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Passive radiative cooling is a promising technology for heat dissipation that does not consume energy. However, current radiative cooling materials can only exhibit subambient cooling under atmospheric conditions and struggle to process specific heat accumulation. Thus, a passive thermal regulation mechanism adapted to wide-temperature-range applications is required to match device heating systems. Herein, a heteroporous nanocomposite film (HENF) with thermo-adaptive radiation cooling performance is reported. Compared to conventional porous cooling films with limited scattering efficiencies, the HENFs with multistage scattering have a strong emissivity of 96.5% (8-13 µm) and a high reflectivity of 97.3% (0.3-2.5 µm), resulting in an ultrahigh cooling power of 114 W m-2. In such HENFs, theoretical analyses have confirmed the spectrum management superiority of the heteroporous unit in terms of the scattering efficiency strength, with their cascading effect enhancing the overall film-cooling efficiency. The high mechanical performance, phase-transition features, and environmental adaptive properties of HENFs are also exhibited. Importantly, HENFs synergistically couple thermal dissipation and absorption to effectively process heat accumulation and counteract thermal shock in heating devices. It is anticipated that thermo-adaptive HENFs will act as a promising platform for device surface thermal regulation over a wide temperature range.
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Background: Psoriasis is a frequent form of chronic inflammation in dermatology that is unmistakably linked to the metabolic syndrome (MetS) and its elements. This study was to explore the current status and new developments in the global research, and the holistic landscape of this field more intuitively through bibliometric analysis of scientific output and activity. Methods: Publications regarding psoriasis and MetS were searched and chosen from the database of the Web of Science Core Collection. Excel 2019, VOSviewer, and CiteSpace software were utilized to conduct bibliometric analysis. Results: There were 1096 publications included. The scientific outputs in this field had increased from 2004 to 2022, and the expansion could continue in the following years. The United States contributed the most publications (241, 21.99%) and had the most citation frequency (13,489 times). The University of California System was the most productive affiliation. Girolomoni G., Armstrong A.W., Gisondi P. and Gelfand J.M. were key and influential researchers. Journal of the European Academy of Dermatology and Venereology published the greatest number of articles (65 articles). By analyzing keyword frequency and clustering, we have identified the following areas of research interest and frontiers: prevalence, risk, association, gene expression, waist circumference, adipose tissue inflammation, vascular inflammation, cardiovascular disease, psoriatic arthritis, and fibrosis. Conclusion: This bibliometric analysis elucidates research domain of psoriasis and MetS, portraying present hotspots and future emerging trends. This field has generated significant interest and displays potential for further growth. The United States has made distinguished contributions, and currently dominates this field.
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In vivo quantitative assessment of oxyhaemoglobin saturation (sO2) status in tumour-associated vessels could provide insights into cancer metabolism and behaviour. Here we develop a non-invasive in vivo sO2 imaging technique to visualize the sO2 levels of healthy and tumour tissue based on photoluminescence bioimaging in the near-infrared IIb (NIR-IIb; 1,500-1,700 nm) window. Real-time dynamic sO2 imaging with a high frame rate (33 Hz) reveals the cerebral arteries and veins through intact mouse scalp/skull, and this imaging is consistent with the haemodynamic analysis results. Utilizing our non-invasive sO2 imaging, the tumour-associated-vessel sO2 levels of various cancer models are evaluated. A positive correlation between the tumour-associated-vessel sO2 levels and the basal oxygen consumption rate of corresponding cancer cells at the early stages of tumorigenesis suggests that cancer cells modulate the tumour metabolic microenvironment. We also find that a positive therapeutic response to the checkpoint blockade cancer immunotherapy could lead to a dramatic decrease of the tumour-associated-vessel sO2 levels. Two-plex dynamic NIR-IIb imaging can be used to simultaneously observe tumour-vessel sO2 and PD-L1, allowing a more accurate prediction of immunotherapy response.
