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OBJECTIVE: To observe the effect of early cervical functional exercise (CFE) on clinical outcomes and safety of patients after anterior cervical discectomy and fusion (ACDF). METHODS: Sixty patients who underwent ACDF from September 2019 to September 2020 were analyzed and randomly divided into two groups: the CFE group (27 cases) and the usual care (UC) group (33 cases). Then, all patients in the two groups received routine postoperative guidance care at the same time. Besides, the patients of the CFE group underwent a cervical functional exercise program after on the third day after ACDF. The evaluation was conducted preoperatively and at 1 week, 1 month and 6 months after surgery. The Visual Analogue Scale (VAS), Neck Disability Index (NDI) and Japanese Orthopaedic Association scores (JOA) were used to assess clinical outcomes and the safety was confirmed with routine postoperative radiological visits to ensure intervertebral stability. RESULTS: The CFE group reported lower neck pain scores on VAS at 1 month after surgery (P = 0.02) and higher postoperative scores by JOA at 1 month and 6 months, neck disability on NDI at 1 week, 1 month and 6 months after surgery (P < 0.05) compared to the UC group. For postoperative dysfunction, the CFE group had more significant changes than the UC group at 1 month and 6 months after surgery (P < 0.05). There was no statistical difference in cervical curves, fusion rate and fusion status between the two groups, and no revision surgery was recorded although a patient has one screw partially back out in UC group. CONCLUSION: Our study suggested that the cervical functional exercise could decrease cervical pain and improve postoperative function in patients after ACDF. It was a safe and effective treatment for postoperative rehabilitation. The use of a postoperative collar, especially for one or two-level ACDF may not be needed. PROTOCOL IDENTIFYING NUMBER: This trial was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR1900025569) on 01/09/2019.
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BACKGROUND: Folic acid (FA) supplementation during pregnancy aims to protect foetal development. However, maternal over-supplementation of FA has been demonstrated to cause metabolic dysfunction and increase the risk of autism, retinoblastoma, and respiratory illness in the offspring. Moreover, FA supplementation reduces the risk of congenital heart disease. However, little is known about its possible adverse effects on cardiac health resulting from maternal over-supplementation. In this study, we assessed the detrimental effects of maternal FA over-supplementation on the cardiac health of the offspring. METHODS AND RESULTS: Eight-week-old C57BL/6J pregnant mice were randomly divided into control and over-supplemented groups. The offspring cardiac function was assessed using echocardiography. Cardiac fibrosis was assessed in the left ventricular myocardium by histological analysis. Proteomic, protein, RNA, and DNA methylation analyses were performed by liquid chromatography-tandem mass spectrometry, western blotting, real-time quantitative PCR, and bisulfite sequencing, respectively. We found that maternal periconceptional FA over-supplementation impaired cardiac function with the decreased left ventricular ejection fraction in the offspring. Biochemical indices and tissue staining further confirmed impaired cardiac function in offspring caused by maternal FA over-supplementation. The combined proteomic, RNA expression, and DNA methylation analyses suggested that key genes involved in cardiac function were inhibited at the transcriptional level possibly due to increased DNA methylation. Among these, superoxide dismutase 1 was downregulated, and reactive oxygen species (ROS) levels increased in the mouse heart. Inhibition of ROS generation using the antioxidant N-acetylcysteine rescued the impaired cardiac function resulting from maternal FA over-supplementation. CONCLUSIONS: Our study revealed that over-supplementation with FA during mouse pregnancy is detrimental to cardiac function with the decreased left ventricular ejection fraction in the offspring and provides insights into the mechanisms underlying the association between maternal FA status and health outcomes in the offspring.
