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Purpose: Bone loss is a common complication of type 2 diabetes mellitus (T2DM). Circadian rhythms play a significant role in T2DM and bone remodeling. Eldecalcitol (ED-71), a novel active vitamin D analog, has shown promise in ameliorating T2DM. We aimed to investigate whether the circadian rhythm coregulator BMAL1 mediates the anti-osteoporotic effect of ED-71 in T2DM and its associated mechanisms. Methods: A T2DM mouse model was established using high-fat diet (HDF) and streptozotocin (STZ) injection, and blood glucose levels were monitored weekly. HE staining, Masson staining, and Micro-CT were performed to assess the changes in bone mass. IHC staining and IF staining were used to detect osteoblast status and BMAL1 expression and RT-qPCR was applied to detect the change of oxidative stress factors. In vitro, high glucose (HG) stimulation was used to simulate the cell environment in T2DM. RT-qPCR, Western blot, IF, ALP staining and AR staining were used to detect osteogenic differentiation and SIRT1/GSK3ß signaling pathway. DCFH-DA staining was used to detect reactive oxygen species (ROS) levels. Results: ED-71 increased bone mass and promoted osteogenesis in T2DM mice. Moreover, ED-71 inhibited oxidative stress and promoted BMAL1 expression in osteoblasts The addition of STL1267, an agonist of the BMAL1 transcriptional repressor protein REV-ERB, reversed the inhibitory effect of ED-71 on oxidative stress and the promotional effect on osteogenic differentiation. In addition, ED-71 facilitated SIRT1 expression and reduced GSK3ß activity. The inhibition of SIRT1 with EX527 partially attenuated ED-71's effects, whereas the GSK3ß inhibitor LiCl further enhanced ED-71's positive effects on BMAL1 expression. Conclusion: ED-71 ameliorates bone loss in T2DM by upregulating the circadian rhythm coregulator BMAL1 and promoting osteogenesis through inhibition of oxidative stress. The SIRT1/GSK3ß signaling pathway is involved in the regulation of BMAL1.
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Factores de Transcripción ARNTL , Ritmo Circadiano , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Ratones Endogámicos C57BL , Osteogénesis , Regulación hacia Arriba , Animales , Factores de Transcripción ARNTL/metabolismo , Factores de Transcripción ARNTL/genética , Ratones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Osteogénesis/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Masculino , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Ritmo Circadiano/efectos de los fármacos , Estreptozocina , Vitamina D/farmacología , Vitamina D/análogos & derivados , Dieta Alta en Grasa , Células CultivadasRESUMEN
OBJECTIVES: To evaluate the safety of ultrasound-guided thermal ablation (UGTA) for thyroid nodules (TNs) by analysing complications and related risks. MATERIALS AND METHODS: This retrospective, single-centre study reviewed patients who underwent UGTA (microwave or radiofrequency ablation) between January 2018 and March 2023. The incidence of complications was recorded and assessed during and immediately after ablation,1-3 h later, and at 1 month, 3 months, and 6 months. Univariate and multivariate analyses were performed to identify risk factors for hoarseness and haemorrhagic complications. RESULTS: We reviewed 9667 cases in this study. Overall, 4494 (46.49%) cases underwent microwave ablation, while 5173 (53.51%) cases underwent radiofrequency ablation. The overall complication rate was 4.43%. The incidence of major complications was 1.94% (haemorrhage, 1.32%; hoarseness, 0.54%; and symptomatic aseptic necrosis, 0.08%). The incidence of minor complications was 2.45%. A large nodule volume, radiofrequency ablation, hyper-enhancing nodules, benign nodules, higher preoperative blood pressure, hyperthyroidism, and higher ablation power were independent risk factors for haemorrhage. Dorsal nodules and a higher ablation power were independent risk factors for hoarseness. All complications were resolved. CONCLUSION: This study suggests that UGTA is a safe treatment for TNs. Several risk factors for haemorrhage and hoarseness should be considered before performing UGTA. Different ablation modalities should be considered for patients with different conditions. CLINICAL RELEVANCE STATEMENT: Thermal ablation may be a safe treatment for eligible patients with TNs. KEY POINTS: We analysed the complications and risk factors associated with UGTA in 9667 cases. The complication rate was 4.43%; 1.94% were major complications. Risk factors of haemorrhage and hoarseness should be considered. UGTA was a safe method for the treatment of TNs.
