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The occupancy of the binding pocket by the substrate ultimately determines the outcome of enzyme catalysis. Previous engineering and substrate scope of phenylalanine aminomutase from Taxus chinensis (TcPAM) has generated valuable knowledge about the regioselectivity with biocatalytic potentials for the preparation of α- and ß-phenylalanine and their derivatives. However, the significantly different regioselectivity during the amination of cinnamates by TcPAM is not fully understood. In this study, we take a reconstruction approach to change the whole binding pocket of TcPAM for probing the factors affecting the regioselectivity, resulting in variant C107S/Q319M/I431V reaching a 25.5-fold enhancement of the ß/α product ratio toward trans-cinnamate acid. Furthermore, when substituted cinnamates were used as substrates, the regioselectivity was strongly correlated with various changes in the binding pocket, and value-added 2-Cl-α-Phe (100% α-selectivity) and 4-CH3-ß-Phe (98% ß-selectivity) were individually verified by the mutants L104A and Q319M at a preparative scale, exemplifying the application feasibility of our engineering strategy. The present study uncovered the cooperative connection between aromatic binding and carboxylate binding to affect the regioselectivity, which provides new insights into the determinants of the regioselectivity possessed by TcPAM and paves the way for its biocatalytic applications on phenylalanine derivatives.
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BACKGROUND: Overlapping clinical manifestations of irritable bowel syndrome (IBS) and IBS-like symptoms in patients with inflammatory bowel disease (IBD-IBS) present challenges in diagnosis and management. Both conditions are associated with alterations in metabolites, but few studies have described the lipid profiles. Our aim was to pinpoint specific lipids that contribute to the pathogenesis of IBS and IBD-IBS by analyzing multiple biologic samples. METHODS: Diarrhea-predominant IBS (IBS-D) patients (n = 39), ulcerative colitis in remission with IBS-like symptoms patients (UCR-IBS) (n = 21), and healthy volunteers (n = 35) were recruited. IBS-D patients meet the Rome IV diagnostic criteria, and UCR-IBS patients matched mayo scores ≤ two points and Rome IV diagnostic criteria. Serum, feces, and mucosa were collected for further analysis. Lipid extraction was carried out by ultra-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS). RESULTS: Lipidomics of mucosa and serum samples significantly differed among the three groups. Feces showed the most altered lipid species, and the enrichment analysis of 347 differentially abundant metabolites via KEGG pathway analysis revealed that alpha-linolenic acid metabolism was significantly altered in the two groups (P < 0.01). The ratio of omega-6/omega-3 fatty acid were imbalance in serum samples. CONCLUSIONS: This study revealed a comprehensive lipid composition pattern between IBS-D patients and UCR-IBS patients. We found several distinctive lipids involved in alpha-linolenic acid metabolism, reflecting an imbalance in the omega-6/omega-3 fatty acid ratio. Compared to mucosa and serum samples, fecal samples might have more advantages in lipidomics studies due to the convenience of sample collection and effectiveness in reflecting metabolic information.
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The Omicron subvariants of SARS-CoV-2, especially for BA.2.86 and JN.1, have rapidly spread across multiple countries, posing a significant threat in the ongoing COVID-19 pandemic. Distinguished by 34 additional mutations on the Spike (S) protein compared to its BA.2 predecessor, the implications of BA.2.86 and its evolved descendant, JN.1 with additional L455S mutation in receptor-binding domains (RBDs), are of paramount concern. In this work, we systematically examine the neutralization susceptibilities of SARS-CoV-2 Omicron subvariants and reveal the enhanced antibody evasion of BA.2.86 and JN.1. We also determine the cryo-EM structures of the trimeric S proteins from BA.2.86 and JN.1 in complex with the host receptor ACE2, respectively. The mutations within the RBDs of BA.2.86 and JN.1 induce a remodeling of the interaction network between the RBD and ACE2. The L455S mutation of JN.1 further induces a notable shift of the RBD-ACE2 interface, suggesting the notably reduced binding affinity of JN.1 than BA.2.86. An analysis of the broadly neutralizing antibodies possessing core neutralizing epitopes reveals the antibody evasion mechanism underlying the evolution of Omicron BA.2.86 subvariant. In general, we construct a landscape of evolution in virus-receptor of the circulating Omicron subvariants.
