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A cell membrane-derived vesicle (MV) that has cell-mimicking features with characteristic functionalities holds vast appeal for biomimetic nanomedicine and drug delivery but suffers from a major limitation of innate fragility and poor stability. Herein, we report a lipid-anchoring strategy for stabilizing MV for enhanced drug delivery. An array of amphiphilic mono-acyl phosphatidylcholines (MPCs) with specific hydrophobic moieties are synthesized and readily engineered on MV based on their commendable aqueous solubility and efficient membrane insertability. Incorporation of MPCs containing rigid ring structures in the hydrophobic segment demonstrates the potency of stabilizing MV by the combined ordering and condensing effects. The optimized MPC-stabilized MV exhibits prolonged circulation in the bloodstream, elevated accumulation within a tumor, and enhanced therapeutic effects of chemotherapeutic and photothermal drugs. Moreover, doxorubicin-loaded MV, engineered with mono-all-trans retinoyl phosphatidylcholine as an MV stabilizer and a therapeutic prodrug, potently suppresses growth and metastasis of high-stemness tumors.

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Aging is a complex biological process that involves multi-level structural and physiological changes. Aging is a major risk factor for many chronic diseases. The accumulation of senescent cells changes the tissue microenvironment and is closely associated with the occurrence and development of tissue and organ fibrosis. Fibrosis is the result of dysregulated tissue repair response in the development of chronic inflammatory diseases. Recent studies have clearly indicated that SIRT2 is involved in regulating the progression of fibrosis, making it a potential target for anti-fibrotic drugs. SIRT2 is a NAD+ dependent histone deacetylase, shuttling between nucleus and cytoplasm, and is highly expressed in liver, kidney and heart, playing an important role in the occurrence and development of aging and fibrosis. Therefore, we summarized the role of SIRT2 in liver, kidney and cardiac fibrosis during aging.

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Introduction: Perceived stress and depression were indirect effects of the COVID-19 pandemic, especially in square-cabin hospitals. It was paramount to understand their mediating effects, which might detonate factors that led to mental illness. Materials and methods: We conducted a cross-sectional study to investigate perceived stress and depressive symptoms among patients with COVID-19 in Shanghai square-cabin hospitals from April 18 to May 19, 2022. The questionnaire included the Perceived Stress Scale 10, Patient Health Questionnaire 9, Perceived Social Support Scale, and the Connor-Davidson Resilience Scale 10. Results: This study investigated the chain-mediating roles of perceived social support and resilience in the relationship between perceived stress and depression. Perceived stress positively predicted depression (r = 0.613, p < 0.01), negatively correlated with perceived social support (r = -0.318, p < 0.01) and resilience (r = -0.398, p < 0.01). In the chain mediating model, perceived stress had significant direct predictive effects on depression, and significant indirect predictive effects on depression through perceived social support and/or resilience. Conclusion: It showed that higher perceived social support and resilience were associated with lower perceived stress among COVID-19 patients, which might lead to symptoms of mild depression, and highlights the importance of resilience and perceived social support in reducing depressive symptoms.

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The sluggish dissociation of water in alkaline electrolytes significantly hinders the kinetics of the hydrogen evolution reaction (HER), particularly on surfaces of Ru-based catalysts. The structure of water at the water-catalyst interface influences this dissociation process, yet controlling the configuration of water molecules is challenging due to their random distribution. In this study, a NiRu alloy supported on nitrogen-doped carbon (NiRu/NC) is selected as a model catalyst to investigate the electron distribution of the catalyst manipulating the adsorption configuration and orientation of water molecules. The introduction of Ni leads to charge transfer from Ni to Ru atoms within the NiRu alloy, causing a notable redistribution of charge that strengthens the local electric fields surrounding the NiRu alloy. These electron-rich Ru sites attract K+ cations to the surface, resulting in an increased presence of K+ cation-hydrated water molecules, which is an H-down configuration with a reduced Ru-H distance. This phenomenon is confirmed by in situ Raman spectroscopy. Consequently, NiRu/NC exhibits outstanding HER performance, achieving low overpotentials of 16 and 344 mV at current densities of 10 and 1000 mA cm-2, respectively.

