ABSTRACT
Plasmonics enables the manipulation of light beyond the optical diffraction limit1-4 and may therefore confer advantages in applications such as photonic devices5-7, optical cloaking8,9, biochemical sensing10,11 and super-resolution imaging12,13. However, the essential field-confinement capability of plasmonic devices is always accompanied by a parasitic Ohmic loss, which severely reduces their performance. Therefore, plasmonic materials (those with collective oscillations of electrons) with a lower loss than noble metals have long been sought14-16. Here we present stable sodium-based plasmonic devices with state-of-the-art performance at near-infrared wavelengths. We fabricated high-quality sodium films with electron relaxation times as long as 0.42 picoseconds using a thermo-assisted spin-coating process. A direct-waveguide experiment shows that the propagation length of surface plasmon polaritons supported at the sodium-quartz interface can reach 200 micrometres at near-infrared wavelengths. We further demonstrate a room-temperature sodium-based plasmonic nanolaser with a lasing threshold of 140 kilowatts per square centimetre, lower than values previously reported for plasmonic nanolasers at near-infrared wavelengths. These sodium-based plasmonic devices show stable performance under ambient conditions over a period of several months after packaging with epoxy. These results indicate that the performance of plasmonic devices can be greatly improved beyond that of devices using noble metals, with implications for applications in plasmonics, nanophotonics and metamaterials.
ABSTRACT
The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small-molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic, there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high-resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 153 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated conformational changes within the active site, and key inhibitor motifs that will template future drug development against Mac1.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Crystallography , Pandemics , Ligands , Molecular Docking Simulation , Protease Inhibitors/pharmacology , Antiviral Agents/pharmacology , Antiviral Agents/chemistryABSTRACT
The glycosaminoglycan hyaluronan (HA) plays an important role in tumor progression. However, its biological and clinical significance in papillary thyroid cancer (PTC) remains unknown. Immunohistochemistry was performed to examine HA expression in tissues from PTC patients. Two PTC cell lines were treated with HA synthesized inhibitor against HA production to assess its function. Serum HA levels from 107 PTC patients, 30 Hashimoto thyroiditis patients, and 45 normal controls (NC) were measured by chemiluminescence immunoassay. HA levels in fine needle aspiration (FNA) washouts obtained from thyroid nodules and lymph nodes (LNs) were measured by chemiluminescence immunoassay. Area under the curve (AUC) was computed to evaluate HA's clinical value. HA was highly expressed in PTC. Reducing HA production significantly inhibited PTC cell proliferation and invasion. Importantly, serum HA levels in PTC were significantly higher than those in NCs and Hashimoto thyroiditis and allowed distinguishing of thyroid cancers from NCs with high accuracy (AUC = 0.782). Moreover, elevated serum HA levels in PTC correlate with LN metastasis. HA levels in FNA washouts from PTC patients were significantly higher than those in benign controls, with a high AUC value (0.8644) for distinguishing PTC from benign controls. Furthermore, HA levels in FNA washouts from metastatic LN were significantly higher than those in nonmetastatic LN, with a high AUC value (0.8007) for distinguishing metastatic LNs from nonmetastatic LNs. HA levels in serum and FNA washout exhibited a potential significance for PTC diagnosis and an indicator for LN metastasis in patients with PTC.
