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BACKGROUND: Diabetes mellitus (DM) and coronary microvascular dysfunction (CMD) increase the risk of adverse cardiac events in patients with non-ST-segment elevation myocardial infarction (NSTEMI). This study aimed to evaluate the combined risk estimates of DM and CMD, assessed by the angiography-derived index of microcirculatory resistance (angio-IMR), in patients with NSTEMI. METHODS: A total of 2212 patients with NSTEMI who underwent successful percutaneous coronary intervention (PCI) were retrospectively enrolled from three centers. The primary outcome was a composite of cardiac death or readmission for heart failure at a 2-year follow-up. RESULTS: Post-PCI angio-IMR did not significantly differ between the DM group and the non-DM group (20.13 [17.91-22.70] vs. 20.19 [18.14-22.77], P = 0.530). DM patients exhibited a notably higher risk of cardiac death or readmission for heart failure at 2 years compared to non-DM patients (9.5% vs. 5.4%, P < 0.001). NSTEMI patients with both DM and CMD experienced the highest cumulative incidence of cardiac death or readmission for heart failure at 2 years (24.0%, P < 0.001). The combination of DM and CMD in NSTEMI patients were identified as the most powerful independent predictor for cardiac death or readmission for heart failure at 2 years (adjusted HR: 7.894, [95% CI, 4.251-14.659], p < 0.001). CONCLUSIONS: In patients with NSTEMI, the combination of DM and CMD is an independent predictor of cardiac death or readmission for heart failure. Angio-IMR could be used as an additional evaluation tool for the management of NSTEMI patients with DM. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT05696379.
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Angiografía Coronaria , Circulación Coronaria , Diabetes Mellitus , Microcirculación , Infarto del Miocardio sin Elevación del ST , Readmisión del Paciente , Intervención Coronaria Percutánea , Valor Predictivo de las Pruebas , Resistencia Vascular , Humanos , Masculino , Femenino , Persona de Mediana Edad , Infarto del Miocardio sin Elevación del ST/diagnóstico por imagen , Infarto del Miocardio sin Elevación del ST/mortalidad , Infarto del Miocardio sin Elevación del ST/terapia , Infarto del Miocardio sin Elevación del ST/fisiopatología , Anciano , Medición de Riesgo , Estudios Retrospectivos , Intervención Coronaria Percutánea/efectos adversos , Factores de Riesgo , Factores de Tiempo , Diabetes Mellitus/epidemiología , Diabetes Mellitus/diagnóstico , Resultado del Tratamiento , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca/epidemiología , China/epidemiologíaRESUMEN
BACKGROUND: The index of microcirculatory resistance is a reliable measure for evaluating coronary microvasculature, but its prognostic value in patients with non-ST-segment elevation myocardial infarction (NSTEMI) remains unclear. OBJECTIVES: This study aimed to evaluate the prognostic impact of post-percutaneous coronary intervention (PCI) angiography-derived index of microcirculatory resistance (angio-IMR) in patients with NSTEMI. METHODS: The culprit vessel's angio-IMR was measured after PCI in 2,212 NSTEMI patients at 3 sites. The primary endpoint was 2-year major adverse cardiac events (MACEs), defined as a composite of cardiac death, readmission for heart failure, myocardial reinfarction, and target vessel revascularization. RESULTS: The mean post-PCI angio-IMR was 20.63 ± 4.17 in NSTEMI patients. Two hundred six patients were categorized as the high post-PCI angio-IMR group according to maximally selected log-rank statistics. Patients with angio-IMR >25 showed a higher rate of MACEs than those with angio-IMR ≤25 (32.52% vs 9.37%; P < 0.001). Post-PCI angio-IMR >25 was an independent predictor of MACEs (HR: 4.230; 95% CI: 3.151-5.679; P < 0.001) and showed incremental prognostic value compared with conventional risk factors (AUC: 0.774 vs 0.716; P < 0.001; net reclassification index: 0.317; P < 0.001; integrated discrimination improvement: 0.075; P < 0.001). CONCLUSIONS: In patients undergoing PCI for NSTEMI, an increased post-PCI angio-IMR is associated with a higher risk of MACEs. The addition of post-PCI angio-IMR into conventional risk factors significantly improves the ability to reclassify patients and estimate the risk of MACEs. (Angiograph-Derived Index of Microcirculatory Resistance in Patients With Acute Myocardial Infarction; NCT05696379).