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Background: Lung cancer is a highly prevalent malignancy with significant morbidity and mortality rates. MiR-489-3p, a microRNA, has been identified as a regulator of tumor cell proliferation and invasion. Its expression is downregulated in non-small cell lung cancer (NSCLC). Elucidating the molecular mechanisms underlying miR-489-3p's role in NSCLC pathogenesis is crucial for identifying potential diagnostic and therapeutic targets. Methods: To investigate the molecular mechanism of miR-489-3p in NSCLC, this study utilized A549, a commonly used NSCLC cell line. MiR-489-3p mimics and inhibitors were transfected into A549 cells. Additionally, co-transfection experiments using wortmannin, an inhibitor of the PI3K/AKT pathway, were performed. Expression of miR-489-3p and related proteins was analyzed by Western blotting and quantitative real-time PCR (qRT-PCR). Cell migration and proliferation were assessed by wound healing and colony formation assays, respectively. Results: Overexpression of miR-489-3p significantly inhibited the proliferation and migration of A549 cells. This inhibitory effect was further enhanced upon co-transfected with wortmannin. Analysis of human lung specimens showed increased expression of HER2, PI3K, and AKT in lung adenocarcinoma tissues compared to adjacent non-cancerous tissues. Conclusions: These findings suggest that miR-489-3p overexpression may inhibit NSCLC cell proliferation and migration by suppressing the HER2/PI3K/AKT/Snail signaling pathway. This study elucidates miR-489-3p's molecular mechanisms in NSCLC and provides experimental basis for identifying early diagnostic markers and novel therapeutic targets.
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Based on the modified cross-linking of the degradable natural polymers chitosan oligosaccharides (COS) and gelatin (GEL) via introduction of a functional bridge 3,3'-dithiodipropionic acid, this study constructed an environmentally responsive dinotefuran (DNF) delivery system (DNF@COS-SS-GEL). The introduction of the disulfide bond (-S-S-) endowed DNF@COS-SS-GEL with redox-responsive properties, allowing for the rapid release of pesticides when stimulated by glutathione (GSH) in the simulated insect. Compared with commercial DNF suspension concentrate (DNF-SC), DNF@COS-SS-GEL showed superior wet spreading and retention performance on cabbage leaves with a reduced contact angle (57°) at 180 s and 4-fold increased retention capacity after rainfall washout. Nanoencapsulation effectively improved the UV-photostability with only a 31.4% decomposition rate of DNF@COS-SS-GEL at 96 h. The small scale and large specific surface area resulted in excellent uptake and transportation properties in plants as well as higher bioactivity against Plutella xylostella larvae. This study will help promote sustainable agricultural development by reducing environmental pollution through improved pesticide utilization.
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Gliomas are the most common malignant intracranial tumors, with no effective treatments. Better understanding and identification of novel targets are urgently warranted. Actin-binding Rho activating C-terminal like (ABRACL) has been reported as an oncogene in several cancer types. However, the potential roles of ABRACL in the tumorigenesis of malignant glioma remain unknown. We discovered that ABRACL is highly expressed in different sub-types of gliomas in both CGGA and TCGA databases, which was further validated in glioblastoma cell lines and normal human astrocyte lines. RT-qPCR, Western blotting and immunohistochemistry demonstrated that ABRACL expression in glioma tissues was upregulated along with the increasing WHO grades. Further survival analysis of glioma patients also revealed that the overall survival of patients in the ABRACL high expression level group were significantly shorter than those in the low expression level group. Knockdown of ABRACL inhibited the proliferation, cell migration, invasion and cytodynamics behaviors in glioma cell lines via activating STAT3 signaling, which also induced apoptosis and cell cycle arrest. Conversely, overexpressing ABRACL promoted cell renewing and migration, enabled more flexible cell deformation, supporting ABRACL being a bona fide oncogene. Intracranial orthotopic xenograft experiment further confirmed that ABRACL downregulation significantly suppressed glioma growth. These results have demonstrated that the tumorigenic effect of ABRACL is partly mediated by STAT3, whose expression also correlates with clinical prognosis. ABRACL facilitates glioma malignancy phenotype through regulating the cytoskeleton by activating STAT3 pathway, suggesting that it may represent a potential therapeutic target for glioblastoma.
