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Altered intestinal microbial composition promotes intestinal barrier dysfunction and triggers the initiation and recurrence of inflammatory bowel disease (IBD). Current treatments for IBD are focused on control of inflammation rather than on maintaining intestinal epithelial barrier function. Here, we show that the internalization of Gram-negative bacterial outer membrane vesicles (OMVs) in human intestinal epithelial cells promotes recruitment of caspase-5 and PIKfyve to early endosomal membranes via sorting nexin 10 (SNX10), resulting in LPS release from OMVs into the cytosol. Caspase-5 activated by cytosolic LPS leads to Lyn phosphorylation, which in turn promotes nuclear translocalization of Snail/Slug, downregulation of E-cadherin expression, and intestinal barrier dysfunction. SNX10 deletion or treatment with DC-SX029, a novel SNX10 inhibitor, rescues OMV-induced intestinal barrier dysfunction and ameliorates colitis in mice by blocking cytosolic LPS release, caspase-5 activation, and downstream signaling. Our results show that targeting SNX10 may be a new therapeutic approach for restoring intestinal epithelial barrier function and promising strategy for IBD treatment.
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Membrana Externa Bacteriana/química , Caspases/metabolismo , Colite/patologia , Lipopolissacarídeos/metabolismo , Nexinas de Classificação/genética , Nexinas de Classificação/metabolismo , Animais , Células CACO-2 , Colite/induzido quimicamente , Colite/genética , Citosol/metabolismo , Modelos Animais de Doenças , Endossomos/metabolismo , Endossomos/transplante , Feminino , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/metabolismoRESUMO
BACKGROUND: Aortic dissection (AD) is a macrovascular disease which is pathologically characterized by aortic media degeneration.This experiment aims to explore how iron deficiency (ID) affects the function of vascular smooth muscle cell (VSMC) and participates in the occurrence and development of AD by regulating gene expression. METHODS: The relationship between iron and AD was proved by Western-blot (WB) and immunostaining experiments in human and animals. Transcriptomic sequencing explored the transcription factors that were altered downstream. WB, flow cytometry and immunofluorescence were used to demonstrate whether ID affected HIF1 expression through oxygen transport. HIF1 signaling pathway and phenotypic transformation indexes were detected in cell experiments. The use of the specific HIF1 inhibitor PX478 further demonstrated that ID worked by regulating HIF1. RESULTS: The survival period of ID mice was significantly shortened and the pathological staining results were the worst. Transcriptomic sequencing indicated that HIF1 was closely related to ID and the experimental results indicated that ID might regulate HIF1 expression by affecting oxygen balance. HIF1 activation regulates the phenotypic transformation of VSMC and participates in the occurrence and development of AD in vivo and in vitro.PX478, the inhibition of HIF1, can improve ID-induced AD exacerbation.
