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BACKGROUND: Sepsis-induced cardiomyopathy (SIC) is a cardiac dysfunction caused by sepsis, with mitochondrial dysfunction being a critical contributor. Pyruvate dehydrogenase kinase 4 (PDK4) is a kinase of pyruvate dehydrogenase with multifaceted actions in mitochondrial metabolism. However, its role in SIC remains unknown. METHODS: Serum PDK4 levels were measured and analyzed in 27 children with SIC, 30 children with sepsis, and 29 healthy children. In addition, for mice exhibiting SIC, the effects of PDK4 knockdown or inhibition on the function and structure of the myocardium and mitochondria were assessed. RESULTS: The findings from the analysis of children with SIC revealed that PDK4 was significantly elevated and correlated with disease severity and organ injury. Nonsurvivors displayed higher serum PDK4 levels than survivors. Furthermore, mice with SIC benefited from PDK4 knockdown or inhibition, showing improved myocardial contractile function, reduced myocardial injury, and decreased mitochondrial structural injury and dysfunction. In addition, inhibition of PDK4 decreased the inhibitory phosphorylation of PDHE1α (pyruvate dehydrogenase complex E1 subunit α) and improved abnormal pyruvate metabolism and mitochondrial dysfunction. CONCLUSIONS: PDK4 is a potential biomarker for the diagnosis and prognosis of SIC. In experimental SIC, PDK4 promoted mitochondrial dysfunction with increased phosphorylation of PDHE1α and abnormal pyruvate metabolism.
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Cardiomiopatias , Doenças Mitocondriais , Proteínas Quinases , Sepse , Animais , Criança , Humanos , Camundongos , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Miocárdio/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Piruvatos/metabolismo , Sepse/complicações , Sepse/metabolismoRESUMO
The presence of Helicobacter pylori (H. pylori) infection poses a substantial risk for the development of gastric adenocarcinoma. The primary mechanism through which H. pylori exerts its bacterial virulence is the cytotoxin CagA. This cytotoxin has the potential to induce inter-epithelial mesenchymal transition, proliferation, metastasis, and the acquisition of stem cell-like properties in gastric cancer (GC) cells infected with CagA-positive H. pylori. Cancer stem cells (CSCs) represent a distinct population of cells capable of self-renewal and generating heterogeneous tumor cells. Despite evidence showing that CagA can induce CSCs-like characteristics in GC cells, the precise mechanism through which CagA triggers the development of GC stem cells (GCSCs) remains uncertain. This study reveals that CagA-positive GC cells infected with H. pylori exhibit CSCs-like properties, such as heightened expression of CD44, a specific surface marker for CSCs, and increased ability to form tumor spheroids. Furthermore, we have observed that H. pylori activates the PI3K/Akt signaling pathway in a CagA-dependent manner, and our findings suggest that this activation is associated with the CSCs-like characteristics induced by H. pylori. The cytotoxin CagA, which is released during H. pylori infection, triggers the activation of the PI3K/Akt signaling pathway in a CagA-dependent manner. Additionally, CagA inhibits the transcription of FOXO3a and relocates it from the nucleus to the cytoplasm by activating the PI3K/Akt pathway. Furthermore, the regulatory function of the Akt/FOXO3a axis in the transformation of GC cells into a stemness state was successfully demonstrated.
