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Obesity is a global issue that warrants the identification of more effective therapeutic targets and a better understanding of the pivotal molecular pathogenesis. Annexin A1 (ANXA1) is known to inhibit phospholipase A2, exhibiting anti-inflammatory activity. However, the specific effects of ANXA1 in obesity and the underlying mechanisms of action remain unclear. Our study reveals that ANXA1 levels are elevated in the adipose tissue of individuals with obesity. Whole-body or adipocyte-specific ANXA1 deletion aggravates obesity and metabolic disorders. ANXA1 levels are higher in stromal vascular fractions (SVFs) than in mature adipocytes. Further investigation into the role of ANXA1 in SVFs reveals that ANXA1 overexpression induces lower numbers of mature adipocytes, while ANXA1-knockout SVFs exhibit the opposite effect. This suggests that ANXA1 plays an important role in adipogenesis. Mechanistically, ANXA1 competes with MYC binding protein 2 (MYCBP2) for interaction with PDZ and LIM domain 7 (PDLIM7). This exposes the MYCBP2-binding site, allowing it to bind more readily to the SMAD family member 4 (SMAD4) and promoting its ubiquitination and degradation. SMAD4 degradation downregulates peroxisome proliferator-activated receptor gamma (PPARγ) transcription and reduces adipogenesis. Treatment with Ac2-26, an active peptide derived from ANXA1, inhibits both adipogenesis and obesity through the mechanism. In conclusion, the molecular mechanism of ANXA1 inhibiting adipogenesis was first uncovered in our study, which is a potential target for obesity prevention and treatment.
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Adipócitos , Adipogenia , Anexina A1 , Obesidade , PPAR gama , Anexina A1/genética , Anexina A1/metabolismo , Adipogenia/genética , Animais , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Humanos , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Adipócitos/metabolismo , Adipócitos/patologia , Proteína Smad4/genética , Proteína Smad4/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células 3T3-L1 , PeptídeosRESUMO
RATIONALE: Periprosthetic fractures (PPF) are rare complications of total knee arthroplasty (TKA). The most common PPF after TKA is supracondylar femoral fracture, which is a relatively rare complication that is usually associated with high-energy trauma, with a reported incidence ranging from 0.4 to 1.7% according to the AOANJRR. However, in TKA patients, it is rarer that the stress fracture around the tibial prosthesis occurs due to changes in the lower limb force line, increasing weight-bearing, and changes in walking gait. PATIENT CONCERNS: A 68-year-old woman visited our hospital with "both knees had aggravated pain and deformity for 8 years." TKA was performed first on the left knee and the patient was discharged within 1 week. Three months later, the patient complained of pain in the upper middle 1/3 part of the medial tibia for 2 weeks, which gradually worsened and affected weight-bearing. DIAGNOSES: Physical examination showed that the left knee joint presented varus deformity, and the right valgus deformity, which diagnosed as osteoarthritis of both knees and was so-called "blownknee". The disease was initially diagnosed as osteoarthritis of both knees on first admission and PPF of the tibia in second. INTERVENTIONS: Three operations were performed on this patient. The first was TKA of the left knee, the second was open reduction and internal fixation of the PPF of the tibia 3 months after the first operation, and the third was TKA of the right knee. OUTCOMES: Until now, the patient has had no recurrent PPF, and the fracture is healing from the last X-ray. LESSONS: Clinicians should be aware of the possibility of PPF after TKA, especially in such patients, the most preferred surgical treatment method was open reduction and internal fixation of fractures using locking plates, and if the PPF with loosened implants, Revision TKA, or megaprosthesis was the better choice.
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Artroplastia do Joelho , Fraturas de Estresse , Fraturas da Tíbia , Humanos , Feminino , Artroplastia do Joelho/efeitos adversos , Idoso , Fraturas de Estresse/etiologia , Fraturas de Estresse/cirurgia , Fraturas da Tíbia/cirurgia , Fraturas da Tíbia/etiologia , Fraturas Periprotéticas/etiologia , Fraturas Periprotéticas/cirurgia , Osteoartrite do Joelho/cirurgiaRESUMO
The skin is the largest organ of the human body and is widely considered to be the first-line defense of the body, providing essential protection against mechanical, physical, and chemical damage. Keratinocytes are the primary cells of the outer layer of the epidermis, which acts as a mechanical and permeability barrier. The epidermis is a permanently renewed tissue where undifferentiated keratinocytes located at the basal layer proliferate and migrate to the overlying layers. Here we report that some components of keratinocytes affect the formation and differentiation of the stratum corneum, which is the most specialized layer of the epidermis.