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Exposure to fine particulate matter (PM) is associated with the neurodegenerative diseases. Coke oven emissions (COEs) in occupational environment are important sources of PM. However, its neurotoxicity is still unclear. Therefore, evaluating the toxicological effects of COE on the nervous system is necessary. In the present study, we constructed mouse models of COE exposure by tracheal instillation. Mice exposed to COE showed signs of cognitive impairment. This was accompanied by a decrease in miR-145a-5p and an increase in SIK1 expression in the hippocampus, along with synaptic structural damage. Our results demonstrated that COE-induced miR-145a-5p downregulation could increase the expression of SIK1 and phosphorylated SIK1, inhibiting the cAMP/PKA/CREB pathway by activating PDE4D, which was associated with reduced synaptic structural plasticity. Furthermore, restoring of miR-145a-5p expression based on COE exposure in HT22 cells could partially reversed the negative effects of COE exposure through the SIK1/PDE4D/cAMP axis. Collectively, our findings link epigenetic regulation with COE-induced neurotoxicity and imply that miR-145a-5p could be an early diagnostic marker for neurological diseases in patients with COE occupational exposure.
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Disfunción Cognitiva , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , MicroARNs , Plasticidad Neuronal , Proteínas Serina-Treonina Quinasas , Animales , MicroARNs/genética , Ratones , Disfunción Cognitiva/inducido químicamente , Plasticidad Neuronal/efectos de los fármacos , Masculino , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , AMP Cíclico/metabolismo , Hipocampo/efectos de los fármacos , Ratones Endogámicos C57BL , Contaminantes Atmosféricos/toxicidad , Material Particulado/toxicidadAsunto(s)
Angiografía Coronaria , Circulación Coronaria , Microcirculación , Valor Predictivo de las Pruebas , Infarto del Miocardio con Elevación del ST , Resistencia Vascular , Humanos , Infarto del Miocardio con Elevación del ST/fisiopatología , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/terapia , Masculino , Femenino , Persona de Mediana Edad , Anciano , Pronóstico , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/fisiopatología , Intervención Coronaria PercutáneaRESUMEN
Substituted para-phenylenediamines (PPDs) are synthetic chemicals used globally for rubber antioxidation, with their quinone derivatives (PPD-Qs) raising particular environmental concerns due to their severe toxicity to aquatic organisms. Emerging research has identified a variety of novel PPD-Qs ubiquitously detected in the environment, yet experimental proof for the toxicity of PPD-Qs has not been forthcoming due to the unavailability of bulk standards, leaving substantial gaps in the prioritization and mechanistic investigation of such novel pollutants. Here, we use synthesized chemical standards to study the acute toxicity and underlying mechanism of 18 PPD-Qs and PPDs to the aquatic bacterium V. fischeri. Bioluminescence inhibition EC50 of PPD-Qs ranged from 1.76-15.6 mg/L, with several emerging PPD-Qs demonstrating significantly higher toxicity than the well-studied 6PPD-Q. This finding suggests a broad toxicological threat PPD-Qs pose to the aquatic bacterium, other than 6PPD-Q. Biological response assays revealed that PPD-Qs can reduce the esterase activity, cause cell membrane damage and intracellular oxidative stress. Molecular docking unveiled multiple interactions of PPD-Qs with the luciferase in V. fischeri, suggesting their potential functional impacts on proteins through competitive binding. Our results provided crucial toxicity benchmarks for PPD-Qs, prioritized these novel pollutants and shed light on the potential toxicological mechanisms.