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Here, we present a protocol for conducting bibliometric analysis in biomedicine using CiteSpace and VOSviewer. We describe the steps for extracting data from Web of Science, data cleaning, and preprocessing. We then detail procedures for identifying research trends and collaboration networks by visualizing data with CiteSpace; mapping co-authorship, co-citation, and keyword co-occurrence using VOSviewer; and analyzing highly cited literature to identify key publications and trends. Finally, we outline techniques for interpreting the visualizations to draw meaningful conclusions about the research landscape. For complete details on the use and execution of this protocol, please refer to Li et al.1.
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OBJECTIVE: Plastic pollution has become a global pollution problem that cannot be ignored. As the main destination of human oral intake, the toxic effects of plastic on the digestive system represented by the intestine and liver are the focus of current research. Marine-derived DHA-PS has a variety of biological activities, mainly focusing on improving brain function and regulating lipid metabolism. However, whether it has an improvement effect on PS-NPs-induced hepato-intestinal injury and the underlying mechanism remain unclear. METHODS: A murine liver injury model was established by gavage of PS-NPs for six weeks. By integrating approaches from lipidomics, transcriptomics, and gut microbiota analysis, the molecular mechanism by which DHA-PS alleviates PS-NPs-induced murine hepatotoxicity was explored through the "gut-liver axis". RESULTS: Our findings reveal that prolonged exposure to PS-NPs results in significant murine liver damage and dysfunction, characterized by increased oxidative stress and inflammation, along with exacerbated hepatic lipid accumulation. Mechanistically, PS-NPs disrupt the hepatic SIRT1-AMPK pathway by suppressing the expression of SIRT1, AMPKα, and PPARα, while enhancing the expression of SREBP-1c, ultimately leading to disordered hepatic lipid metabolism. The sphingolipid and glycerophospholipid metabolic pathways were particularly affected. Additionally, in agreement with transcriptomic analyses, PS-NPs activate the hepatic TLR4/NF-κB pathway. At the same time, exposure to PS-NPs decreases the expression of ZO-1, occludin, and claudin-1, diminishes the relative abundance of beneficial gut bacteria (norank_f_Muribaculaceae, Akkermansia, and norank_f_norank_o_Clostridia_UCG-014), and increases the prevalence of pathogenic gut bacteria (Coriobacteriaceae_UCG-002 and Desulfovibrio), exacerbating liver injury through the gut-liver axis. However, administering DHA-PS (50 mg/kg) effectively alleviated these injuries. CONCLUSION: This study was the first to employ multi-omics techniques to elucidate the potential mechanisms underlying hepatotoxicity induced by PS-NPs, thereby supporting the use of DHA-PS as a dietary supplement to mitigate the effects of nanoplastic pollutants.
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Expansins are cell wall (CW) proteins that mediate the CW loosening and regulate salt tolerance in a positive or negative way. However, the role of Populus trichocarpa expansin A6 (PtEXPA6) in salt tolerance and the relevance to cell wall loosening is still unclear in poplars. PtEXPA6 gene was transferred into the hybrid species, Populus alba × P. tremula var. glandulosa (84K) and Populus tremula × P. alba INRA '717-1B4' (717-1B4). Under salt stress, the stem growth, gas exchange, chlorophyll fluorescence, activity and transcription of antioxidant enzymes, Na+ content, and Na+ flux of root xylem and petiole vascular bundle were investigated in wild-type and transgenic poplars. The correlation analysis and principal component analysis (PCA) were used to analyze the correlations among the characteristics and principal components. Our results show that the transcription of PtEXPA6 was downregulated upon a prolonged duration of salt stress (48 h) after a transient increase induced by NaCl (100 mM). The PtEXPA6-transgenic poplars of 84K and 717-1B4 showed a greater reduction (42-65%) in stem height and diameter growth after 15 days of NaCl treatment compared with wild-type (WT) poplars (11-41%). The Na+ accumulation in roots, stems, and leaves was 14-83% higher in the transgenic lines than in the WT. The Na+ buildup in the transgenic poplars affects photosynthesis; the activity of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT); and the transcription of PODa2, SOD [Cu-Zn], and CAT1. Transient flux kinetics showed that the Na+ efflux of root xylem and leaf petiole vascular bundle were 1.9-3.5-fold greater in the PtEXPA6-transgenic poplars than in the WT poplars. PtEXPA6 overexpression increased root contractility and extensibility by 33% and 32%, indicating that PtEXPA6 increased the CW loosening in the transgenic poplars of 84K and 717-1B4. Noteworthily, the PtEXPA6-promoted CW loosening was shown to facilitate Na+ efflux of root xylem and petiole vascular bundle in the transgenic poplars. We conclude that the overexpression of PtEXPA6 leads to CW loosening that facilitates the radial translocation of Na+ into the root xylem and the subsequent Na+ translocation from roots to leaves, resulting in an excessive Na+ accumulation and consequently, reducing salt tolerance in transgenic poplars. Therefore, the downregulation of PtEXPA6 in NaCl-treated Populus trichocarpa favors the maintenance of ionic and reactive oxygen species (ROS) homeostasis under long-term salt stress.