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Enzima Convertidora de Angiotensina 2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19 , Microscopía por Crioelectrón , Evasión Inmune , Mutación , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Humanos , COVID-19/inmunología , COVID-19/virología , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/inmunología , Enzima Convertidora de Angiotensina 2/genética , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/química , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/química , Evolución Molecular , Unión Proteica , Modelos MolecularesRESUMEN
BACKGROUND: Hemiptera is the fifth species-rich order of insects and the most species-rich order of hemimetabolous insects, including numerous insect species that are of agricultural or medical significance. Despite much effort and recent advance in inferring the Hemiptera phylogeny, some high-level relationships among superfamilies remain controversial. RESULTS: We sequenced the genomes of 64 hemipteran species from 15 superfamilies and the transcriptomes of two additional scale insect species, integrating them with existing genomic and transcriptomic data to conduct a comprehensive phylogenetic analysis of Hemiptera. Our datasets comprise an average of 1625 nuclear loci of 315 species across 27 superfamilies of Hemiptera. Our analyses supported Cicadoidea and Cercopoidea as sister groups, with Membracoidea typically positioned as the sister to Cicadoidea + Cercopoidea. In most analyses, Aleyrodoidea was recovered as the sister group of all other Sternorrhyncha. A sister-group relationship was supported between Coccoidea and Aphidoidea + Phylloxeroidea. These relationships were further supported by four-cluster likelihood mapping analyses across diverse datasets. Our ancestral state reconstruction indicates phytophagy as the primary feeding strategy for Hemiptera as a whole. However, predation likely represents an ancestral state for Heteroptera, with several phytophagous lineages having evolved from predatory ancestors. Certain lineages, like Lygaeoidea, have undergone a reversal transition from phytophagy to predation. Our divergence time estimation placed the diversification of hemipterans to be between 60 and 150 million years ago. CONCLUSIONS: By expanding phylogenomic taxon sampling, we clarified the superfamily relationships within the infraorder Cicadomorpha. Our phylogenetic analyses supported the sister-group relationship between the superfamilies Cicadoidea and Cercopoidea, and the superfamily Membracoidea as the sister to Cicadoidea + Cercopoidea. Our divergence time estimation supported the close association of hemipteran diversification with the evolutionary success and adaptive radiation of angiosperms during the Cretaceous period.
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Genoma de los Insectos , Hemípteros , Filogenia , Transcriptoma , Animales , Hemípteros/genética , Hemípteros/clasificación , Genómica , Evolución Molecular , Evolución BiológicaRESUMEN
Factor XII (FXII) is the zymogen of the plasma protease FXIIa that activates the intrinsic coagulation pathway and the kallikrein kinin-system. The role of FXII in inflammation has been obscure. Here, we report a single-domain antibody (nanobody, Nb) fused to the Fc region of a human immunoglobulin (Nb-Fc) that recognizes FXII in a conformation-dependent manner and interferes with FXIIa formation. Nb-Fc treatment inhibited arterial thrombosis in male mice without affecting hemostasis. In a mouse model of extracorporeal membrane oxygenation (ECMO), FXII inhibition or knockout reduced thrombus deposition on oxygenator membranes and systemic microvascular thrombi. ECMO increased circulating levels of D-dimer, alkaline phosphatase, creatinine and TNF-α and triggered microvascular neutrophil adherence, platelet aggregation and their interaction, which were substantially attenuated by FXII blockade. Both Nb-Fc treatment and FXII knockout markedly ameliorated immune complex-induced local vasculitis and anti-neutrophil cytoplasmic antibody-induced systemic vasculitis, consistent with selectively suppressed neutrophil migration. In human blood microfluidic analysis, Nb-Fc treatment prevented collagen-induced fibrin deposition and neutrophil adhesion/activation. Thus, FXII is an important mediator of inflammatory responses in vasculitis and ECMO, and Nb-Fc provides a promising approach to alleviate thrombo-inflammatory disorders.