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Underwater mass spectrometry is characterized by excellent consistency, strong specificity, and the ability to simultaneously detect multiple substances, making it a valuable tool in research fields such as aquatic ecosystems, hydrothermal vents, and the global carbon cycle. Nevertheless, current underwater mass spectrometry encounters challenges stemming from the high-water vapor content, constituting proportions of nearly 90%. This results in issues such as peak overlap, interference with peak height, decreased ionization efficiency and, consequently, make it difficult to achieve low detection limits for extremely low concentrations of gases, such as methane, and impede the detection of background CH4 levels. In this study, we optimized the design of the sampling gas path and developed a high gas-tightness, high pressure-resistant membrane inlet system, coupled with a small-volume, low-power online water vapor removal system. This innovation efficiently eliminates water vapor while maintaining a high permeation flux of the target gases. By elevating the vacuum level to the order of 1E-6 Torr, the ionization efficiency and detection performance were improved. Based on this, we created an online water vapor removal membrane inlet mass spectrometer and conducted experimental research. Results indicated that the water removal efficiency approached 100%, and the vacuum level was elevated by more than 2 orders of magnitude. The detection limit for CH4 increased from over 600 nmol/L to 0.03 nmol/L, representing an improvement of over 4 orders of magnitude, and reaching the level of detecting background CH4 signals in deep-sea and lakes. Furthermore, the instrument exhibited excellent responsiveness and tracking capability to concentration changes on the second scale, enabling in situ analysis of rapidly changing concentration scenarios.
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Evidence of the precise biological pathway responsible for acute cardiovascular events triggered by particulate matter (PM) exposure from anthropogenic emissions is sparse. We investigated the associations of biomarkers relevant to the pathophysiology of atherothrombosis (ceramide metabolism, pro-inflammatory response, and blood coagulation) with primary and secondary components in particulate matter with aerodynamic diameters less than 2.5 µm (PM2.5). A total of 152 healthy participants were followed with four repeated clinical visits between September 2019 and January 2020 in Beijing. Exposure to ambient inorganic aerosols (sulfate, nitrate, ammonium, and chloride), as well as organic aerosols (OA) in PM2.5, was measured by a real-time aerosol chemical speciation monitor, and sources of OA were performed by positive matrix factorization. We found significant increases of 101.9-397.9% in ceramide indicators associated with interquartile-range increases in inorganic aerosols and OA prior to 72 h of exposure. Higher levels of organic and inorganic aerosols in PM2.5 were associated with increases of 3.1-6.0% in normal T cells regulated upon activation and expressed and secreted relevant to the pro-inflammatory response; increases of 276.9-541.5% were observed in D-dimers relevant to coagulation. Detrimental effects were further observed following OA exposure from fossil fuel combustion. Mediation analyses indicated that ceramide metabolism could mediate the associations of PM2.5 components with pro-inflammatory responses. Our findings expand upon the current understanding of potential pathophysiological pathways of cardiovascular events posed by ambient particulates and highlight the importance of reducing primary and secondary PM from anthropogenic combustions.
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Air pollution has been associated with the development of atherosclerosis; however, the pathophysiological mechanisms underlying pro-atherosclerotic effects of air pollution exposure remain unclear. We conducted a prospective panel study in Beijing and recruited 152 participants with four monthly visits from September 2019 to January 2020. Linear mixed-effect models were applied to estimate the associations linking short-term air pollution exposure to biomarkers relevant to ceramide metabolism, pro-inflammation (neutrophil extracellular traps formation and systemic inflammation) and pro-atherosclerotic responses (endothelial stimulation, plaque instability, coagulation activation, and elevated blood pressure). We further explored whether ceramides and inflammatory indicators could mediate the alterations in the profiles of pro-atherosclerotic responses. We found that significant increases in levels of circulating ceramides of 9.7% (95% CIs: 0.7, 19.5) to 96.9% (95% CIs: 23.1, 214.9) were associated with interquartile range increases in moving averages of ambient air pollutant metrics, including fine particulate matter (PM2.5), black carbon, particles in size fractions of 100-560 nm, nitrogen dioxide, carbon monoxide and sulfur dioxide at prior up to 7 days. Higher air pollution levels were also associated with activated neutrophils (increases in citrullinated histone H3, neutrophil elastase, double-stranded DNA, and myeloperoxidase) and exacerbation of pro-atherosclerotic responses (e.g., increases in vascular endothelial growth factor, lipoprotein-associated phospholipase A2, matrix metalloproteinase-8, P-selectin, and blood pressure). Mediation analyses further showed that dysregulated ceramide metabolism and potentiated inflammation could mediate PM2.5-associated pro-atherosclerotic responses. Our findings extend the understanding on potential mechanisms of air pollution-associated atherosclerosis, and suggest the significance of reducing air pollution as priority in urban environments.