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Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas , Plantas Modificadas Genéticamente , Populus , Estrés Salino , Sodio , Populus/genética , Populus/metabolismo , Populus/crecimiento & desarrollo , Populus/efectos de los fármacos , Sodio/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Xilema/metabolismo , Xilema/genética , Raíces de Plantas/metabolismo , Raíces de Plantas/genética , Raíces de Plantas/crecimiento & desarrollo , Tolerancia a la Sal/genética , Transporte BiológicoRESUMEN
A self-corrosion microelectrolysis (SME)-enhanced membrane-aerated biofilm reactor (eMABR) was developed for the removal of pollutants and reduction of antibiotic resistance genes (ARGs). Fe2+ and Fe3+ formed iron oxides on the biofilm, which enhanced the adsorption and redox process. SME can induce microorganisms to secrete more extracellular proteins and up-regulate the expression of ammonia monooxygenase (AMO) (0.92 log2). AMO exposed extra binding sites (ASP-69) for antibiotics, weakening the competition between NH4+-N and sulfamethoxazole (SMX). The NH4+-N removal efficiency in the S-eMABR (adding SMX and IC) increased by 44.87 % compared to the S-MABR (adding SMX). SME increased the removal performance of SMX by approximately 1.45 times, down-regulated the expressions of sul1 (-1.69 log2) and sul2 (-1.30 log2) genes, and controlled their transfer within the genus. This study provides a novel strategy for synergistic reduction of antibiotics and ARGs, and elucidates the corresponding mechanism based on metatranscriptomic and molecular docking analyses.
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Amoníaco , Biopelículas , Sulfametoxazol , Amoníaco/metabolismo , Reactores Biológicos , Nitrógeno , Farmacorresistencia Microbiana/genética , Simulación del Acoplamiento Molecular , Antibacterianos/farmacología , Difusión , Genes Bacterianos , Contaminantes Químicos del AguaRESUMEN
Staphylococcus aureus is a notorious pathogen predominantly involved in skin and soft tissue infections, exhibiting a distinct innate sex bias. This study explores the influence of testosterone on the virulence of S. aureus and elucidates its underlying mechanisms. Utilizing a skin abscess model in intact and castrated male mice, we assessed the effects of testosterone on S. aureus pathogenicity. Compared to controls, castrated mice showed significantly reduced abscess sizes and decreased bacterial loads, highlighting the role of testosterone in modulating the severity of S. aureus infections. In vitro experiments revealed that testosterone enhances the hemolytic activity, cytotoxicity, and oxidative stress resistance of S. aureus. Real-time quantitative PCR analysis showed a significant upregulation of the genes encoding α-hemolysin (hla) and phenol-soluble modulin (psmα). Importantly, testosterone treatment significantly enhanced the expression of the accessory gene regulator (Agr) quorum-sensing system components (agrC, agrA, agrB, agrD), while the SaeRS system (saeR, saeS, and sbi) exhibited only slight changes. Gene knockout experiments revealed that deletion of agrC, rather than saeRS and agrBD, abolishes the testosterone-induced enhancement of hemolysis and gene expression, underscoring the key role of AgrC. Molecular docking simulations indicated a direct interaction between testosterone and AgrC protein, with a strong binding affinity at the active site residue SER201. This study provides new insights into the mechanistic basis of how testosterone enhances the pathogenicity of S. aureus, potentially contributing to increased male susceptibility to S. aureus infections and offering a targeted approach for therapeutic interventions.