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Surface-driven capacitive storage enhances rate performance and cyclability, thereby improving the efficacy of high-power electrode materials and fast-charging batteries. Conventional defect engineering, widely-employed capacitive storage optimization strategy, primarily focuses on the influence of defects themselves on capacitive behaviors. However, the role of local environment surrounding defects, which significantly affects surface properties, remains largely unexplored for lack of suitable material platform and has long been neglected. As proof-of-concept, typical Ti3C2Tx MXenes are chosen as model materials owing to metallic conductivity and tunable surface properties, satisfying the requirements for capacitive-type electrodes. Using density functional theory (DFT) calculations, the potential of MXenes with modulated local atomic environment is anticipated and introducing new carbon sites found near pores can activate electrochemically inert surface, attaining record theoretical potassium storage capacities of MXenes (291 mAh g-1). This supposition is realized through atomic tailoring via chemical scissor within sublayers, exposing new sp3-hybridized carbon active sites. The resulting MXenes demonstrate unprecedented rate performance and cycling stability. Notably, MXenes with higher carbon exposure exhibit a record-breaking capacity over 200 mAh g-1 and sustain a capacity retention higher than 80% after 20 months. These findings underscore the effectiveness of regulating defects' neighboring environment and illuminate future high-performance electrode design.

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Background: Oral insulin delivery is considered a revolutionary alternative to daily subcutaneous injection. However, the oral bioavailability of insulin is very low due to the poor oral absorption into blood circulation. Methods: To promote penetration across the intestinal epithelium and achieve enhanced and safe glucose-responsive oral insulin delivery, pH and H2O2 dual-sensitive nanoparticles (NPs) were constructed. The NPs were loaded of glucose oxidase (GOx) and insulin by pH and H2O2 dual-sensitive amphiphilic polymer incorporated with phenylboronic ester-conjugated poly(2-hydroxyethyl methacrylate) and poly(carboxybetaine) (PCB). The dual-sensitive NPs were utilized for the treatment of type 1 diabetes mellitus (T1DM) after oral administration. Results: The dual-sensitive NPs could enhance the transport of insulin across the intestinal epithelium into blood facilitated by zwitterionic PCB. By virtue of the generated low pH and high H2O2 with GOx in hyperglycemic environment, the pH and H2O2 dual-sensitive NPs were disassembled to achieve rapid and sustained release of insulin. After oral administration of the dual-sensitive NPs in enteric capsules into T1DM mouse model, the oral bioavailability of insulin reached 20.24%, and the NPs achieved hypoglycemic effect for a few hours longer than subcutaneously injected insulin. Importantly, the pH and H2O2 dual-sensitive NPs could ameliorate the local decline of pH and rise of H2O2 to avoid the toxic side effect. Conclusion: Therefore, this work would provide a promising platform for the enhanced and safe treatment of diabetes mellitus.

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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Peróxido de Hidrogênio , Hipoglicemiantes , Insulina , Nanopartículas , Animais , Administração Oral , Insulina/administração & dosagem , Insulina/farmacocinética , Nanopartículas/química , Peróxido de Hidrogênio/metabolismo , Concentração de Íons de Hidrogênio , Camundongos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Diabetes Mellitus Experimental/tratamento farmacológico , Glucose Oxidase/administração & dosagem , Humanos , Sistemas de Liberação de Medicamentos/métodos , Masculino , Glicemia/efeitos dos fármacos , Glucose/metabolismo , Disponibilidade Biológica

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BACKGROUND: Hyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Inhibiting tumor intrinsic PRMT5 was reported to potentiate antitumor immune responses, highlighting the possibility of combining PRMT5 inhibitors (PRMT5i) with cancer immunotherapy. However, global suppression of PRMT5 activity impairs the effector functions of immune cells. Here, we sought to identify strategies to specifically inhibit PRMT5 activity in tumor tissues and develop effective PRMT5i-based immuno-oncology (IO) combinations for cancer treatment, particularly for methylthioadenosine phosphorylase (MTAP)-loss cancer. METHODS: Isogeneic tumor lines with and without MTAP loss were generated by CRISPR/Cas9 knockout. The effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) were evaluated in these isogenic tumor lines and T cells in vitro and in vivo. Transcriptomic and proteomic changes in tumors and T cells were characterized in response to PRMT5i treatment. Furthermore, the efficacy of MRTX1719 in combination with immune checkpoint blockade was assessed in two syngeneic murine models with MTAP-loss tumor. RESULTS: GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of the MTAP status. However, MRTX1719, a methylthioadenosine-cooperative PRMT5 inhibitor, exhibits tumor-specific PRMT5 inhibition in MTAP-loss tumors with limited immunosuppressive effects. Mechanistically, transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces the activation of the PI3K pathway, a well-documented immune-resistant pathway. It highlights the potential of MRTX1719 to overcome immune resistance in MTAP-loss tumors. In addition, MRTX1719 sensitizes MTAP-loss tumor cells to the killing of tumor-reactive T cells. Combining MRTX1719 and anti-PD-1 leads to superior antitumor activity in mice bearing MTAP-loss tumors. CONCLUSION: Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors.