Subject(s)
Carcinoma, Papillary , Hyaluronic Acid , Lymphatic Metastasis , Thyroid Cancer, Papillary , Thyroid Neoplasms , Humans , Hyaluronic Acid/blood , Hyaluronic Acid/metabolism , Thyroid Neoplasms/pathology , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/diagnosis , Male , Female , Middle Aged , Thyroid Cancer, Papillary/pathology , Thyroid Cancer, Papillary/metabolism , Thyroid Cancer, Papillary/diagnosis , Adult , Carcinoma, Papillary/metabolism , Carcinoma, Papillary/diagnosis , Cell Line, Tumor , Carcinoma/metabolism , Carcinoma/diagnosis , Carcinoma/pathology , Lymph Nodes/pathology , Lymph Nodes/metabolism , Hashimoto Disease/metabolism , Hashimoto Disease/blood , Hashimoto Disease/pathology , Hashimoto Disease/diagnosis , Biopsy, Fine-Needle , Aged , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/blood , Cell ProliferationABSTRACT
Epithelial-mesenchymal transition (EMT) is a complex process that plays a critical role in tumor progression. In this study, we present an EMT sensing panel for the classification of cancer cells at different EMT stages. This sensing panel consists of three types of fluorescent probes based on boronic acid-functionalized carbon-nitride nanosheet (BCN) derivatives. The selective response toward different EMT-associated biomarkers, namely, EpCAM, N-cadherin, and sialic acid (SA), was achieved by conjugating the corresponding antibodies to each BCN derivative, whereas the rare-earth-doping ensures simultaneous sensing of the three biomarkers with fluorescent emission of the three probes at different wavelengths. Sensitive sensing of the three biomarkers was achieved at the protein level with LODs reaching 1.35 ng mL-1 for EpCAM, 1.62 ng mL-1 for N-cadherin, and 1.54 ng mL-1 for SA. The selective response of these biomarkers on the cell surface also facilitated sensitive detection of MCF-7 cells and MDA-MB-231 cells with LODs of 2 cells/mL and 2 cells/mL, respectively. Based on the simultaneous sensing of the three biomarkers on cancer cells that underwent different extents of EMT, precise discrimination and classification of cells at various EMT stages were also achieved with an accuracy of 93.3%. This EMT sensing panel provided a versatile tool for monitoring the EMT evolution process and has the potential to be used for the evaluation of the EMT-targeting therapy and metastasis prediction.
Subject(s)
Biomarkers, Tumor , Cadherins , Epithelial-Mesenchymal Transition , Humans , Biomarkers, Tumor/analysis , Biomarkers, Tumor/metabolism , Cadherins/analysis , Cadherins/metabolism , Fluorescent Dyes/chemistry , Cell Line, Tumor , Epithelial Cell Adhesion Molecule/metabolism , MCF-7 Cells , Boronic Acids/chemistry , N-Acetylneuraminic Acid/analysis , N-Acetylneuraminic Acid/metabolismABSTRACT
BACKGROUND: The atherogenic index of plasma (AIP) and cardiovascular disease (CVD) in participants with abnormal glucose metabolism have been linked in previous studies. However, it was unclear whether AIP control level affects the further CVD incidence among with diabetes and pre-diabetes. Therefore, our study aimed to investigate the association between AIP control level with risk of CVD in individuals with abnormal glucose metabolism. METHODS: Participants with abnormal glucose metabolism were included from the China Health and Retirement Longitudinal Study. CVD was defined as self-reporting heart disease and/or stroke. Using k-means clustering analysis, AIP control level, which was the log-transformed ratio of triglyceride to high-density lipoprotein cholesterol in molar concentration, was divided into five classes. The association between AIP control level and incident CVD among individuals with abnormal glucose metabolism was investigated multivariable logistic regression analysis and application of restricted cubic spline analysis. RESULTS: 398 (14.97%) of 2,659 participants eventually progressed to CVD within 3 years. After adjusting for various confounding factors, comparing to class 1 with the best control of the AIP, the OR for class 2 with good control was 1.31 (95% CI, 0.90-1.90), the OR for class 3 with moderate control was 1.38 (95% CI, 0.99-1.93), the OR for class 4 with worse control was 1.46 (95% CI, 1.01-2.10), and the OR for class 5 with consistently high levels was 1.56 (95% CI, 1.03-2.37). In restricted cubic spline regression, the relationship between cumulative AIP index and CVD is linear. Further subgroup analysis demonstrated that the similar results were observed in the individuals with agricultural Hukou, history of smoking, diastolic blood pressure ≥ 80mmHg, and normal body mass index. In addition, there was no interaction between the AIP control level and the subgroup variables. CONCLUSIONS: In middle-aged and elderly participants with abnormal glucose metabolism, constant higher AIP with worst control may have a higher incidence of CVD. Monitoring long-term AIP change will contribute to early identification of high risk of CVD among individuals with abnormal glucose metabolism.
