Rotundic acid alleviates hyperlipidemia in rats by regulating lipid metabolism and gut microbiota.

Disturbances in lipid metabolism and dysbiosis of the gut microbiota play an important role in the progression of hyperlipidemia. Previous study indicated that Ilicis Rotundae Cortex possesses anti-hyperlipidemic activity, and rotundic acid (RA) identified as a key active compound to be incorporated into the body. The study aimed to evaluate the anti-hyperlipidemia effects of RA and explored its impact on gut microbiota and lipid metabolism, as well as its possible mechanisms for improving hyperlipidemia. The study methodology included a comprehensive evaluation of the effects of RA on steatosis markers of hyperlipidemia, lipid metabolism, and gut microbiota by assessing biochemical parameters and histopathology, lipidomics, 16S rRNA gene sequencing, and short-chain fatty acid (SCFA) assays. The results showed that RA effectively reduced body weight and the steatosis markers in serum and liver. Moreover, the lipidomic analysis revealed significant changes in plasmatic and hepatic lipid levels, and these were restored by RA. According to the results of 16S rRNA gene sequencing, RA supplementation raised the relative abundance of Bacteroidetes and Proteobacteria while decreasing the relative abundance of Firmicutes. RA significantly boosted the relative abundance of SCFAs by increasing SCFAs-producing bacteria such as Bacteroides, Alloprevotella, Desulfovibrio, etc. In summary, RA could regulate triglyceride metabolism and glycerophospholipid metabolism, restore gut microbiota structure, and increase the relative abundance of SCFAs-producing bacteria to exert its hypolipidemic effects. These findings suggest RA to be a promising therapeutic agent for hyperlipidemia.

Chamomile Essential Oil: Chemical Constituents and Antitumor Activity in MDA-MB-231 Cells through PI3K/Akt/mTOR Signaling Pathway.

Chamomile essential oil (CEO) is extracted from chamomile and mainly used in aromatherapy. The chemical constituents and its antitumor activity on Triple-negative breast cancer (TNBC) was explored in the present study. Gas chromatography-mass spectrometry (GC/MS) was employed to analyze the chemical constituents of CEO. The cell viability, migration and invasion of TNBC cell MDA-MB-231 were measured using MTT, wound scratch and Transwell assay, respectively. The protein expression of PI3K/Akt/mTOR signaling pathway was determined by Western blot. CEO is rich in terpenoids (63.51 %), among which the identified terpenoids and their derivatives are mainly Caryophyllene (29.57 %), d-Cadinene (12.81 %), Caryophyllene oxide (14.51 %), etc. Three concentration of CEO (1, 1.5, 2 µg/mL) significantly inhibited the proliferation, migration and invasion of MDA-MB-231 cells with a dose dependent manner. Moreover, the phosphorylation of PI3K, Akt and mTOR was inhibited by CEO. The results revealed that there was abundant terpenoids in the CEO which account for 63.51 %. CEO significantly inhibited the proliferation, migration and invasion of MDA-MB-231 cells, exhibiting antitumor effect on TNBC. The antitumor effect of CEO might attribute to its inhibition on PI3K/Akt/mTOR signaling pathway. However, further study should be conducted in more TNBC cell lines and animal models to provide further evidence for TNBC treatment by CEO.

Fluorescence Enhancement by Supramolecular Sequestration of a C54-Nanographene Trisimide by Hexabenzocoronene.

A supramolecular trilayer nanographene complex consisting of a newly synthesized D3h-symmetric C54-nanographene trisimide (NTI 1) and two hexabenzocoronenes (HBC) has been obtained by self-assembly. This 1:2 complex is structurally well-defined according to UV/vis and single crystal X-ray studies and exhibits high thermodynamic stability even in polar halogenated solvents. Complexation of NTI 1 by two HBC molecules protects the NTI 1 π-surface efficiently from oxygen quenching, thereby leading to a sequestration-induced fluorescence enhancement under ambient conditions.

Organoplatinum(II) Cruciform: A Versatile Building Block to Fabricate 2D Microcrystals with Full-Color and White Phosphorescence and Anisotropic Photon Transport.