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Neoplasias , Oxiemoglobinas , Animais , Camundongos , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Diagnóstico por Imagem , Imunoterapia , Microambiente TumoralRESUMO
Metastatic skin cutaneous melanoma (SKCM) is a common malignancy that accounts for low morbidity but high mortality of skin cancer. SKCM is characterized by high lymphocytic infiltration, whereas the states of infiltrated cells are variable in patients leading to a heterogeneous prognosis and hindering appropriate clinical decisions. It is therefore urgent to identify markers associated with lymphocytic infiltration, cellular conditions, and the prognosis of SKCM. In this study, we report that CEBPB, a transcriptional factor, is mainly expressed in macrophages in metastatic SKCM and associated with an active tumor immune environment and a favorable prognosis through integrated analysis of single-cell and bulk RNA-seq datasets. High CEBPB expression is significantly associated with active inflammation and immune response pathways in both macrophages and bulk SKCM tumor tissues. A signature based on CEBPB-associated genes that are specifically expressed in macrophages could robustly and prognostically separate different metastatic SKCM patients. In addition, the associations between the metastatic SKCM tumor signature and microenvironment with respect to T-cell recruitment and state, inflammation response, angiogenesis, and so on were also determined. In conclusion, we present here the first report on CEBPB in tumor immune environment and prognosis regulation in metastatic SKCM and construct a reliable signature, which should provide a useful biomarker for stratification of the patient's prognosis and therapeutic selection.
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Melanoma , Segunda Neoplasia Primária , Neoplasias Cutâneas , Humanos , Melanoma/patologia , Neoplasias Cutâneas/patologia , Prognóstico , Biomarcadores , Inflamação , Microambiente Tumoral , Proteína beta Intensificadora de Ligação a CCAAT/genética , Melanoma Maligno CutâneoRESUMO
Keloid is a poorly understood fibrotic skin disease that commonly occurs during wound-healing. As a polymer composed of nucleic acid and proteins, the structure of chromatin could be dynamically regulated in the nucleus. In this study, we explored the dynamics of chromatin accessibility and the transcriptome in dermal fibroblasts (DFs) in keloid formation. Compared to normal samples, chromatin accessibility and transcriptome were extensively altered in keloid DFs. In addition, changes in chromatin accessibility were closely associated with changes in gene expression in DFs. Breast cancer type 1 (BRCA1) was significantly downregulated in keloid DFs, and its knockdown promoted the proliferation and attenuated the migration ability of normal DF cells. Mechanistically, BRCA1 suppression significantly reduced the expression of neuronal pentraxin 2 (NPTX2), a cell viability-related gene. BRCA1 binding affinity at the NPTX2 enhancer and the chromatin accessibility in the same region were significantly lower in keloid DFs than in normal DFs, which might contribute to NPTX2 inhibition. In conclusion, this study identified BRCA1 inhibition in DFs as a novel pathological factor in keloids and preliminarily explored its potential mechanisms, which will help us understand the formation of keloids.
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Halide double perovskites present a new branch for versatile optoelectronic devices because of their huge structural compatibility and environmental friendliness, whereas nonlinear optics (NLO) devices remain blank for this fascinating family. Simultaneously, the precise patterning of single-crystalline perovskite microwire arrays remains a challenge for the integration of NLO devices. Herein, we designed lead-free chiral 2D double perovskites with the nonsymmetrical structure presenting second-harmonic generation (SHG). Furthermore, perovskite single-crystalline arrays with regulated geometry, pure orientation, and high crystallinity are prepared using the capillary-bridge confined assembly technique. The efficient SHG originates from the asymmetric crystal structure and high crystallinity of the microwire arrays. Compared with their polycrystalline thin-film counterparts, linearly polarized SHG and a higher SHG conversion efficiency are demonstrated based on microwire arrays. The results not only expand the applications of lead-free double perovskites in the NLO-integrated fields but also provide a viable way for lead-free optoelectronic devices.