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Objective: Head-down training can affect behavioural and neurocognitive control while performing dual tasks (DT). Breathing training improves motor and cognitive performance in patients with chronic obstructive pulmonary disease (COPD). As a neurorehabilitation tool, functional near-infrared spectroscopy (fNIRS) has been demonstrated to be an effective method for detecting changes in brain activation during motor recovery, as well as monitoring patients' long-term progress during DT in motor and cognitive performance. However, no studies have examined the combined effect of head-down position and breathing exercises on motor and cognitive performance during DT. This study will employ a novel intervention involving head-down strong abdominal breathing training to investigate its effects on motor and cognitive performance during DT in patients with COPD aiming to inform future training modalities in the community and at home. Methods: We will recruit participants from Anqing, China, through community announcements, bulletin board postings, WeChat, and offline visits and screen 72 patients with stable COPD, classified as Global Initiative for Chronic Obstructive Lung Disease (GOLD) I-II, by pulmonologists at the university hospital. All participants will be randomly assigned to the head-down strong abdominal breathing (tilt angle 0-30° on the inversion apparatus, respiratory rate 20-30 breaths/min), head-down training, and strong abdominal breathing training groups in a 1:1:1 ratio. The intervention will last 12 weeks, with sessions performed thrice weekly for 1 h. Results: The primary outcomes will be motor-cognitive DT time, dual-task effects, correct responses to cognitive tasks, and gait characteristics assessed at baseline, 6 and 12 weeks of intervention. The patient's dorsolateral prefrontal cortex (PFC) will also be stimulated with fNIRS at wavelengths of 730 and 850 nm, with a sampling rate of 11 Hz, to record oxy-haemoglobin (oxy-Hb), deoxy-haemoglobin (deoxy-Hb), and total oxyhaemoglobin (total-Hb). Secondary outcomes will include pre- and post-intervention scales for dyspnoea, overall cognitive function, balance, and anxiety and depression. Conclusion: Alterations in the PFC involved in attentional control, planning, and decision-making may partially explain cognitive and motor deficits (such as impaired balance and slower walking speed) in patients with COPD. This study may help to understand the effects of head-down strong abdominal breathing training on cognitive and motor performance under DT in patients with COPD and compare it with head-down training and breathing training alone. It may also help to determine whether it is a simple and effective form of exercise at home and in the community.
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Very-long-chain fatty acids (VLCFAs) regulate biophysical properties of cell membranes to determine growth and development of eukaryotes, such as the pathogenesis of the rice blast fungus Magnaporthe oryzae. The fatty acid elongase Elo1 regulates pathogenesis of M. oryzae by modulating VLCFA biosynthesis. However, it remains unknown whether and how Elo1 associates with other factors to regulate VLCFA biosynthesis in fungal pathogens. Here, we identified Ifa38, Phs1 and Tsc13 as interacting proteins of Elo1 by proximity labelling in M. oryzae. Elo1 associated with Ifa38, Phs1 and Tsc13 on the endoplasmic reticulum (ER) membrane to control VLCFA biosynthesis. Targeted gene deletion mutants Δifa38, Δphs1 and Δtsc13 were all similarly impaired as Δelo1 in vegetative growth, conidial morphology, stress responses in ER, cell wall and membrane. These deletion mutants also displayed severe damage in cell membrane integrity and failed to organize the septin ring that is essential for penetration peg formation and pathogenicity. Our study demonstrates that M. oryzae employs a fatty acid elongase complex to regulate VLCFAs for maintaining or remodelling cell membrane structure, which is important for septin-mediated host penetration.
