [11C]1 provides a valuable tool for noninvasive imaging investigations in rodent models with aberrant sirtuin 1 expression. This novel radiotracer holds promise for advancing our understanding of sirtuin 1's role in disease mechanisms and may facilitate the validation of sirtuin 1 inhibitors in clinical trials.
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Benzoxazinas , Radioisótopos de Carbono , Sirtuina 1 , Animales , Sirtuina 1/metabolismo , Benzoxazinas/metabolismo , Tomografía de Emisión de Positrones/métodos , Neuroimagen/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Mamíferos/metabolismoRESUMEN
Targeting receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic strategy for various neurodegenerative disorders. The development of a positron emission tomography (PET) probe for brain RIPK1 imaging could offer a valuable tool to assess therapeutic effectiveness and uncover the neuropathology associated with RIPK1. In this study, we present the development and characterization of two new PET radioligands, [11C]PB218 and [11C]PB220, which have the potential to facilitate brain RIPK1 imaging. [11C]PB218 and [11C]PB220 were successfully synthesized with a high radiochemical yield (34 % - 42 %) and molar activity (293 - 314 GBq/µmol). PET imaging characterization of two radioligands was conducted in rodents, demonstrating that both newly developed tracers have good brain penetration (maximum SUV = 0.9 - 1.0) and appropriate brain clearance kinetic profiles. Notably, [11C]PB218 has a more favorable binding specificity than [11C]PB220. A PET/MR study of [11C]PB218 in a non-human primate exhibited good brain penetration, desirable kinetic properties, and a safe profile, thus supporting the translational applicability of our new probe. These investigations enable further translational exploration of [11C]PB218 for drug discovery and PET probe development targeting RIPK1.
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Encéfalo , Tomografía de Emisión de Positrones , Animales , Tomografía de Emisión de Positrones/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Radiofármacos/química , Radioquímica , Piridinas/metabolismoRESUMEN
Trimethylamine oxide (TMAO) is a microbiota-derived metabolite, and numerous studies have shown that it could regulate fat metabolism in humans and mice. However, few studies have focused on the effects of TMAO on fat deposition in growing-finishing pigs. This study aimed to investigate the effect of TMAO on fat deposition and intestinal microbiota in growing-finishing pigs. Sixteen growing pigs were randomly divided into 2 groups and fed with a basal diet with 0 or 1 g/kg TMAO for 149 d. The intestinal microbial profiles, fat deposition indexes, and fatty acid profiles were measured. These results showed that TMAO supplementation had a tendency to decrease lean body mass (P < 0.1) and significantly increased backfat thickness (P < 0.05), but it did not affect growth performance. TMAO significantly increased total protein (TP) concentration, and reduced alkaline phosphatase (ALP) concentration in serum (P < 0.05). TMAO increased the α diversity of the ileal microbiota community (P < 0.05), and it did not affect the colonic microbial community. TMAO supplementation significantly increased acetate content in the ileum, and Proteobacteria and Escherichia-Shigella were significantly enriched in the TMAO group (P < 0.05). In addition, TMAO decreased fat content, as well as the ratio of linoleic acid, n-6 polyunsaturated fatty acids (PUFA), and PUFA in the liver (P < 0.05). On the contrary, TMAO increased intramuscular fat content of the longissimus dorsi muscle, whereas the C18:2n6c ratio was increased, and the n-6 PUFA:PUFA ratio was decreased (P < 0.05). In vitro, 1 mM TMAO treatment significantly upregulated the expression of FASN and SREBP1 in C2C12 cells (P < 0.05). Nevertheless, TMAO also increased adipocyte area and decreased the CPT-1B expression in subcutaneous fat (P < 0.05). Taken together, TMAO supplementation regulated ileal microbial composition and acetate production, and regulated fat distribution and fatty acid composition in growing-finishing pigs. These results provide new insights for understanding the role of TMAO in humans and animals.