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Patterning organic semiconductors directly on Au electrodes possesses the advantages of eliminating metal atomic penetration effect, compatibility with fine lithography processes, and feasibility of work function modification on electrodes, and it is therefore of value in the commercial manufacturability application of optoelectronic devices with low cost, large scale, and high efficiency. Solution processing, is relatively inexpensive and is scalable to large areas. Nonetheless, conventional solution processing approaches have trade-offs among controllable morphology, regular alignment, precise position, and ordered molecular packing arising from the uncontrollable dewetting kinetics. Here, one-step patterning of 1D polymer nanowire arrays directly on Au source-drain electrodes with precise position, controlled orientation, regulated distribution, and tunable width size were realized by employing a capillary-bridge manipulation method to guide the processes of liquid dewetting and nanowire assembly. Organic field-effect transistors (OFETs) with mobility of 10.1 cm2 V-1 s-1 and on/off current ratio of 1.9 × 104 were fabricated. Moreover, we verified generality of our method by patterning different solution-processable optoelectronic materials, including small molecules, quantum dot (QD) nanoparticles, and metal-halide perovskites, into ordered structures directly on the target substrate. The work provides a novel insight into efficient manufacturing the regular aligned and precisely positioned 1D organic semiconductors directly on the channel region of prefabricated Au electrodes in one step and facilitates their applications in high-performance electronic devices.
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BACKGROUND: Deep learning has the potential to improve diagnostic accuracy and efficiency in medical image recognition. In the current study, we developed a deep learning algorithm and assessed its performance in discriminating melanoma from nevus using whole-slide pathological images (WSIs). METHODS: The deep learning algorithm was trained and validated using a set of 781 WSIs (86 melanomas, 695 nevi) from PLA General Hospital. The diagnostic performance of the algorithm was tested on an independent test set of 104 WSIs (29 melanomas, 75 nevi) from Tianjin Chang Zheng Hospital. The same test set was also diagnostically classified by 7 expert dermatopathologists. RESULTS: The deep learning algorithm receiver operating characteristic (ROC) curve achieved a sensitivity 100% at the specificity of 94.7% in the classification of melanoma and nevus on the test set. The area under ROC curve was 0.99. Dermatopathologists achieved a mean sensitivity and specificity of 95.1% (95% confidence interval [CI]: 92.0%-98.2%) and 96.0% (95% CI: 94.2%-97.8%), respectively. At the operating point of sensitivity of 95.1%, the algorithm revealed a comparable specificity with 7 dermatopathologists (97.3% vs. 96.0%, P = 0.11). At the operating point of specificity of 96.0%, the algorithm also achieved a comparable sensitivity with 7 dermatopathologists (96.5% vs. 95.1%, P = 0.30). A more transparent and interpretable diagnosis could be generated by highlighting the regions of interest recognized by the algorithm in WSIs. CONCLUSION: The performance of the deep learning algorithm was on par with that of 7 expert dermatopathologists in interpreting WSIs with melanocytic lesions. By pre-screening the suspicious melanoma regions, it might serve as a supplemental diagnostic tool to improve working efficiency of pathologists.
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Lubricant-infused slippery surface exhibits a series of superior properties such as pressure tolerance, self-healing, oil-repellence, etc. Especially when being applied in an aqueous environment, the reliable bubble manipulating ability of slippery surface offers great opportunities to develop advanced systems in the field of gas transport, water splitting, etc. To improve the strength and the functionality of slippery surfaces, a sliced lubricant-infused slippery (SLIS) track is presented here, possessing both flexibility and toughness for underwater bubble manipulation. The rigid slippery slices with hydrophobic porous structure are linked by the liquid bridge of silicone oil, resulting in a continuous lubricant layer for bubble transfer. Taking advantage of this unique assembled structure, the in situ bubble controlling process, that is, pinning and moving, is achieved via the stretching/releasing of an elastic SLIS track. Besides, on the basis of the integrated design, a hypothesis of underwater gas mining is proved in the all-in-one process including the micro-bubble generation, bubble collection, and gas transport. The current design paves an avenue to reinforce the structure of slippery surfaces, and should promote the function of underwater bubble manipulation toward real-world applications.