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Membrana Celular , Elongasas de Ácidos Grasos , Proteínas Fúngicas , Oryza , Enfermedades de las Plantas , Membrana Celular/metabolismo , Elongasas de Ácidos Grasos/metabolismo , Elongasas de Ácidos Grasos/genética , Oryza/microbiología , Enfermedades de las Plantas/microbiología , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Septinas/metabolismo , Septinas/genética , Retículo Endoplásmico/metabolismo , Ácidos Grasos/metabolismo , Ascomicetos/patogenicidad , Ascomicetos/genéticaRESUMEN
In emergencies, uncontrolled severe bleeding can result in undesired complications and even death of the injured. Designing advanced hemostatic agents is a potential solution for emergency hemostasis, yet it remains challenging to realize the persistent adhesion in a wet wound environment. In this study, based on dynamic reversible Schiff base bond and photo-initiated double-bond polymerization, a novel injectable hemostatic hydrogel (L-COC) consisting of methacrylated carboxymethyl chitosan (CMCSMA), oxidized konjac glucomannan (OKGM) and (+)-catechin hydrate (CH) was synthesized for emergency hemostasis. To our delight, the incorporated CH imparted enhanced blood procoagulantion to the L-COC hydrogel by intensifying the hydrogel-red blood cell interactions. As a result, the hemostatic effect of the engineered L-COC hydrogel was significantly superior to that of fluid gelatin SurgifloTM for liver bleeding wounds in rats (Blood loss: 0.62 ± 0.11 g (L-COC), 0.90 ± 0.08 g (SurgifloTM); hemostasis time: 69.0 ± 2.9 s (L-COC), 84.0 ± 2.2 s (SurgifloTM)). With the favorable antioxidant and antibacterial activities, as well as multifunctional properties, the bio-adhesive L-COC hydrogel and the underlying design principles may facilitate further development of practical hemostatic hydrogels.
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Antibacterianos , Antioxidantes , Quitosano , Hemorragia , Hemostáticos , Hidrogeles , Ratas Sprague-Dawley , Animales , Hidrogeles/química , Hidrogeles/farmacología , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/administración & dosificación , Antioxidantes/síntesis química , Hemostáticos/farmacología , Hemostáticos/química , Hemostáticos/administración & dosificación , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/administración & dosificación , Ratas , Hemorragia/tratamiento farmacológico , Quitosano/química , Quitosano/farmacología , Quitosano/análogos & derivados , Hemostasis/efectos de los fármacos , Masculino , Inyecciones , Adhesivos/química , Adhesivos/farmacología , Tamaño de la Partícula , Escherichia coli/efectos de los fármacos , MananosRESUMEN
[This corrects the article DOI: 10.3389/fimmu.2022.1020056.].
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Purpose: Drawing upon the cognitive-behavioral model of pathological Internet use (PIU) and tunnel effect, this study aimed to construct a moderated mediation model from the perspective of social ecology. Specifically, the model investigated the relationship between perceived social mobility and smartphone dependence, with a focus on the mediating role of hope and the moderating effect of family socioeconomic status (SES) underlying this relationship. Methods: A cross-sectional study was conducted with 718 Chinese university students (Mage = 19.19, 70.2% female) from Beijing, Henan, and Tianjin, who anonymously filled out the Perceptions of Socioeconomic Mobility Scale, Mobile Phone Addiction Index Scale, Openness to the Future Scale, and family socioeconomic status questionnaire. Preliminary data analysis was executed using SPSS 22.0, and the moderated mediation effect was tested using the latent moderated structural equations approach in Mplus 8.3. Results: The results showed that (a) less perceived social mobility was linked with greater smartphone dependence; (b) hope mediated the aforementioned relationship; and (c) family SES moderated the first-stage path of the indirect effect through hope. For university students with low (rather than high) family SES, their level of hope increased with the improvement of perceived social mobility, and in turn, that of smartphone dependence decreased. Conclusion: These findings suggest that positive perceptions of upward social class mobility and hopeful attitudes toward future opportunities and personal development among disadvantaged university students may alleviate their reliance on smartphones. Researchers and policymakers should pay attention to the role of individuals' perceptions of the macro environment in motivating specific risky behaviors among university students. Future interventions are essential to mitigate pessimistic environmental perceptions and foster a sense of hope among university students.