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Proteína-Arginina N-Metiltransferases , Purina-Núcleosídeo Fosforilase , Animais , Camundongos , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/metabolismo , Humanos , Purina-Núcleosídeo Fosforilase/antagonistas & inibidores , Purina-Núcleosídeo Fosforilase/metabolismo , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Isoquinolinas , Pirimidinas

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BACKGROUND: There is a scarcity of evidence regarding the potential relationship between the size and location of necrotic lesions, which must be understood to provide optimal joint-preserving treatment. The purpose of this study was to characterize the distribution patterns of necrotic lesions of varying sizes in early-stage osteonecrosis of femoral head (ONFH) with the use of three-dimensional mapping. METHODS: We retrospectively evaluated clinical CT images of the hips that were performed in the Third Hospital of Hebei Medical University from January 2018 to December 2022 and collected all CT images diagnosed with stage I and II ONFH. Three-dimensional structures that included both necrotic lesions and normal areas of the femoral heads were reconstructed and divided into eight regions to record their size and location. CT images for all lesions were superimposed onto a standard template, and three-dimensional mapping was created to determine the presence of concentrated areas of lesions. RESULTS: In a cohort of 143 patients with stage I and II ONFH, a total of 150 hips were reviewed. For lesions with less than 15% of the femoral head volume, necrotic lesions predominantly involve regions I, III, and V, with region I showing concentration. For lesions with volumes ranging from 15 to 30%, necrotic lesions exhibited a wider distribution across regions I, II, III, IV, V, and VII, with significant concentrations in regions I, III, and V. For lesions exceeding 30% of the femoral head volume, the necrotic lesions were extensively distributed across nearly the entire femoral head, with a notable expansion of the concentrated necrotic areas. CONCLUSIONS: The distribution of necrotic lesions varies with lesion size, with smaller lesions primarily concentrated in the anterior and medial regions of the femoral head, particularly in the anterosuperior region, while larger lesions expand to the lateral and inferior regions. These findings enhance existing classification systems and provide crucial insights for guiding hip-preserving surgical planning and approaches.

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Necrose da Cabeça do Fêmur , Imageamento Tridimensional , Tomografia Computadorizada por Raios X , Humanos , Necrose da Cabeça do Fêmur/diagnóstico por imagem , Necrose da Cabeça do Fêmur/patologia , Estudos Retrospectivos , Feminino , Masculino , Imageamento Tridimensional/métodos , Adulto , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X/métodos , Cabeça do Fêmur/diagnóstico por imagem , Cabeça do Fêmur/patologia , Adulto Jovem , Idoso

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Background: Daily use of low concentrations of atropine is recommended for children undergoing myopia control therapy. While the benefits of controlling myopia progression have been confirmed, the potential unwanted side effects on the ocular surface, pupil size, and quality of vision following the administration of 0.01% atropine have not been investigated. Objective: This single-arm, self-control study aimed to investigate the short-term effects of 0.01% atropine topical eye drop (He Eye Hospital Co., Ltd., Shenyang, China) on pupil size and subjective quality of vision in participants with myopia. Each 3 mL vial of eye drops contains atropine (0.01%), sodium chloride (0.9%), and benzalkonium chloride (0.005%) in an aqueous solution. Methods: Thirty-three adults (66 eyes) were recruited for the study. The mean age of the participants recruited for this study was 24.91 ± 3.36 years. This study is registered with Clinical Trials.gov (NCT06071260). Assessments were performed at baseline and 10 h, 14 h, and 18 h following the administration of 0.01% topical atropine drop (TAD). Mesopic pupil diameter (MPD), photopic pupil diameter (PPD), higher order aberration (HOA), non-invasive tear breakup time (NITBUT), tear meniscus height (TMH), tear film lipid layer (TFLL), and Redness score (RS). Subjective assessments included the quality of vision (QoV) and the ocular surface disease index (OSDI) questionnaires. Results: Following the use of 0.01% atropine, PPD significantly increased at all the time points (p < 0.001); MPD increased significantly at 10 h and 14 h (p < 0.001 and p < 0.05, respectively). A decrease in TMH and an increase in the OSDI questionnaire scores were observed up to 10 and 14 h, respectively, after using atropine (p < 0.001). Glare (p = 0.004 at 10 h and p = 0.003 at 14 h), blurred vision (p < 0.0001 at 10 h and p = 0.035 at 14 h), and focusing difficulties (p < 0.0001 at 10 h and p < 0.0001 at 14 h) were significantly higher at both 10 h and 14 h after using atropine. No significant changes were observed in the HOA, NITBUT, and RS scores (all p > 0.05) at all time points. Conclusion: Decreased TMH, dry eye symptoms, and visual symptoms will likely persist overnight but often diminish within 18 h after using 0.01% atropine eye drops.