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Lubrificantes , Água , Interações Hidrofóbicas e Hidrofílicas , PorosidadeRESUMO
Global efforts have been undertaken to define the genome-wide distribution of epigenetic markers in cancerous tissues, which provide an invaluable opportunity to understand cancer biology and identify predictive signatures. Several studies have focused on the gene expression patterns of squamous carcinoma to identify tumor subtypes and find prognostic and therapeutic targets because squamous carcinoma genomes showed high instability. However, the number of reliable reports referring prognostic significance of genes and their role in squamous carcinoma is still quite limited. Krüppel-like factor 7 (KLF7) is a transcription factor that is widely expressed in numerous human tissues at low levels. Members of the KLF family have established roles in tumor cell fate, stress response, cell survival and the tumor-initiating properties of cancer stem-like cells. Hence to investigate whether KFL7 expression from cancer tissue holds promise as a prognostic and/or therapeutic target, we analyzed gene expression profiles from squamous carcinoma and surgical margin tissues in The Cancer Genome Atlas. We identified significant up-regulation of KLF7 in squamous carcinoma, which was confirmed by immunohistochemical staining. Elevated KLF7 expression was associated with poor squamous carcinoma prognosis before and after correcting for confounding factors by multivariate Cox regression analysis. Several pathways, such as Neurotrophin and GnRH pathways, were activated in KLF7-up-regulated squamous carcinoma samples through Gene Set Enrichment Analysis. In conclusion, we consolidate the potential role(s) of KLF7 in squamous carcinoma carcinogenesis from The Cancer Genome Atlas surgical margin tissue, offering insights into expression signatures that are potentially useful for prognosis modalities.
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Carcinoma de Células Escamosas/genética , Fatores de Transcrição Kruppel-Like/genética , Carcinoma de Células Escamosas/diagnóstico , Linhagem Celular Tumoral , Humanos , PrognósticoRESUMO
AIMS: Head and neck squamous cell carcinoma (HNSCC) is an highly aggressive tumor with heterogeneous prognosis. We here report that immune-related genes (IRGs) could effectively distinguish prognostically different HNSCC patients. MATERIALS AND METHODS: MRNA levels of 1333 IRGs that from ImmPort database in HNSCC samples were acquired from the Cancer Genome Atlas (TCGA). H2o, a machine learning-based R package, was used for screening the top most representative genes from the IRGs. Univariate Cox-regression analysis was performed to identify prognostically-related genes based on the randomly generated training samples from TCGA set. LASSO Cox-regression analysis was applied for the construction of prognostic model for HNSCC. A total of six IRGs were finally retained for their prognostic significance and used for LASSO Cox-regression analysis. KEY FINDINGS: Samples from exclusive training and testing set that randomly generated from TCGA, and another independent validation set from the Gene Expression Omnibus (GEO) were divided into high- and low-risk groups according to the prognostic model. HNSCC samples within high-risk groups have significantly inferior overall survival (OS) compared with those within low-risk groups. Differences in genomic mutation landscape and tumor infiltration immune cells also exist between the two sample groups. What's more, risk score was proved to be an independent prognostic factor for HNSCC by stratification analysis. SIGNIFICANCE: IRGs are pivotal HNSCC prognostic signatures and should be helpful for its clinical decision-making.