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Poluentes Atmosféricos , Poluição do Ar , Aterosclerose , Armadilhas Extracelulares , Humanos , Ceramidas/análise , Esfingolipídeos/análise , Estudos Prospectivos , Fator A de Crescimento do Endotélio Vascular , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Poluentes Atmosféricos/toxicidade , Poluentes Atmosféricos/análise , Inflamação/induzido quimicamente , Material Particulado/análise , Aterosclerose/induzido quimicamente , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análiseRESUMO
Previous research studies have confirmed that Zn and Cd are the most predominant heavy metals in the Baiyin district, Gansu province, China. Furthermore, the speciation of Zn and Cd is a key factor in controlling the mobility, bioavailability, and toxicity of metals in Zn/Cd co-contaminated soil. In this study, the speciation of Zn and Cd in different types of agricultural soils including the Yellow River irrigated soil (s3) and sewage irrigated soil (s1 and s2) was investigated and compared by a combination of sequential extraction, bulk X-ray absorption fine structure (XAFS), and micro-X-ray fluorescence (µ-XRF) techniques. The results of the speciation quantified by XAFS were in general agreement with those obtained by sequential extraction, and the combination of both approaches allowed a reliable description of Zn/Cd speciation in soil. The speciation of Zn in the s1 soil exposed around the smelter was similar to speciation of Zn in the sewage irrigated s2 soil. In both soils, Zn was predominantly present as Zn-Al LDH (31-36%), Zn adsorbed on calcite (37-47%), and primary minerals (14-18% sphalerite and 9% franklinite). In contrast, the proportions of organic Zn (23%) and Zn-Al LDH (53%) were significantly higher in the Yellow River irrigated s3 soil, while that of Zn-calcite (24%) was lower. This indicated that Zn in s3 was less mobile and bioavailable than that in s1 and s2 soils. The content of bioavailable Zn in s3 was much lower than the background value and Zn did not pose a threat to the Yellow River irrigated soil. In addition, Cd was strongly correlated with Zn content and exhibited a simpler speciation. Cd adsorbed on illite and calcite was found as the major species in both soil types, posing higher migration and toxicity to the environment. Our study reported the speciation and correlation of Zn/Cd in sierozem soil for the first time and provided a significant theoretical basis for remediation actions to minimize Zn/Cd risks.
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Metais Pesados , Poluentes do Solo , Solo/química , Cádmio , Raios X , Fluorescência , Esgotos , Síncrotrons , Metais Pesados/análise , Zinco/análise , Carbonato de Cálcio , China , Poluentes do Solo/análiseRESUMO
RATIONALE: Position-specific (PS) δ13 C values of propane have proven their ability to provide valuable information on the evolution history of natural gases. Two major approaches to measure PS δ13 C values of propane are isotopic 13 C nuclear magnetic resonance (NMR) and gas chromatography-pyrolysis-gas chromatography-isotope ratio mass spectrometry (GC-Py-GC-IRMS). Measurement accuracy of the isotopic 13 C NMR has been verified, but the requirements of large sample size and long experimental time limit its applications. GC-Py-GC-IRMS is a more versatile method with a small sample size, but its accuracy has not been demonstrated. METHODS: We measured the PS δ13 C values of propane from nine natural gases using both 13 C NMR and GC-Py-GC-IRMS, then evaluated the accuracy of the GC-Py-GC-IRMS method. RESULTS: The results show that large carbon isotope fractionations occurred for both terminal and central carbons within propane during pyrolysis. The isotope fractionations during the pyrolysis are reproducible at optimum conditions, but vary between the two GC-Py-GC-IRMS systems tested, affected by experimental conditions (e.g., pyrolysis temperature, flow rate, and reactor conditions). CONCLUSIONS: It is necessary to evaluate and calibrate each GC-Py-GC-IRMS system using propane gases with accurately determined PS δ13 C values. This study also highlights a need for PS isotope standards for propane and other molecules (e.g., butane and acetic acid).