Conventional square-planar platinum complexes typically form one-dimensional assemblies as a result of unidirectional metallophilic and/or π⋅⋅⋅π intermolecular interactions. Organoplatinum(II) complexes with a cruciform shape are presented herein to construct two-dimensional (2D) microcrystals with full-color and white phosphorescence. These 2D crystals show unique monocomponent π⋅⋅⋅π stacking, from either the cyclometalating or noncyclometalating ligand, and the bicomponent alternate π⋅⋅⋅π stacking from both ligands along different facet directions. Anisotropic tri-directional waveguiding is further implemented on a single hexagonal microcrystal. These results demonstrate the great capability of the organoplatinum(II) cruciform as a general platform to fabricate 2D phosphorescent micro-/nanocrystals for advanced photonic applications.

Establishment of the circadian metabolic phenotype strategy in spontaneously hypertensive rats: a dynamic metabolomics study.

BACKGROUND: Circadian rhythms play a fundamental role in the progression of cardiovascular events. Almost all cardiovascular diseases have a circadian misalignment usually characterized by changes in metabolites. This study aimed to dynamically monitor rhythmic biomarkers, to elucidate the metabolic pathways that are potentially under circadian control in spontaneously hypertensive rats (SHRs), and to eventually establish a circadian metabolic phenotype strategy based on metabolomics. METHODS: In this study, an untargeted metabolomics technology was used to dynamically monitor changes in serum metabolites between SHR model group and WKY control group. Liquid chromatography-mass spectrometry (LC-MS) combined with multivariate statistical analysis was applied to identify markers of hypertension rhythm imbalance. The concentrations of amino acids and their metabolites identified as markers were quantified by a subsequent targeted metabolomics analysis. Overall, these approaches comprehensively explored the rhythm mechanism and established a circadian metabolic phenotype strategy. RESULTS: The metabolic profile revealed a disorder in the diurnal metabolism pattern in SHRs. Moreover, multivariate statistical analysis revealed metabolic markers of rhythm homeostasis, such as arginine, proline, phenylalanine, citric acid, L-malic acid, succinic acid, etc., accompanied by an imbalance in hypertension. The key metabolic pathways related to rhythm imbalance in hypertension were found by enrichment analysis, including amino acid metabolism, and the tricarboxylic acid cycle (TCA). In addition, the quantitative analysis of amino acids and their metabolites showed that the changes in leucine, isoleucine, valine, taurine, serine, and glycine were the most obvious. CONCLUSIONS: In summary, this study illustrated the relationship between metabolites and the pathways across time on hypertension. These results may provide a theoretical basis for personalized treatment programmes and timing for hypertension.

Effect of the Fluoro-Substituent Position on the Crystal Structure and Photoluminescence of Microcrystals of Platinum ß-Diketonate Complexes.

Molecular packing has an important effect on the photophysical properties of crystalline materials. We demonstrate in this work the modulation of molecular packing and emission properties of microcrystals by minor molecular structural variations. Four platinum ß-diketonate complexes, with two fluoro substituents (1) or one fluoro atom substituted on different positions of the auxiliary phenylpyridine ligand (2-4) have been synthesized. These complexes were used to prepare one-dimensional microcrystals with well-defined shapes and uniform sizes. Although 1-4 display similar emission spectra in the solution state, the corresponding microcrystals display different emission colors from green to yellow and orange. In addition, different temperature-responsive (80-298 K) emission spectral changes have been observed from these microcrystals, including the intensity variation of the locally excited (LE) emission without obvious wavelength shifts, competition between the LE and metal-metal-to-ligand charge-transfer emissions, and the sole wavelength shift of the π-π excimer emissions. These differences in emission properties are rationalized by different molecular packings of these materials, as revealed by single-crystal X-ray analyses.

Basil polysaccharides: A review on extraction, bioactivities and pharmacological applications.

Traditional Chinese Medicine has been widely used in China and is regarded as the most commonly used treatment. As a natural plant used in traditional Chinese Medicine, Basil has various functions associated with a number of its components. There are many compositions in basil including polysaccharides, naphtha, steroids, flavone, coumarins, vitamins, and so on. Among these, polysaccharides play a significant role in based therapeutics. The article summarizes that basil polysaccharides have a lot of biological activities and pharmacological applications, such as their antitumor activity, antioxidant activity, anti-aging activity, immunity enhancement effect, hypolipidemic and anti-atherosclerotic effects, antibacterial effect, treatment of diabetes mellitus, and so on. This review summarized the extraction method, purification method, compositions, pharmacological applications, molecular weight, biological activities, and prospects of basil polysaccharides, providing a basis for further study of basil and basil polysaccharides.

