RESUMEN
Millions of patients suffer from rare diseases around the world. However, the samples of rare diseases are much smaller than those of common diseases. Hospitals are usually reluctant to share patient information for data fusion due to the sensitivity of medical data. These challenges make it difficult for traditional AI models to extract rare disease features for disease prediction. In this paper, we propose a Dynamic Federated Meta-Learning (DFML) approach to improve rare disease prediction. We design an Inaccuracy-Focused Meta-Learning (IFML) approach that dynamically adjusts the attention to different tasks according to the accuracy of base learners. Additionally, a dynamic weight-based fusion strategy is proposed to further improve federated learning, which dynamically selects clients based on the accuracy of each local model. Experiments on two public datasets show that our approach outperforms the original federated meta-learning algorithm in accuracy and speed with as few as five shots. The average prediction accuracy of the proposed model is improved by 13.28% compared with each hospital's local model.
RESUMEN
Doxorubicin (DOX) is a most common anthracycline chemotherapeutic agent; however, its clinical efficacy is limited due to its severe and irreversible cardiotoxicity. Ferroptosis, characterized by iron overload and lipid peroxidation, plays a pivotal role in DOX-induced cardiotoxicity. Resveratrol (RSV) displays cardioprotective and anticancer effects, owing to its antioxidative and anti-inflammatory properties. However, the role and mechanism of RSV in DOX-mediated ferroptosis in cardiomyocytes is unclear. This study showed that DOX decreased cell viability, increased iron accumulation and lipid peroxidation in H9c2 cells; however, these effects were reversed by RSV and ferroptosis inhibitor ferrostatin-1 (Fer-1) pre-treatment. Additionally, RSV significantly increased the cell viability of H9c2 cells treated with ferroptosis inducers Erastin (Era) and RSL3. Mechanistically, RSV inhibited mitochondrial reactive oxygen species (mtROS) overproduction and upregulated the p62-NRF2/HO-1 pathway. RSV-induced NRF2 activation was partially dependent on p62, and the selective inhibition of p62 (using p62-siRNA interference) or NRF2 (using NRF2 specific inhibitor, ML385) significantly abolished the anti-ferroptosis function of RSV. Furthermore, RSV treatment protected mice against DOX-induced cardiotoxicity, including significantly improving left ventricular function, ameliorating myocardial fibrosis and suppressing ferroptosis. Consistent with in vitro results, RSV also upregulated the p62-NRF2/HO-1 expression, which was inhibited by DOX, in the myocardium. Notably, the protective effect of RSV in DOX-mediated ferroptosis was similar to that of Fer-1 in vitro and in vivo. Thus, the p62-NRF2 axis plays a critical role in regulating DOX-induced ferroptosis in cardiomyocytes. RSV as a potent p62 activator has potential as a therapeutic target in preventing DOX-induced cardiotoxicity via ferroptosis modulation.
Asunto(s)
Miocitos Cardíacos , Factor 2 Relacionado con NF-E2 , Ratones , Animales , Miocitos Cardíacos/metabolismo , Resveratrol/farmacología , Resveratrol/uso terapéutico , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Cardiotoxicidad/etiología , Cardiotoxicidad/metabolismo , Estrés Oxidativo , Doxorrubicina/efectos adversosRESUMEN
Atherosclerotic vascular disease (ASVD) is the leading cause of death worldwide. Hyperuricemia is the fourth risk factor for atherosclerosis after hypertension, diabetes, and hyperlipidemia. The mechanism of hyperuricemia affecting the occurrence and development of atherosclerosis has not been fully elucidated. Mononuclear macrophages play critical roles in all stages of atherosclerosis. Studies have confirmed that both hyperuricemia and ferroptosis promote atherosclerosis, but whether high level of uric acid (HUA) promotes atherosclerosis by regulating ferroptosis in macrophages remains unclear. We found that HUA significantly promoted the development of atherosclerotic plaque and downregulated the protein level of the NRF2/SLC7A11/GPX4 signaling pathway in ApoE-/- mice. Next, we evaluated the effect of HUA and ferroptosis inhibitor ferrostatin-1 (Fer-1) treatment on the formation of macrophage-derived foam cells. HUA promoted the formation of foam cells, decreased cell viability, and increased iron accumulation and lipid peroxidation in macrophages treated with oxidized low-density lipoprotein (oxLDL); these effects were reversed by Fer-1 treatment. Mechanistically, HUA significantly inhibited autophagy and the protein level of the NRF2/SLC7A11/GPX4 signaling pathway. Fer-1 activated autophagy and upregulated the level of ferroptosis-associated proteins. Moreover, an NRF2 inducer (tertbutyl hydroquinone (TBHQ)) and autophagy activator (rapamycin (RAPA)) could reverse the inhibitory effect of HUA on foam cell survival. Our results suggest that HUA-induced ferroptosis of macrophages is involved in the formation of atherosclerotic plaques. More importantly, enhancing autophagy and inhibiting ferroptosis by activating NRF2 may alleviate HUA-induced atherosclerosis. These findings might contribute to a deeper understanding of the role of HUA in the pathogenesis of atherosclerosis and provide a therapeutic target for ASVD associated with hyperuricemia.
