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PURPOSE: This study aimed to validate the correlation between the Global Limb Anatomic Staging System (GLASS) and primary limb-based patency (LBP) and to identify the risk factors associated with LBP loss. MATERIALS AND METHODS: A single-center retrospective analysis was performed on patients with chronic limb-threatening ischemia (CLTI) who underwent endovascular therapy (EVT) between January 2018 and May 2022. All lesions were categorized into three groups (GLASS I, II, and III). The primary LBP rates were analyzed and compared across the GLASS stages. The risk factors for the loss of primary LBP were identified using Cox regression analysis. RESULTS: In total, 236 limbs from 231 patients were included, with 52 (22%) limbs stratified as GLASS I, 59 (25%) limbs as GLASS II, and 125 (53%) limbs as GLASS III. The one-year LBP rates for limbs classified as GLASS I, II, and III were 78.8%, 69.5%, and 41.6%, respectively (P <0.001). The long-term LBP rate was 54.2% in GLASS I, 38.6% in GLASS II, and 10.5% in, GLASS III (P < 0.001). Multivariate analysis revealed that GLASS stages (GLASS â vs GLASS â ¢: Hazard Ratio [HR]: 0.36; 95% Confidence Interval [CI]: 0.18-0.72; P = 0.004, GLASS â ¡ vs GLASS â ¢: HR: 0.47; 95%CI: 0.25-0.86; P = 0.02), diabetes, smoking, and sex were independently associated with LBP. CONCLUSIONS: GLASS stage III was associated with lower LBP rates in patients with CLTI who underwent EVT. The GLASS stages may serve as prognostic indicators for patients with CLTI after intervention.
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BACKGROUND: This study aimed to compare clinical outcomes associated with the duration of postoperative direct oral anticoagulant (DOACs) therapy in patients with nonthrombotic iliac vein lesions. METHODS: We retrospectively analyzed 176 consecutive patients who underwent stenting for nonthrombotic iliac vein lesions between March 2018 and December 2021. In total, 99 and 77 patients were discharged on a 3-month and >3-month regimen of DOAC therapy, respectively. The primary cumulative endpoint was a composite of thrombotic complications, bleeding complications, primary patency, primary-assisted patency, and secondary patency within 1 year. RESULTS: Patients undergoing 3-month and >3-month DOAC therapy were similar in age, sex, lesion site, symptoms, and average stent diameter and length. Upon multivariate analysis, the primary cumulative endpoint did not differ between the 2 groups (hazard ratio [HR]: 1.18; 95% confidence interval [CI]: 0.42-3.30; P = 0.76). Moreover, the primary patency at 1 year did not differ between the groups (HR: 1.50; 95% CI: 0.14-16.54; P = 0.74). Furthermore, there were no discernible differences in the secondary endpoints of bleeding complications (HR: 0.66; 95% CI: 0.22-1.96; P = 0.45) or thrombotic complications (HR: 1.79; 95% CI: 0.55-5.80; P = 0.34) between the groups. CONCLUSIONS: The 3-month regimen of DOAC therapy showed a similar risk of postoperative thrombosis and bleeding when compared to longer DOAC therapy durations over the course of 1 year following endovascular intervention. This could be a preferred option for patients with a higher estimated bleeding risk after venous stenting.