Photoluminescent Anisotropy Amplification in Polymorphic Organic Nanocrystals by Light-Harvesting Energy Transfer.

Polymorphism and anisotropy are fundamental phenomena of crystalline materials. However, the structure-dependent photoluminescent (PL) anisotropy in polymorphic organic crystals has remained unexplored. Herein, two polymorphic nanocrystals, green-emitting nanorods (PtD-g) and yellow-emitting nanoplates (PtD-y), were obtained from a platinum(II)-ß-diketonate complex. The PtD-y crystals display remarkable PL anisotropy with an anisotropy ratio of up to 0.87 whereas the emission of the PtD-g crystals is nearly unpolarized. The polarization properties are rationalized on the different molecular packing of these crystals. By light-harvesting energy transfer, the PtD-y crystals are successfully used to amplify the emission polarization of a red-emitting platinum acceptor (PtA) doped into the donor crystalline matrix, which is otherwise weakly polarized as pure crystals.

In Situ Visualization of Assembly and Photonic Signal Processing in a Triplet Light-Harvesting Nanosystem.

Real-time visualization of assembly processes and sophisticated signal processing at the nanoscale are two challenging topics in photonic nanomaterials. Here, high-quality light-harvesting crystalline nanorods were developed by the coassembly of two polypyridyl Ir(III) and Ru(II) metallophosphors, behaving as the antenna chromophore and energy acceptor, respectively. By using a one-pot or stepwise growth condition, homogeneous and multiblock heterojunction nanorods were prepared, respectively. These nanostructures display multicolor phosphorescence from green to red due to the efficient triplet energy transfer and light-harvesting capability at low acceptor doping ratios. Heterojunction nanorods show gradient emission-color switches during different growth stages, in which the real-time stepwise assembly can be vividly visualized using fluorescence microscopy techniques. Triplet excitons were successfully manipulated in both homogeneous and heterojunction nanorods to realize waveguided green, orange, and red emissions and advanced photonic signal logics and encoding/decoding on single multiblock heterojunction nanorod.

Thermal-Responsive Phosphorescent Nanoamplifiers Assembled from Two Metallophosphors.

Thermal-responsive phosphorescent nanotubes have been fabricated from the co-assembly of two neutral iridium complexes, which behave as the antenna chromophores and energy acceptors, respectively, in these highly ordered crystalline superstructures. By tuning the acceptor doping ratio in a range of 0 to 0.5 %, these tubes display color-tunable phosphorescence from green to red at room temperature, and it is attributed to the highly efficient light-harvesting and energy transfer within these materials. For the same reason, the acceptor emission in the nanotubes is amplified more than 800 times with respect to its pure non-emissive solid sample. The doped tubes show reversible thermal-responsiveness, in which the energy transfer was completely suppressed at 77 K and reactivated at room temperature. These processes were characterized by the in situ emission color (green, orange, and red) and spectral changes and lifetime measurements of isolated nanotubes. The temperature-controlled exciton dynamics are responsible for the luminescent thermochromism in these crystalline materials.

Tunable Self-Assembly and Morphology-Dependent Photoconductivity of a Donor-Acceptor-Structured Diruthenium Complex.

A donor-acceptor-structured diruthenium complex, 1(PF6)4, that contains an electron-deficient bridging ligand and electron-rich distal diarylamines modified with long aliphatic chains has been synthesized. By varying the solvent environments and assembly conditions, we obtained three different self-assembled nanostructures of 1(PF6)4, including zero-dimensional nanospheres, one-dimensional nanofibers, and thin films with interconnected nanowire networks. These structures were investigated by scanning electron microscopy, transmission electron microscopy, dynamic light scattering, X-ray diffraction, and atomic force microscopy (AFM) analysis. Conductive AFM analysis shows that the nanowire networks exhibit a high conductivity of 0.023 S/cm and an enhanced photoconductivity of 0.59 S/cm under visible light irradiation.

Osmium Bisterpyridine Complexes with Redox-Active Amine Substituents: A Comparison Study with Ruthenium Analogues.