Asunto(s)
Aterosclerosis , Ferroptosis , Hiperuricemia , Placa Aterosclerótica , Animales , Aterosclerosis/patología , Autofagia , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Ácido ÚricoRESUMEN
Insulin resistance (IR) promotes atherosclerosis and increases the risk of diabetes and cardiovascular diseases. Our previous studies have demonstrated that high uric acid (HUA) increased oxidative stress, leading to IR in cardiomyocytes and pancreatic ß cells. However, whether HUA can induce IR in monocytes/macrophages, which play critical roles in all stages of atherosclerosis, is unclear. Recent findings revealed that thioredoxin-interacting protein (TXNIP) negatively regulates insulin signaling; however, the roles and mechanisms of TXNIP in HUA-induced IR remain unclear. Therefore, in this study, we investigated the function of TXNIP in macrophages treated with UA. Transcriptomic profiling revealed TXNIP as one of the most upregulated genes, and subsequent RT-PCR and Western blot analyses confirmed that TXNIP was upregulated by HUA. HUA treatment significantly increased mitochondrial reactive oxygen species (MtROS) levels and decreased insulin-stimulated glucose uptake. Silencing TXNIP by RNA interference significantly diminished HUA-induced oxidative stress and IR. Mechanistically, silencing TXNIP reversed the inhibition of the phosphorylation of insulin receptor substrate 2 (IRS2)/protein kinase B (AKT) pathway induced by HUA. Additional study revealed that HUA induced the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway, but silencing TXNIP abolished it. Moreover, Nrf2 inhibitor (ML385) ameliorated HUA-induced IR independent of IRS2/AKT signaling. Probenecid, a well-known UA-lowering drug, significantly suppressed the activation of TXNIP and Nrf2/HO-1 signaling. Furthermore, RNA-seq revealed that activation of the TXNIP-related redox pathway may be a key regulator in patients with asymptomatic hyperuricemia. These data suggest that silencing TXNIP could ameliorate HUA-induced IR via the IRS2/AKT and Nrf2/HO-1 pathways in macrophages. Additionally, TXNIP might be a promising therapeutic target for preventing and treating oxidative stress and IR induced by HUA.