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Procedimientos Endovasculares , Trombosis , Humanos , Resultado del Tratamiento , Estudios Retrospectivos , Vena Ilíaca/diagnóstico por imagen , Vena Ilíaca/cirugía , Anticoagulantes/efectos adversos , Trombosis/etiología , Stents , Procedimientos Endovasculares/efectos adversos , Grado de Desobstrucción VascularRESUMEN
BACKGROUND: Myocardial microvascular injury is the key event in early diabetic heart disease. The injury of myocardial microvascular endothelial cells (CMECs) is the main cause and trigger of myocardial microvascular disease. Mitochondrial calcium homeostasis plays an important role in maintaining the normal function, survival and death of endothelial cells. Considering that mitochondrial calcium uptake 1 (MICU1) is a key molecule in mitochondrial calcium regulation, this study aimed to investigate the role of MICU1 in CMECs and explore its underlying mechanisms. METHODS: To examine the role of endothelial MICU1 in diabetic cardiomyopathy (DCM), we used endothelial-specific MICU1ecKO mice to establish a diabetic mouse model and evaluate the cardiac function. In addition, MICU1 overexpression was conducted by injecting adeno-associated virus 9 carrying MICU1 (AAV9-MICU1). Transcriptome sequencing technology was used to explore underlying molecular mechanisms. RESULTS: Here, we found that MICU1 expression is decreased in CMECs of diabetic mice. Moreover, we demonstrated that endothelial cell MICU1 knockout exacerbated the levels of cardiac hypertrophy and interstitial myocardial fibrosis and led to a further reduction in left ventricular function in diabetic mice. Notably, we found that AAV9-MICU1 specifically upregulated the expression of MICU1 in CMECs of diabetic mice, which inhibited nitrification stress, inflammatory reaction, and apoptosis of the CMECs, ameliorated myocardial hypertrophy and fibrosis, and promoted cardiac function. Further mechanistic analysis suggested that MICU1 deficiency result in excessive mitochondrial calcium uptake and homeostasis imbalance which caused nitrification stress-induced endothelial damage and inflammation that disrupted myocardial microvascular endothelial barrier function and ultimately promoted DCM progression. CONCLUSIONS: Our findings demonstrate that MICU1 expression was downregulated in the CMECs of diabetic mice. Overexpression of endothelial MICU1 reduced nitrification stress induced apoptosis and inflammation by inhibiting mitochondrial calcium uptake, which improved myocardial microvascular function and inhibited DCM progression. Our findings suggest that endothelial MICU1 is a molecular intervention target for the potential treatment of DCM.
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Proteínas de Unión al Calcio , Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Proteínas de Transporte de Membrana Mitocondrial , Animales , Ratones , Calcio , Dependovirus , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/prevención & control , Células Endoteliales , InflamaciónRESUMEN
PURPOSE: The purpose of this study was to analyze the clinical and radiological outcomes of two different zero-profile spacers (ROI-C and anchor-C) in contiguous two-level ACDF for CDDD patients. METHODS: We retrospectively analyzed patients who underwent contiguous two-level ACDF due to CDDD between January 2015 and December 2020 in our hospital. Patients who received ROI-C and anchor-C were included as the study groups, and those who underwent plate-cage construct (PCC) were included as the control group. The primary outcome measures were radiographical parameters, and the secondary outcome measures were dysphagia, JOA scores and VAS scores for these patients. RESULTS: A total of 91 patients were enrolled in the study; there were 31, 21 and 39 patients in the ROI-C, anchor-C and PCC groups, respectively. The mean follow-up duration was 24.52 months (range, 18-48 months) in the ROI-C group, 24.38 months (range, 16-52 months) in the anchor-C group and 25.18 months (range, 15-54 months) in the PCC group. The loss of the intervertebral space height and cage subsidence rate in the ROI-C group were significantly higher than those in the anchor-C group and PCC group at the final follow-up (P < 0.05). The ROI-C group showed a lower incidence of adjacent segment degeneration than the anchor-C group and PCC group, but the difference was not significant. The fusion rates were not different among these three groups. The early dysphagia rate was significantly lower in the patients with zero-profile spacers than in the PCC group (P < 0.05), but the difference was not significant at the last follow-up. No relevant differences were found in the JOA scores and VAS scores. CONCLUSIONS: Zero-profile spacers showed promising clinical outcomes in CDDD patients having contiguous two-level ACDF. However, ROI-C resulted in a higher intervertebral space height loss and a higher cage subsidence rate than anchor-C during the follow-up.