Subject(s)
Cardiovascular Diseases , Middle Aged , Aged , Humans , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Glucose , Risk Factors , Longitudinal Studies , Triglycerides , China/epidemiologyABSTRACT
OBJECTIVE: The effects of air pollution on metabolism have become a popular research topic, and a large number of studies had confirmed that air pollution exposure could induce insulin resistance (IR) to varying degrees, but the results were inconsistent, especially for the long-term exposures. The aim of the current study was to further investigate the potential effects of air pollution on IR. METHODS: A systematic review and meta-analysis of four electronic databases, including PubMed, Embase, Web of Science and Cochrane were conducted, searching for relevant studies published before June 10, 2023, in order to explore the potential relationships between long-term exposure to air pollution and IR. A total of 10 studies were included for data analysis, including seven cohort studies and three cross-sectional studies. Four major components of air pollution, including PM2.5 (particulate matter with an aerodynamic diameter of 2.5 µm or less), PM10 (particulate matter with an aerodynamic diameter of 10 µm or less), NO2, and SO2 were selected, and each analyzed for the potential impacts on insulin resistance, in the form of adjusted percentage changes in the homeostasis assessment model of insulin resistance (HOMA-IR). RESULTS: This systematic review and meta-analysis showed that for every 1 µg/m³ increase in the concentration of selected air pollutants, PM2.5 induced a 0.40% change in HOMA-IR (95%CI: -0.03, 0.84; I2 =67.4%, p = 0.009), while PM10 induced a 1.61% change (95%CI: 0.243, 2.968; I2 =49.1%, p = 0.001). Meanwhile, the change in HOMA-IR due to increased NO2 or SO2 exposure concentration was only 0.09% (95%CI: -0.01, 0.19; I2 =83.2%, p = 0.002) or 0.01% (95%CI: -0.04, 0.06; I2 =0.0%, p = 0.638), respectively. CONCLUSIONS: Long-term exposures to PM2.5, PM10, NO2 or SO2 are indeed associated with the odds of IR. Among the analyzed pollutants, inhalable particulate matters appear to exert greater impacts on IR.
Subject(s)
Air Pollutants , Air Pollution , Insulin Resistance , Humans , Nitrogen Dioxide/analysis , Cross-Sectional Studies , Environmental Exposure/adverse effects , Environmental Exposure/analysis , Air Pollution/adverse effects , Air Pollution/analysis , Air Pollutants/toxicity , Air Pollutants/analysis , Particulate Matter/toxicity , Particulate Matter/analysisABSTRACT
Six novel withanolides, along with nine known related compounds were isolated from the leaves of Datura stramonium L. The structures and absolute configurations of the new withanolides were elucidated by employing various spectral techniques and comparing them with those previously reported in the literature. In addition, four withanlides demonstrated interesting cytotoxic activity on LN229 cells with IC50 <20â µM.
Subject(s)
Antineoplastic Agents , Datura stramonium , Withanolides , Withanolides/pharmacology , Withanolides/chemistry , Molecular Structure , Plant Leaves/chemistryABSTRACT
The DABB proteins, which are characterized by stress-responsive dimeric A/B barrel domains, have multiple functions in plant biology. In Arabidopsis thaliana, these proteins play a crucial role in defending against various pathogenic fungi. However, the specific roles of DABB proteins in Brassica napus remain elusive. In this study, 16 DABB encoding genes were identified, distributed across 10 chromosomes of the B. napus genome, which were classified into 5 branches based on phylogenetic analysis. Genes within the same branch exhibited similar structural domains, conserved motifs, and three-dimensional structures, indicative of the conservation of BnaDABB genes (BnaDABBs). Furthermore, the enrichment of numerous cis-acting elements in hormone induction and light response were revealed in the promoters of BnaDABBs. Expression pattern analysis demonstrated the involvement of BnaDABBs, not only in the organ development of B. napus but also in response to abiotic stresses and Sclerotinia sclerotiorum infection. Altogether, these findings imply the significant impacts of BnaDABBs on plant growth and development, as well as stress responses.