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Emerging evidence is examining the precise role of intestinal microbiota in the pathogenesis of type 2 diabetes. The aim of this study was to investigate the association of intestinal microbiota and microbiota-generated metabolites with glucose metabolism systematically in a large cross-sectional study in China. 1160 subjects were divided into three groups based on their glucose level: normal glucose group (n=504), prediabetes group (n=394), and diabetes group (n=262). Plasma concentrations of TMAO, choline, betaine, and carnitine were measured. Intestinal microbiota was measured in a subgroup of 161 controls, 144 prediabetes and 56 diabetes by using metagenomics sequencing. We identified that plasma choline [Per SD of log-transformed change: odds ratio 1.36 (95 confidence interval 1.16, 1.58)] was positively, while betaine [0.77 (0.66, 0.89)] was negatively associated with diabetes, independently of TMAO. Individuals with diabetes could be accurately distinguished from controls by integrating data on choline, and certain microbiota species, as well as traditional risk factors (AUC=0.971). KOs associated with the carbohydrate metabolism pathway were enhanced in individuals with high choline level. The functional shift in the carbohydrate metabolism pathway in high choline group was driven by species Ruminococcus lactaris, Coprococcus catus and Prevotella copri. We demonstrated the potential ability for classifying diabetic population by choline and specific species, and provided a novel insight of choline metabolism linking the microbiota to impaired glucose metabolism and diabetes.
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Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Estado Pré-Diabético , Adulto , Betaína/metabolismo , Colina/metabolismo , Estudos Transversais , Microbioma Gastrointestinal/genética , Glucose , Humanos , Aprendizado de Máquina , Metagenômica , Metilaminas/metabolismoRESUMO
Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through the production of gut-derived metabolites. However, the specific metabolites and their pathophysiological contribution to cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine through the gut microbiota, was elevated with gradually increased risk of cardiac mortality and transplantation in a prospective heart failure cohort (n = 1647). TMAVA treatment aggravated cardiac hypertrophy and dysfunction in high-fat diet-fed mice. Decreased fatty acid oxidation (FAO) is a hallmark of metabolic reprogramming in the diseased heart and contributes to impaired myocardial energetics and contractile dysfunction. Proteomics uncovered that TMAVA disturbed cardiac energy metabolism, leading to inhibition of FAO and myocardial lipid accumulation. TMAVA treatment altered mitochondrial ultrastructure, respiration and FAO and inhibited carnitine metabolism. Mice with γ-butyrobetaine hydroxylase (BBOX) deficiency displayed a similar cardiac hypertrophy phenotype, indicating that TMAVA functions through BBOX. Finally, exogenous carnitine supplementation reversed TMAVA induced cardiac hypertrophy. These data suggest that the gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent FAO.
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Microbioma Gastrointestinal , Aminoácidos Neutros , Animais , Cardiomegalia/metabolismo , Ácidos Graxos/metabolismo , Humanos , Camundongos , Estudos Prospectivos , ValeratosRESUMO
Pyrite nodules up to 20 cm in diameter are found at the top of the Marinoan (~ 635 Ma) Nantuo glacial diamictite as well as in the cap dolostones and shale/siltstones in the lower Doushantuo Formation in eastern Guizhou, southern China. Field occurrences, petrography, and stable sulfur isotopic compositions of pyrite nodules were studied from a section at Taoying, eastern Guizhou, China. Pyrite δ34S values from different nodules varied from 7.3 to 60.5 at different stratigraphic levels. No stratigraphic trend existed for the δ34S, supporting the scenario of pyrite formation in sediments before the precipitation of the cap dolostone. Pyrite δ34S values were also homogeneous within individual nodules at a 0.3 to 1 cm sampling scale, but were more heterogeneous at a 2 mm sampling scale. Homogeneity was not expected from the particular model for pyrite nodule formation in a largely closed or semi-closed environment. Thus, differential cementation and compaction of the pyrite-bearing sediments may have produced the nodular shape of the pyrite deposit.
