ABSTRACT
A novel water-soluble polysaccharide, named PF90-1, with a molecular weight of 1.8 kDa, was isolated and purified from the fibrous root of Pseudostellaria heterophylla. PF90-1 is composed of Gal, Glc and Man in a molar ratio of 73.61: 19.11: 7.28. Methylation analysis revealed that PF90-1 comprises of T-Galp, 1,4-Galp, 1,3,4-Galp, 1,2,3,4-Galp, T-Glcp and 1,3-Manp in a molar ratio of 37.89: 9.37: 17.01: 12.01: 15.88: 7.83. Bioactivity experiments showed that PF90-1 significantly improved lipopolysaccharide (LPS)-induced inflammatory damage in RAW264.7 cells by inhibiting nitric oxide (NO) production and reducing the levels of pro-inflammatory factors (IL-1ß and TNF-α). In addition, PF90-1 exhibited strong antioxidant effects, protecting PC12 cells from H2O2-induced oxidative damage. This findings suggest that PF90-1 holds potential therapeutic value for the treatment of inflammatory and oxidative injuries.
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BACKGROUND: Atrioventricular block (AVB) is common in the elderly and therefore considered to be a degenerative disease of the cardiac conduction system. However, there exist other etiologies contributing to AVB in young patients. This study aimed to determine the etiologies in patients aged before 60 years receiving their first pacemaker implantation for AVB in China. METHODS AND RESULTS: Medical records and diagnostic tests of AVB patients were reviewed to identify the etiologies between 2010 and 2021 at Guangdong Provincial People's Hospital. Eight hundred and twenty-six patients (median age 47 years; 47.9% males) were included. The etiologies were identified in 336 (40.7%) cases, including complications to cardiac surgery (n = 190 [23.0%]), myocarditis (n = 57 [6.9%]), myocardial infarction (n = 25 [3.0%]), complications to catheter-based interventional procedures (n = 21 [2.5%]) and others (n = 43 [5.2%]). AVB caused by myocardial infarction was more common in men (5.8% vs. 0.5%, p < .001), while women received pacing treatment earlier (48 vs. 46 years, p = .019). Men were more likely to suffer from dilated cardiomyopathy (6.6% vs. 2.1%, p = .001) and atrial fibrillation/flutter (23.0% vs. 12.8%, p < .001). The number of first pacemaker implantation increased with age especially among patients with unclear etiologies. CONCLUSION: The etiology of AVB was only determined in approximately 40% of patients receiving their first pacemaker implantation aged before 60 years. The predominance of AVB with unknown etiology and potential gender differences warrants further studies.
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OBJECTIVE: Whether physical activity could reduce the risk of atrial fibrillation (AF) remains unclear. This study was to investigate the relationship of leisure-time physical activity (LTPA) with AF incidence among Chinese older adults. METHODS: A total of 3253 participants aged ≥60 years from the Guangzhou Heart Study were successfully followed between March 2018 and September 2019. LTPA was assessed using a modified Global Physical Activity Questionnaire. AF was ascertained by 12-lead electrocardiograms, 24-hour single-lead Holter and clinical examination. The Cox proportional hazards model was used to the estimate hazard ratio (HR) and 95% confidence interval (CI) after adjustment for confounders, and the population-attributable fraction (PAF) was estimated. RESULTS: A total of 76 (2.34%) new-onset cases of AF were identified during a median of 31.13 months of follow-up. After adjustment for confounders, subjects who had LTPA at least 10.0 metabolic equivalent (MET)-hours/week had a 55% lower risk of developing AF (HR: 0.45, 95%CI: 0.25-0.81), and at least 20 MET-hours/week reduced the risk by 45% (HR: 0.55, 95%CI: 0.34-0.92). At least 11% (PAF: 11%, 95%CI: 0%-20%) or 14% (PAF: 14%, 95%CI: 0%-26%) of AF cases could be avoided, respectively, if the subjects do LTPA at least 10 MET-hours/week or 20 MET-hours/week. A significant exposure-response trend was also observed between LTPA and AF risk (Plinear-trend = 0.002). For a specific LTPA, doing housework was associated with a 43% reduced risk, while engaging in ball games was associated with an increased risk. CONCLUSION: This prospective cohort study indicated that a higher LTPA volume was associated with a lower AF risk in Chinese older adults.