Subject(s)
Brassica napus , Gene Expression Regulation, Plant , Phylogeny , Plant Proteins , Stress, Physiological , Brassica napus/genetics , Brassica napus/microbiology , Brassica napus/metabolism , Plant Proteins/genetics , Plant Proteins/metabolism , Stress, Physiological/genetics , Genome, Plant , Ascomycota/genetics , Plant Diseases/microbiology , Plant Diseases/geneticsABSTRACT
Drainage modeling that accurately captures urban storm inundation serves as the foundation for flood warning and drainage scheduling. In this paper, we proposed a novel coupling ideology that, by integrating 2D-1D and 1D-2D unidirectional processes, overcomes the drawback of the conventional unidirectional coupling approach that fails to properly represent the rainfall surface catchment dynamics, and provides more coherent hydrological implications compared to the bidirectional coupling concept. This paper first referred to a laboratory experimental case from the literature, applied and analyzed the coupling scheme proposed in this paper and the bidirectional coupling scheme that has been widely studied in recent years, compared the two coupling solutions in terms of the resulting accuracy and applicability, and discussed their respective strengths and weaknesses to validate the reliability of the proposed method. The verified proposed coupling scheme was then applied to the modeling of a real drainage system in a region of Nanjing, China, and the results proved that the coupling mechanism proposed in this study is of practical application value.
Subject(s)
Cities , Floods , Hydrodynamics , Models, Theoretical , China , Sewage , Drainage, SanitaryABSTRACT
BACKGROUND: The outer membrane vesicles (OMVs) derived from Porphyromonas gingivalis (P. gingivalis) have long been acknowledged for their crucial role in the initiation of periodontitis. However, the implications of P. gingivalis OMVs in the context of cardiovascular disease (CVD) remain incompletely understood. This study aimed to clarify both the impact and the underlying mechanisms through which P. gingivalis OMVs contribute to the propagation of distal cardiovascular inflammation and trauma. METHODS: In this study, various concentrations (0, 1.25, 2.5, and 4.5 µg/µL) of P. gingivalis OMVs were microinjected into the common cardinal vein of zebrafish larvae at 48 h post-fertilization (hpf) to assess changes in cardiovascular injury and inflammatory response. Zebrafish larvae from both the PBS and the 2.5 µg/µL injection cohorts were harvested at 30 h post-injection (hpi) for transcriptional analysis. Real-time quantitative PCR (RT-qPCR) was employed to evaluate relative gene expression. RESULTS: These findings demonstrated that P. gingivalis OMVs induced pericardial enlargement in zebrafish larvae, caused vascular damage, increased neutrophil counts, and activated inflammatory pathways. Transcriptomic analysis further revealed the involvement of the immune response and the extracellular matrix (ECM)-receptor interaction signaling pathway in this process. CONCLUSION: This study illuminated potential mechanisms through which P. gingivalis OMVs contribute to CVD. It accentuated their involvement in distal cardiovascular inflammation and emphasizes the need for further research to comprehensively grasp the connection between periodontitis and CVD.