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Purpose: Estrogen deficiency is the main reason of postmenopausal osteoporosis. Eldecalcitol (ED-71) is a new active vitamin D analogue clinically used in the treatment of postmenopausal osteoporosis. We aimed to investigate whether EphrinB2-EphB4 and RANKL/RANK/OPG signaling cooperate in mediating the process of osteoporosis by ED-71. Methods: In vivo, the ovariectomized (OVX) rats were administered orally with 30 ng/kg ED-71 once a day for 8 weeks. HE staining, Masson staining and Immunofluorescence staining were used to evaluate bone mass, bone formation, osteoclastogenesis associated factors and the expression of EphrinB2, EphB4, RANKL and OPG. In vitro, H2O2 stimulation was used to simulate the cell environment in osteoporosis. Immunofluorescence, quantitative real time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and Western Blot were applied to detect the expression of EphrinB2, EphB4, RANKL and OPG. In osteoblasts, EphB4 was knocked down by EphB4 small-interfering RNA (siRNA) transfection. LY294002 (PI3K inhibitor) or ARQ092 (AKT inhibitor) was used to block PI3K/AKT pathway. An indirect co-culture system of osteoblasts and osteoclasts was established. The mRNA and protein expression of osteoclastogenes is associated factors were tested by qRT-PCR and Western Blot. Results: ED-71 increased bone mass and decreased the number of osteoclasts in OVX rats. Moreover, ED-71 promoted the expression of EphrinB2, EphB4, and decreased the RANKL/OPG ratio in osteoblasts. Osteoclastogenesis was restrained when osteoclasts were indirectly co-cultured with ED-71-treated osteoblasts. After silencing of EphB4 expression in osteoblasts, ED-71 inhibited the expression of P-PI3K and P-AKT and increased the ratio of RANKL/OPG. This reversed the inhibitory effect of ED-71 on osteoclastogenes. Therefore, in ED-71-inhibited osteoclastogenes, EphB4 is a key factor affecting the secretion of RANKL and OPG by osteoblasts. EphB4 suppressed the RANKL/OPG ratio through activating PI3K/AKT signaling in osteoblasts. Conclusion: ED-71 inhibits osteoclastogenesis through EphrinB2-EphB4-RANKL/OPG axis, improving bone mass in ovariectomized rats. PI3K/AKT pathway is involved this process.