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BACKGROUND: Assessment of postoperative ambulation in osteonecrosis of the femoral head (ONFH) patients treated with total hip arthroplasty (THA) is limited. This study aimed to define the incidence and risk factors for losing walking independence (LWI) at one-year postoperatively in patients with ONFH undergoing primary THA, and to establish and validate a predictive nomogram. METHODS: This was a retrospective analysis of prospective collected data from patients admitted to a tertiary referral hospital with ONFH who underwent primary unilateral THA from October 2014 to March 2018. The Functional Independence Measure-Locomotion scale was used to quantify walking independence and was documented at a one-year continuous postoperative follow-up, which classified patients with a final score below 6 as LWI. Multivariate logistic regression identified independent risk factors for LWI, and a predictive nomogram was constructed based on the analysis results. The stability of the model was assessed using patients from April 2018 to April 2019 as an external validation set. RESULTS: 1152 patients were enrolled in the study, of which 810 were used in the training cohort and the other 342 for the validation cohort. The incidence of LWI was 5.93%. Multivariate analysis revealed that age 62 years or older (odd ratio (OR) = 2.37, 95% confidence interval (CI) 1.07-5.24), Charlson's comorbidity index 3 or higher (OR = 3.64, 95% CI 1.09-12.14), Association Research Circulation Osseous stage IV (OR = 2.16, 95% CI 1.03-4.54), reduced femoral offset (OR = 2.41, 95% CI 1.16-5.03), and a higher controlling nutritional status score (OR = 1.14, 95% CI 1.01-1.30) were independent risk factors of LWI. The nomogram had a concordance index of 0.773 and a Brier score of 0.049 in the training set, with corrected values of 0.747 and 0.051 after internal validation. The receiver-operating characteristic curve, calibration curve, Hosmer-Lemeshow test, and decision curve analysis all performed well in both the training and validation cohorts. CONCLUSIONS: This study reported a 5.93% incidence of LWI and established a risk prediction model in patients undergoing THA for ONFH, supporting targeted screening and intervention to assist surgeons in assessing ambulation capacity and managing rehabilitation.

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Artroplastia de Quadril , Necrose da Cabeça do Fêmur , Nomogramas , Caminhada , Humanos , Artroplastia de Quadril/reabilitação , Artroplastia de Quadril/efeitos adversos , Pessoa de Meia-Idade , Masculino , Feminino , Necrose da Cabeça do Fêmur/cirurgia , Necrose da Cabeça do Fêmur/epidemiologia , Necrose da Cabeça do Fêmur/etiologia , Incidência , Caminhada/fisiologia , Estudos Retrospectivos , Fatores de Risco , Adulto , Idoso , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Fatores de Tempo

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Although endocrine therapies and Cdk4/6 inhibitors have produced significantly improved outcomes for patients with estrogen receptor positive (ER+) breast cancer, continuous application of these drugs often results in resistance. We hypothesized that cancer cells acquiring drug resistance might increase their dependency on negative regulators of the cell cycle. Therefore, we investigated the effect of inhibiting WEE1 on delaying the development of resistance to palbociclib and fulvestrant. We treated ER+ MCF7 breast cancer cells with palbociclib alternating with a combination of fulvestrant and a WEE1 inhibitor AZD1775 for 12 months. We found that the alternating treatment prevented the development of drug resistance to palbociclib and fulvestrant compared to monotherapies. Furthermore, we developed a mathematical model that can simulate cell proliferation under monotherapy, combination or alternating drug treatments. Finally, we showed that the mathematical model can be used to minimize the number of fulvestrant plus AZD1775 treatment periods while maintaining its efficacy.