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AIM: To construct a nursing assessment framework for patients in anaesthesia recovery period. DESIGN: A three-round modified Delphi method was employed to capture the consensus of 22 panellists. METHODS: The initial items in the nursing assessment framework for patients in anaesthesia recovery period were developed based on the mini-clinical evaluation exercise (mini-CEX). A panel of 22 experts participated in this study. The panellists have more than 10 years of experience in either clinical anaesthesia, or post-anesthesia nursing, or operating room nursing, or surgical intensive nursing. Between March and April 2023, the panellists evaluated and recommended revisions to the initial framework. RESULTS: This study resulted in the development of a nursing assessment framework for patients in anaesthesia recovery period. The initial version of the framework consisted of six dimensions with 27 items. Six items were modified after the first round of consultation. After the second round, five modifications and four deletions were made based on expert opinion. The third round resulted in a convergence of expert opinion. The framework, which consists of 24 items across five dimensions, was refined. The five dimensions are as follows: History-taking, Physical assessment, Clinical judgement, Organizational efficiency and Humanistic concern. CONCLUSION: The nursing assessment framework for patients in anaesthesia recovery period was reached consensus between the 22 experts' opinions. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: The assessment framework constructed in this study could be used for the process evaluation of post-anesthesia nursing. The framework may guide perianesthesia nurses in the timely and effective assessment of patients during this critical phase of care. It may be used for perianesthesia nursing education or to evaluate nurses' assessment skills. REPORTING METHOD: The study is reported in accordance with the Guidance on Conducting and Reporting DElphi Studies (CREDES) recommendations. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.
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Periodo de Recuperación de la Anestesia , Técnica Delphi , Evaluación en Enfermería , Humanos , Evaluación en Enfermería/métodos , Femenino , Masculino , Adulto , Persona de Mediana Edad , ConsensoRESUMEN
The study entailed the investigation of the roots of Euphorbia wallichii, which resulted in the isolation of 29 ent-atisane diterpenoids (1-29), 14 of which were previously unknown. These previously undescribed ones were named euphorwanoids A-N (3-5, 7, 9, and 10-18). Various techniques, including comprehensive spectroscopic methods and calculated electronic circular dichroism, were employed to determine their molecular structures. Additionally, the absolute configurations of ten ent-atisane diterpenoids (1, 2, 5, 6, 8, 9, 11, 12, 14 and 16) were established through X-ray crystallographic analyses. All isolated compounds' potential to inhibit the influenza A virus in vitro were evaluated. Compounds 18, 20, and 24 exhibited notable antiviral activity against the A/Puerto Rico/8/1934 strain. Their effective concentrations for reducing viral activity (EC50 values) were found to be 8.56, 1.22, and 4.97 µM, respectively. An intriguing aspect of this research is that it marks the first instance of ent-atisane diterpenes displaying anti-H1N1 activity. Empirical NMR rules were established with Δδ to distinguish the R/S configurations of C-13 and C-16 in ent-atisanes.
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Diterpenos , Euphorbia , Euphorbia/química , Estructura Molecular , Diterpenos/química , Dicroismo Circular , Espectroscopía de Resonancia MagnéticaRESUMEN
Magnesium ions are highly enriched in early stage of biological mineralization of hard tissues. Paradoxically, hydroxyapatite (HAp) crystallization is inhibited significantly by high concentration of magnesium ions. The mechanism to regulate magnesium-doped biomimetic mineralization of collagen fibrils has never been fully elucidated. Herein, it is revealed that citrate can bioinspire the magnesium-stabilized mineral precursors to generate magnesium-doped biomimetic mineralization as follows: Citrate can enhance the electronegativity of collagen fibrils by its absorption to fibrils via hydrogen bonds. Afterward, electronegative collagen fibrils can attract highly concentrated electropositive polyaspartic acid-Ca&Mg (PAsp-Ca&Mg) complexes followed by phosphate solution via strong electrostatic attraction. Meanwhile, citrate adsorbed in/on fibrils can eliminate mineralization inhibitory effects of magnesium ions by breaking hydration layer surrounding magnesium ions and thus reduce dehydration energy barrier for rapid fulfillment of biomimetic mineralization. The remineralized demineralized dentin with magnesium-doped HAp possesses antibacterial ability, and the mineralization mediums possess excellent biocompatibility via cytotoxicity and oral mucosa irritation tests. This strategy shall shed light on cationic ions-doped biomimetic mineralization with antibacterial ability via modifying collagen fibrils and eliminating mineralization inhibitory effects of some cationic ions, as well as can excite attention to the neglected multiple regulations of small biomolecules, such as citrate, during biomineralization process.