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Proteínas Bacterianas , Infecciones Estafilocócicas , Staphylococcus aureus , Testosterona , Masculino , Testosterona/farmacología , Testosterona/metabolismo , Animales , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidad , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/metabolismo , Ratones , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Virulencia , Infecciones Estafilocócicas/microbiología , Transactivadores/genética , Transactivadores/metabolismo , Regulación Bacteriana de la Expresión Génica , Percepción de Quorum , Simulación del Acoplamiento Molecular , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/genética , Absceso/microbiología , Hemólisis , Proteínas Hemolisinas/metabolismo , Proteínas Hemolisinas/genéticaRESUMEN
Gilteritinib is the current standard of care for relapsed or refractory FLT3-mutated AML in many countries, however outcomes for patients relapsing after contemporary first-line therapies (intensive chemotherapy with midostaurin, or non-intensive chemotherapy with venetoclax) are uncertain. Moreover, reported data on toxicity and healthcare resource use is limited. Here we describe a large real-world cohort of 152 patients receiving single-agent gilteritinib in 38 UK hospitals. Median age was 61 and 36% had received ï³2 prior lines of therapy, including a FLT3 inhibitor in 41% and venetoclax in 24%. A median of 4 cycles of gilteritinib were administered, with 56% of patients requiring hospitalisation in the first cycle (median 10 days). Over half of patients required transfusion in each of the first 4 cycles. Complete remission (CR) was achieved in 21% and CR with incomplete recovery in a further 9%. Remission rates were lower for patients with FLT3-TKD or adverse karyotype. Day 30 and day 60 mortality were 1% and 10.6% and median overall survival was 9.5 months. On multivariable analysis, increasing age, KMT2A rearrangement and complex karyotype were associated with worse survival while RUNX1 mutations were associated with improved survival. Twenty patients received gilteritinib as first salvage having progressed following first-line therapy with venetoclax, with CR/CRi achieved in 25% and median survival 4.5 months. Real-world results with gilteritinib mirror those seen in the clinical trials but outcomes remain suboptimal, with more effective strategies needed.
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The sudden inrush of water poses a serious threat to the safety of workers during tunnel construction in the karst region of southwest China. To mitigate this risk, a model is proposed to assess the risk of water surge through a tunnel by combining improved game theory with uncertainty measure theory. Eight indicators of risk were extracted based on the solubility of rock, its geological structure, capacity for surface catchment, and hydrogeological factors, and were incorporated into the proposed model. The subjective weights of these indicators were obtained using the analytic hierarchy process, while their objective weights were calculated through the entropy weighting method and the criteria importance through intercriteria correlation method. An improved game theory-based method of combinatorial weighting was then used to construct the corresponding weight vectors. Single-indicator measurement functions and multi-indicator measurement matrices were utilized to classify and evaluate the indicators of the risk of a surge in water level based on a confidence criterion. The proposed method was applied to five typical karst sections of the Yanjin Tunnel of the Chongqing-Kunming High-speed Railway Project, and the method was validated by comparing the recorded and estimated inflow volume ranges during the project's construction, showing consistency with the actual evaluation results. This proposed model thus offers a practical tool for assessing the risk of water inrush in karst tunnels.