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Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Citotoxinas/metabolismo , Mucosa Gástrica/metabolismo , Infecções por Helicobacter/patologia , Células-Tronco Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismoRESUMO
The structural dynamics of artificial assemblies, in aspects such as molecular recognition and structural transformation, provide us with a blueprint to achieve bioinspired applications. Here, we describe the assembly of redox-switchable chiral metal-organic cages Λ8/Δ8-[Pd6(CoIIL3)8]28+ and Λ8/Δ8-[Pd6(CoIIIL3)8]36+. These isomeric cages demonstrate an on-off chirality logic gate controlled by their chemical and stereostructural dynamics tunable through redox transitions between the labile CoII-state and static CoIII-state with a distinct Cotton effect. The transition between different states is enabled by a reversible redox process and chiral recognition originating in the tris-chelate Co-centers. All cages in two states are thoroughly characterized by NMR, ESI-MS, CV, CD, and X-ray crystallographic analysis, which clarify their redox-switching behaviors upon chemical reduction/oxidation. The stereochemical lability of the CoII-center endows the Λ8/Δ8-CoII-cages with efficient chiral-induction by enantiomeric guests, leading to enantiomeric isomerization to switch between Λ8/Δ8-CoII-cages, which can be stabilized by oxidation to their chemically inert forms of Λ8/Δ8-CoIII-cages. Kinetic studies reveal that the isomerization rate of the Δ8-CoIII-cage is at least an order of magnitude slower than that of the Δ8-CoII-cage even at an elevated temperature, while its activation energy is 16 kcal mol-1 higher than that of the CoII-cage.
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OBJECTIVE: To investigate the effect of ferroptosis in BMSCs and explore the protective metabolism of ferrostatin-1 under GSDH treatment. METHODS: BMSCs were treated with GSDH to simulate the damaged microenvironment in vivo to establish a cell injury model. Propidium iodide and CCK8 were utilized to detect the ratio of dead cells and cell viability. DCFH-DA and Amplex Red, FerroOrange, and BPDIPY were used to visualize the cellular fluorescent images of ROS, Fe2+, and lipid droplets, respectively. The quantified detection of MDA was conducted by a Lipid Peroxidation MDA Assay Kit. JC-1 staining, Mito-Tracker staining, and TEM were implemented to detect the membrane potential, morphology, and ultrastructure of mitochondria, respectively. The expression levels of ferroptosis-related proteins such as GPX4 and FTH1 were measured by Western blotting. RESULTS: GSDH treatment induced ferroptosis in BMSCs based on an increased ratio of cell death, Fe2+, ROS, lipid droplets, and MDA in cells plus decreased protein levels of antioxidant systems, such as GPX4, and increased protein levels related to fatty acid synthesis. Compared to the blank group, mitochondria in the GSDH group underwent lower membrane potential, damaged morphology, and shrunken ultrastructure; Ferr-1 rescued the injured BMSCs to a certain extent as the declined ratio of cell death, Fe2+, ROS, lipid droplets, MDA, and the increased level antioxidant protein. AMPK was phosphorylated and activated after Ferr-1 treatment, and its downstream lipid peroxidation and antioxidation proteins changed accordingly. Inhibition of AMPK hindered the curative effect of Ferr-1. CONCLUSION: Ferr-1 rescued ferroptosis-induced injury to BMSCs under GSDH conditions, and AMPK might have a relationship with the mitigative effect of Ferr-1.
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Proteínas Quinases Ativadas por AMP , Ferroptose , Antioxidantes , Espécies Reativas de OxigênioRESUMO
BACKGROUND: Lymph node (LN) status is vital to evaluate the curative potential of relatively early gastric cancer (GC; T1-T2) treatment (endoscopic or surgery). Currently, there is a lack of robust and convenient methods to identify LN metastasis before therapeutic decision-making. METHODS: Genome-wide expression profiles of long noncoding RNA (lncRNA) in primary T1 gastric cancer data from The Cancer Genome Atlas (TCGA) was used to identify lncRNA expression signature capable of detecting LN metastasis of GC and establish a 10-lncRNA risk-prediction model based on deep learning. The performance of the lncRNA panel in diagnosing LN metastasis was evaluated both in silico and clinical validation methods. In silico validation was conducted using TCGA and Asian Cancer Research Group (ACRG) datasets. Clinical validation was performed on T1 and T2 patients, and the panel's efficacy was compared with that of traditional tumor markers and computed tomography (CT) scans. RESULTS: Profiling of genome-wide RNA expression identified a panel of lncRNA to predict LN metastasis in T1 stage gastric cancer (AUC = 0.961). A 10-lncRNA risk-prediction model was then constructed, which was validated successfully in T1 and T2 datasets (TCGA, AUC = 0.852; ACRG, AUC = 0.834). Thereafter, the clinical performance of the lncRNA panel was validated in clinical cohorts (T1, AUC = 0.812; T2, AUC = 0.805; T1 + T2, AUC = 0.764). Notably, the panel demonstrated significantly better performance compared with CT and traditional tumor markers. CONCLUSIONS: The novel 10-lncRNA could diagnose LN metastasis robustly in relatively early gastric cancer (T1-T2), with promising clinical potential.