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Dissecção Aórtica , Músculo Liso Vascular , Miócitos de Músculo Liso , Oxigênio , Transdução de Sinais , Animais , Humanos , Masculino , Camundongos , Dissecção Aórtica/metabolismo , Dissecção Aórtica/etiologia , Dissecção Aórtica/genética , Dissecção Aórtica/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Fator 1 Induzível por Hipóxia/metabolismo , Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Deficiências de Ferro , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Oxigênio/metabolismo , FenótipoRESUMO
BACKGROUND: Diabetic cardiomyopathy (DCM), a serious complication of diabetes, leads to structural and functional abnormalities of the heart and ultimately evolves to heart failure. IL-37 exerts a substantial influence on the regulation of inflammation and metabolism. Whether IL-37 is involved in DCM is unknown. METHODS: The plasma samples were collected from healthy controls, diabetic patients and DCM patients, and the level of IL-37 and its relationship with heart function were observed. The changes in cardiac function, myocardial fibrosis and mitochondrial injury in DCM mice with or without IL-37 intervention were investigated in vivo. By an in vitro co-culture approach involving HG challenge of cardiomyocytes and fibroblasts, the interaction carried out by cardiomyocytes on fibroblast profibrotic activation was studied. Finally, the possible interactive mediator between cardiomyocytes and fibroblasts was explored, and the intervention role of IL-37 and its relevant molecular mechanisms. RESULTS: We showed that the level of plasma IL-37 in DCM patients was upregulated compared to that in healthy controls and diabetic patients. Both recombinant IL-37 administration or inducing IL-37 expression alleviated cardiac dysfunction and myocardial fibrosis in DCM mice. Mechanically, hyperglycemia impaired mitochondria through SIRT1/AMPK/PGC1α signaling, resulting in significant cardiomyocyte apoptosis and the release of extracellular vesicles containing mtDNA. Fibroblasts then engulfed these mtDNA-enriched vesicles, thereby activating TLR9 signaling and the cGAS-STING pathway to initiate pro-fibrotic process and adverse remodeling. However, the presence of IL-37 ameliorated mitochondrial injury by preserving the activity of SIRT1-AMPK-PGC1α axis, resulting in a reduction in release of mtDNA-enriched vesicle and ultimately attenuating the progression of DCM. CONCLUSIONS: Collectively, our study demonstrates a protective role of IL-37 in DCM, offering a promising therapeutic agent for this disease.
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DNA Mitocondrial , Cardiomiopatias Diabéticas , Fibrose , Interleucina-1 , Miócitos Cardíacos , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Apoptose/efeitos dos fármacos , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/tratamento farmacológico , DNA Mitocondrial/metabolismo , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Interleucina-1/metabolismo , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismoRESUMO
Aging is a normal and complex biological process. Skin is located in the most superficial layer of the body, and its degree of aging directly reflects the aging level of the body. Endoplasmic reticulum stress refers to the aggregation of unfolded or misfolded proteins in the endoplasmic reticulum and the disruption of the calcium ion balance when cells are stimulated by external stimuli. Mild endoplasmic reticulum stress can cause a series of protective mechanisms, including the unfolded protein response, while sustained high intensity stimulation leads to endoplasmic reticulum stress and eventually apoptosis. Photoaging caused by ultraviolet radiation is an important stimulus in skin aging. Many studies have focused on oxidative stress, but increasing evidence shows that endoplasmic reticulum stress plays an important role in photoaging. This paper reviews the development and mechanism of endoplasmic reticulum stress (ERS) in skin photoaging, and provides research directions for targeting the ERS pathway to slow aging.
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Envelhecimento da Pele , Dermatopatias , Humanos , Raios Ultravioleta , Estresse do Retículo Endoplasmático , Resposta a Proteínas não Dobradas , Pele/metabolismo , Dermatopatias/metabolismo , ApoptoseRESUMO
Abdominal aortic aneurysm (AAA) is a dangerous condition affecting the aorta. Macrophage pyroptosis, phenotypic transformation, and apoptosis of aortic smooth muscle cells (ASMCs) are pivotal mechanisms in AAA pathogenesis. This study explores how Gasdermin B (GSDMB) regulates macrophage non-canonical pyroptosis and its impact on the phenotypic transformation and apoptosis of ASMCs, thereby unveiling the role of GSDMB in AAA pathogenesis. Immunofluorescence analysis was used to assess the expression levels and localization of GSDMB, cysteinyl aspartate-specific protease-4 (Caspase-4), and N-terminal of cleaved GSDMD (N-GSDMD) in AAA tissues. A cell model that mimics macrophage non-canonical pyroptosis was established by treating THP-1 cells with lipopolysaccharide (LPS). THP-1 cells with reduced or increased GSDMB were generated using small interfering RNA (siRNA) or plasmids. Co-culture experiments involving THP-1 cells and HASMCs were conducted to explore the impact of GSDMB on HASMCs. The mitochondrial reactive oxygen species (mtROS) scavenger Mito-TEMPO lowered mtROS levels in THP-1 cells. Our findings revealed that GSDMB was significantly upregulated in AAA macrophages, which was accompanied by robust non-canonical pyroptosis. THP-1 cells showed non-canonical pyroptosis in response to LPS, which was accompanied by an increase in GSDMB. Further research demonstrated that altering GSDMB, either by knockdown or overexpression, can affect macrophage non-canonical pyroptosis as well as the phenotypic transformation and apoptosis of HASMCs. LPS-induced non-canonical pyroptosis in THP-1 cells was associated with an increase in mtROS, whereas Mito-TEMPO effectively decreased non-canonical pyroptosis and the expression of GSDMB. These findings suggest that GSDMB plays a role in AAA macrophage non-canonical pyroptosis, which influences the phenotypic transformation and apoptosis of HASMCs. The mtROS-Dynamin-Related Protein 1 (Drp1) axis is likely to regulate the GSDMB-mediated non-canonical pyroptosis.