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Regulação Neoplásica da Expressão Gênica , Imunidade/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Adulto JovemRESUMO
The stroke incidence in menopausal women was abruptly increased combining with much worse stoke outcomes. Estrogen replacement therapy has the potential to become a new neuroprotective strategy against stroke. But the adverse oncogenic events extremely limited its clinical application. As estrogen receptor (ER) ß is seldom expressed in the female reproductive organs, selective activation of ERß is a promising alternative therapy. However, the role and mechanism of ERß in stroke neuroprotection remain largely unknown. In this study, we investigated the effects of activating ERß on microglia and astrocyte activation and NF-κB mediated neuroinflammatory injury induced by middle cerebral artery occlusion and reperfusion (MCAO-R) or oxygen and glucose deprivation and reperfusion (OGD-R). We found that 8â¯mg/kg DPN (ERß-specific agonist) replacement therapy (3â¯weeks) to the ovariectomized (OVX) mice significantly reduced ischemia injury and alleviated microglia and astrocyte activation, and markedly inhibited the expression of NF-κB and proinflammatory cytokines (TNF-α, IL-1ß, and IL-6). Moreover, pretreatment (72â¯h) with 10â¯nM DPN to the cell line of microglia (N9) or astrocyte (MA1800) significantly increased the cell viability and decreased the cell apoptosis and damage after OGD-R injury, and significantly inhibited the expression of NF-κB and proinflammatory cytokines. These results concluded that DPN replacement treatment alleviated the cerebral ischemia-reperfusion injury via inhibiting the activation of microglia and astrocyte and NF-κB mediated neruoinflammation. As ERß agonist have only minor effects in classic estrogen target tissues, we propose that selective activating ERß is a promising therapy to suppress stroke neuroinflammatory injury in menopausal women.
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Isquemia Encefálica/metabolismo , Encefalite/metabolismo , Receptor beta de Estrogênio/metabolismo , Animais , Astrócitos/metabolismo , Isquemia Encefálica/complicações , Isquemia Encefálica/prevenção & controle , Citocinas/metabolismo , Encefalite/complicações , Encefalite/prevenção & controle , Feminino , Camundongos Endogâmicos C57BL , Microglia/metabolismoRESUMO
Lymphomatoid papulosis (LyP) type E is a recently described variant characterized by the occurrence of large necrotic eschar-like lesions displaying microscopically angioinvasive and angiodestructive infiltrates of CD30+ lymphocytes, frequently coexpressing CD8. Rare cases of LyP type E with a CD56+ immunophenotype have been described. Herein, we describe a 36-year-old woman with LyP type E, characterized by purpura-like lesions on her left ankle. Initially, she presented with left ankle swelling, petechiae and ecchymosis, and rapidly developing necrotic papules, all of which resolved spontaneously over a period of a few months without intentional therapy. Biopsy revealed CD30 and CD56 positive atypical cell infiltrates with marked angiocentricity and angiodestruction. Awareness of this rare LyP variant and its correct recognition, even if the clinical presentation is unusual, is important to avoid aggressive treatment.
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Antígeno CD56 , Papulose Linfomatoide , Proteínas de Neoplasias , Púrpura , Neoplasias Cutâneas , Adulto , Antígeno CD56/imunologia , Antígeno CD56/metabolismo , Feminino , Humanos , Imunofenotipagem , Papulose Linfomatoide/imunologia , Papulose Linfomatoide/metabolismo , Papulose Linfomatoide/patologia , Proteínas de Neoplasias/imunologia , Proteínas de Neoplasias/metabolismo , Púrpura/imunologia , Púrpura/metabolismo , Púrpura/patologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
Psoriasis is a prevalent, chronic inflammatory skin disease that arises from rapid and excessive growth of keratinocytes induced by abnormal inflammatory responses. Metformin is the first-line drug in type 2 diabetes and has been proven to possess significant anti-inflammatory effects in various diseases. In the present study, we examined the role of metformin in nuclear factor kappa B (NF-κB)-mediated inflammatory responses in HaCaT cells, a cell line for the keratinocyte. Our results demonstrated that metformin significantly decreased the mRNA and protein levels of tumour necrosis factor-α (TNFα), interleukin (IL)-6, IL-8, and IL-1ß induced by TNFα. Immunofluorescence staining and western blot analysis showed that metformin inhibited the nuclear localization of p65, a subunit of nuclear factor NF-κB. In addition, metformin suppressed the transcription activity of NF-κB by inhibiting the degradation of IκBα. The inhibitory effect of metformin on NF-κB signalling is comparable with a specific IKKß inhibitor BI605906. Collectively, our data suggest that metformin may be a potential therapeutic agent in inflammatory skin diseases like psoriasis.