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RNA Longo não Codificante , Neoplasias Gástricas , Humanos , Metástase Linfática/patologia , RNA Longo não Codificante/genética , Transcriptoma , Neoplasias Gástricas/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linfonodos/patologiaRESUMO
BACKGROUND: Knee osteoarthritis (OA) is a chronic, degenerative bone and joint disease. It can lead to major pressure to the quality of life and mental health of patients, and also brings a serious economic burden to society. However, it is difficult for patients with knee OA to access rehabilitation when discharging from the hospital. Internet-based rehabilitation is one of the promising telemedicine strategies for the improvement of knee OA, but the effect of different telerehabilitation strategies on knee OA is not clear. OBJECTIVE: The aim of this systematic review and meta-analysis was to identify telerehabilitation strategies attributing to the improvement of pain and physical function outcomes in patients with knee OA. METHODS: We reviewed and analyzed telerehabilitation strategies from randomized controlled trials (RCTs) comparing telerehabilitation with conventional treatment or usual care. For each strategy, we examined whether RCTs that applied the telerehabilitation strategy resulted in a significant improvement in pain or physical function compared with conventional treatment or usual care. RESULTS: We included 6 RCTs (n=734) incorporating 8 different telerehabilitation strategies. The duration of the interventions ranged from 1 to 48 weeks, and sample sizes ranged from 20 to 350 patients. The results showed that RCTs that provided telerehabilitation were found to be more effective than conventional treatments for improving pain (P=.003; standardized mean difference [SMD] -0.21, 95% CI -0.35 to -0.07), but not physical function (P=.24; SMD -0.09, 95% CI -0.25 to 0.06). Furthermore, this systematic review and meta-analysis indicated that there is no significant correlation between different telerehabilitation strategies and the pain and physical function of patients with knee OA. CONCLUSIONS: This systematic review and meta-analysis showed that telerehabilitation programs could relieve pain but not improve physical function for patients with knee OA. These results indicated that telerehabilitation is beneficial for the implementation of home rehabilitation exercises for patients with knee OA, thereby reducing the economic burden of health. However, there were limitations in terms of the number of search results and the number of studies that were eligible for this review and meta-analysis. Therefore, the results need to be interpreted with caution, and more high-quality studies with large samples are needed to focus on the long-term outcomes of telerehabilitation for patients with knee OA to address this limitation.
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Osteoartrite do Joelho , Telemedicina , Telerreabilitação , Humanos , Osteoartrite do Joelho/reabilitação , Telerreabilitação/métodos , Dor , Terapia por Exercício/métodosRESUMO
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are cells with promising applications. However, their immaturity has restricted their use in cell therapy, disease modeling, and other studies. Therefore, the current study focused on inducing the maturation of CMs. We supplemented hiPSC-CMs with fatty acids (FAs) to promote their phenotypic maturity. Proteomic sequencing was performed to identify regulators critical for promoting the maturation of hiPSC-CMs. AKAP1 was found to be significantly increased in FA-treated hiPSC-CMs, and the results were verified. Therefore, we inhibited AKAP1 expression in the FA-treated cells and analyzed the outcomes. FA supplementation promoted the morphological and functional maturation of the hiPSC-CMs, which was accompanied by the development of a mitochondrial network. Proteomic analysis results revealed that AKAP1 expression was significantly higher in FA-treated hiPSC-CMs than in control cells. In addition, increased phosphorylation of the mitochondrial dynamin Drp1 and an increased mitochondrial fusion rate were found in FA-treated hiPSC-CMs. After AKAP1 was knocked down, the level of DRP1 phosphorylation in the cell was decreased, and the mitochondrial fusion rate was reduced. FA supplementation effectively promoted the maturation of hiPSC-CMs, and in these cells, AKAP1 regulated mitochondrial dynamics, possibly playing a significant role.