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Aneurisma da Aorta Abdominal , Macrófagos , Piroptose , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Humanos , Macrófagos/metabolismo , Células THP-1 , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Proteínas de Ligação a Fosfato/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Lipopolissacarídeos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Caspases Iniciadoras/metabolismo , Masculino , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Mitocôndrias/metabolismo , GasderminasRESUMO
The damage of integrated epithelial epithelium is a key pathogenic factor and closely associated with the recurrence of ulcerative colitis (UC). Here, we reported that vanillic acid (VA) exerted potent therapeutic effects on DSS-induced colitis by restoring intestinal epithelium homeostasis via the inhibition of ferroptosis. By the CETSA assay and DARTS assay, we identified carbonic anhydrase IX (CAIX, CA9) as the direct target of VA. The binding of VA to CA9 causes insulin-induced gene-2 (INSIG2) to interact with stromal interaction molecule 1 (STIM1), rather than SREBP cleavage-activating protein (SCAP), leading to the translocation of SCAP-SREBP1 from the endoplasmic reticulum (ER) to the Golgi apparatus for cleavage into mature SREBP1. The activation of SREBP1 induced by VA then significantly facilitated the transcription of stearoyl-CoA desaturase 1 (SCD1) to exert an inhibitory effect on ferroptosis. By inhibiting the excessive death of intestinal epithelial cells caused by ferroptosis, VA effectively preserved the integrity of intestinal barrier and prevented the progression of unresolved inflammation. In conclusion, our study demonstrated that VA could alleviate colitis by restoring intestinal epithelium homeostasis through CA9/STIM1-mediated inhibition of ferroptosis, providing a promising therapeutic candidate for UC.
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Colite , Ferroptose , Humanos , Animais , Camundongos , Ácido Vanílico , Molécula 1 de Interação Estromal , Colite/induzido quimicamente , Colite/tratamento farmacológico , Homeostase , Mucosa Intestinal , Sulfato de Dextrana , Camundongos Endogâmicos C57BL , Anidrase Carbônica IX , Antígenos de Neoplasias , Proteínas de NeoplasiasRESUMO
BACKGROUND AND AIMS: Evidence has indicated that serum uric acid (UA) and high-density lipoprotein cholesterol (HDL-C) are positively and negatively associated with coronary artery disease (CAD). The UA to HDL-C ratio (UHR) has recently drawn attention as a new predictor for metabolic syndrome, inflammation and atherosclerosis. However, the association between the UHR and CAD in nondialysis chronic kidney disease (CKD) patients is still unclear. METHODS AND RESULTS: We retrospectively analysed 733 nondialysis patients with CKD stage 3-5 who received their first coronary artery angiography (CAG), including 510 participants with CAD. All laboratory indicators were collected within one week before CAG. The median UHR of CAD and non-CAD patients was 15.52% and 12.29%, respectively. In multivariate analysis, female patients with a high UHR were 4.7 times more at risk of CAD than those with a lower UHR. Meanwhile, the positive association of the UHR with the severity of coronary artery stenosis (CAS) persisted significantly in female CAD subjects but not in males. In addition, receiver operating characteristic (ROC) curves were constructed for CAD and severe CAS. The area under the curve (AUC) for the UHR was higher than that for UA and HDL-C alone in female patients [UHR (AUC): 0.715 for CAD and 0.716 for severe CAS]. CONCLUSIONS: An elevated UHR was independently related to an increased CAD risk and the severity of CAS in nondialysis female patients with CKD stage 3-5, and was more predictive of the onset of CAD and the severity of CAS than UA or HDL-C alone.