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Contaminantes Ambientales , Quinonas , Quinonas/toxicidad , Antioxidantes , Simulación del Acoplamiento Molecular , Fenilendiaminas/toxicidad , Benzoquinonas/toxicidadRESUMEN
Despite significant advances in understanding the general health impacts of air pollution, the toxic effects of air pollution on cells in the human respiratory tract are still elusive. A robust, biologically relevant in vitro model for recapitulating the physiological response of the human airway is needed to obtain a thorough understanding of the molecular mechanisms of air pollutants. In this study, by using 1-nitropyrene (1-NP) as a proof-of-concept, we demonstrate the effectiveness and reliability of evaluating environmental pollutants in physiologically active human airway organoids. Multimodal imaging tools, including live cell imaging, fluorescence microscopy, and MALDI-mass spectrometry imaging (MSI), were implemented to evaluate the cytotoxicity of 1-NP for airway organoids. In addition, lipidomic alterations upon 1-NP treatment were quantitatively analyzed by nontargeted lipidomics. 1-NP exposure was found to be associated with the overproduction of reactive oxygen species (ROS), and dysregulation of lipid pathways, including the SM-Cer conversion, as well as cardiolipin in our organoids. Compared with that of cell lines, a higher tolerance of 1-NP toxicity was observed in the human airway organoids, which might reflect a more physiologically relevant response in the native airway epithelium. Collectively, we have established a novel system for evaluating and investigating molecular mechanisms of environmental pollutants in the human airways via the combinatory use of human airway organoids, multimodal imaging analysis, and MS-based analyses.
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Contaminantes Atmosféricos , Pirenos , Sistema Respiratorio , Humanos , Reproducibilidad de los Resultados , Organoides , Imagen MultimodalRESUMEN
Mass spectrometry imaging (MSI) is a high-throughput imaging technique capable of the qualitative and quantitative in situ detection of thousands of ions in biological samples. Ion image representation is a technique that produces a low-dimensional vector embedded with significant spectral and spatial information on an ion image, which further facilitates the distance-based similarity measurement for the identification of colocalized ions. However, given the low signal-to-noise ratios inherent in MSI data coupled with the scarcity of annotated data sets, achieving an effective ion image representation for each ion image remains a challenge. In this study, we propose DeepION, a novel deep learning-based method designed specifically for ion image representation, which is applied to the identification of colocalized ions and isotope ions. In DeepION, contrastive learning is introduced to ensure that the model can generate the ion image representation in a self-supervised manner without manual annotation. Since data augmentation is a crucial step in contrastive learning, a unique data augmentation strategy is designed by considering the characteristics of MSI data, such as the Poisson distribution of ion abundance and a random pattern of missing values, to generate plentiful ion image pairs for DeepION model training. Experimental results of rat brain tissue MSI show that DeepION outperforms other methods for both colocalized ion and isotope ion identification, demonstrating the effectiveness of ion image representation. The proposed model could serve as a crucial tool in the biomarker discovery and drug development of the MSI technique.