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Densidad Ósea , Efrina-B2 , Ovariectomía , Ligando RANK , Receptor EphB4 , Vitamina D , Animales , Femenino , Ratas , Densidad Ósea/efectos de los fármacos , Células Cultivadas , Efrina-B2/metabolismo , Efrina-B2/antagonistas & inhibidores , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteogénesis/efectos de los fármacos , Osteoprotegerina/metabolismo , Ligando RANK/metabolismo , Ligando RANK/antagonistas & inhibidores , Ratas Sprague-Dawley , Receptor EphB4/metabolismo , Receptor EphB4/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Vitamina D/farmacología , Vitamina D/análogos & derivadosRESUMEN
Aims: Downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) contributes to doxorubicin (DOX)-induced myocardial oxidative stress, and inhibition of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) increased Nrf2 protein level in rat heart suffering ischemia/reperfusion, indicating a connection between MALT1 and Nrf2. This study aims to explore the role of MALT1 in DOX-induced myocardial oxidative stress and the underlying mechanisms. Results: The mice received a single injection of DOX (15 mg/kg, i.p.) to induce myocardial oxidative stress, evidenced by increases in the levels of reactive oxidative species as well as decreases in the activities of antioxidative enzymes, concomitant with a downregulation of Nrf2; these phenomena were reversed by MALT1 inhibitor. Similar phenomena were observed in DOX-induced oxidative stress in cardiomyocytes. Mechanistically, knockdown or inhibition of MALT1 notably attenuated the interaction between Nrf2 and MALT1 and decreased the k48-linked ubiquitination of Nrf2. Furthermore, inhibition or knockdown of calcium/calmodulin-dependent protein kinase II (CaMKII-δ) reduced the phosphorylation of caspase recruitment domain-containing protein 11 (CARD11), subsequently disrupted the assembly of CARD11, B cell lymphoma 10 (BCL10), and MALT1 (CBM) complex, and reduced the MALT1-dependent k48-linked ubiquitination of Nrf2 in DOX-treated mice or cardiomyocytes. Innovation and Conclusion: The E3 ubiquitin ligase function of MALT1 accounts for the downregulation of Nrf2 and aggravation of myocardial oxidative stress in DOX-treated mice, and CaMKII-δ-dependent phosphorylation of CARD11 triggered the assembly of CBM complex and the subsequent activation of MALT1.
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BACKGROUND AND OBJECTIVE: Prevention of periodontal bone resorption triggered by Porphyromonas gingivalis (P. gingivalis) is crucial for dental stability. Capsaicin, known as the pungent ingredient of chili peppers, can activate key signaling molecules involved in osteogenic process. However, the effect of capsaicin on osteogenesis of periodontal ligament stem cells (PDLSCs) under inflammation remains elusive. METHODS: P. gingivalis culture suspension was added to mimic the inflammatory status after capsaicin pretreatment. The effects of capsaicin on the osteogenesis of PDLSCs, as well as mitochondrial morphology, Ca2+ level, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and osteogenesis-regulated protein expression levels were analyzed. Furthermore, a mouse experimental periodontitis model was established to evaluate the effect of capsaicin on alveolar bone resorption and the expression of osteogenesis-related proteins. RESULTS: Under P. gingivalis stimulation, capsaicin increased osteogenesis of PDLSCs. Not surprisingly, capsaicin rescued the damage to mitochondrial morphology, decreased the concentration of intracellular Ca2+ and ROS, enhanced MMP and activated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. The in vivo results showed that capsaicin significantly attenuated alveolar bone loss and augmented the expression of bone associated proteins. CONCLUSION: Capsaicin increases osteogenesis of PDLSCs under inflammation and reduces alveolar bone resorption in mouse experimental periodontitis.
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Capsaicina , Mitocondrias , Osteogénesis , Ligamento Periodontal , Porphyromonas gingivalis , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Células Madre , Serina-Treonina Quinasas TOR , Ligamento Periodontal/citología , Ligamento Periodontal/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Animales , Células Madre/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Capsaicina/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Humanos , Especies Reactivas de Oxígeno/metabolismo , Pérdida de Hueso Alveolar/prevención & control , Periodontitis/microbiología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Células Cultivadas , Modelos Animales de EnfermedadRESUMEN
Triple-negative breast cancer (TNBC) typically manifests as higher invasive carcinoma correlated with a worse prognosis that primarily relies on chemotherapy. There is growing evidence that nitric oxide (NO) donor drugs have the potential for anticancer therapy. On this basis, we constructed and evaluated a novel coumarin-furoxan hybrid 4A93 as an effective antitumor candidate drug. 4A93 exhibits low IC50 values in three TNBC cell lines and inhibits colony formation and DNA synthesis, probably due to the release of high concentrations of NO in mitochondria, which induces oxidative stress, mitochondrial dysfunction, and apoptosis. Further research suggests that 4A93 might destroy mitochondria by opening the mitochondrial permeability transition pore (mPTP), depolarizing the mitochondrial membrane potential (MMP), and promoting the release of cytochrome c into the cytoplasm. Intrinsic apoptosis is induced finally, along with Akt/Erk signaling suppression. Additionally, 4A93 underregulates the Epithelial-mesenchymal transition process to inhibit cell migration and invasion. In 4T1 subcutaneous and hematogenous models of mice, 4A93 therapy suppresses the tumor growth and prevented lung metastasis with favorable biosafety. Our results provide insights into 4A93 in TNBC treatment and validate the contribution of NO donors in tumor therapy.