Subject(s)
Cardiovascular Diseases , Embryonic Structures , Periodontitis , Portal System/embryology , Humans , Animals , Porphyromonas gingivalis/genetics , Zebrafish , InflammationABSTRACT
BACKGROUND: Supracrestal gingival tissue dimensions (SGTDs) has been considered to be an essential element of periodontal phenotype (PP) components. This study aimed to explore the relationship between SGTDs and other PP components by digital superposition method that integrated cone beam computed tomography (CBCT) with intraoral scanning. METHODS: This cross-sectional study was conducted at the Stomatology Hospital of Fujian Medical University. Participants were recruited based on the inclusion and exclusion criteria. The data obtained from the digital scanner (TRIOS 3, 3Shape, Denmark) and CBCT images were imported into the TRIOS software (Implant Studio, 3Shape, Denmark) for computing relevant parameters. The significant level was set at 0.05. RESULTS: A total of 83 participants with 498 maxillary anterior teeth were finally included. The mean values of supracrestal gingival height (SGH) and the distance from the cementoenamel junction (CEJ) to the crest of the alveolar ridge (CEJ-ABC) on the buccal site were significantly higher than palatal SGH (SGH-p) and palatal CEJ-ABC (CEJ-ABC-p). Men exhibited taller CEJ-ABC and SGH-p than women. Additionally, tooth type was significantly associated with the SGH, SGH-p and CEJ-ABC-p. Taller SGH was associated with wider crown, smaller papilla height (PH), flatter gingival margin, thicker bone thickness (BT) and gingival thickness (GT) at CEJ, the alveolar bone crest (ABC), and 2 mm apical to the ABC. Smaller SGH-p displayed thicker BT and GT at CEJ, the ABC, and 2 and 4 mm apical to the ABC. Higher CEJ-ABC showed lower interproximal bone height, smaller PH, flatter gingival margin, thinner GT and BT at CEJ, and 2 mm apical to the ABC. Smaller CEJ-ABC-p displayed thicker BT at CEJ and 2 and 4 mm apical to the ABC. On the buccal, thicker GT was correlated with thicker BT at 2 and 4 mm below the ABC. CONCLUSION: SGTDs exhibited a correlation with other PP components, especially crown shape, gingival margin and interdental PH. The relationship between SGTDs and gingival and bone phenotypes depended on the apico-coronal level evaluated. TRIAL REGISTRATION: This study was approved by the Biomedical Research Ethics Committee of Stomatology Hospital of Fujian Medical University (approval no. 2023-24).
Subject(s)
Breast Cyst , Gingiva , Maxilla , Male , Humans , Female , Cross-Sectional Studies , Maxilla/diagnostic imaging , Gingiva/diagnostic imaging , Tooth Crown , Cone-Beam Computed Tomography/methods , ChinaABSTRACT
Herein, we report a manganese-catalyzed three-component coupling of ß-H containing alcohols, methanol, and phosphines for the synthesis of γ-hydroxy phosphines via a borrowing hydrogen strategy. In this development, methanol serves as a sustainable C1 source. A variety of aromatic and aliphatic substituted alcohols and phosphines could undergo the dehydrogenative cross-coupling process efficiently and deliver the corresponding ß-phosphinomethylated alcohol products in moderate to good yields. Mechanistic studies suggest that this transformation proceeds in a sequential manner including catalytic dehydrogenation, aldol condensation, Michael addition, and catalytic hydrogenation.
ABSTRACT
Delineating the fingerprint or feature vector of a receptor/protein will facilitate the structural and biological studies, as well as the rational design and development of drugs with high affinities and selectivity. However, protein is complicated by its different functional regions that can bind to some of its protein partner(s), substrate(s), orthosteric ligand(s) or allosteric modulator(s) where cogent methods like molecular fingerprints do not work well. We here elaborate a scoring-function-based computing protocol Molecular Complex Characterizing System to help characterize the binding feature of protein-ligand complexes. Based on the reported receptor-ligand interactions, we first quantitate the energy contribution of each individual residue which may be an alternative of MD-based energy decomposition. We then construct a vector for the energy contribution to represent the pattern of the ligand recognition at a receptor and qualitatively analyze the matching level with other receptors. Finally, the energy contribution vector is explored for extensive use in similarity and clustering. The present work provides a new approach to cluster proteins, a perspective counterpart for determining the protein characteristics in the binding, and an advanced screening technique where molecular docking is applicable.
Subject(s)
Proteins/chemistry , Software , Binding Sites , Ligands , Molecular Docking Simulation , Protein Binding , Proteins/metabolismABSTRACT
We present a bismuth (Bi)-doped fiber amplifier (BDFA) operating in the 1400-1480â nm range using 35 m of Bi-doped germanosilicate fiber. A maximum gain of 23â dB for an input signal of -23dBm at 1440â nm has been achieved, which, to the best of our knowledge, is the highest gain per unit length of 0.66â dB/m reported for a BDFA. The 3â dB bandwidth is measured to be 40â nm (1415-1455â nm), and the gain coefficient is 0.2â dB/mW. A further temperature dependence study of BDFA across the temperature range of -60°C to 80°C also showed a negligible effect of temperature on the E + S band BDFA gain.