Asunto(s)
Resistencia a la Insulina , Ácido Úrico , Proteínas Portadoras/genética , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Humanos , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Macrófagos/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The eight novel ivangustin enantiomer analogues possessing α-methylene-γ-butyrolactone moiety have been synthesized using (4S6R, 4S6S)-4-tert-butyldimethylsilyloxy-6-methylcyclohex-2-en-1-one (1) as starting material. These transformations were mainly carried out by aldol condensation reaction and one-pot annelation procedure. The stereochemistry of these synthesized analogues was determined by NOE analysis. Their cytoxicity was evaluated against the human cancer cell lines HCT-116 (colon), HL-60 (leukemia), QGY-7701 (liver), SMMC-7721 (liver), A549 (lung), MCF-7 (breast). The results showed that these analogues were more selective against the cell lines HL-60 and QGY-7701. Analogue 17 exhibited potent cytotoxicity and high selectivity toward HL-60 cell line with IC50 value of 1.02 µM, which suggested that it might be a promising anti-cancer lead compound. The inhibitory activities against NO production and the cytotoxicities in RAW 264.7 macrophages were determined at the same time. All of the analogues significantly inhibited the NO production with IC50 value in the range of 3.44-6.99 µM. Analogues 17, 22, 23 and 7 showed higher cytotoxicities, indicated their inhibitory activities against NO production may be influenced by the cytotoxicities.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/farmacología , Compuestos Heterocíclicos con 3 Anillos/toxicidad , Lactonas/farmacología , Lactonas/toxicidad , Macrófagos/efectos de los fármacos , Óxido Nítrico/biosíntesis , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/química , Humanos , Lactonas/síntesis química , Lactonas/química , Ratones , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Astragaloside IV (AGS-IV) is a main active ingredient of Astragalus membranaceus Bunge, a medicinal herb prescribed as an immunostimulant, hepatoprotective, antiperspirant, a diuretic or a tonic as documented in Chinese Materia Medica. In the present study, we employed a high-throughput comparative proteomic approach based on 2D-nano-LC-MS/MS to investigate the possible mechanism of action involved in the neuroprotective effect of AGS-IV against glutamate-induced neurotoxicity in PC12 cells. Differential proteins were identified, among which 13 proteins survived the stringent filter criteria and were further included for functional discussion. Two proteins (vimentin and Gap43) were randomly selected, and their expression levels were further confirmed by western blots analysis. The results matched well with those of proteomics. Furthermore, network analysis of protein-protein interactions (PPI) and pathways enrichment with AGS-IV associated proteins were carried out to illustrate its underlying molecular mechanism. Proteins associated with signal transduction, immune system, signaling molecules and interaction, and energy metabolism play important roles in neuroprotective effect of AGS-IV and Raf-MEK-ERK pathway was involved in the neuroprotective effect of AGS-IV against glutamate-induced neurotoxicity in PC12 cells. This study demonstrates that comparative proteomics based on shotgun approach is a valuable tool for molecular mechanism studies, since it allows the simultaneously evaluate the global proteins alterations.
Asunto(s)
Ácido Glutámico/toxicidad , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Saponinas/farmacología , Transducción de Señal/efectos de los fármacos , Triterpenos/farmacología , Animales , Diferenciación Celular , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ensayos Analíticos de Alto Rendimiento , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Anotación de Secuencia Molecular , Neuronas/citología , Neuronas/metabolismo , Células PC12 , Análisis de Componente Principal , Mapeo de Interacción de Proteínas , Ratas , Transducción de Señal/genética , Quinasas raf/genética , Quinasas raf/metabolismoRESUMEN
A series of new α-methylene-γ-lactone carbamates were synthesized by an asymmetric synthetic route. The activities on inhibiting nitric oxide (NO) release of these compounds were evaluated in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. The results indicated that most of the compounds except one exhibited potent NO inhibitory effect with IC50 value more than 2 µΜ. The cytotoxicities of these compounds were estimated via MTT assays. The results suggested that six compounds were accompanied by low cytotoxicity. The structure-activity relationships were also discussed. The S configuration of C3 on lactones ring would be more helpful to NO inhibitory effect.