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Highly integrated information sharing among people, vehicles, roads, and cloud systems, along with the rapid development of autonomous driving technologies, has spurred the evolution of automobiles from simple "transportation tools" to interconnected "intelligent systems". The intelligent cockpit is a comprehensive application space for various new technologies in intelligent vehicles, encompassing the domains of driving control, riding comfort, and infotainment. It provides drivers and passengers with safety, comfort, and pleasant driving experiences, serving as the gateway for traditional automobile manufacturing to upgrade towards an intelligent automotive industry ecosystem. This is the optimal convergence point for the intelligence, connectivity, electrification, and sharing of automobiles. Currently, the form, functions, and interaction methods of the intelligent cockpit are gradually changing, transitioning from the traditional "human adapts to the vehicle" viewpoint to the "vehicle adapts to human", and evolving towards a future of natural interactive services where "humans and vehicles mutually adapt". This article reviews the definitions, intelligence levels, functional domains, and technical frameworks of intelligent automotive cockpits. Additionally, combining the core mechanisms of human-machine interactions in intelligent cockpits, this article proposes an intelligent-cockpit human-machine interaction process and summarizes the current state of key technologies in intelligent-cockpit human-machine interactions. Lastly, this article analyzes the current challenges faced in the field of intelligent cockpits and forecasts future trends in intelligent cockpit technologies.
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The centralized coordination of Connected and Automated Vehicles (CAVs) at unsignalized intersections aims to enhance traffic efficiency, driving safety, and passenger comfort. Autonomous Intersection Management (AIM) systems introduce a novel approach for centralized coordination. However, existing rule-based and optimization methods often face the challenges of poor generalization and low computational efficiency when dealing with complex traffic environments and highly dynamic traffic conditions. Additionally, current Reinforcement Learning (RL)-based methods encounter difficulties around policy inference and safety. To address these issues, this study proposes Constraint-Guided Behavior Transformer for Safe Reinforcement Learning (CoBT-SRL), which uses transformers as the policy network to achieve efficient decision-making for vehicle driving behaviors. This method leverages the ability of transformers to capture long-range dependencies and improve data sample efficiency by using historical states, actions, and reward and cost returns to predict future actions. Furthermore, to enhance policy exploration performance, a sequence-level entropy regularizer is introduced to encourage policy exploration while ensuring the safety of policy updates. Simulation results indicate that CoBT-SRL exhibits stable training progress and converges effectively. CoBT-SRL outperforms other RL methods and vehicle intersection coordination schemes (VICS) based on optimal control in terms of traffic efficiency, driving safety, and passenger comfort.
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OBJECTIVES: Newly detected hepatic nodules during follow-up of cancer survivors receiving chemotherapy may pose a diagnostic dilemma. We investigated a series of hepatic focal nodular hyperplasia (FNH) diagnosed by either typical MRI features and follow-up or pathology in cancer survivors. METHODS: This retrospective study evaluated 38 patients with tumours who developed new hepatic FNH after cyclophosphamide-based (n = 19) and oxaliplatin-based (n = 19) chemotherapies. The main tumour types were breast cancer (n = 18) and colorectal cancer (n = 17). MRI findings, clinical features, and temporal evolution of all target hepatic lesions (n = 63) were reported. In addition, the two chemotherapy drug groups were compared. RESULTS: The median interval between chemotherapy completion and FNH detection was 30.4 months (12.9, 49.4). Six patients underwent biopsy or surgery, while the remaining patients were diagnosed based on typical MRI features and long-term follow-up. Among the patients, 60.5% (23/38) presented with multiple nodules and 63 target lesions were detected. The median size of target lesions was 11.5 mm (8.4, 15.1). The median follow-up time was 32.5 months (21.2, 48.6), and 15 patients experienced changes in their lesions during the follow-up period (11 increased and 4 decreased). The cyclophosphamide-based treatment group had a younger population, a greater proportion of females, and a shorter time to discovery than the oxaliplatin-based chemotherapy group (all p ≤ 0.016). CONCLUSIONS: FNH may occur in cancer survivors after cyclophosphamide- or oxaliplatin-based chemotherapy. Considering a patient's treatment history and typical MRI findings can help avoid misdiagnosis and unnecessary invasive treatment. CLINICAL RELEVANCE STATEMENT: When cancer survivors develop new hepatic nodules during follow-up, clinicians should think of the possibility of focal nodular hyperplasia in addition to liver metastasis, especially if the cancer survivors were previously treated with cyclophosphamide or oxaliplatin. KEY POINTS: Cancer survivors, after chemotherapy, can develop hepatic focal nodular hyperplasia. Cyclophosphamide and oxaliplatin are two chemotherapeutic agents that predispose to focal nodular hyperplasia development. Focal nodular hyperplasia occurs at shorter intervals in patients treated with cyclophosphamide.