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Background: The prevalence of myopia among adolescents is increasing precipitously in China, and the popularity of orthokeratology (OK) lenses as an effective treatment for controlling myopia progression is rising. This protocol assessed and compared the clinical dry eye parameters in children and adolescents with myopia treated with spectacles or OK lenses. Methods and analysis: This single-masked randomized control trial will include 300 participants (aged 8-17 years) with myopia treated with OK lens (study group) or spectacles (control group). We will record the ocular surface disease index, visual analog scale score, noninvasive tear breakup time, tear meniscus height, meibomian gland score, ocular redness score, visual acuity, tear Matrix Metalloproteinase-9 concentration, tear Lymphotoxin alpha levels at baseline, and after 1-, 3-, 6-, and 12-month. Discussion: This study will be a standardized, scientific, clinical trial designed to evaluate the dry eye parameters in children and adolescents with myopia treated with OK lenses for myopia control. Ethics and dissemination: This study has been approved by the Ethics Committee of He Eye Specialist Hospital [ethics approval number: IRB(2023)K024.01]. Before participating in the trial, written informed consent will be obtained from all patient's parents or guardians. The findings of this study will be showcased at both local and international conferences and will also be submitted for publication in reputable peer-reviewed journals. Trial registration number: Clinicaltrials.gov: NCT06023108 {2a, 2b}.

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PURPOSE: Vascular smooth muscle cell (VSMC) phenotype switch and dysfunctions have been reported to participate in aortic dissection (AD) progression. This study was aimed to investigate the role of angiopoietin-like 4 (ANGPTL4) in regulating VSMCs phenotype switch. MATERIALS AND METHODS: Key genes were analyzed in AD using public datasets, and it was found that the central differential gene ANGPTL4 was up-regulated in AD. The KEGG signaling pathway annotation was performed to validate the associated pathways, and the expression of ANGPTL4 was verified using multiple datasets and clinical samples. Furthermore, the specific functions of ANGPTL4 on platelet-derived growth factor-BB (PDGF-BB)-treated human aortic smooth muscle cell (HASMC) phenotypes were investigated. The dynamic effects of ANGPTL4 and core signaling antagonists on HASMC phenotypes were examined. RESULTS: Hub gene ANGPTL4 was significantly up-regulated in AD. ANGPTL4 was linked to the PI3K/Akt signaling, angiogenesis, and neovascularization and remodeling. ANGPTL4 overexpression further enhanced PDGF-BB effects on HASMC phenotypes, including promoted cell viability and migration, decreased contractile VSMC markers α-SMA and SM22α, elevated ECM degradation markers MMP-2 and MMP-9, and promoted phosphorylation of PI3K and Akt. ANGPTL4 knockdown partially abolished PDGF-BB-induced contractile/synthetic VSMCs imbalance and HASMC dysfunctions. Furthermore, in ANGPTL4-overexpressing HASMCs pre-treated with PDGF-BB, the PI3K/Akt signaling inhibitor LY294002 also partially eliminated the effects caused by the PDGF-BB treatment and ANGPTL4 overexpression. CONCLUSIONS: ANGPTL4 is significantly up-regulated in AD. ANGPTL4 overexpression further enhanced PDGF-BB effects on HASMC phenotype switch and dysfunctions, which might be involved in the PI3K/Akt signaling.

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BACKGROUND: Schizophrenic patients are prone to violence, frequent recurrence, and difficult to predict. Emotional and behavioral abnormalities during the onset of the disease, resulting in active myocardial enzyme spectrum. AIM: To explored the expression level of myocardial enzymes in patients with schizophrenia and its predictive value in the occurrence of violence. METHODS: A total of 288 patients with schizophrenia in our hospital from February 2023 to January 2024 were selected as the research object, and 100 healthy people were selected as the control group. Participants' information, clinical data, and laboratory examination data were collected. According to Modified Overt Aggression Scale score, patients were further divided into the violent (123 cases) and non-violent group (165 cases). RESULTS: The comparative analysis revealed significant differences in serum myocardial enzyme levels between patients with schizophrenia and healthy individuals. In the schizophrenia group, the violent and non-violent groups also exhibited different levels of serum myocardial enzymes. The levels of myocardial enzymes in the non-violent group were lower than those in the violent group, and the patients in the latter also displayed aggressive behavior in the past. CONCLUSION: Previous aggressive behavior and the level of myocardial enzymes are of great significance for the diagnosis and prognosis analysis of violent behavior in patients with schizophrenia. By detecting changes in these indicators, we can gain a more comprehensive understanding of a patient's condition and treatment.