Subject(s)
Atrial Fibrillation , Exercise , Leisure Activities , Humans , Atrial Fibrillation/epidemiology , Atrial Fibrillation/diagnosis , Atrial Fibrillation/prevention & control , Male , Female , Aged , Prospective Studies , Incidence , Middle Aged , China/epidemiology , Risk FactorsABSTRACT
Background: The reported anticoagulation rate may be overestimated among Chinese patients with atrial fibrillation (AF). Therefore, we aimed to understand the current status and time trends of anticoagulation among older people in the Chinese community. Methods: Data were obtained from the physical examination program for the elderly (aged ≥ 65 years) in Guangzhou. During 2017-2020, a total of 31,829, 58,573, 55,483, and 54,845 older people underwent annual physical examinations, respectively, where their general information, AF-related medical history, and use of oral anticoagulants (OACs) were collected for analysis. Results: From 2017 to 2020, the estimated annual prevalence of older people with nonvalvular atrial fibrillation (NVAF) in Guangzhou was 0.99%, 0.92%, 1.05%, and 1.14%, respectively. In patients with high stroke risk (CHA2DS2-VASc score ≥ 2 for males or ≥ 3 for females), the annual anticoagulation rates were 2.83%, 2.05%, 5.29%, and 5.82%, respectively. The proportion of NVAF patients prescribed non-vitamin K antagonist oral anticoagulants (NOACs) increased gradually over the same period (p = 0.004). Males (odds ratios (OR), 1.797; 95% confidence interval (CI), 1.169-2.763; p = 0.008), ages over 75 (OR, 1.858; 95% CI, 1.212-2.849; p = 0.005), low education levels (OR, 1.737; 95% CI, 1.132-2.665; p = 0.011), and lacking the ability for self-care (OR, 4.432; 95% CI, 1.067-18.418; p = 0.041) were less likely to receive OAC therapy. Conclusions: The low anticoagulation rate of older people with NVAF in the Chinese community has not significantly improved in recent years, with only 5.82% of patients with high stroke risk being prescribed OACs. Therefore, it is necessary to establish an appropriate mode of anticoagulant management to improve the current situation.
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Glass formers are, in general, classified as strong or fragile depending on whether their relaxation rates follow Arrhenius or super-Arrhenius temperature dependence. There are, however, notable exceptions, such as water, which exhibit a fragile-to-strong (FTS) transition and behave as fragile and strong, respectively, at high and low temperatures. In this work, the FTS transition is studied using a distinguishable-particle lattice model previously demonstrated to be capable of simulating both strong and fragile glasses [C.-S. Lee, M. Lulli, L.-H. Zhang, H.-Y. Deng, and C.-H. Lam, Phys. Rev. Lett. 125, 265703 (2020)0031-900710.1103/PhysRevLett.125.265703]. Starting with a bimodal pair-interaction distribution appropriate for fragile glasses, we show that by narrowing down the energy dispersion in the low-energy component of the distribution, a FTS transition is observed. The transition occurs at a temperature at which the stretching exponent of the relaxation is minimized, in agreement with previous molecular dynamics simulations.
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Correction for 'Surface mobility gradient and emergent facilitation in glassy films' by Qiang Zhai et al., Soft Matter, 2024, https://doi.org/10.1039/D4SM00221K.