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Pancreatic ductal adenocarcinoma (PDAC) features substantial matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, the complex interplay between these traits and their impact on tumor advancement remains inadequately explored. Here, we integrated clinical, cellular, and bioinformatics approaches to explore the connection between matrix stiffness and the Warburg effect in PDAC, identifying CLIC1 as a key mediator. Elevated CLIC1 expression, induced by matrix stiffness through Wnt/ß-catenin/TCF4 signaling, signifies poorer prognostic outcomes in PDAC. Functionally, CLIC1 serves as a catalyst for glycolytic metabolism, propelling tumor proliferation. Mechanistically, CLIC1 fortifies HIF1α stability by curbing hydroxylation via reactive oxygen species (ROS). Collectively, PDAC cells elevate CLIC1 levels in a matrix-stiffness-responsive manner, bolstering the Warburg effect to drive tumor growth via ROS/HIF1α signaling. Our insights highlight opportunities for targeted therapies that concurrently address matrix properties and metabolic rewiring, with CLIC1 emerging as a promising intervention point.
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Carcinoma Ductal Pancreático , Proliferación Celular , Canales de Cloruro , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neoplasias Pancreáticas , Efecto Warburg en Oncología , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Canales de Cloruro/metabolismo , Canales de Cloruro/genética , Línea Celular Tumoral , Animales , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Especies Reactivas de Oxígeno/metabolismo , Glucólisis , Ratones Desnudos , Matriz Extracelular/metabolismo , Regulación Neoplásica de la Expresión GénicaRESUMEN
Aging is an inevitable and complex biological process involving multi-factorial mechanisms. Mitochondrial dysfunction is a critical factor in the aging process, characterized by a decline in mitochondrial quality and activity, leading to aging and aging-related diseases. Therefore, mitochondria have become an attractive target in anti-aging therapies. Several senolytic drugs targeting mitochondria and antioxidant agents have been used in anti-aging research in the past few years. However, these strategies may cause adverse effects with long-term medication. In this extensive review, we propose "mitochondrial transplantation," which transfers healthy mitochondria from donor cells to recipient cells to replace damaged or dysfunctional mitochondria, as a new alternative strategy for treating mitochondrial dysfunction and aging-associated diseases. In this review, we introduce the contemporary landscape of mitochondrial transplantation, then discuss intensely the successful applications of mitochondrial transplantation therapy in aging diseases such as neurodegenerative diseases, cardiovascular aging, and reproductive aging, highlighting its translational potential. Finally, we summarize and prospect the challenges and opportunities mitochondrial transplantation faces in anti-aging therapy.
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Sleep is essential for overall health, and its disruption is linked to increased risks of metabolic, cognitive, and cardiovascular dysfunctions; however, the molecular mechanisms remain poorly understood. This study investigated how sleep disturbances contribute to metabolic imbalance and cognition impairment using a chronic sleep fragmentation (SF) mouse model. SF mice exhibited impaired cognition, glucose metabolism, and insulin sensitivity compared with controls. We identified increased acetate levels in hypothalamic astrocytes as a defensive response in SF mice. Through acetate infusion or astrocyte-specific Acss1 deletion to elevate acetate levels, we observed mitigated metabolic and cognitive impairments in SF mice. Mechanistically, acetate binds and activates pyruvate carboxylase, thereby restoring glycolysis and the tricarboxylic acid cycle. Among individuals most commonly affected by SF, patients with obstructive sleep apnea exhibited elevated acetate levels when coupled with type 2 diabetes. Our study uncovers the protective effect of acetate against sleep-induced metabolic and cognitive impairments.