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Biomarcadores , HDL-Colesterol , Angiografia Coronária , Doença da Artéria Coronariana , Insuficiência Renal Crônica , Índice de Gravidade de Doença , Ácido Úrico , Humanos , Feminino , Ácido Úrico/sangue , Masculino , HDL-Colesterol/sangue , Pessoa de Meia-Idade , Estudos Retrospectivos , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/complicações , Idoso , Biomarcadores/sangue , Fatores Sexuais , Medição de Risco , China/epidemiologia , Valor Preditivo dos Testes , Prognóstico , Disparidades nos Níveis de Saúde , Estenose Coronária/sangue , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/diagnóstico , Estenose Coronária/epidemiologia , Fatores de Risco , Hiperuricemia/sangue , Hiperuricemia/diagnóstico , Hiperuricemia/epidemiologia , Fatores de Risco de Doenças Cardíacas , População do Leste AsiáticoRESUMO
Legubicin, a novel prodrug based on doxorubicin, has both albumin-binding and legumain-activating properties. The aim of this study was to develop and validate a UHPLC-MS/MS method for investigating the in vivo pharmacokinetics and tissue distribution profiles of legubicin in rats and tumor-bearing mice following intravenous administration, and to compare this prodrug with the positive control drug doxorubicin. The study employed a UHLC-MS/MS method to determine the levels of albumin-bound of legubicin and two metabolites (free Leu-DOX and DOX) in plasma, tumor, and tissue samples. This method was validated for good selectivity, high sensitivity, excellent extraction recovery, and short run time. The results showed that legubicin was present in the circulation in vivo mainly in a protein-bound form with larger AUC values and lower clearance and distribution, and essentially released small amounts of doxorubicin. Compared to administration of equimolar doses of doxorubicin, legubicin showed increased exposure of the active drug in the tumor and decreased the level of the active drug in the heart and kidney. This study provides valuable information on the pharmacokinetics and tissue distribution of legubicin, implicating its potential as a novel and effective drug candidate for anti-cancer therapies.
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Cisteína Endopeptidases , Neoplasias , Pró-Fármacos , Camundongos , Ratos , Animais , Pró-Fármacos/química , Cromatografia Líquida de Alta Pressão , Distribuição Tecidual , Espectrometria de Massas em Tandem , Doxorrubicina/química , AlbuminasRESUMO
In brain imaging segmentation, precise tumor delineation is crucial for diagnosis and treatment planning. Traditional approaches include convolutional neural networks (CNNs), which struggle with processing sequential data, and transformer models that face limitations in maintaining computational efficiency with large-scale data. This study introduces MambaBTS: a model that synergizes the strengths of CNNs and transformers, is inspired by the Mamba architecture, and integrates cascade residual multi-scale convolutional kernels. The model employs a mixed loss function that blends dice loss with cross-entropy to refine segmentation accuracy effectively. This novel approach reduces computational complexity, enhances the receptive field, and demonstrates superior performance for accurately segmenting brain tumors in MRI images. Experiments on the MICCAI BraTS 2019 dataset show that MambaBTS achieves dice coefficients of 0.8450 for the whole tumor (WT), 0.8606 for the tumor core (TC), and 0.7796 for the enhancing tumor (ET) and outperforms existing models in terms of accuracy, computational efficiency, and parameter efficiency. These results underscore the model's potential to offer a balanced, efficient, and effective segmentation method, overcoming the constraints of existing models and promising significant improvements in clinical diagnostics and planning.