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Aprendizaje Profundo , Ratas , Animales , Espectrometría de Masas , Diagnóstico por Imagen , Iones , IsótoposAsunto(s)
Angioplastia Coronaria con Balón , Fármacos Cardiovasculares , Materiales Biocompatibles Revestidos , Enfermedad de la Arteria Coronaria , Stents Liberadores de Fármacos , Reserva del Flujo Fraccional Miocárdico , Humanos , Resultado del Tratamiento , Angioplastia Coronaria con Balón/instrumentación , Angioplastia Coronaria con Balón/efectos adversos , Enfermedad de la Arteria Coronaria/terapia , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/fisiopatología , Fármacos Cardiovasculares/administración & dosificación , Catéteres Cardíacos , Intervención Coronaria Percutánea/instrumentación , Intervención Coronaria Percutánea/efectos adversos , Diseño de Prótesis , Factores de Riesgo , Valor Predictivo de las Pruebas , Factores de TiempoRESUMEN
Mitochondrial dysfunction is one of the triggers for obesity-induced neuron apoptosis. Thinned young apple is getting more attention on account of the extensive biological activities because of rich polyphenols and polysaccharides. However, the neuroprotective effect of thinned young apple powder (YAP) is still unclear. The aim of the present study was to investigate the preventive effect of YAP on obesity-induced neuronal apoptosis. C57BL/6J male mice were divided into 5 groups, control (CON), high fat diet (HFD), HFD + orlistat (ORL), HFD + low-dose young apple powder (LYAP) and HFD + high-dose young apple powder (HYAP) groups and intervened for 12 weeks. It was found that the YAP effectively reduced body weight gain. Importantly, the levels of pro-apoptosis protein were lower in LYAP and HYAP groups than the HFD group, such as Bak/Bcl2 and cleaved caspase3/caspase3. Pathway analysis based on untargeted metabolomics suggested that YAP alleviated obesity-induced neuronal apoptosis by three main metabolic pathway including arginine metabolism, citrate cycle (TCA cycle) and glutathione metabolism. Meanwhile, YAP improved the protein expression of mitochondrial respiratory chain complex, maintained the homeostasis of TCA cycle intermediates, protected the balance of mitochondrial dynamics and alleviated lipid accumulation. In addition, the levels of several antioxidants in cerebral cortex were higher in HYAP group than the HFD group like superoxide dismutase (SOD) and catalase (CAT). In summary, YAP supplementation suppressed neuronal apoptosis in the cerebral cortex of HFD-induced obesity mice by improving mitochondrial function and inhibiting oxidative stress.
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Malus , Ratones , Masculino , Animales , Polvos/farmacología , Ratones Endogámicos C57BL , Obesidad/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo , Dieta Alta en Grasa/efectos adversos , Apoptosis , Corteza Cerebral/metabolismoRESUMEN
Antibody-Drug Conjugates (ADCs) represent a rapidly advancing category of oncology therapeutics, spanning the targeted therapy for both hematologic malignancies and solid cancers. A crucial aspect of ADC research involves the identification of optimal surface antigens that can effectively differentiate target cells from most mammalian cell types. Herein, we have devised an algorithm and compiled an extensive dataset annotating cell membrane proteins. This dataset is derived from comprehensive transcriptomic, proteomic, and genomic data encompassing 19 types of solid cancer as well as normal tissues. The aim is to uncover potential therapeutic surface antigens for precise ADC targeting. The resulting target landscape comprises 165 combinations of targets and indications, along with 75 candidates of cell surface proteins. Notably, 35 of these candidates possess characteristics suitable for ADC targeting, and have not been previously reported in ADC research and development. Additionally, we have identified a total of 159 ADCs from a pool of 760 clinical trials. Of these, 72 ADCs are presently undergoing interventional evaluation for a variety of solid cancer types, targeting 36 unique antigens. We conducted an analysis of their expression in normal tissues using this comprehensive annotation dataset, revealing a diverse range of profiles for the current ADC targets. Moreover, we emphasize that the biological impacts of target antigens have the potential to enhance their clinical effectiveness. We propose a comprehensive assessment of the drugability of target antigens, considering multiple facets. This study represents a thorough exploration of pan-cancer ADC targets over the past two decades, underscoring the potential of a comprehensive solid cancer target atlas to broaden the scope of ADC therapies.