Five osmium complexes with redox-active amine substituents, [Os(ttpy)(Ntpy)](PF6)2 (1(PF6)2), [Os(Ntpy)2](PF6)2 (2(PF6)2), [Os(ttpy)(NPhtpy)](PF6)2 (3(PF6)2), [Os(Ntpy)(NPhtpy)](PF6)2 (4(PF6)2), and [Os(NPhtpy)2](PF6)2 (5(PF6)2), have been prepared, where ttpy is 4'-tolyl-2,2':6',2″-terpyridine, Ntpy is 4'-(di-p-anisylamino)-2,2':6',2″-terpyridine, and NPhtpy is 4'-(di-p-anisylaminophen-4-yl)-2,2':6',2″-terpyridine. X-ray crystallographic data of 2(PF6)2 and 4(PF6)2 are presented. These complexes show rich visible absorptions attributed to the singlet metal-to-ligand charge-transfer ((1)MLCT), triplet MLCT, and intraligand charge-transfer transitions. Complexes 3(PF6)2 and 5(PF6)2 show weak emissions around 720 nm at room temperature. All complexes show stepwise oxidations of the osmium ion and the amine segment. However, the redox potentials and the order of the Os(III/II) and N(•+/0) processes vary significantly, depending on the electronic nature of the amine substituents. In the singly oxidized state, either Os(II) → N(•+) MLCT or N → Os(III) ligand-to-metal charge-transfer transitions in the near-infrared region have been observed. For complexes 2(PF6)2, 4(PF6)2, and 5(PF6)2 with two amine substituents, no evidence has been observed for the presence of osmium-mediated amine-amine electronic coupling. Density functional theory (DFT) and time-dependent DFT calculations have been performed to complement these experimental results. The one-electron-oxidized forms 3(3+) and 5(3+) show distinct electron paramagnetic resonance (EPR) signals in CH3CN at room temperature. However, complexes 1(3+), 2(3+), and 4(3+) are EPR silent under similar conditions. In addition, a comparison study has been made between these osmium complexes and the previously reported ruthenium analogues.

Overexpression of BRD4 in Gastric Cancer and its Clinical Significance as a Novel Therapeutic Target.

BACKGROUND: BRD4 is a member of the bromodomain and extra terminal domain (BET) family of proteins, containing two bromodomains and one extra terminal domain, and is overexpressed in several human malignancies. However, its expression in gastric cancer has not yet been well illustrated. OBJECTIVE: This study aimed to elucidate the overexpression of BRD4 in gastric cancer and its clinical significance as a novel therapeutic target. METHODS: Fresh gastric cancer tissues and paraffin-embedded specimens of gastric cancer patients were collected, and the BRD4 expression was examined by Western Blot Analysis (WB) and Immunohistochemistry Analysis (IHC), respectively. The possible relationship between BRD4 expression and the clinicopathological features as well as survival in gastric cancer patients was analyzed. The effect of BRD4 silencing on human gastric cancer cell lines was investigated by MTT assay, WB, wound healing assay, and Transwell invasion. RESULTS: The results showed that the expression level in tumor tissues and adjacent tissues was significantly higher than that in normal tissues, respectively (P < 0.01). BRD4 expression level in gastric cancer tissues was strongly correlated with the degree of tumor differentiated degree (P = 0.033), regional lymph nodes metastasis (P = 0.038), clinical staging (P = 0.002), and survival situation (P = 0.000), while the gender (P = 0.564), age (P = 0.926) and infiltrating depth (P = 0.619) of patients were not associated. Increased BRD4 expression resulted in poor overall survival (P = 0.003). In in vitro assays, BRD4 small interfering RNA resulted in significantly decreased BRD4 protein expression, therefore inhibiting proliferation, migration, and invasion of gastric cancer cells. CONCLUSION: BRD4 might be a novel biomarker for the early diagnosis, prognosis, and therapeutic target in gastric cancer.

Effect of ubiquinol on electrophysiology during high-altitude acclimatization and de-acclimatization: A substudy of the Shigatse CARdiorespiratory fitness (SCARF) randomized clinical trial.