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Trastornos de Deglución , Degeneración del Disco Intervertebral , Fusión Vertebral , Humanos , Estudios de Seguimiento , Resultado del Tratamiento , Estudios Retrospectivos , Trastornos de Deglución/diagnóstico por imagen , Trastornos de Deglución/etiología , Discectomía/métodos , Fusión Vertebral/métodos , Degeneración del Disco Intervertebral/diagnóstico por imagen , Degeneración del Disco Intervertebral/cirugía , Degeneración del Disco Intervertebral/complicaciones , Placas Óseas/efectos adversos , Vértebras Cervicales/diagnóstico por imagen , Vértebras Cervicales/cirugíaRESUMEN
OBJECTIVES: To study outcomes in patients with non-thrombotic iliac vein lesions (NIVLs) treated by stents. METHODS: We performed a retrospective study that collected 109 patients from January 2016 to August 2020 diagnosed with symptomatic NIVLs. The patients underwent endovenous stenting using the Wallstents. Clinical severity was assessed using the venous clinical severity score and the Villalta scores. The patency was assessed using duplex ultrasound, while the diameters and the blood flow velocities (BFVs) in the proximal, middle, and distal stented segments were recorded simultaneously. RESULTS: A total of 128 stents were placed in 115 limbs (median age, 61 years), with a mean follow-up of 32 months. At 36 months, the Villalta scores went from 12.17 to 3.64 (p < .001). The VCSS went from 9.41 to 3.31 (p < .001). The mean diameters in the proximal, middle, and distal stented segments were 8.52 ± 2.15 mm, 10.13 ± 1.75 mm, and 10.17 ± 1.69 mm in the first month, while the mean BFVs were 31.17 ± 13.66 cm/s, 31.07 ± 11.90 cm/s, and 36.39 ± 18.41 cm/s, respectively. Repeated-measures analysis in 55 consecutive patients from 1 month to 3 years after procedure revealed a decrease of the stent diameter in the proximal stented segment (p = .004); a stabilization of the stent diameter in the middle (p = .43) or distal (p = .45) stented segment; a steadiness of the BFVs in the proximal (p = .40), middle (p = .93), and distal (p = .25) stented segments; and an improvement in the VCSS (p = .03) and Villalta scores (p = .006). CONCLUSIONS: BFVs in stented segments remained steady and the symptoms in lower extremities improved after surgery, while stent compression was observed in the diameter of the proximal stented segment, with no impact on BFVs or symptoms.
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RATIONALE: Doxorubicin is one of the most potent antitumor agents available; however, its clinical use is restricted because it poses a risk of severe cardiotoxicity. Previous work has established that CircITCH (circular RNA ITCH [E3 ubiquitin-protein ligase]) is a broad-spectrum tumor-suppressive circular RNA and that its host gene, ITCH (E3 ubiquitin protein ligase), is involved in doxorubicin-induced cardiotoxicity (DOXIC). Whether CircITCH plays a role in DOXIC remains unknown. OBJECTIVE: We aimed to dissect the role of CircITCH in DOXIC and further decipher its potential mechanisms. METHODS AND RESULTS: Circular RNA sequencing was performed to screen the potentially involved circRNAs in DOXI pathogenesis. Quantitative polymerase chain reaction and RNA in situ hybridization revealed that CircITCH was downregulated in doxorubicin-treated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as well as in the autopsy specimens from cancer patients who suffered from doxorubicin-induced cardiomyopathy. Cell death/viability assays, detection of cardiomyocyte necrosis markers, microelectrode array, and cardiomyocyte functional assays revealed that CircITCH ameliorated doxorubicin-induced cardiomyocyte injury and dysfunction. Detection of cellular/mitochondrial oxidative stress and DNA damage markers verified that CircITCH alleviated cellular/mitochondrial oxidative stress and DNA damage induced by doxorubicin. RNA pull-down assays, Ago2 immunoprecipitation and double fluorescent in situ hybridization identified miR-330-5p as a direct target of CircITCH. Moreover, CircITCH was found to function by acting as an endogenous sponge that sequestered miR-330-5p. Bioinformatic analysis, luciferase reporter assays, and quantitative polymerase chain reaction showed that SIRT6 (sirtuin 6), BIRC5 (baculoviral IAP repeat containing 5, Survivin), and ATP2A2 (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2, SERCA2a [SR Ca2+-ATPase 2]) were direct targets of miR-330-5p and that they were regulated by the CircITCH/miR-330-5p axis in DOXIC. Further experiments demonstrated that CircITCH-mediated alleviation of DOXIC was dependent on the interactions between miR-330-5p and the 3'-UTRs of SIRT6, BIRC5, and ATP2A2 mRNA. Finally, AAV9 (adeno-associated virus serotype 9) vector-based overexpression of the well-conserved CircITCH partly prevented DOXIC in mice. CONCLUSIONS: CircITCH represents a novel therapeutic target for DOXIC because it acts as a natural sponge of miR-330-5p, thereby upregulating SIRT6, Survivin and SERCA2a to alleviate doxorubicin-induced cardiomyocyte injury and dysfunction.