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The molecular mechanisms of air pollution-associated adverse cardiovascular effects remain largely unknown. In the present study, we investigated the impacts of ambient air pollution on vascular function and the potential mediation effects of amino acids in a longitudinal follow-up of 73 healthy adults living in Beijing, China, between 2014 and 2016. We estimated associations between air pollutants and serum soluble intercellular adhesion molecule 1 (sICAM-1) and plasma levels of amino acids using linear mixed-effects models, and elucidated the biological pathways involved using mediation analyses. Higher air pollutant levels were significantly associated with increases in sICAM-1 levels. Metabolomics analysis showed that altered metabolites following short-term air pollution exposure were mainly involved in amino acid metabolism. Significant reductions in levels of plasma alanine, threonine and glutamic acid of 2.1 µM [95% confidence interval (CI): -3.8, -0.3] to 62.0 µM (95% CI: -76.1, -47.9) were associated with interquartile range increases in moving averages of PM2.5, BC, CO and SO2 in 1-7 days prior to clinical visits. Mediation analysis also showed that amino acids can mediate up to 48% of the changes in sICAM-1 associated with increased air pollution exposure. Our results indicated that air pollution may prompt vascular dysfunction through perturbing amino acid metabolism.
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Poluentes Atmosféricos , Poluição do Ar , Adulto , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Aminoácidos , China , Exposição Ambiental/análise , Humanos , Material Particulado/análise , Material Particulado/toxicidadeRESUMO
Inflammation and abnormal metabolism play important roles in the pathogenesis of diabetic nephropathy (DN). Annexin A1 (ANXA1) contributes to inflammation resolution and improves metabolism. In this study, we assess the effects of ANXA1 in diabetic mice and proximal tubular epithelial cells (PTECs) treated with high glucose plus palmitate acid (HGPA) and explore the association of ANXA1 with lipid accumulation in patients with DN. It is found that ANXA1 deletion aggravates renal injuries, including albuminuria, mesangial matrix expansion, and tubulointerstitial lesions in high-fat diet/streptozotocin-induced diabetic mice. ANXA1 deficiency promotes intrarenal lipid accumulation and drives mitochondrial alterations in kidneys. In addition, Ac2-26, an ANXA1 mimetic peptide, has a therapeutic effect against lipid toxicity in diabetic mice. In HGPA-treated human PTECs, ANXA1 silencing causes FPR2/ALX-driven deleterious effects, which suppress phosphorylated Thr172 AMPK, resulting in decreased peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase 1b expression and increased HGPA-induced lipid accumulation, apoptosis, and elevated expression of proinflammatory and profibrotic genes. Last but not least, the extent of lipid accumulation correlates with renal function, and the level of tubulointerstitial ANXA1 expression correlates with ectopic lipid deposition in kidneys of patients with DN. These data demonstrate that ANXA1 regulates lipid metabolism of PTECs to ameliorate disease progression; hence, it holds great potential as a therapeutic target for DN.
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Anexina A1/fisiologia , Nefropatias Diabéticas/genética , Metabolismo dos Lipídeos/genética , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Anexina A1/genética , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR alfa/genética , PPAR alfa/metabolismo , Transdução de Sinais/genética , EstreptozocinaRESUMO
Compound-specific isotope analysis (CSIA), position-specific isotope analysis (PSIA), and computational modeling (e.g., quantum mechanical models; reactive-transport models) are increasingly being used to monitor and predict biotic and abiotic transformations of organic contaminants in the field. However, identifying the isotope effect(s) associated with a specific transformation remains challenging in many cases. Here, we describe and interpret the position-specific isotope effects of C and N associated with a SN2Ar reaction mechanism by a combination of CSIA and PSIA using quantitative 13C nuclear magnetic resonance spectrometry, and density-functional theory, using 2,4-dinitroanisole (DNAN) as a model compound. The position-specific 13C enrichment factor of O-C1 bond at the methoxy group attachment site (εC1) was found to be approximately -41, a diagnostic value for transformation of DNAN to its reaction products 2,4-dinitrophenol and methanol. Theoretical kinetic isotope effects calculated for DNAN isotopologues agreed well with the position-specific isotope effects measured by CSIA and PSIA. This combination of measurements and theoretical predictions demonstrates a useful tool for evaluating degradation efficiencies and/or mechanisms of organic contaminants and may promote new and improved applications of isotope analysis in laboratory and field investigations.