BACKGROUND: High-altitude exposure changes the electrical conduction of the heart. However, reports on electrocardiogram (ECG) characteristics and potent prophylactic agents during high-altitude acclimatization and de-acclimatization are inadequate. This study aimed to investigate the effects of ubiquinol on electrophysiology after high-altitude hypoxia and reoxygenation. METHODS: The study was a prospective, randomized, double-blind, placebo-controlled trial. Forty-one participants were randomly divided into two groups receiving ubiquinol 200 mg daily or placebo orally 14 days before flying to high altitude (3900 m) until the end of the study. Cardiopulmonary exercise testing was performed at baseline (300 m), on the third day after reaching high altitude, and on the seventh day after returning to baseline. RESULTS: Acute high-altitude exposure prolonged resting ventricular repolarization, represented by increased corrected QT interval (455.9 ± 23.4 vs. 427.1 ± 19.1 ms, P < 0.001) and corrected Tpeak-Tend interval (155.5 ± 27.4 vs. 125.3 ± 21.1 ms, P < 0.001), which recovered after returning to low altitude. Ubiquinol supplementation shortened the hypoxia-induced extended Tpeak-Tend interval (-7.7 ms, [95% confidence interval (CI), -13.8 to -1.6], P = 0.014), Tpeak-Tend /QT interval (-0.014 [95% CI, -0.027 to -0.002], P = 0.028), and reserved maximal heart rate (11.9 bpm [95% CI, 3.2 to 20.6], P = 0.013) during exercise at high altitude. Furthermore, the decreased resting amplitude of the ST-segment in the V3 lead was correlated with decreased peak oxygen pulse (R = 0.713, P < 0.001) and maximum oxygen consumption (R = 0.595, P < 0.001). CONCLUSIONS: Our results illustrated the electrophysiology changes during high-altitude acclimatization and de-acclimatization. Similarly, ubiquinol supplementation shortened the prolonged Tpeak-Tend interval and reserved maximal heart rate during exercise at high altitude. REGISTRATION: URL: www.chictr.org.cn; Unique identifier: ChiCTR2200059900.

Bacterial community structure in cooling water and biofilm in an industrial recirculating cooling water system.

Microbial fouling is a serious problem in open recirculating cooling water systems. The bacterial communities that cause it have not been fully understood. In this study, we analyzed the community structure of free-living bacteria and particle-attached bacteria in cooling water, and bacteria in biofilm collected from the wall of the water reservoir in an industrial recirculating cooling water system by construction of a 16S rRNA gene clone library. Based on amplified ribosomal DNA restriction analysis, clones of all three libraries were clustered into 45 operational taxonomic units (OTUs). Thirteen OTUs displaying 91-96% sequence similarity to a type strain might be novel bacterial species. Noted differences in community structure were observed among the three libraries. The relative species richness of the free-living bacteria in cooling water was much lower than that of particle-attached bacteria and bacteria in biofilm. The majority of the free-living bacterial community (99.0%) was Betaproteobacteria. The predominant bacteria in the particle-attached bacterial community were Alphaproteobacteria (20.5%), Betaproteobacteria (27.8%) and Planctomycetes (42.0%), while those in the biofilm bacterial community were Alphaproteobacteria (47.9%), Betaproteobacteria (11.7%), Acidobacteria (13.1%) and Gemmatimonadetes (11.3%). To control microbial fouling in industrial recirculating cooling water systems, additional physiological and ecological studies of these species will be essential.

Isorhynchophylline Regulates the Circadian Rhythm of the Hypothalamus in Spontaneously Hypertensive Rats to Treat Hypertension.

BACKGROUND: The neurotransmitter metabolism in spontaneously hypertensive rats (SHR) is disordered, and these disturbances in neurotransmitter levels can further exacerbate the development of hypertension. Neurotransmitters can affect the expression of circadian clock genes. OBJECTIVE: To clarify the time-dependent internal mechanism of the imbalance of the target neurotransmitter metabolic rhythm of spontaneously hypertensive rats, the circadian research was carried out by the method of targeted metabolomics and molecular biology technology. METHODS: We have explored the mechanism of isorhynchophylline regulating the circadian rhythm through the ERK signaling pathway and thus treating hypertension by detecting the changes of central hypothalamic biological clock rhythm genes after isorhynchophylline intervention, from hypothalamic neurotransmitter rhythmicity. RESULTS: The expression of rhythm genes in normal rats showed a certain rhythm at 6 time points, while the expression of rhythm genes in model rats decreased, and the gene rhythm returned to normal after isorhynchophylline treatment. Cosine analysis of 12 neurotransmitters in hypothalamus showed that there were 6 rhythmic neurotransmitters in the normal group, while in the model group, 4 of the 6 neurotransmitters lost their rhythmicity, and the rhythmicity returned to normal after isorhynchophylline intervention. Compared with the normal group, the expression of ERK protein in the model group increased significantly and decreased after isorhynchophylline treatment. CONCLUSION: The mechanism of isorhynchophylline treating hypertension is not only the regulation of serum neurotransmitters rhythm, but also acting on rhythm genes in the feedback loop of the central biological clock.