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Células-Tronco Pluripotentes Induzidas , Miócitos Cardíacos , Humanos , Diferenciação Celular , Células Cultivadas , Ácidos Graxos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Dinâmica Mitocondrial , Miócitos Cardíacos/metabolismo , ProteômicaRESUMO
Our study aims to explore changes in bladder contractility and the phosphodiesterase type 5 (PDE5) signalling pathway in response to partial bladder outlet obstruction (PBOO). A surgically induced male rat PBOO model and human obstructed bladder tissues were used. Histological changes were examined by H&E and Masson's trichrome staining. Bladder strip contractility was measured via organ bath. The expressions of nitric oxide synthase (NOS) isoforms, PDE5, muscarinic cholinergic receptor (CHRM) isoforms and PDE4 isoforms in bladder were detected by RT-PCR and Western blotting. The immunolocalization of the PDE5 protein and its functional activity were also determined. PBOO bladder tissue exhibited significant SM hypertrophy and elevated responsiveness to KCl depolarization and the muscarinic receptor agonist carbachol. NOS isoforms, PDE5, CHRM2, CHRM3 and PDE4A were up-regulated in obstructed bladder tissue, whereas no change in PDE4B and PDE4D isoform expression was observed. With regard to PDE5, it was expressed in the SM bundles of bladder. Interestingly, obstructed bladder exhibited less relaxation responsiveness to sodium nitroprusside (SNP), but an exaggerated PDE5 inhibition effect. The up-regulation of PDE5 could contribute to the lack of effect on Qmax for benign prostatic hyperplasia/lower urinary tract symptom (BPH/LUTS) patients treated with PDE5 inhibitors. Moreover, PDE5 (with presence of NO) and PDE4 may serve as new therapeutic targets for bladder diseases such as BPH-induced LUTS and overactive bladder (OAB).
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Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Perfilação da Expressão Gênica , Obstrução do Colo da Bexiga Urinária/enzimologia , Bexiga Urinária/enzimologia , Animais , Peso Corporal , Humanos , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Nitroprussiato/química , Tamanho do Órgão , Hiperplasia Prostática/metabolismo , Isoformas de Proteínas , Ratos , Ratos Sprague-Dawley , Receptores Muscarínicos/metabolismo , Bexiga Urinária Hiperativa/enzimologiaRESUMO
BACKGROUND: High levels of the post-translational modification O-GlcNAcylation (O-GlcNAc) are found in multiple cancers, including bladder cancer. Autophagy, which can be induced by stress from post-translational modifications, plays a critical role in maintaining cellular homeostasis and regulating tumorigenesis. The impact of O-GlcNAcylation on autophagy in bladder cancer remains unclear. Here, we evaluate the change in autophagic activity in response to O-GlcNAcylation and explore the potential mechanisms. METHODS: O-GlcNAcylation levels in bladder cancer cells were altered through pharmacological or genetic manipulations: treating with 6-diazo-5-oxo-norleucine (DON) or thiamet-G (TG) or up- and downregulation of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA). Autophagy was determined using fluorescence microscopy and western blotting. Co-immunoprecipitation (Co-IP) assays were performed to evaluate whether the autophagy regulator AMP-activated protein kinase (AMPK) was O-GlcNAc modified. RESULTS: Cellular autophagic flux was strikingly enhanced as a result of O-GlcNAcylation suppression, whereas it decreased at high O-GlcNAcylation levels. Phosphorylation of AMPK increased after the suppression of O-GlcNAcylation. We found that O-GlcNAcylation of AMPK suppressed the activity of this regulator, thereby inhibiting ULK1 activity and autophagy. CONCLUSION: We characterized a new function of O-GlcNAcylation in the suppression of autophagy via regulation of AMPK. GRAPHICAL ABSTRACT: Blockage of O-linked GlcNAcylation induces AMPK dependent autophagy in bladder cancer cells.