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Hipoglicemiantes/farmacologia , Inflamação/tratamento farmacológico , Metformina/farmacologia , NF-kappa B/metabolismo , Psoríase/tratamento farmacológico , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Inflamação/metabolismo , Psoríase/metabolismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Chronic pain aggravates cardiovascular injury via incompletely understood mechanisms. While melatonin may participate in the pathophysiological process of chronic pain, its cardiovascular effects under chronic pain states remains unknown. In this study, chronic pain was induced by spared nerve injury model (SNI) for 4â¯weeks. We showed decreased the ipsilateral hind paw withdrawal mechanical threshold (PWMT) in SNI mice. High dose melatonin treatment (60â¯mg/kg, i.p.) could reversed nociceptive threshold in SNI mice. To verify the effect of chronic pain on the cardiac tolerance to ischemic stress, mice were subjected to myocardial ischemia-reperfusion (MI/R) in vivo. SNI mice showed exaggerated MI/R-induced detrimental effects and myocardial necroptosis compared with control group (Pâ¯<â¯.05). Mechanically, an increased level of tumor necrosis factor-α (TNF-α) was found in SNI group following by a robust interaction of RIP1/RIP3. RIP3-induced phosphor-MLKL and CaMKII more significantly in SNI mice (Pâ¯<â¯.05). We found that RIP3 deficiency provided a comparable protection against MI/R-induced necroptosis under chronic pain conditions. More importantly, low dose melatonin (20â¯mg/kg, i.p.) treatment 10â¯min before reperfusion decreased the level of TNF-α following with a negatively regulating the RIP3 induced phosphor-MLKL/CaMKII signaling, thus significantly reduced ROS production and cardiomyocyte necroptosis and ameliorated cardiac function. In summarize, our results demonstrated that chronic pain sensitizes heart to MI/R injury and myocardial necrosis plays an important role in this pathophysiological process. We also define melatonin acted as triple cardioprotective effects: ameliorating TNF-α level, suppressing RIP3-MLKL/CaMKII signaling induced necroptosis and exerting analgesia effect.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Dor Crônica/tratamento farmacológico , Melatonina/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Necrose/metabolismo , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases/genética , Espécies Reativas de Oxigênio , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
Clinical observations have demonstrated a link between chronic pain and increased ischemic heart disease mortality, but the mechanisms remain elusive. Reactive aldehydes have recently been confirmed as a new player in pain pathologies, while our previous study demonstrated that reactive aldehydes (4-HNE) induced carbonyl stress contributing to myocardial ischemic intolerance. The aim of this study was to explore whether chronic pain increases susceptibility to myocardial ischemia/reperfusion (MI/R) injury and to investigate the underlying mechanisms focusing on toxic aldehyde and carbonyl stress. Methods: Chronic pain was induced by chronic compression of the dorsal root ganglion (CCD). After 2 weeks CCD, aldehyde dehydrogenase (ALDH2) KO or wild-type (WT) littermate mice were then subjected to in vivo MI/R. Results: In CCD-WT mice, heightened nociception paralleled circulating aldehyde (4-HNE) accumulation and cardiac protein carbonylation. Mechanistically, CCD-induced 4-HNE overload provoked cardiac Sirtuin 1 (SIRT1) carbonylative inactivation and inhibited Liver kinase B1 (LKB1) - AMP-activated protein kinase (LKB1-AMPK) interaction, which resulted in exacerbated MI/R injury and higher mortality compared with non-CCD WT mice. ALDH2 deficiency further aggravated CCD-induced susceptibility to MI/R injury. Exogenous 4-HNE exposure in peripheral tissue mimicked chronic pain-induced aldehyde overload, elicited sustained allodynia and increased MI/R injury. However, cardiac-specific ALDH2 upregulation by AAV9-cTNT-mediated gene delivery significantly ameliorated chronic pain-induced SIRT1 carbonylative inactivation and decreased MI/R injury (minor infarct size, less apoptosis, and improved cardiac function). Conclusion: Collectively, chronic pain-enhanced carbonyl stress promotes myocardial ischemic intolerance by SIRT1 carbonylative inactivation and impairment of LKB1-AMPK interaction. ALDH2 activation and prevention of protein carbonylation may be a potential therapeutic target for myocardial ischemic vulnerability in chronic pain patients. Our results newly provided overlapping cellular mechanisms of chronic pain and myocardial dysfunction interplay.