Effect of ubiquinol on cardiorespiratory fitness during high-altitude acclimatization and de-acclimatization in healthy adults: the Shigatse CARdiorespiratory fitness study design.

Cardiorespiratory function influences exercise capacity and is an important determinant of high-altitude adaptation. Some studies have investigated the characteristics of changes in cardiorespiratory fitness during high-altitude acclimatization. However, studies on changes in cardiorespiratory fitness during high-altitude de-acclimatization are still lacking and have not yet been elucidated. Furthermore, few drugs have been studied to improve cardiorespiratory function during both processes. The Shigatse CARdiorespiratory Fitness (SCARF) study is a single-center, randomized, double-blind, placebo-control clinical trial to explore the effects of ubiquinol on cardiorespiratory fitness during high-altitude acclimatization and de-acclimatization in healthy adults. Participants will be randomly assigned 1:1 to ubiquinol 200 mg daily or a placebo for 14 days before departure until the end of data collection after return in 7 days. Cardiorespiratory fitness is the primary outcome, while acute mountain sickness and high-altitude de-acclimatization symptoms are secondary endpoints. In addition, laboratory measurements, including routine blood tests and serological measurements, will be performed. To the best of our knowledge, the SCARF study will be the first to reveal the changes in the cardiorespiratory fitness characteristics during high-altitude acclimatization and de-acclimatization. Furthermore, the results of this study will contribute to exploring whether ubiquinol supplementation could be beneficial for endurance exercise capacity at different altitudes and help improve adaptation to acute hypoxia and de-acclimatization. Clinical Trial Registration: This study has been registered in the Chinese Clinical Trial Register (www.chictr.org.cn) as ChiCTR2200059900 and ChiCTR2200066328.

Smartwatch-Based Maximum Oxygen Consumption Measurement for Predicting Acute Mountain Sickness: Diagnostic Accuracy Evaluation Study.

BACKGROUND: Cardiorespiratory fitness plays an important role in coping with hypoxic stress at high altitudes. However, the association of cardiorespiratory fitness with the development of acute mountain sickness (AMS) has not yet been evaluated. Wearable technology devices provide a feasible assessment of cardiorespiratory fitness, which is quantifiable as maximum oxygen consumption (VO2max) and may contribute to AMS prediction. OBJECTIVE: We aimed to determine the validity of VO2max estimated by the smartwatch test (SWT), which can be self-administered, in order to overcome the limitations of clinical VO2max measurements. We also aimed to evaluate the performance of a VO2max-SWT-based model in predicting susceptibility to AMS. METHODS: Both SWT and cardiopulmonary exercise test (CPET) were performed for VO2max measurements in 46 healthy participants at low altitude (300 m) and in 41 of them at high altitude (3900 m). The characteristics of the red blood cells and hemoglobin levels in all the participants were analyzed by routine blood examination before the exercise tests. The Bland-Altman method was used for bias and precision assessment. Multivariate logistic regression was performed to analyze the correlation between AMS and the candidate variables. A receiver operating characteristic curve was used to evaluate the efficacy of VO2max in predicting AMS. RESULTS: VO2max decreased after acute high altitude exposure, as measured by CPET (25.20 [SD 6.46] vs 30.17 [SD 5.01] at low altitude; P<.001) and SWT (26.17 [SD 6.71] vs 31.28 [SD 5.17] at low altitude; P<.001). Both at low and high altitudes, VO2max was slightly overestimated by SWT but had considerable accuracy as the mean absolute percentage error (<7%) and mean absolute error (<2 mL·kg-1·min-1), with a relatively small bias compared with VO2max-CPET. Twenty of the 46 participants developed AMS at 3900 m, and their VO2max was significantly lower than that of those without AMS (CPET: 27.80 [SD 4.55] vs 32.00 [SD 4.64], respectively; P=.004; SWT: 28.00 [IQR 25.25-32.00] vs 32.00 [IQR 30.00-37.00], respectively; P=.001). VO2max-CPET, VO2max-SWT, and red blood cell distribution width-coefficient of variation (RDW-CV) were found to be independent predictors of AMS. To increase the prediction accuracy, we used combination models. The combination of VO2max-SWT and RDW-CV showed the largest area under the curve for all parameters and models, which increased the area under the curve from 0.785 for VO2max-SWT alone to 0.839. CONCLUSIONS: Our study demonstrates that the smartwatch device can be a feasible approach for estimating VO2max. In both low and high altitudes, VO2max-SWT showed a systematic bias toward a calibration point, slightly overestimating the proper VO2max when investigated in healthy participants. The SWT-based VO2max at low altitude is an effective indicator of AMS and helps to better identify susceptible individuals following acute high-altitude exposure, particularly by combining the RDW-CV at low altitude. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200059900; https://www.chictr.org.cn/showproj.html?proj=170253.