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Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/genética , N-Acetilglucosaminiltransferases/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Neoplasias da Bexiga Urinária/metabolismo , beta-N-Acetil-Hexosaminidases/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Acilação/efeitos dos fármacos , Acilação/genética , Autofagia/efeitos dos fármacos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Compostos Azo/farmacologia , Linhagem Celular Tumoral , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , N-Acetilglucosaminiltransferases/genética , Norleucina/análogos & derivados , Norleucina/farmacologia , Fosforilação , Processamento de Proteína Pós-Traducional/genética , Piranos/farmacologia , RNA Interferente Pequeno , Tiazóis/farmacologia , Neoplasias da Bexiga Urinária/enzimologia , Neoplasias da Bexiga Urinária/genética , beta-N-Acetil-Hexosaminidases/genéticaRESUMO
The aim of this study was to access whether microsurgical subinguinal varicocelectomy (MSV) with testicular delivery has a better therapeutic effect than MSV without testicular delivery, including semen quality, serum testosterone (T) level and International Index of Erectile Function (IIEF)-5 score in infertility male patients with varicocele. In this prospective study, 181 patients were included and they chose the treatment by themselves. A total of 114 patients who received MSV without testicular delivery (TD) and 67 patients who received MSV with TD were followed-up 6 months after the operation. Semen parameters, serum T level and IIEF-5 scores were recorded before and 6 months after the operation. Results showed that MSV with or without TD could improve semen quality, serum T level and IIEF-5 score. For semen quality 6 months after the operation, there was no significant difference between patients received MSV with or without TD. But in patients with varicocele of grade III, MSV without testicular delivery improved the sperm concentration and motility more. And patients received MSV without TD have a higher T level 6 months after the operation, especially in patients ≤27 years. MSV with TD is not superior to that without, but this should be verified in more samples and a better designed randomised controlled study in the future.
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Infertilidade Masculina/cirurgia , Microcirurgia/métodos , Testículo/irrigação sanguínea , Procedimentos Cirúrgicos Urológicos Masculinos/métodos , Varicocele/cirurgia , Veias/cirurgia , Adulto , Humanos , Infertilidade Masculina/etiologia , Canal Inguinal , Ligadura , Masculino , Ereção Peniana , Estudos Prospectivos , Análise do Sêmen , Contagem de Espermatozoides , Motilidade dos Espermatozoides , Testosterona/metabolismo , Resultado do Tratamento , Varicocele/complicações , Varicocele/metabolismo , Procedimentos Cirúrgicos Vasculares/métodos , Adulto JovemRESUMO
BACKGROUND: Reactive oxygen species (ROS) levels largely determine pulmonary fibrosis. Antioxidants have been found to ameliorate lung fibrosis after long-term paraquat (PQ) exposure. The effects of antioxidants, however, on the signalling pathways involved in PQ-induced lung fibrosis have not yet been investigated sufficiently. Here, we examined the impacts of ligustrazin on lung fibrosis, in particular ROS-related autophagy and pro-fibrotic signalling pathways, using a murine model of PQ-induced lung fibrosis. METHODS: We explored the effects of microRNA-193 (miR-193a) on Hedgehog (Hh) and PI3K/Akt/mTOR signalling and oxidative stress in lung tissues. Levels of miR-193a, protein kinase B (Akt), phosphoinositide 3-Kinase (PI3K), ceclin1, mammalian target of rapamycin (mTOR), sonic hedgehog (SHH), myosin-like Bcl2 interacting protein (LC3), smoothened (Smo), and glioma-associated oncogene-1 (Gli-1) mRNAs were determined with quantitative real-time PCR. Protein levels of PI3K, p-mTOR, p-Akt, SHH, beclin1, gGli-1, LC3, smo, transforming growth factor-ß1 (TGF-ß1), mothers against DPP homologue-2 (Smad2), connective tissue growth factor (CTGF), collagen