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Learning interest (internal driving motivation) and learning persistence (explicit behaviors) are important factors affecting students' academic development, yet whether they operate reciprocally and how to bolster them are still issues requiring attention. This study aimed to examine the reciprocal relationship between learning interest and persistence as well as the potential mechanisms behind the relationship from the perspectives of internal self-regulation and external feedback (i.e., academic performance). 510 students (Mage = 13.71, SD = 1.77, 44.1% girls) were tracked for one year using questionnaires. Results showed that higher learning interest was linked to greater subsequent learning persistence and vice versa; and both predicted each other over time indirectly through academic performance and the multiple mediating paths from strategies for self-regulated learning behaviors to academic performance. Ancillary analysis verifies the robustness of these results. The findings not only provide evidence of a dynamic relationship between learning motivation and behaviors, highlighting the important role of positive performance feedback in leading to a benign cycle, but also contribute to understanding the potential avenue (i.e., teaching strategies for self-regulation) for optimizing student learning.
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Rendimiento Académico , Aprendizaje , Motivación , Autocontrol , Estudiantes , Humanos , Femenino , Masculino , Rendimiento Académico/psicología , Autocontrol/psicología , Adolescente , Estudiantes/psicología , Encuestas y Cuestionarios , Conducta del Adolescente/psicologíaRESUMEN
Non-small cell lung cancer (NSCLC) still lacks effective treatment because of its extensive mutation diversity and frequent drug resistance. Therefore, it is urgent to develop new therapeutic strategies for NSCLC. In this study, we evaluated the inhibitory effect of a new coumarin-furoxan hybrid compound 9, a nitric oxide (NO) donor drug, on NSCLC proliferation and its mechanism. Our results show that compound 9 can inhibit the growth of four NSCLC cell lines and H1975 xenograft model in a dose-dependent manner. Compound 9 effectively releases high concentrations of NO within the mitochondria, leading to cellular oxidative stress, mitochondrial dysfunction, and apoptosis. Moreover, compound 9 inhibits JAK2/STAT3 protein phosphorylation and induces S-nitrosylation modification of STAT3, ultimately resulting in endogenous apoptosis in NSCLC. Additionally, compound 9 significantly induces NSCLC ferroptosis by depleting intracellular GSH, elevating MDA levels, inhibiting SLC7A11/GSH protein expression, and negatively regulating the JAK2/STAT3 pathway. In summary, this study elucidates the inhibitory effects of compound 9 on NSCLC proliferation and provides insights into the underlying mechanisms, offering new possibilities for NSCLC treatment strategies.
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Carcinoma de Pulmón de Células no Pequeñas , Ferroptosis , Neoplasias Pulmonares , Oxadiazoles , Humanos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/uso terapéutico , Factor de Transcripción STAT3/metabolismo , Apoptosis , Cumarinas/farmacología , Cumarinas/uso terapéutico , Línea Celular Tumoral , Proliferación Celular , Janus Quinasa 2/metabolismoRESUMEN
The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.