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Factor XII , Inflamación , Ratones Noqueados , Neutrófilos , Anticuerpos de Dominio Único , Trombosis , Animales , Humanos , Trombosis/inmunología , Trombosis/metabolismo , Anticuerpos de Dominio Único/farmacología , Anticuerpos de Dominio Único/inmunología , Masculino , Factor XII/metabolismo , Factor XII/antagonistas & inhibidores , Inflamación/metabolismo , Ratones , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/efectos de los fármacos , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Agregación Plaquetaria/efectos de los fármacos , Factor XIIa/metabolismo , Factor XIIa/antagonistas & inhibidores , Fibrina/metabolismo , Productos de Degradación de Fibrina-Fibrinógeno/metabolismoRESUMEN
Background: Life's Essential 8 (LE8), an indicator of cardiovascular health (CVH), can predict overall and cardiovascular mortality in the general population. Considering that cancer survivors have a higher risk of cardiovascular disease (CVD), our study aimed to investigate the association between LE8 and the prognosis of cancer survivors. Methods: A total of 2191 cancer survivors were included from the National Health and Nutrition Examination Survey (2005-2018). LE8 scores, derived from eight individual metrics, were categorized into three groups: low (0-49), moderate (50-79), and high (80-100). Cox regression analysis, nonlinear analysis, sensitivity analysis, and subgroup analysis were conducted to explore the association between LE8 scores and mortality risks, adjusting for potential confounders. Results: During a median follow-up of six years, 479 deaths were recorded, including 118 CVD events and 156 cancer events. LE8 scores showed an inverse linear relationship with all-cause and cardiovascular mortality. A 10-point increase in LE8 scores was associated with a 25 % reduction in all-cause mortality (hazard ratio [HR], 0.75; 95 % CI, 0.66-0.85) and a 29 % reduction in cardiovascular mortality (HR, 0.71; 95 % CI, 0.57-0.89). Additionally, moderate CVH was linked to a lower risk of all-cause mortality (HR, 0.55; 95 % CI, 0.37-0.81), while high CVH was associated with an even lower risk (HR, 0.35; 95 % CI, 0.19-0.68). Similarly, moderate CVH demonstrated a decreased risk of cardiovascular mortality (HR, 0.31; 95 % CI, 0.15-0.63), with high CVH showing an even lower risk (HR, 0.23; 95 % CI, 0.09-0.58). However, LE8 scores was not associated with cancer-specific mortality. Conclusions: A higher LE8 score was independently associated with a decreased risk of both all-cause and cardiovascular mortality in cancer survivors, underscoring the significance of optimizing CVH during the survivorship phase of cancer care.
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Cerebral lymphatic drainage is an important pathway for metabolic waste clearance in the brain, which plays a crucial role in the progression of central nervous system diseases. Recent studies have shown that norepinephrine (NE) is involved in the regulation of cerebral lymphatic drainage function, but the modulation mechanism remains unknown. In this study, we confirmed that NE rapidly reduced glymphatic influx and enhanced meningeal lymphatic clearance. Moreover, the transverse sinus (TS) was the vital region of cerebral lymphatic drainage regulation by NE. Further analysis revealed that NE inhibition could simultaneously enhance glymphatic drainage and dorsal meningeal lymphatic drainage, mainly acting on the TS region. This study demonstrated that the cerebral lymphatic drainage system can be regulated by NE, with the TS region serving as the primary modulating site. The findings provide a potential regulatory target for the amelioration of neurological diseases associated with cerebral lymphatic drainage function.
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Background: Emerging evidence indicated that depression is currently one of the most burdensome diseases worldwide, and it can lead to a variety of functional physical impairments. However, the studies estimated the association between depression and thyroid function remain sparse. We aimed to investigate the association between depression and thyroid function in the American population. Methods: A cross-sectional analysis was performed using the data from the National Health and Nutrition Examination Survey conducted from 2007 to 2012. In the 12,502 adults aged 20-80 years, weighted linear regression models and multiple logistic regression models were applied to evaluate the association between depression and thyroid function indicators. The thyroid indicators investigated were mainly free thyroxine (FT4), total T4 (TT4), free triiodothyronine (FT3), total T3 (TT3), thyroid-stimulating hormone (TSH), and antithyroperoxidase antibody (TPOAb), thyroglobulin (Tg) and antithyroglobulin antibody (TgAb). Results: The final results were reached after adjusting for various confounding factors. In the stratification analysis of subgroups divided by age, depression was significantly negatively correlated with FT4, FT3, and TT3 in both younger adults (p = 0.00122, p < 0.00001, and p = 0.00003) and older adults (p = 0.00001, p = 0.00004, and p < 0.00001). In contrast, depression was significantly negatively correlated with TT4 and Tg in older adults (p = 0.00054, p = 0.00695) and positively correlated in younger adults (p = 0.01352, p < 0.00001). The subgroup analysis by gender revealed that depression was significantly negatively correlated with FT4, FT3, and TT3 in both adult males (p = 0.0164, p = 0.0204, and p = 0.0050) and adult females (p ≤ 0.0001, p < 0.0001, and p < 0.0001), which was more prominent in females. The positive correlation between depression symptoms and TPOAb was only found in adult females (p = 0.0282) and younger adults (p = 0.00488). Conclusion: This study confirmed a significant correlation between depressive and thyroid function and it varied among different genders or age. In the future, more prospective studies are needed to reveal these findings and confirm a causal relationship between them.