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Antineoplásicos , Inmunoconjugados , Neoplasias , Animales , Humanos , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Proteómica , Antígenos de Superficie/uso terapéutico , Antineoplásicos/uso terapéutico , MamíferosRESUMEN
The emerging toxicant N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q) is of wide concern due to its ubiquitous occurrence and high toxicity. Despite regular human exposure, limited evidence exists about its presence in the body and potential health risks. Herein, we analyzed cerebrospinal fluid (CSF) samples from Parkinson's disease (PD) patients and controls. The CSF levels of 6PPD-Q were twice as high in PD patients compared to controls. Immunostaining assays performed with primary dopaminergic neurons confirm that 6PPD-Q at environmentally relevant concentrations can exacerbate the formation of Lewy neurites induced by α-synuclein preformed fibrils (α-syn PFF). Assessment of cellular respiration reveals a considerable decrease in neuronal spare respiratory and ATP-linked respiration, potentially due to changes in mitochondrial membrane potential. Moreover, 6PPD-Q-induced mitochondrial impairment correlates with an upsurge in mitochondrial reactive oxygen species (mROS), and Mito-TEMPO-driven scavenging of mROS can lessen the amount of pathologic phospho-serine 129 α-synuclein. Untargeted metabolomics provides supporting evidence for the connection between 6PPD-Q exposure and changes in neuronal metabolite profiles. In-depth targeted metabolomics further unveils an overall reduction in glycolysis metabolite pool and fluctuations in the quantity of TCA cycle intermediates. Given its potentially harmful attributes, the presence of 6PPD-Q in human brain could potentially be a risk factor for PD.
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Enfermedades Mitocondriales , Enfermedad de Parkinson , Humanos , alfa-Sinucleína/metabolismo , Neuronas Dopaminérgicas , Cuerpos de Lewy/metabolismo , Cuerpos de Lewy/patología , Enfermedades Mitocondriales/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Quinonas/metabolismoRESUMEN
Both epidemiological and preclinical studies have shown the benefits of n-3 polyunsaturated fatty acid (n-3 PUFA) on dementia and cognitive impairment, yet the results of clinical randomized controlled trials (RCTs) performed to date are conflicting. The difference in the baseline omega-3 index (O3i) of subjects is a potential cause for this disparity, yet this is usually ignored. The present meta-analysis aimed to evaluate the effect of n-3 polyunsaturated fatty acid (n-3 PUFA) on cognitive function in the elderly and the role of baseline O3i. A systematic literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science up to June 27th, 2023. The mean changes in the mini-mental state examination (MMSE) score were calculated as weighted mean differences by using a fixed-effects model. Fifteen random controlled trials were included in the meta-analysis. Pooled analysis showed that n-3 PUFA supplementation did not significantly improve the MMSE score (WMD = 0.04, [-0.08, 0.16]; Z = 0.62, P = 0.53; I2 = 0.00%, P(I2) = 0.49). Out of the 15 studies included in the meta-analysis, only 7 reported O3i at baseline and outcome, so only these 7 articles were used for subgroup analysis. Subgroup analysis showed that the MMSE score was significantly improved in the higher baseline O3i subgroup (WMD = 0.553, [0.01, 1.095]; I2 = 0.00%, P(I2) = 0.556) and higher O3i increment subgroup (WMD = 0.525, [0.023, 1.026]; I2 = 0.00%, P(I2) = 0.545). The overall effect demonstrated that n-3 PUFA supplementation exerted no improvement on global cognitive function. However, a higher baseline O3i and higher O3i increment were associated with an improvement in cognitive function in the elderly.
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Disfunción Cognitiva , Ácidos Grasos Omega-3 , Humanos , Anciano , Ácidos Grasos Omega-3/farmacología , Cognición , Disfunción Cognitiva/tratamiento farmacológico , Suplementos DietéticosRESUMEN
Epidemiological and experimental data have associated exposure to fine particulate matter (PM2.5) with various metabolic dysfunctions and diseases, including overweight and type 2 diabetes. Adipose tissue is an energy pool for storing lipids, a necessary regulator of glucose homeostasis, and an active endocrine organ, playing an essential role in developing various related diseases such as diabetes and obesity. However, the molecular mechanisms underlying PM2.5-impaired functions in adipose tissue have rarely been explored. In this work, metabolomics based on liquid chromatography-mass spectrometry was performed to study the adverse impacts of PM2.5 exposure on brown adipose tissue (BAT) and white adipose tissue (WAT) in the diabetic mouse model. We found the effects of PM2.5 exposure by comparing the different metabolites in both adipose tissues of male db/db mice using real-ambient PM2.5 exposure. The results showed that PM2.5 exposure changed the purine metabolism in mice, especially the dramatic increase of xanthine content in both WAT and BAT. These changes led to significant oxidative stress. Then the results from real-time quantitative polymerase chain reaction showed that PM2.5 exposure could cause the production of inflammatory factors in both adipose tissues. Moreover, the increased reactive oxygen species (ROS) promoted triglyceride accumulation in WAT and inhibited its decomposition, causing increased WAT content in db/db mice. In addition, PM2.5 exposure significantly suppressed thermogenesis and affected energy metabolism in the BAT of male db/db mice, which may deteriorate insulin sensitivity and blood glucose regulation. This research demonstrated the impact of PM2.5 on the adipose tissue of male db/db mice, which may be necessary for public health.