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Glioblastoma, a formidable brain tumor characterized by dysregulated NAD metabolism, poses a significant therapeutic challenge. The NAMPT inhibitor FK866, which induces NAD depletion, has shown promise in controlling tumor proliferation and modifying the tumor microenvironment. However, the clinical efficacy of FK866 as a single drug therapy for glioma is limited. In this study, we aim to disrupt NAD metabolism using fluorinated NAD precursors and explore their synergistic effect with FK866 in inducing cytotoxicity in glioblastoma cells. The synthesized analogue of nicotinamide riboside (NR), ara-F nicotinamide riboside (F-NR), inhibits nicotinamide ribose kinase (NRK) activity in vitro, reduces cellular NAD levels, and enhances FK866's cytotoxicity in U251 glioblastoma cells, indicating a collaborative impact on cell death. Metabolic analyses reveal that F-NR undergoes conversion to fluorinated nicotinamide mononucleotide (F-NMN) and other metabolites, highlighting the intact NAD metabolic pathway in glioma cells. The activation of SARM1 by F-NMN, a potent NAD-consuming enzyme, is supported by the synergistic effect of CZ-48, a cell-permeable SARM1 activator. Temporal analysis underscores the sequential nature of events, establishing NAD depletion as a precursor to ATP depletion and eventual massive cell death. This study not only elucidates the molecular intricacies of glioblastoma cell death but also proposes a promising strategy to enhance FK866 efficacy through fluorinated NAD precursors, offering potential avenues for innovative therapeutic interventions in the challenging landscape of glioblastoma treatment.

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We assessed the effect of GBT1118, a sickle hemoglobin polymerization inhibitor on bone loss in humanized sickle cell disease (SCD) mice. Healthy control (Ctrl) 4-months-old female and male mice were fed Vehicle-chow for 2-months, while SCD mice were fed Vehicle-chow or GBT1118-chow. By micro-CT, GBT1118 significantly increased femur metaphyseal trabecular thickness (Tb.Th) and tissue mineral density (TMD), and significantly decreased trabecular spacing in female SCD mice. In SCD male mice, there was significant reduction in epiphyseal trabecular bone volume fraction (BV/TV), Tb.Th and TMD and GBT1118 significantly increased BV/TV and TMD but not Tb.Th. A significant decrease in cortical area fraction in SCD female mice was rescued by GBT1118 but not SCD males. Markedly decreased mineralized femur trabeculae in SCD females and males was partially rescued by GBT1118. Bone histomorphometry of femurs demonstrated significantly decreased bone formation parameters and increased bone resorption parameters in SCD mice of both sex that were rescued by GBT1118. Significant alteration in bone and hypoxia related genes of SCD mice of both sexes were differentially modulated by GBT1118. We conclude that "a sickle hemoglobin polymerization inhibitor" might be efficacious in improving some parameters of SCD bone loss.

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Anemia Falciforme , Densidade Óssea , Fêmur , Animais , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/complicações , Anemia Falciforme/patologia , Feminino , Camundongos , Masculino , Densidade Óssea/efeitos dos fármacos , Fêmur/efeitos dos fármacos , Fêmur/diagnóstico por imagem , Fêmur/patologia , Modelos Animais de Doenças , Doenças Ósseas/tratamento farmacológico , Doenças Ósseas/etiologia , Doenças Ósseas/patologia , Doenças Ósseas/diagnóstico por imagem , Microtomografia por Raio-X , Hemoglobina Falciforme/metabolismo , Osso Esponjoso/efeitos dos fármacos , Osso Esponjoso/patologia , Osso Esponjoso/diagnóstico por imagem , Humanos , Benzaldeídos , Pirazinas , Pirazóis