Asunto(s)
Carbamatos/química , Carbamatos/farmacología , Lactonas/química , Lipopolisacáridos/efectos adversos , Macrófagos/efectos de los fármacos , Óxido Nítrico/biosíntesis , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Carbamatos/síntesis química , Técnicas de Química Sintética , Ratones , Células RAW 264.7RESUMEN
(E)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeine (HOEC), a naturally caffeic ester isolated from Incarvillea mairei, has been reported to possess anti-inflammatory activity by targeting 5-lipoxygenase. However, its other potential activities have yet to be explored. In this study, we measured antioxidant activity of HOEC using the DPPH free radical-scavenging assay. Then, we exposed rat pheochromocytoma (PC12) cells to hydrogen peroxide (H2O2)-induced damage and investigated the antioxidant activity of HOEC. Cell viability, lactate dehydrogenase (LDH) release, cellular morphology, Hoechst 33342 fluorescent staining, and apoptosis of the PC12 cells were assessed after treatment with 0.3-10 µM HOEC for 2 h and exposure to 600 µM H2O2. Additionally, glutathione reductase (GR), superoxide dismutase (SOD), lipid peroxidation malondialdehyde (MDA), and intracellular reactive oxygen species (ROS) accumulation were assayed after the PC12 cells were exposed to H2O2. To investigate mechanism, apoptosis-related protein were evaluated, including cleaved caspase 3/7, cleaved PARP, Bcl-2, Bcl-XL, and cytochrome c. The results showed that HOEC possessed potent antioxidant activity and pre-treatment with HOEC prior to H2O2 exposure significantly increased cell viability, reduced the release of LDH, ameliorated changes in cell morphology, and inhibited apoptosis. Further, HOEC did the following: reduced intracellular accumulation of ROS and MDA; rescued loss of SOD and GR activities; inhibited activated caspase-3 and caspase-7, cleaved PARP, and cytochrome c release; up-regulated the antiapoptosis-related protein Bcl-2 and Bcl-XL; and down-regulated the apoptosis-related proteins Bax and Bad. These findings suggested that HOEC may be a therapeutic agent for treating oxidative stress-derived neurodegenerative disorders.
Asunto(s)
Cafeína/análogos & derivados , Cafeína/farmacología , Supervivencia Celular/efectos de los fármacos , Peróxido de Hidrógeno/toxicidad , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Peróxido de Hidrógeno/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Células PC12 , Sustancias Protectoras/química , Sustancias Protectoras/farmacología , Ratas , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismoRESUMEN
A guaiane framework was scaffolded by photochemical rearrangement reactions using α-santonin 1 as a starting material. Then, using a series of reactions, we synthesized the guaiane-type sesquiterpene lactone 5 in high yield. The inhibitory activities of compound 5 and of a series of derivatives on nitric oxide (NO) release were evaluated in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Compounds 6g, 7h, 7i, 7k and 8g, exhibited significant inhibitory effects on NO production, with IC50 values of 14.8, 22.3, 18.3, 17.4 and 7.0 µM, respectively. Their cytotoxicities were also estimated using an MTT assay. The structure-activity relationships of these compounds were also discussed.
Asunto(s)
Lactonas/química , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Óxido Nítrico/biosíntesis , Sesquiterpenos de Guayano/química , Sesquiterpenos de Guayano/farmacología , Animales , Línea Celular , Técnicas de Química Sintética , Ratones , Sesquiterpenos de Guayano/síntesis química , Sesquiterpenos de Guayano/toxicidad , Relación Estructura-ActividadRESUMEN
PURPOSE: Inflammation participates centrally in all stages of atherosclerosis (AS), which begins with pro-inflammatory processes and inflammatory changes in the endothelium, related to lipid metabolism. MicroRNA (miRNA) inhibition of inflammation related to SIRT1 has been shown to be a promising therapeutic approach for AS. However, the mechanism of action is unknown. METHODS: We investigated whether miRNAs regulate the SIRT1 and its downstream SREBP-lipogenesis-cholesterogenesis metabolic pathway in human umbilical vein endothelial cells (HUVECs). HUVECs were transfected with miR-132 mimics and inhibitors, and then treated with or without tumor necrosis factor α (TNFα). The effects of miR-132 on pro-inflammatory processes, proliferation and apoptosis were assessed. RESULTS: We identified that the relative 3' UTR luciferase activities of SIRT1 were significantly decreased in miR-132 transfected HUVECs (0.338 ± 0.036) compared to control (P = 0.000). miR-132 inhibited SIRT1 expression of mRNA level in HUVECs (0.53 ± 0.06) (P < 0.01) as well as proteins of SIRT1. mRNA expression and protein levels of SREBP (0.45 ± 0.07), fatty acid synthase (FASN) (0.55 ± 0.09) and 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) (0.62 ± 0.08) (P < 0.01), which are downstream regulated genes, were reduced in HUVECs by miR-132. MiR-132 promoted pro-inflammatory processes and apoptosis of HUVECs induced by TNF-α, and inhibited its proliferation, viability and migration. CONCLUSIONS: SIRT1 mRNAs are direct targets of miR-132. miR-132 controls lipogenesis and cholesterogenesis in HUVECs by inhibiting SIRT1 and SREBP-1c expression and their downstream regulated genes, including FASN and HMGCR. Inhibition of SIRT1 by miR-132 was associated with lipid metabolism-dependent pro-inflammatory processes in HUVECs. The newly identified miRNA, miR-132 represents a novel targeting mechanism for AS therapy.