ABSTRACT
BACKGROUND: Acute lung injury (ALI) is a continuum of lung changes caused by multiple lung injuries, characterized by a syndrome of uncontrolled systemic inflammation that often leads to significant morbidity and death. Anti-inflammatory is one of its treatment methods, but there is no safe and available drug therapy. Syringic acid (SA) is a natural organic compound commonly found in a variety of plants, especially in certain woody plants and fruits. In modern pharmacological studies, SA has anti-inflammatory effects and therefore may be a potentially safe and available compound for the treatment of acute lung injury. PURPOSE: This study attempts to reveal the protective mechanism of SA against ALI by affecting the polarization of macrophages and the activation of NF-κB signaling pathway. Trying to find a safer and more effective drug therapy for clinical use. METHODS: We constructed the ALI model using C57BL/6 mice by intratracheal instillation of LPS (10 mg/kg). Histological analysis was performed with hematoxylin and eosin (H&E). The wet-dry ratio of the whole lung was measured to evaluate pulmonary edema. The effect of SA on macrophage M1-type was detected by flow cytometry. BCA protein quantification method was used to determine the total protein concentration in bronchoalveolar lavage fluid (BALF). The levels of Interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α in BALF were determined by the ELISA kits, and RT-qPCR was used to detect the expression levels of IL-6, IL-1ß and TNF-α mRNA of lung tissue. Western blot was used to detect the expression levels of iNOS and COX-2 and the phosphorylation of p65 and IκBα in the NF-κB pathway in lung tissue. In vitro experiments were conducted with RAW267.4 cell inflammation model induced by 100 ng/ml LPS and A549 cell inflammation model induced by 10 µg/ml LPS. The effects of SA on M1-type and M2-type macrophages of RAW267.4 macrophages induced by LPS were detected by flow cytometry. The toxicity of compound SA to A549 cells was detected by MTT method which to determine the safe dose of SA. The expressions of COX-2 and the phosphorylation of p65 and IκBα protein in NF-κB pathway were detected by Western blot. RESULTS: We found that the pre-treatment of SA significantly reduced the degree of lung injury, and the infiltration of neutrophils in the lung interstitium and alveolar space of the lung. The formation of transparent membrane in lung tissue and thickening of alveolar septum were significantly reduced compared with the model group, and the wet-dry ratio of the lung was also reduced. ELISA and RT-qPCR results showed that SA could significantly inhibit the production of IL-6, IL-1ß, TNF-α. At the same time, SA could significantly inhibit the expression of iNOS and COX-2 proteins, and could inhibit the phosphorylation of p65 and IκBα proteins. in a dose-dependent manner. In vitro experiments, we found that flow cytometry showed that SA could significantly inhibit the polarization of macrophages from M0 type macrophages to M1-type macrophages, while SA could promote the polarization of M1-type macrophages to M2-type macrophages. The results of MTT assay showed that SA had no obvious cytotoxicity to A549 cells when the concentration was not higher than 80 µM, while LPS could promote the proliferation of A549 cells. In the study of anti-inflammatory effect, SA can significantly inhibit the expression of COX-2 and the phosphorylation of p65 and IκBα proteins in LPS-induced A549 cells. CONCLUSION: SA has possessed a crucial anti-ALI role in LPS-induced mice. The mechanism was elucidated, suggesting that the inhibition of macrophage polarization to M1-type and the promotion of macrophage polarization to M2-type, as well as the inhibition of NF-κB pathway by SA may be the reasons for its anti-ALI. This finding provides important molecular evidence for the further application of SA in the clinical treatment of ALI.
Subject(s)
Acute Lung Injury , Gallic Acid , Lipopolysaccharides , Macrophages , Mice, Inbred C57BL , NF-kappa B , Animals , Acute Lung Injury/drug therapy , Acute Lung Injury/chemically induced , Mice , Gallic Acid/pharmacology , Gallic Acid/analogs & derivatives , Macrophages/drug effects , NF-kappa B/metabolism , Male , Signal Transduction/drug effects , Anti-Inflammatory Agents/pharmacology , Disease Models, Animal , Lung/drug effects , Lung/pathology , RAW 264.7 Cells , Interleukin-1beta/metabolism , Bronchoalveolar Lavage Fluid , Nitric Oxide Synthase Type II/metabolism , Interleukin-6/metabolismABSTRACT
Confining glassy polymers into films can substantially modify their local and film-averaged properties. We present a lattice model of film geometry with void-mediated facilitation behaviors but free from any elasticity effect. We analyze the spatially varying viscosity to delineate the transport properties of glassy films. The film mobility measurements reported by Yang et al., Science, 2010, 328, 1676 are successfully reproduced. The flow exhibits a crossover from a simple viscous flow to a surface-dominated regime as the temperature decreases. The propagation of a highly mobile front induced by the free surface is visualized in real space. Our approach provides a microscopic treatment of the observed glassy phenomena.
ABSTRACT
ß-Hydroxy-α-amino acids (ßHAAs) are an essential class of building blocks of therapeutically important compounds and complex natural products. They contain two chiral centers at Cα and Cß positions, resulting in four possible diastereoisomers. Many innovative asymmetric syntheses have been developed to access structurally diverse ßHAAs. The main challenge, however, is the control of the relative and absolute stereochemistry of the asymmetric carbons in a sustainable way. In this respect, there has been considerable attention focused on the chemoenzymatic synthesis of ßHAAs via a one-step process. Nature has evolved different enzymatic routes to produce these valuable ßHAAs. Among these naturally occurring transformations, L-threonine transaldolases present potential biocatalysts to generate ßHAAs in situ. 4-Fluorothreonine transaldolase from Streptomyces sp. MA37 (FTaseMA) catalyzes the cross-over transaldolation reaction between L-Thr and fluoroacetaldehyde to give 4-fluorothreonine and acetaldehyde (Ad). It has been demonstrated that FTaseMA displays considerable substrate plasticity toward structurally diverse aldehyde acceptors, leading to the production of various ßHAAs. In this chapter, we describe methods for the preparation of FTaseMA, and the chemoenzymatic synthesis of ßHAAs from various aldehydes and L-Thr using FTaseMA.