I, collagen III, α-smooth muscle actin (α-SMA) nuclear factor erythroid 2p45-related factor-2 (Nrf2), and p-Smad2 were detected by western blotting. In addition, α-SMA, malondialdehyde, ROS, superoxide dismutase (SOD), oxidised and reduced glutathione, hydroxyproline, and overall collagen levels were identified in lung tissues using immunohistochemistry. RESULTS: Long-term PQ exposure blocked miR-193a expression, reduced PI3K/Akt/mTOR signalling, increased oxidative stress, inhibited autophagy, increased Hh signalling, and facilitated the formation of pulmonary fibrosis. Ligustrazin blocked PI3K/Akt/mTOR and Hh signalling as well as reduced oxidative stress via increasing miR-193a expression and autophagy, all of which reduced pulmonary fibrosis. These effects of ligustrazin were accompanied by reduced TGF-ß1, CTGF, and Collagen I and III expression. CONCLUSIONS: Ligustrazin blocked PQ-induced PI3K/Akt/mTOR and Hh signalling by increasing miR-193a expression, thereby attenuating PQ-induced lung fibrosis.
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Autofagia/efeitos dos fármacos , MicroRNAs/metabolismo , Fibrose Pulmonar/metabolismo , Pirazinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células A549 , Animais , Colágeno Tipo I/metabolismo , Feminino , Humanos , Camundongos , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Paraquat/toxicidade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
In order to measure the temperature of the object in the case of non-diffuse emission within a finite solid angle, a new concept for radiation thermometry, the apparent emissivity, has been presented firstly after a proper mathematical transformation of the radiation measurement equation and its characteristics have also been investigated. The results indicated that although the apparent emissivity is complex in form, it is only the function of the wavelength for one measurement even if the object is non-diffuse. So the temperature of the object in the case of non-diffuse emission within a finite solid angle can be solved by modeling the apparent emissivity. Then the equations for monochromatic and wavelength radiation measurement were deduced. At the same time, the measurement of temperature for a finite area was investigated, and it can be found that if the temperatures of the finite area are the same, they can also be determined by modeling the apparent emissivity.
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Mitochondrial dysfunction is considered one of the major pathogenic mechanisms of sepsis-induced cardiomyopathy (SIC). Pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of mitochondrial metabolism, is essential for maintaining mitochondrial function. However, its specific role in SIC remains unclear. To investigate this, we established an in vitro model of septic cardiomyopathy using lipopolysaccharide (LPS)-induced H9C2 cardiomyocytes. Our study revealed a significant increase in PDK4 expression in LPS-treated H9C2 cardiomyocytes. Inhibiting PDK4 with dichloroacetic acid (DCA) improved cell survival, reduced intracellular lipid accumulation and calcium overload, and restored mitochondrial structure and respiratory capacity while decreasing lactate accumulation. Similarly, Oxamate, a lactate dehydrogenase inhibitor, exhibited similar effects to DCA in LPS-treated H9C2 cardiomyocytes. To further validate whether PDK4 causes cardiomyocyte and mitochondrial damage in SIC by promoting lactate production, we upregulated PDK4 expression using PDK4-overexpressing lentivirus in H9C2 cardiomyocytes. This resulted in elevated lactate levels, impaired mitochondrial structure, and reduced mitochondrial respiratory capacity. However, inhibiting lactate production reversed the mitochondrial dysfunction caused by PDK4 upregulation. In conclusion, our study highlights the pathogenic role of PDK4 in LPS-induced cardiomyocyte and mitochondrial damage by promoting lactate production. Therefore, targeting PDK4 and its downstream product lactate may serve as promising therapeutic approaches for treating SIC.