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Depresión , Encuestas Nutricionales , Pruebas de Función de la Tiroides , Glándula Tiroides , Humanos , Femenino , Masculino , Adulto , Persona de Mediana Edad , Estudios Transversales , Anciano , Depresión/epidemiología , Depresión/sangre , Anciano de 80 o más Años , Glándula Tiroides/fisiopatología , Adulto Joven , Tiroxina/sangre , Tirotropina/sangre , Triyodotironina/sangreRESUMEN
Introduction: The relationships among microelements and soil microbial communities are essential for understanding the maintenance of soil's ecological functions and their effects on fruit quality in orchards. However, these relationships have not been adequately studied, despite the importance of microelements for the growth of microorganisms and plants. Methods: To address this research gap, we investigated the relationships among microelements (K, Ca, Na, Mg, Fe, Mn, Zn, and Cu), the diversity and composition of soil microbiomes, and fruit quality in loquat orchards. Results: We found that microelements explained more variations in microbial community structures than geographic position, basic soil properties, and macroelements, with 19.6-42.6% of bacterial, 4.3-27.7% of fungal, and 5.9-18.8% of protistan genera significantly correlated with microelements. Among the microelements, AMg and ACu were the most influential in determining the soil microbiome. The soil microbes exhibited varied threshold values for environmental breadth among the microelements, with the broadest range for AMg and the narrowest for AZn. Additionally, the microbes showed significant phylogenetic signals for all microelements, with an increasing divergence of soil microelements. The dominant community assembly shifted from homogeneous selection to stochastic, and then to heterogeneous selection. Moreover, microelements and the microbiome were the top two factors individually explaining 11.0 and 11.4% of fruit quality variation, respectively. Discussion: These results highlight the importance of microelement fertilization in orchard management and provide scientific guidance for improving fruit quality.
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Cardiovascular disease (CVD) claims millions of lives every year, with atherosclerotic cardiovascular disease (ASCVD) being the main cause. ASCVD treatment includes drug therapy, lifestyle intervention, and Percutaneous Coronary Intervention (PCI) all of which significantly enhance cardiovascular function and reduce mortality. However, hyperplasia can lead to vascular obstruction, worsen angina symptoms, or even cause heart disease, affecting patients' long-term prognosis. Therefore, finding effective ways to combat hyperplasia is crucial for cardiovascular therapy. In recent years, ferroptosis has gained attention as a new form of cell death closely associated with several diseases, including cardiovascular diseases. It involves complex metabolic processes critical for cellular homeostasis and normal function. Abnormal proliferation and phenotypic transformation of vascular smooth muscle cells (VSMC) are crucial mechanisms underlying cardiovascular disease development. Inhibiting ferroptosis in VSMC has the potential to significantly reduce neointima proliferation. Glucagon-like peptide-1 receptor agonist (GLP-1RA) constitutes a widely employed class of hypoglycemic agents with direct implications for the cardiovascular system, mitigating adverse cardiovascular events. Research indicates that the stimulation of GLP-1 holds promise as a therapeutic strategy in mitigating cardiovascular events such as restenosis. Hence, investigating the potential of GLP-1RA as a treatment option for cardiovascular ailments carries immense clinical significance.