Subject(s)
Streptomyces , Transaldolase , Streptomyces/enzymology , Transaldolase/metabolism , Transaldolase/chemistry , Transaldolase/genetics , Threonine/analogs & derivatives , Threonine/chemistry , Threonine/metabolism , Biocatalysis , Amino Acids/chemistry , Amino Acids/metabolism , Substrate Specificity , Acetaldehyde/analogs & derivatives , Acetaldehyde/metabolism , Acetaldehyde/chemistry , Bacterial Proteins/metabolism , Bacterial Proteins/chemistry , Enzyme Assays/methods , StereoisomerismABSTRACT
BACKGROUND: Cancer patients are increasingly affected by chemotherapy-related cardiac dysfunction. The reported incidence of this condition vary significantly across different studies. HYPOTHESIS: A better comprehensive understanding of chemotherapy-related cardiac dysfunction incidence in cancer patients is imperative. Therefore, we performed a meta-analysis to establish the overall incidence of chemotherapy-related cardiac dysfunction in cancer patients. METHODS: We searched articles in PubMed and EMBASE from database inception to May 1, 2023. Studies that reported the incidence of chemotherapy-related cardiac dysfunction in cancer patients were included. RESULTS: A total of 53 studies involving 35 651 individuals were finally included in the meta-analysis. The overall pooled incidence of chemotherapy-related cardiac dysfunction in cancer patients was 63.21 per 1000 person-years (95% CI: 57.28-69.14). The chemotherapy-related cardiac dysfunction incidence increased steeply within half a year of cancer chemotherapy. Also, the trend of chemotherapy-related cardiac dysfunction incidence appeared to have plateaued after a longer duration of follow-up. In addition, chemotherapy-related cardiac dysfunction incidence rates are significantly higher among patients with age ≥50 years versus patients with age <50 years (99.96 vs. 34.48 per 1000 person-years). The incidence rate of cardiac dysfunction was higher among breast cancer patients (72.97 per 1000 person-years), leukemia patients (65.21 per 1000 person-years), and lymphoma patients (55.43 per 1000 person-years). CONCLUSION: Our meta-analysis unveiled a definitive overall incidence rate of chemotherapy-related cardiac dysfunction in cancer patients. In addition, it was found that the risk of developing this condition escalates within the initial 6 months postchemotherapy, subsequently tapering off to become statistically insignificant after a duration of 6 years.
Subject(s)
Breast Neoplasms , Heart Diseases , Humans , Middle Aged , Female , IncidenceABSTRACT
OBJECTIVE: Research has shown that celastrol can effectively treat a variety of diseases, yet when passing a certain dosage threshold, celastrol becomes toxic, causing complications such as liver and kidney damage and erythrocytopenia, among others. With this dichotomy in mind, it is extremely important to find ways to preserve celastrol's efficacy while reducing or preventing its toxicity. METHODS: In this study, insulin-resistant HepG2 (IR-HepG2) cells were prepared using palmitic acid and used for in vitro experiments. IR-HepG2 cells were treated with celastrol alone or in combination with N-acetylcysteine (NAC) or ferrostatin-1 (Fer-1) for 12, 24 or 48 h, at a range of doses. Cell counting kit-8 assay, Western blotting, quantitative reverse transcription-polymerase chain reaction, glucose consumption assessment, and flow cytometry were performed to measure celastrol's cytotoxicity and whether the cell death was linked to ferroptosis. RESULTS: Celastrol treatment increased lipid oxidation and decreased expression of anti-ferroptosis proteins in IR-HepG2 cells. Celastrol downregulated glutathione peroxidase 4 (GPX4) mRNA. Molecular docking models predicted that solute carrier family 7 member 11 (SLC7A11) and GPX4 were covalently bound by celastrol. Importantly, we found for the first time that the application of ferroptosis inhibitors (especially NAC) was able to reduce celastrol's toxicity while preserving its ability to improve insulin sensitivity in IR-HepG2 cells. CONCLUSION: One potential mechanism of celastrol's cytotoxicity is the induction of ferroptosis, which can be alleviated by treatment with ferroptosis inhibitors. These findings provide a new strategy to block celastrol's toxicity while preserving its therapeutic effects. Please cite this article as: Liu JJ, Zhang X, Qi MM, Chi YB, Cai BL, Peng B, Zhang DH. Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells. J Integr Med. 2024; 22(3): 286-294.