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Ácido Láctico , Lipopolissacarídeos , Miócitos Cardíacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Lipopolissacarídeos/toxicidade , Animais , Ratos , Ácido Láctico/metabolismo , Linhagem Celular , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/antagonistas & inibidores , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/metabolismo , Proteínas QuinasesRESUMO
Background: Early neurological deterioration (END) is a frequent complication in patients with perforating artery territory infarction (PAI), leading to poorer outcomes. Therefore, we aimed to apply machine learning (ML) algorithms to predict the occurrence of END in PAI and investigate related risk factors. Methods: This retrospective study analyzed a cohort of PAI patients, excluding those with severe stenosis of the parent artery. We included demographic characteristics, clinical features, laboratory data, and imaging variables. Recursive feature elimination with cross-validation (RFECV) was performed to identify critical features. Seven ML algorithms, namely logistic regression, random forest, adaptive boosting, gradient boosting decision tree, histogram-based gradient boosting, extreme gradient boosting, and category boosting, were developed to predict END in PAI patients using these critical features. We compared the accuracy of these models in predicting outcomes. Additionally, SHapley Additive exPlanations (SHAP) values were introduced to interpret the optimal model and assess the significance of input features. Results: The study enrolled 1,020 PAI patients with a mean age of 60.46 (range 49.11-71.81) years. Of these, 30.39% were women, and 129 (12.65%) experienced END. RFECV selected 13 critical features, including blood urea nitrogen (BUN), total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB), atrial fibrillation, loading dual antiplatelet therapy (DAPT), single antiplatelet therapy (SAPT), argatroban, the basal ganglia, the thalamus, the posterior choroidal arteries, maximal axial infarct diameter (measured at < 15 mm), and stroke subtype. The gradient-boosting decision tree had the highest area under the curve (0.914) among the seven ML algorithms. The SHAP analysis identified apoB as the most significant variable for END. Conclusion: Our results suggest that ML algorithms, especially the gradient-boosting decision tree, are effective in predicting the occurrence of END in PAI patients.
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The C-5-methylation of cytosine in the CpG islands is an important pattern for epigenetic modification of gene, which plays a key role in regulating gene transcription. G-quadruplex is an unusual DNA secondary structure formed in G-rich regions and is identified as a transcription repressor in some oncogenes, such as c-myc and bcl-2. In the present study, the results from CD spectrum and FRET assay showed that the methylation of cytosine in the CpG islands could induce a conformational change of the G-quadruplex in the P1 promoter of bcl-2, and greatly increase the thermal-stability of this DNA oligomer. Moreover, the methylation of cytosine in the G-quadruplex could protect the structure from the disruption by the complementary strand, showing with the increasing ability to arrest the polymerase in PCR stop assay. This data indicated that the stabilization of the G-quadruplex structure in the CpG islands might be involved in the epigenetical transcriptional regulation for specific genes through the C-5-methylation modification pattern.
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Epigênese Genética , Quadruplex G , Genes bcl-2 , Regiões Promotoras Genéticas , Dicroísmo Circular , Biologia Computacional/métodos , Ilhas de CpG , Citosina/metabolismo , Metilação de DNA , Transferência Ressonante de Energia de Fluorescência , Humanos , Modelos Moleculares , Desnaturação de Ácido Nucleico , Reação em Cadeia da Polimerase/métodos , Temperatura , Transcrição GênicaRESUMO
Apple leaf diseases without timely control will affect fruit quality and yield, intelligent detection of apple leaf diseases was especially important. So this paper mainly focuses on apple leaf disease detection problem, proposes a machine vision algorithm model for fast apple leaf disease detection called LALNet (High-speed apple leaf network). First, an efficient sacked module for apple leaf detection, known as EALD (efficient apple leaf detection stacking module), was designed by utilizing the multi-branch structure and depth-separable modules. In the backbone network of LALNet, (High-speed apple leaf network) four layers of EALD modules were superimposed and an SE(Squeeze-and-Excitation) module was added in the last layer of the model to improve the attention of the model to important features. A structural reparameterization technique was used to combine the outputs of two layers of deeply separable convolutions in branch during the inference phase to improve the model's operational speed. The results show that in the test set, the detection accuracy of the model was 96.07%. The total precision was 95.79%, the total recall was 96.05%, the total F1 was 96.06%, the model size was 6.61 MB, and the detection speed of a single image was 6.68 ms. Therefore, the model ensures both high detection accuracy and fast execution speed, making it suitable for deployment on embedded devices. It supports precision spraying for the prevention and control of apple leaf disease.