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Carcinoma de Células Renales , Neoplasias Renales , Animales , Ratones , Humanos , Proteómica , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Translocación Genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Neoplasias Renales/genética , Cromatina/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Cromosomas Humanos X/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Proteína que Contiene Valosina/genéticaRESUMEN
The Belt and Road Initiative (BRI) is an open platform for international cooperation proposed by China to promote common global development and prosperity. The BRI can promote the optimal allocation of resources and promote in-depth cooperation in international trade. Meanwhile, it can establish a green supply chain cooperation network to help BRI countries achieve green transformation. BRI has made a notable contribution to the rapid growth of cross-border trade. However, it has also brought environmental impacts. Given that little attention has been paid to the trade-embodied particulate matter 2.5 related human health impacts (PM2.5-HHI) throughout the BRI, this study accounts for and traces the embodied PM2.5-HHI flows between the BRI countries and non-Belt and Road Initiative (non-BRI) countries. Moreover, this study also uncovers the critical socioeconomic drivers of PM2.5-HHI changes in BRI countries during 1990-2015, based on the multi-regional input-output based structural decomposition analysis (MRIO-SDA). Results show that, firstly, BRI countries had significantly increased their economic added value by exporting products to the non-BRI countries. They also have brought PM2.5-HHI to themselves. Secondly, the final demand of BRI countries was the largest potential driving force of PM2.5-HHI of BRI countries. Thirdly, the emission intensity change of BRI is the key socioeconomic factor for reducing PM2.5-HHI. While per capita final demand level change of BRI and production structure change of non-BRI are the key socioeconomic factors for increasing PM2.5-HHI. The study's findings on the one hand can help reduce the PM2.5-HHI and impacts of environmental pollution of BRI countries from a global perspective by providing scientific support. On the other hand, they can help provide relevant policy recommendations for the green transformation of BRI and the construction of green BRI.
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Comercio , Internacionalidad , Humanos , China , Ambiente , Material Particulado/análisis , Desarrollo Económico , Dióxido de Carbono/análisisRESUMEN
Peroxiredoxin 1 (Prdx1), a vital antioxidant enzyme, has been proven to play an important role in the occurrence and development of cancers, but its effects on oral squamous cell carcinoma (OSCC) remain unclear. Here, we performed bioinformatics analysis and immunohistochemical (IHC) staining to confirm that Prdx1 was higher in OSCC tissues than in normal tissues. Consistently, RT-PCR and Western blot showed elevated Prdx1 expression in OSCC cell lines compared to human oral keratinocytes (HOK), which could be knockdown by small interfering RNA (siRNA) and Lentiviral vector delivery of short hairpin RNA (shRNA). Prdx1 silencing significantly blocked OSCC cell proliferation and metastasis, as evidenced by the CCK8, colony formation, in vivo tumorigenesis experiment, wound healing, transwell assays, and changes in migration-related factors. siPrdx1 transfection increased intracellular reactive oxygen species (ROS) levels and provoked pyroptosis, proved by the upregulation of pyroptotic factors and LDH release. Prdx1 silencing ROS-independently blocked autophagy. Mature autophagosome failed to form in the siPrdx1 group. Up-regulated autophagy limited pyroptosis triggered by Prdx1 deficiency, and down-regulated pyroptosis partly reversed siPrdx1-induced autophagy defect. Collectively, Prdx1 regulated pyroptosis in a ROS-dependent way and modulated autophagy in a ROS-independent way, involving the crosstalk between pyroptosis and autophagy.
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The t(X,17) chromosomal translocation, generating the ASPSCR1-TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCC), frustrating efforts to identify therapeutic targets for these rare cancers. Proteomic analysis showed that VCP/p97, an AAA+ ATPase with known segregase function, was strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1-TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1-TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributed with ASPSCR1-TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrated the oncogenic transcriptional signature of ASPSCR1-TFE3, by facilitating assembly of higher-order chromatin conformation structures as demonstrated by HiChIP. Finally, ASPSCR1-TFE3 and VCP demonstrated co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.