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Materiales Biomiméticos , Ácido Cítrico , Magnesio , Polielectrolitos , Magnesio/química , Magnesio/farmacología , Polielectrolitos/química , Ácido Cítrico/química , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Animales , Durapatita/química , Durapatita/farmacología , Péptidos/química , Péptidos/farmacología , Calcio/química , Calcio/metabolismo , Humanos , Cationes/química , Antibacterianos/farmacología , Antibacterianos/química , Colágeno/química , Biomimética/métodosRESUMEN
S-doped nickel molybdate nanorods grown on nickel foam (S-NiMoO4/NF) were fabricated by a two-step hydrothermal method. The resultant S-NiMoO4/NF exhibited remarkable bifunctional electrocatalytic activity, with overpotentials of 235 mV for the hydrogen evolution reaction and 150 mV for the oxygen evolution reaction at a current density of 50 mA cm-2. Assembled into the two-electrode S-NiMoO4/NF electrolyzer in alkaline electrolytes for overall water splitting, it required only low cell voltages of 1.55 V and 1.63 V to drive 50 mA cm-2 and 100 mA cm-2, respectively. No significant performance degradation occurred during the water electrolysis process. The experimental results confirmed that S-doping induced the increase of the oxygen vacancies, accelerating the reaction kinetics and thus improving the electrocatalytic performance. Meanwhile, more active sites exposure on the surface of S-NiMoO4/NF enhanced the reactivity. This work may guide the development of efficient bifunctional catalysts in alkaline electrolysis through oxygen vacancy regulation.
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Histone deacetylase 6 (HDAC6) is one of the key histone deacetylases (HDACs) that regulates various cellular functions including clearance of misfolded protein and immunological responses. Considerable evidence suggests that HDAC6 is closely related to amyloid and tau pathology, the two primary hallmarks of Alzheimer's disease (AD). It is still unclear whether HDAC6 expression changes with amyloid deposition in AD during disease progression or HDAC6 may be regulating amyloid phagocytosis or neuroinflammation or other neuropathological changes in AD. In this work, the pathological accumulation of HDAC6 in AD brains over age as well as the relationship of its regulatory activity - with amyloid pathogenesis and pathophysiological alterations is aimed to be enlightened using the newly developed HDAC6 inhibitor (HDAC6i) PB118 in microglia BV2 cell and 3D-AD human neural culture model. Results suggest that the structure-based rational design led to biologically compelling HDAC6i PB118 with multiple mechanisms that clear Aß deposits by upregulating phagocytosis, improve tubulin/microtubule network by enhancing acetyl α-tubulin levels, regulate different cytokines and chemokines responsible for inflammation, and significantly reduce phospho-tau (p-tau) levels associated with AD. These findings indicate that HDAC6 plays key roles in the pathophysiology of AD and potentially serves as a suitable pharmacological target through chemical biology-based drug discovery in AD.
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Enfermedad de Alzheimer , Humanos , Histona Desacetilasa 6 , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/metabolismo , Tubulina (Proteína)/metabolismoRESUMEN
Pseudorabies virus (PRV) belongs to the Alphaherpesvirinae subfamily and serves as an exceptional animal model for investigating the infection mechanism of Herpes simplex virus type 1. Notably, PRV has the capability to infect a wide range of mammals, including humans, highlighting its potential as an overlooked zoonotic pathogen. The attachment and entry steps of PRV into host cells are crucial to accomplish its life cycle, which involve numerous cellular factors. In this mini review, we offer a comprehensive summary of current researches pertaining to the role of cellular factors in PRV attachment and entry stages, with the overarching goal of advancing the development of novel antiviral agents against this pathogen.