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Anisóis , Isótopos , Isótopos de Carbono , Hidrólise , Espectroscopia de Ressonância MagnéticaRESUMO
Since failed resolution of inflammation is a major contributor to the progression of diabetic nephropathy, identifying endogenously generated molecules that promote the physiological resolution of inflammation may be a promising therapeutic approach for this disease. Annexin A1 (ANXA1), as an endogenous mediator, plays an important role in resolving inflammation. Whether ANXA1 could affect established diabetic nephropathy through modulating inflammatory states remains largely unknown. In the current study, we found that in patients with diabetic nephropathy, the levels of ANXA1 were upregulated in kidneys, and correlated with kidney function as well as kidney outcomes. Therefore, the role of endogenous ANXA1 in mouse models of diabetic nephropathy was further evaluated. ANXA1 deficiency exacerbated kidney injuries, exhibiting more severe albuminuria, mesangial matrix expansion, tubulointerstitial lesions, kidney inflammation and fibrosis in high fat diet/streptozotocin-induced-diabetic mice. Consistently, ANXA1 overexpression ameliorated kidney injuries in mice with diabetic nephropathy. Additionally, we found Ac2-26 (an ANXA1 mimetic peptide) had therapeutic potential for alleviating kidney injuries in db/db mice and diabetic Anxa1 knockout mice. Mechanistic studies demonstrated that intracellular ANXA1 bound to the transcription factor NF-κB p65 subunit, inhibiting its activation thereby modulating the inflammatory state. Thus, our data indicate that ANXA1 may be a promising therapeutic approach to treating and reversing diabetic nephropathy.
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Anexina A1 , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Anexina A1/genética , Diabetes Mellitus Experimental/complicações , Humanos , Inflamação , Rim , CamundongosRESUMO
AIMS: Eva-1 homologue 1 (Eva1a) is a novel protein involved in the regulation of cardiac remodelling and plaque stability, but little is known about its role in re-endothelialization and the development of atherosclerosis (AS). Thus, in the present study, we aimed to elucidate the function of Eva1a in re-endothelialization and AS. METHODS AND RESULTS: Wire injuries of carotid and femoral arteries were established in Eva1a-/- mice. Eva1a-deficient mice were crossed with apolipoprotein E-/- (ApoE-/-) mice to evaluate AS development and re-endothelialization of carotid artery injuries. Denudation of the carotid artery at 3, 5, and 7 days was significantly aggravated in Eva1a-/- mice. The neointima of the femoral artery at 14 and 28 days was consequently exacerbated in Eva1a-/- mice. The area of atherosclerotic lesions was increased in Eva1a-/-ApoE-/- mice. To explore the underlying mechanisms, we performed transwell, scratch migration, cell counting kit-8, and bromodeoxyuridine assays using cultured human aorta endothelial cells (HAECs), which demonstrated that EVA1A promoted HAEC migration and proliferation. Proteomics revealed that the level of actin-related protein 2/3 complex subunit 1B (Arpc1b) was decreased, while Eva1a expression was absent. Arpc1b was found to be a downstream molecule of EVA1A by small interfering RNA transfection assay. Activation of Rac1 and Cdc42 GTPases was also regulated by EVA1A. CONCLUSION: This study provides insights into anti-atherogenesis effects of Eva1a by promoting endothelium repair. Thus, Eva1a is a promising therapeutic target for AS.