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Mild cognitive impairment(MCI)has a high risk of progressing to dementia,with no recommended therapies.Recent studies have shown that meditation has huge potential to improve the cognitive function,with low cost and high safety,being suitable to be applied in the treatment of neurological and psychotic disorders.This paper reviews the application and prospects of meditation in treating MCI from the concept,clinical efficacy,and mechanism of meditation,aiming to provide reference for future clinical studies.
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Disfunção Cognitiva , Meditação , Humanos , Disfunção Cognitiva/terapia , Meditação/métodosRESUMO
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. This article shows significant data duplication and overlap with Liu, Weihua et al., Effects of berberine on matrix accumulation and NF-kappa B signal pathway in alloxan-induced diabetic mice with renal injury. European Journal of Pharmacology. 2010 Jul 25; 638(1-3):150-5 (https://doi.org/10.1016/j.ejphar.2010.04.033) without adequate referencing. Although there is a slight difference in the methodology section regarding alloxan-induced diabetes models in the two articles, there is a clear overlap between Table 2 of Lan, Tian et al. (2010); and Tables 1 and 2 of Liu, Weihua et al. (2010). The two manuscripts were submitted from the same laboratory in the same year.
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Eriocalyxin B (EB), 17-hydroxy-jolkinolide B (HJB), parthenolide (PN), xanthatin (XT) and andrographolide (AG) are terpenoid natural products with a variety of promising antitumor activities, which commonly bear electrophilic groups (α,ß-unsaturated carbonyl groups and/or epoxides) capable of covalently modifying protein cysteine residues. However, their direct targets and underlying molecular mechanisms are still largely unclear, which limits the development of these compounds. In this study, we integrated activity-based protein profiling (ABPP) and quantitative proteomics approach to systematically characterize the covalent targets of these natural products and their involved cellular pathways. We first demonstrated the anti-proliferation activities of these five compounds in triple-negative breast cancer cell MDA-MB-231. Tandem mass tag (TMT)-based quantitative proteomics showed all five compounds commonly affected the ubiquitin mediated proteolysis pathways. ABPP platform identified the preferentially modified targets of EB and PN, two natural products with high anti-proliferation activity. Biochemical experiments showed that PN inhibited the cell proliferation through targeting ubiquitin carboxyl-terminal hydrolase 10 (USP10). Together, this study uncovered the covalently modified targets of these natural products and potential molecular mechanisms of their antitumor activities.
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Produtos Biológicos , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Proteômica , Proteínas/metabolismo , UbiquitinasRESUMO
Cr(VI) pollution is a growing problem that causes the deterioration of the environment and human health. We report the development of an effective adsorbent for the removal of Cr(VI) from wastewater. N-doped cellulose-based hydrothermal carbon (N-CHC) was prepared via a two-step hydrothermal method. The morphology and structural properties of N-CHC were investigated by various techniques. N-CHC has many O and N groups, which are suitable for Cr(VI) adsorption and reduction. Intermittent adsorption experiments showed that N-CHC had an adsorption capacity of 151.05 mg/g for Cr(VI) at pH 2, indicating excellent adsorption performance. Kinetic and thermodynamic analyses indicates that the adsorption of Cr(VI) on N-CHC follows a monolayer uniform adsorption process, which is a spontaneous endothermic process dominated by chemical interaction and limited by diffusion within particles. In a multi-ion system (Pb2+, Cd2+, Mn7+, Cl-, and SO42-), the selectivity of N-CHC toward Cr(VI) was 82.62%. In addition, N-CHC demonstrated excellent reuse performance over seven adsorption-desorption cycles; the Cr(VI) removal rate of N-CHC in 5-20 mg/L wastewater was >99.87%, confirming the potential of N-CHC for large-scale applications. CN/C-OR, pyridinic-N, and pyrrolic-N were found to play a critical role in the adsorption process. This study provides a new technology for Cr(VI) pollution control that could be utilized in large-scale production and other environmental applications.