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Objective: This study aimed to compare 9 perfluoroalkyl sulfonic acids (PFSA) with carbon chain lengths (C4-C12) to inhibit human placental 3ß-hydroxysteroid dehydrogenase 1 (3ß-HSD1), aromatase, and rat 3ß-HSD4 activities. Methods: Human and rat placental 3ß-HSDs activities were determined by converting pregnenolone to progesterone and progesterone secretion in JEG-3 cells was determined using HPLC/MS-MS, and human aromatase activity was determined by radioimmunoassay. Results: PFSA inhibited human 3ß-HSD1 structure-dependently in the order: perfluorooctanesulfonic acid (PFOS, half-maximum inhibitory concentration, IC 50: 9.03 ± 4.83 µmol/L) > perfluorodecanesulfonic acid (PFDS, 42.52 ± 8.99 µmol/L) > perfluoroheptanesulfonic acid (PFHpS, 112.6 ± 29.39 µmol/L) > perfluorobutanesulfonic acid (PFBS) = perfluoropentanesulfonic acid (PFPS) = perfluorohexanesulfonic acid (PFHxS) = perfluorododecanesulfonic acid (PFDoS) (ineffective at 100 µmol/L). 6:2FTS (1H, 1H, 2H, 2H-perfluorooctanesulfonic acid) and 8:2FTS (1H, 1H, 2H, 2H-perfluorodecanesulfonic acid) did not inhibit human 3ß-HSD1. PFOS and PFHpS are mixed inhibitors, whereas PFDS is a competitive inhibitor. Moreover, 1-10 µmol/L PFOS and PFDS significantly reduced progesterone biosynthesis in JEG-3 cells. Docking analysis revealed that PFSA binds to the steroid-binding site of human 3ß-HSD1 in a carbon chain length-dependent manner. All 100 µmol/L PFSA solutions did not affect rat 3ß-HSD4 and human placental aromatase activity. Conclusion: Carbon chain length determines inhibitory potency of PFSA on human placental 3ß-HSD1 in a V-shaped transition at PFOS (C8), with inhibitory potency of PFOS > PFDS > PFHpS > PFBS = PFPS = PFHxS = PFDoS = 6:2FTS = 8:2FTS.
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Ácidos Alcanesulfónicos , Fluorocarburos , Humanos , Embarazo , Femenino , Ratas , Animales , Placenta , Progesterona/metabolismo , Progesterona/farmacología , Aromatasa/metabolismo , Aromatasa/farmacología , Línea Celular Tumoral , Relación Estructura-Actividad , Hidroxiesteroide Deshidrogenasas/metabolismo , Hidroxiesteroide Deshidrogenasas/farmacologíaRESUMEN
Recent studies have shown that the epigenetic protein histone deacetylase 11 (HDAC11) is highly expressed in the brain and critically modulates neuroimmune functions, making it a potential therapeutic target for neurological disorders. Herein, we report the development of PB94, which is a novel HDAC11 inhibitor. PB94 exhibited potency and selectivity against HDAC11 with IC50 = 108 nM and >40-fold selectivity over other HDAC isoforms. Pharmacokinetic/pharmacodynamic evaluation indicated that PB94 possesses promising drug-like properties. Additionally, PB94 was radiolabeled with carbon-11 as [11C]PB94 for positron emission tomography (PET), which revealed significant brain uptake and metabolic properties suitable for drug development in live animals. Furthermore, we demonstrated that neuropathic pain was associated with brain upregulation of HDAC11 and that pharmacological inhibition of HDAC11 by PB94 ameliorated neuropathic pain in a mouse model. Collectively, our findings support further development of PB94 as a selective HDAC11 inhibitor for neurological indications, including pain.