Subject(s)
Ferroptosis , Insulin Resistance , Pentacyclic Triterpenes , Humans , Hep G2 Cells , Pentacyclic Triterpenes/pharmacology , Ferroptosis/drug effects , Triterpenes/pharmacology , Cyclohexylamines/pharmacology , Acetylcysteine/pharmacology , Phenylenediamines/pharmacology , Molecular Docking Simulation , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolismABSTRACT
Two novel polyketides, accraspiroketides A (1) and B (2), which feature unprecedented [6 + 6+6 + 6] + [5 + 5] spiro chemical architectures, were isolated from Streptomyces sp. MA37 ΔaccJ mutant strain. Compounds 1-2 exhibit excellent activity against Gram-positive bacteria (MIC = 1.5-6.3 µg/mL). Notably, 1 and 2 have superior activity against clinically isolated Enterococcus faecium K60-39 (MIC = 4.0 µg/mL and 4.7 µg/mL, respectively) than ampicillin (MIC = 25 µg/mL).
Subject(s)
Anti-Bacterial Agents , Enterococcus faecium , Microbial Sensitivity Tests , Polyketides , Streptomyces , Polyketides/pharmacology , Polyketides/chemistry , Polyketides/isolation & purification , Streptomyces/chemistry , Molecular Structure , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Enterococcus faecium/drug effects , Gram-Positive Bacteria/drug effects , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Spiro Compounds/isolation & purification , Naphthacenes/chemistry , Naphthacenes/pharmacologyABSTRACT
BACKGROUND: Natural tetramates are a family of hybrid polyketides bearing tetramic acid (pyrrolidine-2,4-dione) moiety exhibiting a broad range of bioactivities. Biosynthesis of tetramates in microorganisms is normally directed by hybrid polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) machineries, which form the tetramic acid ring by recruiting trans- or cis-acting thioesterase-like Dieckmann cyclase in bacteria. There are a group of tetramates with unique skeleton of 3-(2H-pyran-2-ylidene)pyrrolidine-2,4-dione, which remain to be investigated for their biosynthetic logics. RESULTS: Herein, the tetramate type compounds bripiodionen (BPD) and its new analog, featuring the rare skeleton of 3-(2H-pyran-2-ylidene)pyrrolidine-2,4-dione, were discovered from the sponge symbiotic bacterial Streptomyces reniochalinae LHW50302. Gene deletion and mutant complementation revealed the production of BPDs being correlated with a PKS-NRPS biosynthetic gene cluster (BGC), in which a Dieckmann cyclase gene bpdE was identified by sit-directed mutations. According to bioinformatic analysis, the tetramic acid moiety of BPDs should be formed on an atypical NRPS module constituted by two discrete proteins, including the C (condensation)-A (adenylation)-T (thiolation) domains of BpdC and the A-T domains of BpdD. Further site-directed mutagenetic analysis confirmed the natural silence of the A domain in BpdC and the functional necessities of the two T domains, therefore suggesting that an unusual aminoacyl transthiolation should occur between the T domains of two NRPS subunits. Additionally, characterization of a LuxR type regulator gene led to seven- to eight-fold increasement of BPDs production. The study presents the first biosynthesis case of the natural molecule with 3-(2H-pyran-2-ylidene)pyrrolidine-2,4-dione skeleton. Genomic mining using BpdD as probe reveals that the aminoacyl transthiolation between separate NRPS subunits should occur in a certain population of NRPSs in nature.