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The long-term application of phosphate fertilizers in agricultural production leads to a large accumulation of phosphorus in the soil. When it exceeds a certain limit, phosphorus will migrate to surrounding water bodies through surface runoff and other mechanisms, potentially causing environmental risks such as eutrophication of water bodies and increasing the risk of water source pollution. This study takes Shiyan City, the water resources area of the mid-route of the South-to-North Diversion Project (MSDP), as the study area. Based on 701 sampling points of topsoil, geostatistics and geodetectors were used to explore the spatial heterogeneity and influencing factors of available phosphorus (AP) in the topsoil of the area. The results show that the effective phosphorus content in the topsoil of the study area ranges from 0.30 to 146.00 mg/kg, with an average value of 14.28 mg/kg, showing strong variability characteristics. Geostatistical analysis shows that among all theoretical models, the exponential model has the best fitting effect, with a lump gold effect of 0.447 and a range of 82,000 m. The soil available phosphorus content shows an increasing trend from the Central Valley lowlands to the surrounding mountainous hills. Among them, elevation is the main controlling factor for the spatial variation of available phosphorus in the topsoil, followed by soil types, planting systems, annual precipitation, and organic matter. The non-linear enhancement or dual-factor enhancement among various environmental factors reveals the diversity and complexity of spatial heterogeneity affecting available phosphorus content in cultivated soil. This study could provide scientific references for maintaining ecological security in the water source area of the MSDP, improving the precise management of AP, and enhancing cultivated land quality.
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OBJECTIVE: Few studies have examined the relationship between systemic oxidative stress and prostate cancer (PCa) risk. This study aimed to explore potential correlations between PCa and oxidative balance score (OBS), which measures systemic oxidative stress. DESIGN: A cross-sectional study. SETTING: The National Health and Nutrition Examination Survey. PARTICIPANTS: A total of 8156 individuals were included in this study. PRIMARY AND SECONDARY OUTCOME MEASURES: Weighted logistic regression with multivariable adjustment and restricted cubic splines (RCS) were used to assess the correlation between PCa and OBS. A sensitivity analysis was conducted specifically on patients with PCa to verify the results. RESULTS: The prevalence of PCa was 2.55%. The multivariable logistic regression model revealed no correlation between OBS, dietary OBS, lifestyle OBS and PCa. Compared with the lowest quartile of OBS, the adjusted ORs for the highest quartile of OBS, dietary OBS and lifestyle OBS were 1.852 (95% CI 1.028-3.339), 1.565 (95% CI 0.841-2.913) and 1.575 (95% CI 0.915-2.710), respectively. Additionally, all p values for trend were greater than 0.05. Subgroup analysis revealed a consistent lack of association between OBS and PCa across various population settings. Furthermore, analysis using RCS confirmed this absence of association, indicating no significant relationship in either a linear or non-linear context. A sensitivity analysis focusing exclusively on patients with PCa showed a strong association (OR=2.737, p=0.008). CONCLUSION: This cross-sectional study reveals no significant association between systemic oxidative stress, measured by OBS, and PCa risk. Notably, a sensitivity analysis focusing solely on PCa patients suggested a potential link, warranting further investigation.
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Encuestas Nutricionales , Estrés Oxidativo , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/epidemiología , Estudios Transversales , Persona de Mediana Edad , Anciano , Modelos Logísticos , Estados Unidos/epidemiología , Adulto , Factores de Riesgo , Estilo de Vida , Dieta/estadística & datos numéricosRESUMEN
In light of the escalating global warming and the escalating frequency of extreme weather events, the agricultural sector, being a fundamental and pivotal industry worldwide, is encountering substantial challenges due to climate change. Using Chinese provincial panel data for 2000-2021, this paper utilizes a two-way fixed-effect model to investigate the impact of Climate Risk (CR) on green total factor productivity in agriculture (AGTFP), with China's climate policy uncertainty (CPU) being introduced as a moderating variable within the research framework to scrutinize its influence in this context. The findings reveal a noteworthy adverse effect of CR on AGTFP, further exacerbated by CPU. Heterogeneity analysis results show that there is a clear regional variation in the effect of CR on AGTFP across different Chinese regions, with CR significantly inhibiting AGTFP development in the northern regions and provinces in major grain producing regions. Consequently, there is a pressing necessity to bolster the establishment of climate change monitoring infrastructures, devise tailored climate adaptation strategies at a regional level, and enhance the clarity and predictability of climate policies to fortify the resilience and sustainability of agricultural production systems.
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In this work, a highly efficient rongalite/iodine-mediated oxime formation reaction for the preparation of thiohydroximic acids from methyl ketones by employing copper nitrate as the [NO] reagent has been developed. Notably, copper nitrate participated as both a catalyst and the mild oximation reagent in the transformation. This reaction is highly efficient and facile, with a broad substrate scope, especially for fused ring skeleton substrates, heterocyclic skeleton substrates, and acetyl-substituted natural products. Mechanistic studies revealed that copper nitrate might be converted into a NO2 radical or the NO2 radical dimeric forms as an ion-pair equivalent to participate in the transformation.