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Neuralgia , Enfermedades Neuroinflamatorias , Animales , Ratones , Encéfalo/metabolismo , Histona Desacetilasas/metabolismo , Neuralgia/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéuticoRESUMEN
BACKGROUND: Although colonoscopy is the standard screening test for colorectal cancer (CRC), its use is limited by a poor compliance rate, the need for extensive bowel preparation, and the risk of complications. As an alternative, an FDA-approved stool-based DNA test, Cologuard, has demonstrated satisfactory detection performance for CRC, but its compliance rate remains suboptimal, primarily attributable to individuals' reluctance to provide stool samples. METHODS: We developed a noninvasive blood-based CRC test, ColonSecure, based on cell-free DNA containing cancer-specific CpG island methylation patterns. We initially screened publicly available datasets for differentially methylated CpG sites in CRC with prediction potential. Subsequently, we performed two sequential bisulfite-free methylation sequencing on blood samples obtained from CRC patients and non-cancer controls. Through rigorous evaluation of each marker and machine learning-assisted feature selection, we identified 149 hypermethylated markers from over 193,000 CpG sites. These markers were then utilized to construct the ColonSecure model, enabling accurate CRC detection. RESULTS: We validated the efficacy of our cell-free DNA methylation-based blood test for CRC screening with 3493 high-risk individuals identified from 114,136 urban residents. The ColonSecure test identified 89 out of 103 CRC patients diagnosed by the follow-up colonoscopy, outperforming CEA, CRP, and CA19-9 (with a sensitivity of 86.4% compared to 45.6%, 39.8%, and 25.2% for CEA, CRP, and CA19-9 respectively; an AUROC of 0.956 compared to an AUROC of < 0.77 for other methods). CONCLUSION: Our observations emphasize the potential of our multiple cfDNA methylation marker-based test for CRC screening in high-risk populations.
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Ácidos Nucleicos Libres de Células , Neoplasias Colorrectales , Humanos , Metilación de ADN , Ácidos Nucleicos Libres de Células/genética , Estudios Prospectivos , Antígeno CA-19-9 , Detección Precoz del Cáncer , Islas de CpG , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Biomarcadores de Tumor/genéticaRESUMEN
This work reports a new type of platinum-based heterostructural electrode catalyst that highly dispersed PtCo alloy nanoparticles (NPs) confined in cobalt benzoate (Co-BA) nanowires are supported on a nitrogen-doped ultra-thin carbon nanosheet/Fe3C hybrid (PtCo@Co-BA-Fe3C/NC) to show high electrochemical activity and long-term stability. One-dimensional Co-BA nanowires could alleviate the shedding and agglomeration of PtCo alloy NPs during the reaction so as to achieve satisfactory long-term durability. Moreover, the synergistic effect at the interface optimizes the surface electronic structure and prominently accelerates the electrochemical kinetics. The oxygen reduction reaction half-wave potential is 0.923 V, and the oxygen evolution reaction under the condition of 10 mAâ¢cm-2 is 1.48 V. Higher power density (263.12 mWâ¢cm-2), narrowed voltage gap (0.49 V), and specific capacity (808.5 mAhâ¢g-1) for PtCo@Co-BA-Fe3C/NC in Zn-air batteries are achieved with long-term cycling measurements over 776 h, which is obviously better than the Pt/C + RuO2 catalyst. The interfacial electronic interaction of PtCo@Co-BA-Fe3C/NC is investigated, which can accelerate electron transfer from Fe to Pt. Density functional theory calculations also indicate that the interfacial potential regulates the binding energies of the intermediates to achieve the best performance.
RESUMEN
This review article is an overview of the effectiveness of internet-based cognitive behavioral therapy (iCBT) in Improving Psychological State in Cancer Patients. iCBT's effectiveness has been investigated in treating and managing conditions like depression, psychiatric disorders, generalized anxiety disorder (GAD), panic disorder, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), adjustment disorder, bipolar disorder, chronic pain, and phobias. iCBT's role in the treatment of medical conditions such as diabetes mellitus with comorbid psychiatric illnesses was also explored. We conducted a thorough literature search using PubMed, Embase, Google Scholar, and Wanfang with no restrictions on the date. iCBT's role in treating and controlling psychiatric illnesses in cancer patients has been established in the literature. Development and popularization of iCBT, treament forms of iCBT, platforms for iCBT, application of iCBT, strategies and efficacy of iCBT for insomnia in cancer patients, current status of iCBT application, and genetic researches on iCBT for anxiety disorders were all reviewed and discussed in this review. From the data compiled, we conclude that iCBT is useful in treating or improving psychological state in cancer patients.