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Alzheimer's disease is a common neurological disorder, which has become one of the major factors affecting human health due to its serious impact on individuals, families and society. It has been confirmed that gut microbiota can affect the occurrence and development of Alzheimer's disease. Especially, fecal microbiota transplantation plays a positive role in the treatment of Alzheimer's disease. The mechanisms for improving Alzheimer's disease might include anti-inflammation and regulation of amyloid ß-protein, synaptic plasticity, short-chain fatty acids, and histone acetylation. In this mini-review, the relationship between fecal microbiota transplantation and Alzheimer's disease was summarized. It is hoped that fecal microbiota transplantation would play a positive role in the prevention and treatment of Alzheimer's disease in the future.
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The metabolic patterns and energetics of human induced pluripotent stem cell-derived cardiomyocytes (HiPSC-CMs) are much less than those of normal adult cardiomyocytes, which has limited their application in disease therapy and regenerative medicine. It has been demonstrated that SIRT3, a mitochondria-target deacetylase, controls mitochondrial metabolism in physiological and pathological conditions. In this research, We investigated the role and regulatory mechanism of SIRT3 in energy metabolism in HiPSC-CMs. We found that the expression of SIRT3 was increased during the differentiation and maturation of HiPSC-CMs. Knocking down SIRT3 impaired mitochondrial structure, mitochondrial respiration capacity, and fatty acid oxidation but enhanced glycolysis. However, honokiol, a pharmacological activator of SIRT3, improved the mitochondrial ultrastructure and energetics, and promoted oxidative phosphorylation in HiPSC-CMs. Furthermore, SIRT3 regulated the acetylation of OPA1, and the knockdown of OPA1 blocked the promotion of energy metabolism by honokiol, meanwhile, knocking down OPA1 impaired mitochondrial fusion, mitochondrial respiration capacity, and fatty acid oxidation which were reversed by M1 (a mitochondrial fusion promoter) in HiPSC-CMs. In summary, SIRT3 regulated energetics and promoted metabolism remodeling by targeting the OPA1-controlled mitochondrial dynamics in HiPSC-CMs, and targeting SIRT3 may have revelatory implications in the treatment of cardiovascular diseases and the application of HiPSC-CMs to regenerative medicine.
Assuntos
Células-Tronco Pluripotentes Induzidas , Sirtuína 3 , Humanos , Diferenciação Celular , Ácidos Graxos/metabolismo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Dinâmica Mitocondrial , Miócitos Cardíacos/metabolismo , Sirtuína 3/genética , Sirtuína 3/metabolismoRESUMO
BACKGROUND: Corticosteroids and anti-tumor necrosis factor α mAbs are widely used to treat Crohn's disease (CD). However, one disadvantage of this treatment is impairment of normal immune function, leading to an increased risk of infection. Cryptococcus infection is an opportunistic infection that occurs mainly in immunocompromised patients and poses a significant diagnostic challenge in patients with CD. CASE SUMMARY: Here, we report three cases of pulmonary cryptococcosis in patients with CD after receiving immunomodulatory treatment. The patients presented with no or mild respiratory symptoms. Chest computed tomography scans revealed pulmonary nodules in the unilateral or bilateral lobes. Diagnoses were made using pathological examination and metagenomic sequencing. The patients were treated with fluconazole 400 mg once daily for 1 to 6 mo, and symptoms were resolved. Literature searches were conducted in PubMed, Web of Science, and Embase to retrieve previously reported cases and summarize patient characteristics. CONCLUSION: The incidence of cryptococcus infection has increased along with immunomodulator use. Clinical vigilance is required for early identification and standardized treatment.