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Diabetes Mellitus Tipo 2 , Masculino , Ratones , Animales , Especies Reactivas de Oxígeno/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Xantina/efectos adversos , Xantina/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo Pardo , Material Particulado/efectos adversos , Metabolismo Energético , Ratones Endogámicos C57BLRESUMEN
Dendrobium officinale polysaccharide (DP) has the potential function to prevent diabetes-induced neuronal apoptosis, whereas the mechanism is not completely clear. Ten eleven translocation dioxygenase 2 (TET2) is one of the most important therapeutic target for repairing neuronal damage in diabetic mice. The aim of the present study was to investigate whether DP could prevent neuronal apoptosis by regulating TET2 in the brain of HFD-induced diabetic mice. C57BL/6J mice were randomly divided into four groups (n = 12), control group (CON), high-fat diet group (HFD, negative control), metformin group (MET, positive control), and DP group (DP). Compared with HFD group, the neuronal apoptosis of brain was significantly lower in the DP group. The levels of TET2 protein, 5-hydroxymethylcytosine (5hmC) and 5-formylcytosine (5fC) were significantly lower in the HFD group than in both the DP and CON groups in the cerebral cortex of mice. The ratio of p-AMPK/AMPK and α-KG/(fumaric acid + succinic acid) were significantly lower in the HFD group than in the other groups. The present study suggests that DP has a preventive effect on diabetes-induced neuronal apoptosis by regulating TET2 function through improving phosphorylate AMPK and mitochondrial function, thus remodeling DNA epigenetics profile of mice brain.
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Dendrobium , Diabetes Mellitus Experimental , Dioxigenasas , Ratones , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Dieta Alta en Grasa/efectos adversos , Proteínas Quinasas Activadas por AMP/metabolismo , Desmetilación del ADN , Ratones Endogámicos C57BL , Polisacáridos/farmacología , Polisacáridos/uso terapéutico , Apoptosis , Proteínas de Unión al ADN/metabolismo , Dioxigenasas/metabolismoRESUMEN
Diabetic retinopathy (DR) is a common serious complication of diabetes that accounts for the leading cause of blindness among the working-age population in developed countries. Despite substantial progress in therapeutic approaches, DR remains highly prevalent, indicating deeper pathomechanism studies are urgently needed. Nowadays, natural products with outstanding safety and efficacy play an increasingly vital role in drug discovery research, and some of them have the potential to facilitate the treatment of DR. In this review, we primarily revisit the contribution of redox signaling and its mediators that might be amenable to targeting DR, including Nuclear factor-kappa B (NF-κB), transforming growth factor-ß (TGF-ß), matrix metalloproteinases (MMPs), nuclear factor erythroid 2 related factor 2 (Nrf2), advanced glycation endproducts (AGEs), mammalian target of rapamycin (mTOR) as well as microRNAs. Ultimately, we summarize and evaluate the use of natural products to regulate these signaling pathways, which may increase our understanding and ability to target these important molecules and may help to achieve further clinical benefits.