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Águas Residuárias , Poluentes Químicos da Água , Humanos , Carbono , Celulose , Cromo/análise , Adsorção , Poluentes Químicos da Água/análise , Concentração de Íons de Hidrogênio , CinéticaRESUMO
An indoor localization system based on the RSSI-APIT algorithm is designed in this study. Integrated RSSI (received signal strength indication) and non-ranging APIT (approximate perfect point-in-triangulation test) localization methods are fused with machine learning in order to improve the accuracy of the indoor localization system. The system focuses on the improvement of preprocessing and localization algorithms. The primary objective of the system is to enhance the preprocessing of the acquired RSSI data and optimize the localization algorithm in order to enhance the precision of the coordinates in the indoor localization system. In order to mitigate the issue of significant fluctuations in RSSI, a technique including the integration of Gaussian filtering and an artificial neural network (ANN) is employed. This approach aims to preprocess the acquired RSSI data, thus reducing the impact of multipath effects. In order to address the issue of low localization accuracy encountered by the conventional APIT localization algorithm during wide-area localization, the RSSI ranging function is incorporated into the APIT localization algorithm. This addition serves to further narrow down the localization area. Consequently, the resulting localization algorithm is referred to as the RSSI-APIT positioning algorithm. Experimental results have demonstrated the successful reduction of inherent localization errors within the system by employing the RSSI-APIT positioning algorithm. The present study aims to investigate the impact of the localization scene and the number of anchors on the RSSI-APIT localization algorithm, with the objective of enhancing the performance of the indoor localization system. The conducted experiments demonstrated that the enhanced system exhibits several advantages. Firstly, it successfully decreased the frequency of anchor calls, resulting in a reduction in the overall operating cost of the system. Additionally, it effectively enhanced the accuracy and stability of the system's localization capabilities. In a complex environment of 100 m2 in size, compared with the traditional trilateral localization method and the APIT localization algorithm, the RSSI-APIT localization algorithm reduced the localization error by about 2.9 m and 1.8 m, respectively, and the overall error was controlled within 1.55 m.
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Kidney tubular epithelial cells are high energy-consuming epithelial cells that depend mainly on fatty acid oxidation for an energy supply. AMP-activated protein kinase (AMPK) is a key regulator of energy production in most cells, but the function of AMPK in tubular epithelial cells in acute kidney disease is unclear. Here, we found a rapid decrease in Thr172-AMPKα phosphorylation after ischemia/reperfusion in both in vivo and in vitro models. Mice with kidney tubular epithelial cell-specific AMPKα deletion exhibited exacerbated kidney impairment and apoptosis of tubular epithelial cells after ischemia/reperfusion. AMPKα deficiency was accompanied by the accumulation of lipid droplets in the kidney tubules and the elevation of ceramides and free fatty acid levels following ischemia/reperfusion injury. Mechanistically, ischemia/reperfusion triggered ceramide production and activated protein phosphatase PP2A, which dephosphorylated Thr172-AMPKα. Decreased AMPK activity repressed serine/threonine kinase ULK1-mediated autophagy and impeded clearance of the dysfunctional mitochondria. Targeting the PP2A-AMPK axis by the allosteric AMPK activator C24 restored fatty acid oxidation and reduced tubular cell apoptosis during ischemia/reperfusion-induced injury, by antagonizing PP2A dephosphorylation and promoting the mitophagy process. Thus, our study reveals that AMPKα plays an important role in protecting against tubular epithelial cell injury in ischemia/reperfusion-induced acute kidney injury. Hence, activation of AMPK could be a potential therapeutic strategy for acute kidney injury treatment.