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The treatment of chronic diabetic wounds is a major challenge due to oxidative stress, persistent hyperglycemia, and susceptibility to bacterial infection. In this study, multifunctional sandwich-structured nanofiber dressings (SNDs) are prepared via electrospinning. The SNDs consisted of an outer layer of hydrophobic polylactic acid (PLA) fibers encapsulating MgB2 nanosheets (MgB2 NSs), a middle layer of PLA and polyvinylpyrrolidone (PVP) fibers encapsulating the MgB2 NSs and metformin hydrochloride complex (MgB2-Met), and an inner layer of water-soluble PVP fibers encapsulating MgB2-Met. Because of their special sandwich structure, SNDs have high photothermal conversion efficiency (24.13%) and photothermal cycle performance. SNDs also exhibit a photothermal effect, bacteria-targeting effect of MgB2, electrostatic attraction ability of metformin hydrochloride (Met), and strong antibacterial activity against Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA). SNDs can eliminate intracellular reactive oxygen species (ROS) by regulating the hydrogen release from MgB2. In addition, SNDs have good biocompatibility, can effectively inhibit the inflammatory factor Interleukin-6 (IL-6), and promote granulation tissue formation, collagen deposition, and diabetic wound healing. These findings offer a promising approach for clinical treatment of diabetic wounds.
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Background: Previous epidemiological studies have reported an association between Sjögren's syndrome (SS) and Parkinson's disease (PD); however, the causality and direction of this relationship remain unclear. In this study, we aimed to investigate the causal relationship between genetically determined SS and the risk of PD using bidirectional Mendelian randomization (MR). Methods: Summary statistics for Sjögren's syndrome used as exposure were obtained from the FinnGen database, comprising 1,290 cases and 213,145 controls. The outcome dataset for PD was derived from the United Kingdom Biobank database, including 6,998 cases and 415,466 controls. Various MR methods, such as inverse variance weighted (IVW), Mendelian randomization Egger regression (MR-Egger), weighted median (WM), simple mode, weighted mode, MR-pleiotropy residual sum and outlier (MR-PRESSO), and robust adjusted profile score (RAPS), were employed to investigate the causal effects of SS on PD. Instrumental variable strength evaluation and sensitivity analyses were conducted to ensure the reliability of the results. In addition, reverse MR analysis was performed to examine the causal effects of PD on SS. Results: The WM, IVW, RAPS and MR-PRESSO methods demonstrated a significant association between genetically predicted SS and reduced risk of PD (odds ratio ORWM = 0.9988, ORIVW = 0.9987, ORRAPS = 0.9987, ORMR-PRESSO = 0.9987, respectively, P < 0.05). None of the MR analyses showed evidence of horizontal pleiotropy (P > 0.05) based on the MR-Egger and MR-PRESSO tests, and there was no statistical heterogeneity in the test results of the MR-Egger and IVW methods. The leave-one-out sensitivity analysis confirmed the robustness of the causal relationship between SS and PD. Furthermore, reverse MR analysis did not support any causal effects of PD on SS. Conclusion: Our MR study supports a potential causal association between SS and a reduced risk of PD. Further extensive clinical investigations and comprehensive fundamental research are warranted to elucidate the underlying mechanisms linking SS and PD.
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Candesartan cilexetil (CC) is one of well-tolerated antihypertensive drugs, while its poor solubility and low bioavailability limit its use. Herein, two mesoporous silica (Syloid XDP 3150 and Syloid AL-1 FP) and the corresponding amino-modified products (N-XDP 3150 and N-AL-1 FP) have been selected as the carriers of Candesartan cilexetil to prepare solid dispersion through solvent immersion, and characterized through using powder X-ray diffraction analysis, infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy, and solid-state nuclear magnetic resonance spectroscopy, etc. The state of CC changed from crystalline to amorphous after loading onto the silica carriers, in which no interactions between CC and silica existed. Then, the dissolution behaviors in vitro were studied through using flow-through cell dissolution method. CC-XDP 3150 sample exhibited the most extensive dissolution, and the cumulative release of CC from it was 1.88-fold larger than that of CC. Moreover, the pharmacokinetic results in rats revealed that the relative bioavailability of CC-XDP 3150 and CC-N-XDP 3150 solid dispersions were estimated to be 326 % % and 238 % % in comparison with CC, respectively. Clearly, pore size, pore volume, and surface properties of silica carrier have remarkable effect on loading, dissolution and bioavailability of CC. In brief, this work will provide valuable information in construction of mesoporous silica-based delivery system toward poorly water-soluble drugs.