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Productos Biológicos , Diabetes Mellitus , Retinopatía Diabética , Humanos , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/metabolismo , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Productos Finales de Glicación Avanzada , Oxidación-Reducción , Transducción de Señal/fisiologíaRESUMEN
Exosomes are a pluripotent group of extracellular nanovesicles secreted by all cells that mediate intercellular communications. The effective information within exosomes is primarily reflected in exosomal cargos, including proteins, lipids, DNAs, and non-coding RNAs (ncRNAs), the most intensively studied molecules. Cardiac resident cells (cardiomyocytes, fibroblasts, and endothelial cells) and foreign cells (infiltrated immune cells, cardiac progenitor cells, cardiosphere-derived cells, and mesenchymal stem cells) are involved in the progress of ventricular remodeling (VR) following myocardial infarction (MI) via transferring exosomes into target cells. Here, we summarize the pathological mechanisms of VR following MI, including cardiac myocyte hypertrophy, cardiac fibrosis, inflammation, pyroptosis, apoptosis, autophagy, angiogenesis, and metabolic disorders, and the roles of exosomal cargos in these processes, with a focus on proteins and ncRNAs. Continued research in this field reveals a novel diagnostic and therapeutic strategy for VR.
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Exosomas , MicroARNs , Infarto del Miocardio , Células Endoteliales/metabolismo , Exosomas/metabolismo , Humanos , Lípidos , MicroARNs/metabolismo , Infarto del Miocardio/patología , Miocitos Cardíacos/metabolismo , Remodelación VentricularRESUMEN
Background: Observational studies have shown gut microbiomes were associated with cardiovascular diseases (CVDs), but their roles remain controversial, and these associations have not yet been established causally. Methods: Two-sample Mendelian randomization (MR) was used to investigate whether gut microbiome had a causal effect on the risk of CVDs. To obtain comprehensive results, we performed two sets of MR analyses, one with single nucleotide polymorphisms (SNPs) that smaller than the genome-wide statistical significance threshold (5 × 10-8) as instrumental variables, and the other with SNPs that lower than the locus-wide significance level (1 × 10-5). Summary-level statistics for CVDs, including coronary artery disease (CAD), myocardial infarction, heart failure, atrial fibrillation, stroke and its subtypes were collected. The ME estimation was performed using the inverse-variance weighted and Wald ratio methods. Sensitivity analysis was performed using the weighted median, MR-Egger, leave-one-out analysis, MR pleiotropy residual sum and outlier and MR Steiger. Results: Based on the locus-wide significance level, genetically predicted genus Oxalobacter was positively associated with the risk of CAD (odds ratio (OR) = 1.06, 95% confidence interval (CI), 1.03 - 1.10, P = 1.67 × 10-4), family Clostridiaceae_1 was negatively correlated with stroke risk (OR = 0.83,95% CI, 0.75-0.93, P = 7.76 × 10-4) and ischemic stroke risk (OR = 0.823,95% CI, 0.74-0.92, P = 4.15 × 10-4). There was no causal relationship between other genetically predicted gut microbiome components and CVDs risk. Based on the genome-wide statistical significance threshold, the results showed that the gut microbiome had no causal relationship with CVDs risk. Conclusion: Our findings reveal that there are beneficial or adverse causal effects of gut microbiome components on CVDs risk and provide novel insights into strategies for the prevention and management of CVDs through the gut microbiome.
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Our initial studies detected elevated levels of 3,4-dihydroxyphenyllactic acid (DHPLA) in urine samples of patients with severe heart disease when compared with healthy subjects. Given the reported anti-inflammatory properties of DHPLA and related dihydroxylated phenolic acids (DPAs), we embarked on an exploratory multi-centre investigation in patients with no urinary tract infections to establish the possible pathophysiological significance and therapeutic implications of these findings. Chinese and Caucasian patients being treated for severe heart disease or those conditions associated with inflammation (WBC ≥ 10 ×109/L or hsCRP ≥ 3.0 mg/L) and/or hypoxia (PaO2 ≤ 75 mmHg) were enrolled; their urine samples were analyzed by HPLC, HPLC-MS, GC-MS and biotransformation assays. DHPLA was detected in urine samples of patients, but undetectable in healthy volunteers. Dynamic monitoring of inpatients undergoing treatment showed their DHPLA levels declined in proportion to their clinical improvement. In DHPLA-positive patients' fecal samples, Proteus vulgaris and P. mirabilis were more abundant than healthy volunteers. In culture, these gut bacteria were capable of reversible interconversion between DOPA and DHPLA. Furthermore, porcine and rodent organs were able to metabolize DOPA to DHPLA and related phenolic acids. The elevated levels of DHPLA in these patients suggest bioactive DPAs are generated de novo as part of a human's defense mechanism against disease. Because DHPLA isolated from Radix Salvia miltiorrhizae has a multitude of pharmacological activities, these data underpin the scientific basis of this medicinal plant's ethnopharmacological applications as well as highlighting the therapeutic potential of endogenous, natural or synthetic DPAs and their derivatives in humans.