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Injúria Renal Aguda , Traumatismo por Reperfusão , Proteínas Quinases Ativadas por AMP/metabolismo , Injúria Renal Aguda/induzido quimicamente , Animais , Apoptose , Isquemia/metabolismo , Rim/metabolismo , Camundongos , Mitocôndrias/metabolismo , Reperfusão , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/metabolismoRESUMO
Droplet controllable operation has wide applications in microfluidics, biomedicine, microreactors, and other fields. Droplets can spontaneously transfer from a high-energy state to a low-energy state, but how to reverse transfer the droplets is a difficult task. In this article, we use a special hydrophilic-hydrophobic interphase structure (HHIS) to achieve this reverse transfer. We specifically study the critical conditions under which droplet transfer can be achieved. The length of the hydrophilic surface in this structure and the hydrophilic/hydrophobic properties of the surface must be in the appropriate range. Based on this, an optimized structure used to transfer droplets was designed. Finally, we carried out research on biological applications and successfully achieved the transfer of droplets from zebrafish eggs and zebrafish larvae. This unique method is low-cost, biofriendly, and highly applicable to various surfaces, illustrating the great potential in chemical and biological analysis.
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Microfluídica , Peixe-Zebra , Animais , Interações Hidrofóbicas e Hidrofílicas , Microfluídica/métodosRESUMO
As we all know, chopsticks can hold food, so can we use this method to carry Newtonian fluids such as droplets? This paper studies the process of this transfer and uses this method to realize the manipulation of open microfluidics by robots. To realize this transfer operation, we first analyzed the force of droplets in this chopstick-like structure and found that the bidirectional movement of droplets in this structure can be achieved by changing the structural parameters. Afterward, the whole process of the transfer of droplets using the chopstick-like structure was analyzed, and the parameter requirements for realizing this transfer were determined. The research in this paper provides a theoretical basis for the controllable manipulation of droplets which can be widely used in unmanned laboratories.
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Robótica , Movimento , Microfluídica/métodosRESUMO
RATIONALE: SNX10 (sorting nexin 10) has been reported to play a critical role in regulating macrophage function and lipid metabolism. OBJECTIVE: To investigate the precise role of SNX10 in atherosclerotic diseases and the underlying mechanisms. METHODS AND RESULTS: SNX10 expression was compared between human healthy vessels and carotid atherosclerotic plaques. Myeloid cell-specific SNX10 knockdown mice were crossed onto the APOE-/- (apolipoprotein E) background and atherogenesis (high-cholesterol diet-induced) was monitored for 16 weeks. We found that SNX10 expression was increased in atherosclerotic lesions of aortic specimens from humans and APOE-/- mice. Myeloid cell-specific SNX10 deficiency (Δ knockout [KO]) attenuated atherosclerosis progression in APOE-/- mice. The population of anti-inflammatory monocytes/macrophages was increased in the peripheral blood and atherosclerotic lesions of ΔKO mice. In vitro experiments showed that SNX10 deficiency-inhibited foam cell formation through interrupting the internalization of CD36, which requires the interaction of SNX10 and Lyn-AKT (protein kinase B). The reduced Lyn-AKT activation by SNX10 deficiency promoted the nuclear translocation of TFEB (transcription factor EB), thereby enhanced lysosomal biogenesis and LAL (lysosomal acid lipase) activity, resulting in an increase of free fatty acids to fuel mitochondrial fatty acid oxidation. This further promoted the reprogramming of macrophages and shifted toward the anti-inflammatory phenotype. CONCLUSIONS: Our data demonstrate for the first time that SNX10 plays a crucial role in diet-induced atherogenesis via the previously unknown link between the Lyn-Akt-TFEB signaling pathway and macrophage reprogramming, suggest that SNX10 may be a potentially promising therapeutic target for atherosclerosis treatment.