Subject(s)
Biosynthetic Pathways , Polyketide Synthases , Pyrrolidinones , Polyketide Synthases/metabolism , Bacteria/metabolism , Pyrans/metabolism , Skeleton/metabolism , Peptide Synthases/geneticsABSTRACT
Background: Previously, ablation at the outflow tract was considered to be safe and rarely affected the His-Purkinje system due to their spatial distance. However, we have reported a case of right bundle branch block (RBBB) and junctional beats that were recorded during radiofrequency catheter ablation in a patient who had a history of peri-membranous ventricular septal defect (pmVSD) closure and the implantation of a metallic occluder. Case summary: A 16-year-old girl with a metallic occluder for peri-membranous ventricular septum defect underwent an ablation procedure for premature ventricular complexes. During the ablation at the right ventricular outflow tract (RVOT), RBBB and junctional beats were recorded. His bundle potentials and the high-frequency potential generated by electrical interference were observed when mapping the margin of the occluder. To ensure safety, we attempted ablation at the right coronary cusp in the left ventricular outflow tract, which eventually proved to be successful, presenting an alternative ablation strategy. Conclusion: This is a rare report of RBBB and junctional beats observed during ablation at RVOT in a patient with pmVSD and a metallic occluder. The observed damage to the His-Purkinje system may be attributed to uncontrolled radiofrequency energy heating up caused by the metallic device. This case emphasizes the importance of thorough electroanatomic and activation mapping prior to starting the ablation procedure, especially in complicated cases. Furthermore, it suggests that ablation at a relatively remote position is both feasible and relatively safe for patients with occluder devices.
ABSTRACT
The nature of glassy states in realistic finite dimensions is still under fierce debate. Lattice models can offer valuable insights and facilitate deeper theoretical understanding. Recently, a disordered-interacting lattice model with distinguishable particles in two dimensions (2D) has been shown to produce a wide range of dynamical properties of structural glasses, including the slow and heterogeneous characteristics of the glassy dynamics, various fragility behaviors of glasses, and so on. These findings support the usefulness of this model for modeling structural glasses. An important question is whether such properties still hold in the more realistic three dimensions. In this study, we aim to extend the distinguishable-particle lattice model (DPLM) to three dimensions (3D) and explore the corresponding glassy dynamics. Through extensive kinetic Monte Carlo simulations, we found that the 3D DPLM exhibits many typical glassy behaviors, such as plateaus in the mean square displacement of particles and the self-intermediate scattering function, dynamic heterogeneity, variability of glass fragilities, and so on, validating the effectiveness of the DPLM in a broader realistic setting. The observed glassy behaviors of the 3D DPLM appear similar to those of its 2D counterpart, in accordance with recent findings in molecular models of glasses. We further investigate the role of void-induced motions in dynamical relaxations and discuss their relation to dynamic facilitation. As lattice models tend to keep the minimal but important modeling elements, they are typically much more amenable to analysis. Therefore, we envisage that the DPLM will benefit future theoretical developments, such as the configuration tree theory, towards a more comprehensive understanding of structural glasses.
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Few studies have investigated the association of residential greenness with obstructive sleep apnea (OSA). This study was to comprehensively examine the association of residential greenness exposure with OSA and explore the mediating effect of leisure-time physical activity (LTPA) and PM2.5 on the association among Chinese old adults. A prospective cohort study that enrolled 2027 adults aged ≥65 was conducted between 1st July 2015 and 30th September 2019 in Southern China. OSA was ascertained by Berlin Questionnaire. Greenness exposure was measured by contemporaneous and cumulative average normalized difference vegetation index (NDVI) in the 1000 m radius around each participant's residential address. Hazard ratios (HRs) with 95 % confidence intervals (CIs) were calculated by Cox proportional hazards model to assess the impact of greenness exposure on the incidence of OSA after adjusting for confounders. LTPA and PM2.5 were examined as potential mediators in the aforementioned models. A total of 293, nearly 14.5 %, participants developed OSA within 59,251 person-months of follow-up. When comparing the highest with lowest tertiles, both contemporaneous NDVI (>0.351 vs. ≤0.325: HR = 0.20, 95 % CI = 0.13-0.31) and cumulative NDVI (> 0.346 vs. ≤ 0.317: HR = 0.32, 95 % CI = 0.21-0.47) were associated with a reduced risk of OSA after adjusting for confounders. LTPA and PM2.5 significantly mediated the association between greenness and OSA. In conclusion, this study indicated that exposure to higher residential greenness could decrease OSA risk, and this benefit may be achieved by promoting physical activity and decreasing PM2.5 concentration. The findings suggest to formulate targeted interventional strategies by expanding residential greenness to prevent OSA and reduce disease burden.