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INTRODUCTION: Diabetic kidney disease (DKD) has become the primary cause of chronic renal failure in China, and renal tubulointerstitial fibrosis plays a central role in DKD progression. Urinary exosomes, which reflect kidney changes, are largely influenced by RNA-binding proteins (RBPs) in their miRNA content. OBJECTIVES: Our research aimed to determine the effect of the RNA-binding protein RBMX on exosomal miRNA in DKD. METHODS: We introduced a higher level of Rbmx into diabetic mice using an adenoassociated virus and isolated exosomes from their kidney tissue through advanced centrifugation techniques and specialized kits. We then conducted a series of tests, including qRT-PCR, Western blot, MitoSOX, ATP luminescence, coimmunoprecipitation, SUMOylation assays, RNA immunoprecipitation, and confocal microscopy. RESULTS: RBMX is found in higher levels in DKD and contributes to worsening kidney fibrosis, mitochondrial damage, and miRNA mismanagement in exosomes. It specifically binds with miR-26a, miR-23c, and miR-874 within the exosomes. This dysfunction may be linked to changes in RBMX SUMOylation. These miRNAs seem to protect against mitochondrial damage in kidney cells by targeting CERS6. CONCLUSION: DeSUMOylation of RBMX plays a crucial role in determining the makeup of miRNAs in kidney cell exosomes, impacting the protective miRNAs which regulate mitochondrial damage through their interaction with CERS6 mRNA, ultimately affecting mitochondrial health in DKD.

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BACKGROUND: We aimed to evaluate the role of Contrast-enhanced intraoperative ultrasound (CE-IOUS) with perfluorobutane microbubbles (Sonazoid) in improving the prognosis of patients with unresectable colorectal cancer liver metastases (CRLM). METHODS: A total of 130 Patients with unresectable CRLM who underwent curative hepatic resection at our institute were retrospectively analyzed. Of these 130 enrolled patients, 67 underwent intraoperative ultrasound alone (IOUS group); 63 underwent additional CE-IOUS and IOUS (CE-IOUS group). Normalized inverse probability treatment weighting (IPTW) was employed to balance baseline characteristics between groups. Hepatic recurrence-free survival (HRFS) and overall survival (OS) were compared. RESULTS: The treatment strategy was altered in 25 patients (25/63, 39.9%) due to the additional use of CE-IOUS. After applying IPTW, the CE-IOUS group exhibited a significantly lower rate of hepatic recurrence (hazard ratio [HR], 0.55; 95% confidence interval [CI] 0.32-0.95; P = 0.032). Subgroup analysis showed that CE-IOUS provided a significant benefit over IOUS in patients with bilobar liver metastases (P = 0.007), or with a number of live tumors < 3 (P = 0.021), or without DLM (P = 0.018), or with extrahepatic metastasis (P = 0.034), or with a minimum of 6 cycles of systemic therapy (P = 0.03). CONCLUSIONS: CE-IOUS is necessary for unresectable CRLM after preoperative chemotherapy, as it enhances detection accuracy and improves the prognosis of unresectable CRLM patients.

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PURPOSE: Evidence of an association between leukocyte telomere length (LTL) and prostate cancer (PCa) is accumulating; however, their shared genetic basis remains unclear. MATERIALS AND METHODS: Using summary statistics obtained from the genome-wide association study (GWAS), we quantified the global and local genetic correlations between two traits. Subsequently, we identified potential pleiotropic loci, common tissue-enriched regions, and risk gene loci while inferring assumed causal relationships. RESULTS: Our study demonstrated a global genetic correlation between LTL and PCa (genetic correlation=0.066, p=0.017), which was further confirmed in local genomic regions. Cross-trait GWAS meta-analysis revealed 44 shared loci, including 10 novel pleiotropic single nucleotide polymorphisms appearing concurrently in significant local genetic correlation regions. Notably, two new loci (rs9419958; rs3730668) were additionally validated to co-localize. For the first time, we identified a significant shared genetic enrichment of both traits in the small intestine tissue at the terminal ileum, with functional genes in this region affecting both LTL and PCa. Concurrently, Mendelian randomization analysis indicated a positive causal relationship between LTL and PCa. CONCLUSIONS: In conclusion, our study makes a significant contribution to the ongoing debate concerning the potential association between longer LTL and a higher risk of PCa. Additionally, we provide new evidence for the development of therapeutic targets for PCa and propose new directions for future risk prediction in this regard.