Virtual Screening of Nrf2 Dietary-Derived Agonists and Safety by a New Deep-Learning Model and Verified In Vitro and In Vivo.

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an essential regulatory target of antioxidants, but the lack of Nrf2 active site information has hindered discovery of new Nrf2 agonists from food-derived compounds by large-scale virtual screening. Two deep-learning models were separately trained to screen for Nrf2-agonists and safety. The trained models screened potentially active chemicals from approximately 70,000 dietary compounds within 5 min. Of the 169 potential Nrf2 agonists identified via deep-learning screening, 137 had not been reported before. Six compounds selected from the new Nrf2 agonists significantly increased (p < 0.05) the activity of Nrf2 on carbon tetrachloride (CCl4)-intoxicated HepG2 cells (nicotiflorin (99.44 ± 18.5%), artemetin (97.91 ± 8.22%), daidzin (87.73 ± 3.77%), linonin (74.27 ± 5.73%), sinensetin (72.74 ± 10.41%), and tectoridin (77.78 ± 4.80%)), and their safety were demonstrated by an MTT assay. The safety and Nrf2 agonistic activity of nicotiflorin, artemetin, and daidzin were also reconfirm by a single-dose acute oral toxicity study and CCl4-intoxicated rat assay.

Single-cell RNA sequencing reveals a mechanism underlying the susceptibility of the left atrial appendage to intracardiac thrombogenesis during atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with an increased risk of thrombosis of the left atrial appendage (LAA). However, the molecular mechanisms underlying this site-specificity remain poorly understood. Here, we present a comparative single-cell transcriptional profile of paired atrial appendages from patients with AF and illustrate the chamber-specific properties of the main cell types. METHODS: Single-cell RNA sequencing analysis of matched atrial appendage samples from three patients with persistent AF was evaluated by 10× genomics. The AF mice model was created using Tbx5 knockout mice. Validation experiments were performed by glutathione S-transferase pull-down assays, coimmunoprecipitation (Co-IP), cleavage assays and shear stress experiments in vitro. RESULTS: In LAA, phenotype switching from endothelial cells to fibroblasts and inflammation associated with proinflammatory macrophage infiltration were observed. Importantly, the coagulation cascade is highly enriched in LAA endocardial endothelial cells (EECs), accompanying the up-regulation of a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) and the down-regulation of the tissue factor pathway inhibitor (TFPI) and TFPI2. Similar alterations were verified in an AF mouse model (Tbx5+/- ) and EECs treated with simulated AF shear stress in vitro. Furthermore, we revealed that the cleavage of both TFPI and TFPI2 based on their interaction with ADAMTS1 would lead to loss of anticoagulant activities of EECs. CONCLUSIONS: This study highlights the decrease in the anticoagulant status of EECs in LAA as a potential mechanism underlying the propensity for thrombosis, which may aid the development of anticoagulation therapeutic approaches targeting functionally distinct cell subsets or molecules during AF.