Subject(s)
Air Pollution , Sleep Apnea, Obstructive , Adult , Humans , Prospective Studies , China/epidemiology , Exercise , Particulate Matter/analysis , Leisure ActivitiesABSTRACT
Hyperglycemia exacerbates ischemic brain injury by up-regulating autophagy. However, the underlying mechanisms are unknown. This study aims to determine whether hyperglycemia activates autophagy through the p53-Sesn2-AMPK signaling pathway. Rats were subjected to 30-min middle cerebral artery occlusion (MCAO) with reperfusion for 1- and 3-day under normo- and hyperglycemic conditions; and HT22 cells were exposed to oxygen deprivation (OG) or oxygen-glucose deprivation and re-oxygenation (OGD/R) with high glucose. Autophagy inhibitors, 3-MA and ARI, were used both in vivo and in vitro. The results showed that, compared with the normoglycemia group (NG), hyperglycemia (HG) increased infarct volume and apoptosis in penumbra area, worsened neurological deficit, and augmented autophagy. after MCAO followed by 1-day reperfusion. Further, HG promoted the conversion of LC-3I to LC-3II, decreased p62, increased protein levels of aldose reductase, p53, P-p53ser15, Sesn2, AMPK and numbers of autophagosomes and autolysosomes, detected by transmission electron microscopy and mRFP-GFP-LC3 molecular probe, in the cerebral cortex after ischemia and reperfusion injury in animals or in cultured HT22 cells exposed to hypoxia with high glucose content. Finally, experiments with autophagy inhibitors 3-MA and aldose reductase inhibitor (ARI) revealed that while both inhibitors reduced the number of TUNEL positive neurons and reversed the effects of hyperglycemic ischemia on LC3 and p62, only ARI decreased the levels of p53, P-p53ser15. These results suggested that hyperglycemia might induce excessive autophagy to aggravate the brain injury resulted from I/R and that hyperglycemia might activate the p53-Sesn2-AMPK signaling pathway, in addition to the classical PI3K/AKT/mTOR autophagy pathway.
Subject(s)
Brain Ischemia , Hyperglycemia , Reperfusion Injury , Animals , Rats , Aldehyde Reductase/metabolism , AMP-Activated Protein Kinases/metabolism , Autophagy , Glucose/pharmacology , Infarction, Middle Cerebral Artery , Oxygen/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Reperfusion Injury/metabolism , Signal Transduction , Tumor Suppressor Protein p53/metabolismABSTRACT
Covering: 2000 to up to 2023α,ß-Dehydroamino acids (dhAAs) are unsaturated nonproteinogenic amino acids found in a wide array of naturally occurring peptidyl metabolites, predominantly those from bacteria. Other organisms, such as fungi, higher plants and marine invertebrates, have also been found to produce dhAA-containing peptides. The α,ß-unsaturation in dhAAs has profound effects on the properties of these molecules. They display significant synthetic flexibility, readily undergoing reactions such as Michael additions, transition-metal-catalysed cross-couplings, and cycloadditions. These residues in peptides/proteins also exhibit great potential in bioorthogonal applications using click chemistry. Peptides containing contiguous dhAA residues have been extensively investigated in the field of foldamers, self-assembling supermolecules that mimic biomacromolecules such as proteins to fold into well-defined conformations. dhAA residues in these peptidyl materials tend to form a 2.05-helix. As a result, stretches of dhAA residues arrange in an extended conformation. In particular, peptidyl foldamers containing ß-enamino acid units display interesting conformational, electronic, and supramolecular aggregation properties that can be modulated by light-dependent E-Z isomerization. Among approximately 40 dhAAs found in the natural product inventory, dehydroalanine (Dha) and dehydrobutyrine (Dhb) are the most abundant. Dha is the simplest dehydro-α-amino acid, or α-dhAA, without any geometrical isomers, while its re-arranged isomer, 3-aminoacrylic acid (Aaa or ΔßAla), is the simplest dehydro-ß-amino acid, or ß-enamino acid, and displays E/Z isomerism. Dhb is the simplest α-dhAA that exhibits E/Z isomerism. The Z-isomer of Dhb (Z-Dhb) is sterically favourable and is present in the majority of naturally occurring peptides containing Dhb residues. Dha and Z-Dhb motifs are commonly found in ribosomally synthesized and post-translationally modified peptides (RiPPs). In the last decade, the formation of Dha and Dhb motifs in RiPPs has been extensively investigated, which will be briefly discussed in this review. The formation of other dhAA residues in natural products (NPs) is, however, less understood. In this review, we will discuss recent advances in the biosynthesis of peptidyl NPs containing unusual dhAA residues and cryptic dhAA residues. The proposed biosynthetic pathways of these natural products will also be discussed.