ABSTRACT
Due to the influence of chemical reactions, phase change, and other phenomena, the combustion system is a complicated high-temperature environment. Therefore, the spatio-temporally resolved monitoring of the temperature field is crucial for gaining a comprehensive understanding of the intricate combustion environment. In this study, we proposed a fast and high-precision temperature measurement technique based on mid-infrared (MIR) dual-comb spectroscopy with a high spectral resolution and fast refresh rate. Based on this technique, the spatio-temporally resolved measurement of a non-uniform temperature field was achieved along the laser path. To verify the capability of DCS for temperature measurement, the bandhead ro-vibrational lines of the CO2 molecule were acquired, and the 1-σ uncertainty of the retrieved temperature was 3.2°C at 800°C within 100â ms. The results demonstrate the potential of our fast and high-precision laser diagnostic technique which can be further applied to combustion kinetics.
ABSTRACT
Two-dimensional graphdiyne (GDY) formed by sp and sp2 hybridized carbon has been found to be an efficient toxic gas sensing material by density functional theory (DFT). However, little experimental research concerning its gas sensing capability has been reported owing to the complex preparation process and harsh experimental conditions. Herein, porous GDY nanosheets are successfully synthesized through a facile solvothermal synthesis technique by using CuO microspheres (MSs) as both template and source of catalyst. The porous GDY nanosheets exhibit a broadband optical absorption, rendering it suitable for the light-driven optoelectronic gas sensing applications. The GDY-based gas sensor was demonstrated to have excellent reversible to NO2 behaviors at 25 °C for the first time. More importantly, higher response value and faster response-recovery time once exposed to NO2 gas molecules are achieved by the illumination of UV light. In this way, our work paves the way for the exploration of GDY-based gas detection experimentally.
ABSTRACT
Organoboron showed great potential in the synthesis of various high-value chemical compounds. Direct hydroboration of olefins has been witnessed over time as a mainstream method for the synthesis of organoboron compounds. In this work, an electroreductive anti-Markovnikov hydroboration approach of olefins with readily available B2pin2 to synthesize valuable organoboron compounds with high chemo- and regioselectivities under metal catalyst-free conditions was reported. This protocol exhibited broad substrate scope and good functional-group tolerance on styrenes and heteroaromatic olefins, providing synthetically useful alkylborons with high efficiency and even various deuterium borylation products with good D-incorporation when CD3CN was employed as solvent. Furthermore, gram-scale reactions and extensive functional derivatization further highlighted the potential of this method.
ABSTRACT
Vascular calcification is an actively regulated process resembling bone formation and contributes to the cardiovascular morbidity and mortality of chronic kidney disease (CKD). However, an effective therapy for vascular calcification is still lacking. The ketone body ß-hydroxybutyrate (BHB) has been demonstrated to have health-promoting effects including anti-inflammation and cardiovascular protective effects. However, whether BHB protects against vascular calcification in CKD remains unclear. In this study, Alizarin Red staining and calcium content assay showed that BHB reduced calcification of vascular smooth muscle cells (VSMCs) and arterial rings. Of note, compared with CKD patients without thoracic calcification, serum BHB levels were lower in CKD patients with thoracic calcification. Supplementation with 1,3-butanediol (1,3-B), the precursor of BHB, attenuated aortic calcification in CKD rats and VitD3-overloaded mice. Furthermore, RNA-seq analysis revealed that BHB downregulated HDAC9, which was further confirmed by RT-qPCR and western blot analysis. Both pharmacological inhibition and knockdown of HDAC9 attenuated calcification of human VSMCs, while overexpression of HDAC9 exacerbated calcification of VSMCs and aortic rings, indicating that HDAC9 promotes vascular calcification under CKD conditions. Of note, BHB treatment antagonized HDAC9-induced vascular calcification. In addition, HDAC9 overexpression activated the NF-κB signaling pathway and inhibition of NF-κB attenuated HDAC9-induced VSMC calcification, suggesting that HDAC9 promotes vascular calcification via activation of NF-κB. In conclusion, our study demonstrates that BHB supplementation inhibits vascular calcification in CKD via modulation of the HDAC9-dependent NF-κB signaling pathway. Moreover, we unveil a crucial mechanistic role of HDAC9 in vascular calcification under CKD conditions; thus, nutritional intervention or pharmacological approaches to enhance BHB levels could act as promising therapeutic strategies to target HDAC9 for the treatment of vascular calcification in CKD. © 2022 The Pathological Society of Great Britain and Ireland.