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Ensartinib (X-396) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of ALK-positive patients with locally advanced or metastatic non-small cell lung cancer. Although in vitro experiments and molecular docking suggested its potential as a cytochrome P450 inhibitor, no further investigation or clinical trials have been conducted to assess its drug-drug interaction (DDI) risk. In this study, we conducted a series of in vitro experiments to elucidate the inhibition mechanism of ensartinib. Furthermore, a physiologically-based pharmacokinetic (PBPK) model was developed based on in vitro, in silico, and in vivo parameters, verified using clinical data, and applied to predict the clinical DDI mediated by ensartinib. The in vitro incubation experiments suggested that ensartinib exhibited strong time-dependent inhibition. Simulation results from the PBPK model indicated a significant increase in the exposure of CYP3A substrates in the presence of ensartinib, with the maximal plasma concentration and area under the plasma concentration-time curve increasing up to 12-fold and 29-fold for sensitive substrates. Based on these findings, it is evident that co-administration of ensartinib and CYP3A substrates requires careful regulatory consideration. SIGNIFICANCE STATEMENT: Ensartinib was found to be a strong time-dependent inhibitor of CYP3A for the first time based on in vitro experiments, but there was no research conducted to estimate the risk of drug-drug interaction (DDI) of ensartinib in clinic. Therefore, the first ensartinib physiologically based pharmacokinetic model was developed and applied to predict various untested scenarios. The simulation result indicated that the exposure of CYP3A substrate increased significantly and urged the further clinical DDI study.
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Deep learning has been widely investigated in brain image computational analysis for diagnosing brain diseases such as Alzheimer's disease (AD). Most of the existing methods built end-to-end models to learn discriminative features by group-wise analysis. However, these methods cannot detect pathological changes in each subject, which is essential for the individualized interpretation of disease variances and precision medicine. In this article, we propose a brain status transferring generative adversarial network (BrainStatTrans-GAN) to generate corresponding healthy images of patients, which are further used to decode individualized brain atrophy. The BrainStatTrans-GAN consists of generator, discriminator, and status discriminator. First, a normative GAN is built to generate healthy brain images from normal controls. However, it cannot generate healthy images from diseased ones due to the lack of paired healthy and diseased images. To address this problem, a status discriminator with adversarial learning is designed in the training process to produce healthy brain images for patients. Then, the residual between the generated and input images can be computed to quantify pathological brain changes. Finally, a residual-based multi-level fusion network (RMFN) is built for more accurate disease diagnosis. Compared to the existing methods, our method can model individualized brain atrophy for facilitating disease diagnosis and interpretation. Experimental results on T1-weighted magnetic resonance imaging (MRI) data of 1,739 subjects from three datasets demonstrate the effectiveness of our method.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Cabeza , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodosRESUMEN
OBJECTIVES: This study aimed to explore the role and specific mechanism of the cholesterol-lowering drug simvastatin in inhibiting oral squamous cell carcinoma (OSCC). METHODS: The proliferation, apoptosis, and migration levels of OSCC cells were detected by CCK8, quantitative real-time polymerase chain reaction, Western blot, colony formation, TdT-mediated dUTP Nick-End Labeling assay, and wound healing assay. The inhibitory effect of simvastatin in vivo was detected by a mouse xenograft tumor model. Immunohistochemistry and immunofluorescence staining were used to assess the KLF2 and ß-catenin expressions in cells and tissues. RESULTS: KLF2 expression in OSCC cells and tissues was downregulated. The addition of KLF2 inducer, GGTI298, inhibited the proliferation and migration of OSCC cells. Simvastatin played a role in inhibiting the proliferation and promoting the apoptosis of OSCC cells. Moreover, it inhibited ß-catenin expression and promoted KLF2 expression in OSCC cells. KLF2 siRNA reversed the effect of simvastatin on the proliferation and apoptosis of OSCC cells. CONCLUSIONS: KLF2, as a tumor suppressor gene, may be an important marker for diagnosing and treating OSCC. Simvastatin inhibits the progression of OSCC by regulating the KLF2 signal.