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Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Artérias/enzimologia , Aterosclerose/enzimologia , Proliferação de Células , Células Endoteliais/enzimologia , Proteínas de Membrana/metabolismo , Reepitelização , Lesões do Sistema Vascular/enzimologia , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Animais , Proteínas Reguladoras de Apoptose/genética , Artérias/lesões , Artérias/patologia , Aterosclerose/genética , Aterosclerose/patologia , Movimento Celular , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/patologia , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neointima , Neuropeptídeos , Transdução de Sinais , Lesões do Sistema Vascular/genética , Lesões do Sistema Vascular/patologiaRESUMO
BACKGROUND: Primary malignant melanoma of the esophagus accounts for 0.1%-0.2% of all esophageal malignancies, including melanotic and amelanotic melanomas. Primary amelanotic malignant melanoma of the esophagus is extremely rare, and only about 20 cases have been published in the literature to date. Most primary malignant melanomas of the esophagus are diagnosed following development of metastatic lesions and thus have a very poor prognosis. The median survival duration of patients with metastatic melanoma has been reported to be 6.2 mo. CASE SUMMARY: A 49-year-old woman was referred to our hospital with a diagnosis of esophageal cancer. Endoscopy, biopsy, imaging evaluation, and physical examination at our hospital indicated a diagnosis of advanced primary amelanotic malignant melanoma of the esophagus. Immunohistochemical staining confirmed melanoma. Nuclear medicine examination revealed a left iliac bone metastatic lesion. After discharge, the patient self-administered apatinib for 3 mo, followed by oral treatment with Chinese medicines (also self-administered) for 2 mo. No treatments had been taken since then. The patient has survived with no growth out to the most recent follow-up (24 mo post diagnosis), and she always presented with a positive attitude about her condition during this period. CONCLUSION: Survival following metastatic melanoma might be related to the pharmaceutical and Chinese medicine treatment and the patient's positive attitude.
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Gut microbiota can influence the aging process and may modulate aging-related changes in cognitive function. Trimethylamine-N-oxide (TMAO), a metabolite of intestinal flora, has been shown to be closely associated with cardiovascular disease and other diseases. However, the relationship between TMAO and aging, especially brain aging, has not been fully elucidated. To explore the relationship between TMAO and brain aging, we analysed the plasma levels of TMAO in both humans and mice and administered exogenous TMAO to 24-week-old senescence-accelerated prone mouse strain 8 (SAMP8) and age-matched senescence-accelerated mouse resistant 1 (SAMR1) mice for 16 weeks. We found that the plasma levels of TMAO increased in both the elderly and the aged mice. Compared with SAMR1-control mice, SAMP8-control mice exhibited a brain aging phenotype characterized by more senescent cells in the hippocampal CA3 region and cognitive dysfunction. Surprisingly, TMAO treatment increased the number of senescent cells, which were primarily neurons, and enhanced the mitochondrial impairments and superoxide production. Moreover, we observed that TMAO treatment increased synaptic damage and reduced the expression levels of synaptic plasticity-related proteins by inhibiting the mTOR signalling pathway, which induces and aggravates aging-related cognitive dysfunction in SAMR1 and SAMP8 mice, respectively. Our findings suggested that TMAO could induce brain aging and age-related cognitive dysfunction in SAMR1 mice and aggravate the cerebral aging process of SAMP8 mice, which might provide new insight into the effects of intestinal microbiota on the brain aging process and help to delay senescence by regulating intestinal flora metabolites.
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Encéfalo/metabolismo , Senescência Celular , Disfunção Cognitiva/metabolismo , Metilaminas/metabolismo , Adolescente , Adulto , Idoso , Animais , Humanos , Masculino , Metilaminas/sangue , Camundongos , Pessoa de Meia-Idade , Adulto JovemRESUMO
Amending bulk and nanoscale zero-valent iron (ZVI) with catalytic metals significantly accelerates hydrodechlorination of groundwater contaminants such as trichloroethene (TCE). The bimetallic design benefits from a strong synergy between Ni and Fe in facilitating the production of active hydrogen for TCE reduction, and it is of research and practical interest to understand the impacts of common groundwater solutes on catalyst and ZVI functionality. In this study, TCE hydrodechlorination reaction was conducted using fresh NiFe bimetallic nanoparticles (NiFe BNPs) and those aged in chloride, sulfate, phosphate, and humic acid solutions with concurrent analysis of carbon fractionation of TCE and its daughter products. The apparent kinetics suggest that the reactivity of NiFe BNPs is relatively stable in pure water and chloride or humic acid solutions, in contrast to significant deactivation observed of PdFe bimetallic particles in similar media. Exposure to phosphate at greater than 0.1â¯mM led to a severe decrease in TCE reaction rate. The change in kinetic regimes from first to zeroth order with increasing phosphate concentration is consistent with consumption of reactive sites by phosphate. Despite severe kinetic effect, there is no significant shift in TCE 13C bulk enrichment factor between the fresh and the phosphate-aged particles. Instead, pronounced retardation of TCE reaction by NiFe BNPs in deuterated water (D2O) points to the importance of hydrogen spillover in controlling TCE reduction rate by NiFe BNPs, and such process can be strongly affected by groundwater chemistry.