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Background Tissue engineering based on whole-organ perfusion decellularization has successfully generated small-animal organs, including the heart and limbs. Herein, we aimed to use angiosome-guided perfusion decellularization to generate an acellular fasciocutaneous flap matrix with an intact vascular network. Method Abdominal flaps of rats were harvested, and the vascular pedicle (iliac artery and vein) was dissected and injected with methylene blue to identify the angiosome region and determine the flap dimension for harvesting. To decellularize flaps, the iliac artery was perfused sequentially with 1% sodium dodecyl sulfate, deionized water, and 1% Triton-X100. Gross morphology, histology, and DNA quantity of flaps were then obtained. Flaps were also subjected to glycosaminoglycan and hydroxyproline content assays, as well as computer tomography angiography. Results Histological assessment indicated that cellular content was completely removed in all flap layers following 10-h perfusion in sodium dodecyl sulfate. DNA quantification confirmed 81% DNA removal. Based on biochemical assays, decellularized flaps had hydroxyproline content comparable with that of native flaps, although significantly fewer glycosaminoglycans (p = 0.0019). Histology and computed tomography angiography illustrated the integrity and perfusability of the vascular system. Conclusion The proposed angiosome-guided perfusion decellularization protocol could effectively remove cellular content from rat fasciocutaneous flaps and preserve the integrity of innate vascular networks.
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Why lower low-density lipoprotein cholesterol (LDL-C) was associated with a decreased atherosclerotic cardiovascular disease (ASCVD) risk but an increased hemorrhagic stroke (HS) risk in hypertensive adults remains unclear. We examined whether the inverse LDL-C-HS association partly arises from its effect on ASCVD. We estimated separable effects of LDL-C on HS outside (i.e., separable direct effect) or only through its effect on ASCVD (i.e., separable indirect effect) in hypertensive adults from the Chinese Multi-provincial Cohort Study. We quantified such effects using numbers needed to treat (NNT) to prevent or cause an extra HS based on the restricted mean event-free time till a 25-year follow-up. LDL-C $<$ 70 mg/dL was not associated with an increased HS risk compared to LDL-C $\ge$ 70 mg/dL regarding total and separable direct effects. However, a small separable indirect effect (i.e., NNT to harm: 9722 participants) was noted and validated via a series of sensitivity analyses. Moreover, modified effects were observed, particularly in the 35-49-year age group, men, and those with SBP $\ge$ 140 mm Hg. These results suggest the inverse LDL-C-HS association in hypertensive adults is partly due to its effect on ASCVD. A better understanding of such associations would provide more enlightening into stroke prevention.
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Background: Traumatic injuries, surgery, and chronic diseases lead to soft tissue wounds. Stimulating normal wound healing (WH) is important for tissue repair and restoration of homeostasis. Lack of angiogenesis impedes wound healing and is noted in chronic wounds. The goal of this investigation was to thoroughly assess the present state and patterns of investigations on angiogenesis in WH by the use of bibliometric analysis. Methods: Studies examining angiogenesis and WH were sourced from the database of the Web of Science Core Collection. Only studies that fulfilled the inclusion criteria were chosen for the purpose of investigation. To analyze the publications included in this research, bibliometric and visual analysis techniques were applied utilizing tools like VOSviewer and CiteSpace. Results: For the analysis, 11,558 papers were considered. The number of publications increased annually from 2013 to 2023. China, the USA, and South Korea were the top nations in this subject, accounting for 41.1 %, 19.4 %, and 5.8 % of published articles, respectively. The author and institution with the greatest number of publications were found to be Chang J and Shanghai Jiao Tong University. PLOS One had the greatest publication count among journals, whereas Biomaterials had the greatest number of citations and was often mentioned in co-citations. Angiogenesis-related biomedical engineering and tissue engineering were the topics that received the most research attention. Recent studies have focused on vascular endothelial growth factor and carboxymethyl chitosan as emerging areas of interest. Conclusion: In this investigation, we compiled the features of publications and determined the most impactful nations, organizations, writers, periodicals, popular subjects, and patterns concerning the process of angiogenesis in the context of WH.