Subject(s)
Biological Products , Amino Acids/chemistry , Peptides/chemistry , Proteins , IsomerismABSTRACT
BACKGROUND AND AIMS: Atrioventricular block (AVB) is a degenerative disease and more commonly encountered in elderly patients, but unusual and often of unknown etiology in young patients. This study aimed to investigate the potential contributions of genetic variations to AVB of unknown reasons in young patients. METHODS: We enrolled 41 patients aged <55 years with high-degree AVB of unknown etiology whose clinical and genetic data were collected. RESULTS: Genetic variants were identified in 20 (20/41, 48.8%) patients, 11 (11/20, 55%) of whom had LMNA variants including 3 pathogenic (c.961C > T, c.936+1G > T and c.646C > T), 4 likely pathogenic (c.1489-1G > C, c.265C > A, c.1609-2A > G and c.1129C > T) and 3 of uncertain significance (c.1158-3C > G, c.776A > G and c.674G > T). Compared to those without LMNA variants, patients with LMNA variants demonstrated a later age at onset of AVB (41.45 ± 9.89 years vs 32.93 ± 12.07 years, P = .043), had more prevalent family history of cardiac events (81.8% vs 16.7%, P < .000), suffered more frequently atrial (81.8% vs 10.0%, P < .000) and ventricular (72.7% vs 10.0%, P < .000) arrhythmias, and were more significantly associated with enlargement of left atrium (39.91 ± 7.83 mm vs 34.30 ± 7.54 mm, P = .043) and left ventricle (53.27 ± 8.53 mm vs 47.77 ± 6.66 mm, P = .036). CONCLUSIONS: Our findings provide insights into the genetic etiology of AVB in young patients. LMNA variants are predominant in genotype positive patients and relevant to distinctive phenotypic properties.
Subject(s)
Atrioventricular Block , Aged , Humans , Atrioventricular Block/etiology , Atrioventricular Block/genetics , Prevalence , Arrhythmias, Cardiac , Lamin Type A/geneticsABSTRACT
AIMS: Cardiovascular health (CVH) has been proven to reduce cardiovascular disease burden and mortality, but data are lacking regarding cardiac arrhythmias. The aim of this study was to assess the association between CVH metrics and atrial fibrillation/flutter (AF), ventricular arrhythmias, and bradyarrhythmias. METHODS AND RESULTS: This study analysed data from the Atherosclerosis Risk in Communities (ARIC) cohort, with participants recruited from four different communities across the United States. Cardiovascular health metrics were scored at baseline (1987-89) following the American Heart Association's recommendations and categorized as poor, intermediate, or ideal. Arrhythmia episodes were diagnosed by International Classification of Diseases (ICD)-9 code. Adjusted associations were estimated using Cox models and event rates and population attributable fractions were calculated by CVH metrics category. The study population consisted of 13 078 participants, with 2548 AF, 1363 ventricular arrhythmias, and 706 bradyarrhythmias occurred. The adjusted hazard ratios (HRs) for ideal (vs. poor) CVH metrics were 0.59 [95% confidence interval (CI): 0.50-0.69] for AF, 0.38 (95% CI: 0.28-0.51) for ventricular arrhythmias, and 0.70 (95% CI: 0.51-0.97) for bradyarrhythmia. The risk of incident arrhythmias decreased steadily as the CVH metrics improved from 0 to 14 scores. The adjusted population attributable fractions were calculated to be 29.9% for AF, 54.4% for ventricular arrhythmias, and 21.9% for bradyarrhythmia, respectively. The association between CVH metrics and incident arrhythmias was also seen in people who remained free of coronary heart disease over the follow-up. CONCLUSION: Achieving ideal CVH metrics recommendations by AHA in midlife was associated with a lower risk of incident arrhythmias later in life.
Intermediate and ideal levels of cardiovascular health (CVH) metrics are associated with a markedly reduced risk of developing incident arrhythmias, including atrial fibrillation/flutter, ventricular arrhythmias, and bradyarrhythmia, independent of coronary heart disease. A majority of incident arrhythmias could be prevented if the risk profile of the entire population was optimized. These findings emphasize the significance of public health policies that improve CVH to reduce the social and economic burden of arrhythmias.