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Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Reprogramação Celular/fisiologia , Macrófagos/fisiologia , Nexinas de Classificação/fisiologia , Animais , Apolipoproteínas E/genética , Aterosclerose/sangue , Aterosclerose/patologia , Antígenos CD36/metabolismo , Núcleo Celular/metabolismo , Progressão da Doença , Ácidos Graxos não Esterificados/metabolismo , Células Espumosas/citologia , Humanos , Lisossomos/fisiologia , Macrófagos/citologia , Camundongos , Mitocôndrias/metabolismo , Monócitos/citologia , Oxirredução , Proteínas Proto-Oncogênicas c-akt/metabolismo , Nexinas de Classificação/deficiência , Nexinas de Classificação/genética , Esterol Esterase/metabolismoRESUMO
Diabetic cardiovascular complications contribute more than half of diabetes mortality. Endothelial damage and subsequent pathological changes play a key role in this process. Phloretin, a plant-derived dihydrochalcone compound, was reported to have the activities in regulating metabolism homeostasis and anti-inflammation. However, its effects and the mechanism on early stage endothelial injury caused by diabetes are not clear yet. In our present study, human umbilical vein endothelial cells (HUVECs) were stimulated by high glucose or advanced glycation end products (AGEs) to induce endothelial damage, and streptozotocin (STZ) -induced diabetes mouse model was used for in vivo study. Our results showed that phloretin effectively reduced endothelial damage marker monocyte chemotactic protein-1 (MCP1) as well as pro-calcification factors bone morphogenetic protein-2 (BMP2) and receptor activator of NF-κB ligand (RANKL) expression, reversed the increased vimentin and decreased CD31 dose-dependently in vitro and in vivo. Phloretin had no effect on blood glucose level. However, it ameliorated endothelial injury and vascular fibrosis in diabetic mice. Further experiments revealed that phloretin could enhance AMP activated protein kinase (AMPK) activation and upregulate peroxidase proliferator activated receptor-gamma coactivator-lα (PGC1α) level, and inhibit the activation of TGFß-Smad2-Snail signalling pathway which was abrogated by AMPK inhibitor, providing a rational mechanism that AMPK activation was required for the effects of phloretin on endothelial injury and endothelial-mesenchymal transformation (EndMT). Our data reveal a new role of phloretin in protection of diabetic endothelial damage via AMPK-dependent anti-EndMT activation, and also provide a potential therapeutic way for diabetic endothelial damage and its subsequent cardiovascular complications.
Assuntos
Diabetes Mellitus Experimental , Floretina , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Floretina/farmacologia , Floretina/uso terapêutico , Transdução de SinaisRESUMO
The pathological features of inflammatory bowel disease necessitate therapeutic strategies aimed at restoring intestinal mucosal barrier function in addition to controlling inflammation. Paeoniflorin, a bioactive herbal constituent isolated from the root of Paeonia albiflora Pall, has been reported to protect against acute colitis in mice. However, the direct molecular target of paeoniflorin in preventing colitis remains elusive. Here, we evaluated the therapeutical effects of Paeoniflorin using IL-10-/- chronic colitis model, and explored the precise mechanism of action involved. Our results demonstrated that intragastric administration of Paeoniflorin significantly ameliorated inflammatory response and restored the aberrant intestinal proliferation and differentiation in IL-10-/-colitis mice. By utilizing a chemical biology approach, we identified C1qa, a crucial component of C1q, is the direct target of Paeoniflorin. Binding of Paeoniflorin to C1qa prevented the cleavage of C1q on macrophages, resulting in the aggregation of surface membrane-anchored C1q and the diminished C1q secretion. The excessive surface membrane-anchored C1q significantly enhanced the phagocytic capability of macrophages and promoted the elimination of infiltrated bacteria and inflammatory cells in mouse colon. The reduced C1q secretion conferred by Paeoniflorin dampened Wnt/ß-catenin signaling activation, thereby rectifying the aberrant proliferation and differentiation of intestinal stem cells (ISCs). In summary, our study demonstrates that Paeoniflorin can orchestrate mucosal healing and intestinal inflammation elimination through C1q-bridged macrophage-ISCs crosstalk, highlighting a novel strategy to treat chronic colitis by restoring mucosal homeostasis via targeting C1q.