Subject(s)
Renal Insufficiency, Chronic , Vascular Calcification , 3-Hydroxybutyric Acid/metabolism , Animals , Calcium/metabolism , Cells, Cultured , Down-Regulation , Histone Deacetylases/genetics , Histone Deacetylases/metabolism , Humans , Ketones/metabolism , Mice , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/pathology , NF-kappa B/metabolism , Rats , Renal Insufficiency, Chronic/pathology , Repressor Proteins/metabolism , Vascular Calcification/genetics , Vascular Calcification/prevention & controlABSTRACT
PURPOSE: Childhood absence epilepsy (CAE) is characterized by impaired consciousness and distinct electroencephalogram (EEG) patterns. However, interictal epileptiform discharges (IEDs) do not lead to noticeable symptoms. This study examines the disparity between ictal and interictal generalized spike-and-wave discharges (GSWDs) to determine the mechanisms behind CAE and consciousness. METHODS: We enrolled 24 patients with ictal and interictal GSWDs in the study. The magnetoencephalography (MEG) data were recorded before and during GSWDs at a sampling rate of 6000 Hz and analyzed across six frequency bands. The absolute and relative spectral power were estimated with the Minimum Norm Estimate (MNE) combined with the Welch technique. All the statistical analyses were performed using paired-sample tests. RESULTS: During GSWDs, the right lateral occipital cortex indicated a significant difference in the theta band (5-7 Hz) with stronger power (P = 0.027). The interictal group possessed stronger spectral power in the delta band (P < 0.01) and weaker power in the alpha band (P < 0.01) as early as 10 s before GSWDs in absolute and relative spectral power. Additionally, the ictal group revealed enhanced spectral power inside the occipital cortex in the alpha band and stronger spectral power in the right frontal regions within beta (15-29 Hz), gamma 1 (30-59 Hz), and gamma 2 (60-90 Hz) bands. CONCLUSIONS: GSWDs seem to change gradually, with local neural activity changing even 10 s before discharge. During GSWDs, visual afferent stimulus insensitivity could be related to the impaired response state in CAE. The inhibitory signal in the low-frequency band can shorten GSWD duration, thereby achieving seizure control through inhibitory effect strengthening.
Subject(s)
Epilepsy, Absence , Humans , Epilepsy, Absence/diagnosis , Magnetoencephalography , Brain , Electroencephalography/methods , SeizuresABSTRACT
Cancer has become a grave health crisis that threatens the lives of millions of people worldwide. Because of the drawbacks of the available anticancer drugs, the development of novel and efficient anticancer agents should be encouraged. Epidithiodiketopiperazine (ETP) alkaloids with a 2,5-diketopiperazine (DKP) ring equipped with transannular disulfide or polysulfide bridges or S-methyl moieties constitute a special subclass of fungal natural products. Owing to their privileged sulfur units and intriguing architectural structures, ETP alkaloids exhibit excellent anticancer activities by regulating multiple cancer proteins/signaling pathways, including HIF-1, NF-κB, NOTCH, Wnt, and PI3K/AKT/mTOR, or by inducing cell-cycle arrest, apoptosis, and autophagy. Furthermore, a series of ETP alkaloid derivatives obtained via structural modification showed more potent anticancer activity than natural ETP alkaloids. To solve supply difficulties from natural resources, the total synthetic routes for several ETP alkaloids have been designed. In this review, we summarized several ETP alkaloids with anticancer properties with particular emphasis on their underlying mechanisms of action, structural modifications, and synthetic strategies, which will offer guidance to design and innovate potential anticancer drugs.