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Cardiopatías , Inflamación , Humanos , Porcinos , Animales , Hipoxia , DihidroxifenilalaninaRESUMEN
Fibrosis, as a common disease which could be found in nearly all organs, is normally initiated by organic injury and eventually ended in cellular dysfunction and organ failure. Currently, effective and safe therapeutic strategies targeting fibrogenesis still in highly demand. Natural polysaccharides derived from natural resources possess promising anti-fibrosis potential, with no deleterious side effects. Based on the etiology and pathogenesis of fibrosis, this review summarizes the intervention effects and mechanisms of natural polysaccharides in the prevention and treatment of fibrosis. Natural polysaccharides are able to regulate each phase of the fibrogenic response, including primary injury to organs, activation of effector cells, the elaboration of extracellular matrix (ECM) and dynamic deposition. In addition, polysaccharides significantly reduce fibrosis levels in multiple organs including heart, lung, liver and kidney. The investigation of the pathogenesis of fibrosis indicates that mechanisms including the inhibition of TGF-ß/Smad, NF-κB, HMGB1/TLR4, cAMP/PKA signaling pathways, MMPs/TIMPs system as well as microRNAs are promising therapeutic targets. Natural polysaccharides can target these mediators or pathways to alleviate fibrosis. The information reviewed here offer new insights into the understanding the protective role of natural polysaccharides against fibrosis, help design further experimental studies related to polysaccharides and fibrotic responses, and shed light on a potential treatment for fibrosis.
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Proteína HMGB1 , MicroARNs , Antifibróticos , Fibrosis , Humanos , FN-kappa B , Polisacáridos/farmacología , Polisacáridos/uso terapéutico , Receptor Toll-Like 4 , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Background: The role of a drug-coated balloon (DCB) in the treatment of acute myocardial infarction (AMI) is not well established. Methods: Five databases were searched for randomized controlled trials that compared DCB with stents in the treatment of AMI from their inception to 30 July 2021. The primary clinical endpoint was major adverse cardiac events (MACEs). Summary estimations were conducted using fixed-effects analysis complemented by several subgroups. The protocol was registered with PROSPERO (https://clinicaltrials.gov/ct2/show/CRD42021272886). Results: A total of 4 randomized controlled trials with 485 patients were included. On routine clinical follow-up, DCB was associated with no difference in the incidence of MACEs compared with control (risk ratio [RR] 0.59 [0.31 to 1.13]; P=0.11). DCB was associated with similar MACEs compared with drug-eluting stent and lower MACEs compared with bare-metal stent. There was no difference between DCB and control in terms of all-cause mortality, cardiovascular mortality, stent thrombosis, target lesion revascularization, and minimal lumen diameter during follow-up. However, DCB was associated with a lower incidence of myocardial infarction (RR 0.16 [0.03 to 0.90]; P=0.04) and lower late lumen loss (mean difference -0.20 [-0.27 to -0.13]; P < 0.00001). Conclusions: In treatment of patients with AMI, DCB might be a feasible interventional strategy versus control as it associated with comparable clinical outcomes. Future large-volume, well-designed randomized controlled trials to evaluating the role of the DCB in this setting are warranted.