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Células Endoteliales de la Vena Umbilical Humana/metabolismo , MicroARNs/genética , Sirtuina 1/antagonistas & inhibidores , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/antagonistas & inhibidores , Apoptosis , Células Cultivadas , Endotelio Vascular/metabolismo , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Lipogénesis/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Transducción de Señal , Sirtuina 1/genética , Sirtuina 1/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Transfección , Factor de Necrosis Tumoral alfaRESUMEN
AIMS: Accumulation of advanced glycation endproduct (AGE) contributes to diabetic complication including diabetic cardiomyopathy although the precise underlying mechanism still remains elusive. Recent evidence depicted a pivotal role of protein kinase C (PKC) in diabetic complications. To this end, this study was designed to examine if PKCßII contributes to AGE-induced cardiomyocyte contractile and intracellular Ca(2+) aberrations. MAIN METHODS: Adult rat cardiomyocytes were incubated with methylglyoxal-AGE (MG-AGE) in the absence or presence of the PKCßII inhibitor LY333531 for 12h. Contractile and intracellular Ca(2+) properties were assessed using an IonOptix system including peak shortening (PS), maximal velocity of shortening/relengthening (±dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90), rise in intracellular Ca(2+) Fura-2 fluorescence intensity and intracellular Ca(2+) decay. Oxidative stress, O2(-) production and mitochondrial integrity were examined using TBARS, fluorescence imaging, aconitase activity and Western blotting. KEY FINDINGS: MG-AGE compromised contractile and intracellular Ca(2+) properties including reduced PS, ±dL/dt, prolonged TPS and TR90, decreased electrically stimulated rise in intracellular Ca(2+) and delayed intracellular Ca(2+) clearance, the effects of which were ablated by the PKCßII inhibitor LY333531. Inhibition of PKCßII rescued MG-AGE-induced oxidative stress, O2(-) generation, cell death, apoptosis and mitochondrial injury (reduced aconitase activity, UCP-2 and PGC-1α). In vitro studies revealed that PKCßII inhibition-induced beneficial effects were replicated by the NADPH oxidase inhibitor apocynin and were mitigated by the mitochondrial uncoupler FCCP. SIGNIFICANCE: These findings implicated the therapeutic potential of specific inhibition of PKCßII isoform in the management of AGE accumulation-induced myopathic anomalies.
Asunto(s)
Productos Finales de Glicación Avanzada/metabolismo , Contracción Miocárdica/fisiología , Miocitos Cardíacos/metabolismo , Proteína Quinasa C beta/antagonistas & inhibidores , Piruvaldehído/metabolismo , Aconitato Hidratasa/metabolismo , Animales , Apoptosis , Western Blotting , Calcio/metabolismo , Indoles/farmacología , Masculino , Maleimidas/farmacología , Mitocondrias/patología , Miocitos Cardíacos/patología , Estrés Oxidativo , Ratas , Ratas Sprague-DawleyRESUMEN
A series of novel derivatives of phenyl substituted tetramethoxy xanthone were synthesized and evaluated for their in vitro cytotoxicity against human hepatocellular carcinoma (HCC) and non-tumor hepatic cells. Among these derivatives, compound 6 was more potent than positive control 5-fluorouracil (5-Fu) on QGY-7703 and SMMC-7721 cells with IC50 values of 6.27 µM, 7.50 µM and 15.56 µM, 14.55 µM, respectively. Furthermore, compounds 6, 14, 16, and 29 exhibited much better selectivity toward the normal hepatic cell line QSG-7701 than 5-Fu. Additionally, compound 6 significantly induced cell apoptosis in QGY-7703 cells. Our findings suggested that these phenylxanthone derivatives may hold promise as chemotherapeutic agents for the treatment of human HCC.