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Aldeído-Desidrogenase Mitocondrial/metabolismo , Aldeídos/metabolismo , Dor Crônica/complicações , Isquemia Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Carbonilação Proteica , Aldeído-Desidrogenase Mitocondrial/deficiência , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Camundongos , Camundongos KnockoutRESUMO
Cardiac aging is characterized by accumulation of damaged proteins and decline of autophagic efficiency. Here, by forestalling SIRT1 carbonylated inactivation in aged heart, we determined the benefits of activation of aldehyde dehydrogenase 2 (ALDH2) on the autophagy. In this study, the ALDH2 KO mice progressively developed age-related heart dysfunction and showed reduction in the life span, which strongly suggests that ALDH2 ablation leads to cardiac aging. What's more, aged hearts displayed a significant decrease ALDH2 activity, resulting in accumulation of 4-HNE-protein adducts and protein carbonyls, impairment in the autophagy flux, and, consequently, deteriorated cardiac function after starvation. Sustained Alda-1 (selective ALDH2 activator) treatment increased cardiac ALDH2 activity and abrogated these effects. Using SIRT1 deficient heterozygous (Sirt1+/-) mice, we found that SIRT1 was necessary for ALDH2 activation-induced autophagy. We further demonstrated that ALDH2 activation attenuated SIRT1 carbonylation and improved SIRT1 activity, thereby increasing the deacetylation of nuclear LC3 and FoxO1. Sequentially, ALDH2 enhanced SIRT1 regulates LC3-Atg7 interaction and FoxO1 increased Rab7 expression, which were both necessary and sufficient for restoring autophagy flux. These results highlight that both accumulation of proteotoxic carbonyl stress linkage with autophagy decline contribute to heart senescence. ALDH2 activation is adequate to improve the autophagy flux by reducing the carbonyl modification on SIRT1, which in turn plays an important role in maintaining cardiac health during aging.
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Envelhecimento/metabolismo , Aldeído-Desidrogenase Mitocondrial/metabolismo , Autofagia/fisiologia , Miocárdio/metabolismo , Sirtuína 1/metabolismo , Aldeído-Desidrogenase Mitocondrial/antagonistas & inibidores , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Proteína 7 Relacionada à Autofagia/metabolismo , Benzamidas/farmacologia , Benzodioxóis/farmacologia , Ativação Enzimática , Proteína Forkhead Box O1/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Carbonilação Proteica , Sirtuína 1/química , Sirtuína 1/genética , Inanição/metabolismo , Proteínas rab de Ligação ao GTP/biossíntese , proteínas de unión al GTP Rab7RESUMO
Accidental deaths due to exposure to extremely low natural temperature happen every winter. Exposure to extreme cold causes injury of multiple organs. However, early responses of the bodies to acute extreme cold exposure remain incompletely understood. In this study, we found that hepatic glycogen was rapidly reduced in rats exposed to -15°C, and the key enzymes required for glycogenesis were upregulated in the livers of the cold-exposed rats. In line with the rapid consumption of glycogen, acute cold exposure induced a transient elevation of cellular ATP level, which lasted about one hour. The ATP level went back to basal level after two hours of cold exposure. Four hours of cold exposure resulted in cellular ATP depletion and cell apoptosis. The dynamic change of cellular ATP levels was well associated with Akt activation in cold-exposed liver cells. The activation of Akt was required for cold exposure-induced ATP elevation. Blockade of Akt activation diminished the transient increase of intracellular ATP content and exacerbated cell apoptosis during acute cold exposure. These results suggest that Akt activation plays a pivotal role in maintaining cellular bioenergy balance and promoting liver cell survival during acute cold exposure.