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Antibióticos Antineoplásicos/efectos adversos , Doxorrubicina/efectos adversos , MicroARNs/metabolismo , ARN Circular/fisiología , Proteínas Represoras/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Sirtuinas/metabolismo , Survivin/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Regiones no Traducidas 3'/genética , Adenovirus Humanos , Animales , Proteínas Argonautas/análisis , Sitios de Unión , Biomarcadores , Cardiotoxicidad/genética , Cardiotoxicidad/metabolismo , Cardiotoxicidad/terapia , Muerte Celular , Supervivencia Celular , Daño del ADN , Regulación hacia Abajo , Silenciador del Gen , Genes Supresores de Tumor , Humanos , Inmunoprecipitación/métodos , Hibridación Fluorescente in Situ/métodos , Ratones , MicroARNs/genética , Mitocondrias Cardíacas/metabolismo , Mutación , Contracción Miocárdica/fisiología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Necrosis , Estrés Oxidativo , ARN Circular/efectos de los fármacos , Proteínas Represoras/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , Survivin/genética , Ubiquitina-Proteína Ligasas/genética , Regulación hacia ArribaRESUMEN
RATIONALE: Exercise training, in addition to reducing cardiovascular risk factors, confers direct protection against myocardial ischemia/reperfusion injury and has been associated with improved heart attack survival in humans. However, the underlying mechanisms of exercise-afforded cardioprotection are still unclear. OBJECTIVE: To investigate the role of exercise-derived circulating exosomes in cardioprotection and the molecular mechanisms involved. METHODS AND RESULTS: Circulating exosomes were isolated from the plasma of volunteers with or without exercise training and rats subjected to 4-week swim exercise or sedentary littermates 24 hours after the last training session. Although the total circulating exosome level did not change significantly in exercised subjects 24 hours post-exercise compared with the sedentary control, the isolated plasma exosomes from exercised rats afforded remarkable protection against myocardial ischemia/reperfusion injury. miRNA sequencing combined with quantitative reverse transcription polymerase chain reaction validation identified 12 differentially expressed miRNAs from the circulating exosomes of exercised rats, among which miR-342-5p stood out as the most potent cardioprotective molecule. Importantly, the cardioprotective effects and the elevation of exosomal miR-342-5p were also observed in exercise-trained human volunteers. Moreover, inhibition of miR-342-5p significantly blunted the protective effects of exercise-derived circulating exosomes in hypoxia/reoxygenation cardiomyocytes; in vivo cardiac-specific inhibition of miR-342-5p through serotype 9 adeno-associated virus-mediated gene delivery attenuated exercise-afforded cardioprotection in myocardial ischemia/reperfusion rats. Mechanistically, miR-342-5p inhibited hypoxia/reoxygenation-induced cardiomyocyte apoptosis via targeting Caspase 9 and Jnk2; it also enhanced survival signaling (p-Akt) via targeting phosphatase gene Ppm1f. Of note, exercise training or laminar shear stress directly enhanced the synthesis of miR-342-5p in endothelial cells. CONCLUSIONS: Our findings reveal a novel endogenous cardioprotective mechanism that long-term exercise-derived circulating exosomes protect the heart against myocardial ischemia/reperfusion injury via exosomal miR-342-5p.
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Ejercicio Físico/fisiología , Exosomas/genética , MicroARNs/genética , Animales , Apoptosis/genética , Caspasa 9/genética , Caspasa 9/metabolismo , Células Cultivadas , Humanos , Masculino , Proteína Quinasa 9 Activada por Mitógenos/genética , Proteína Quinasa 9 Activada por Mitógenos/metabolismo , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Condicionamiento Físico Animal/fisiología , Ratas Sprague-Dawley , Adulto JovenRESUMEN
Accumulated pieces of evidence have proved the beneficial effects of melatonin on myocardial ischemia/reperfusion (MI/R) injury, and these effects were largely dependent on melatonin membrane receptor activation. In humans and other mammals, there are two types of melatonin receptors, including the melatonin receptor 1 (MT1, melatonin receptor 1a or MTNR1A) and melatonin receptor 1 (MT2, melatonin receptor 1b or MTNR1B) receptor subtypes. However, which receptor mediates melatonin-conferred cardioprotection remains unclear. In this study, we employed both loss-of-function and gain-of-function approaches to reveal the answer. Mice (wild-type; MT1 or MT2 silencing by in vivo minicircle vector; and those overexpressing MT1 or MT2 by in vivo AAV9 vector) were exposed to MI/R injury. Both MT1 and MT2 were present in wild-type myocardium. MT2, but not MT1, was essentially upregulated after MI/R Melatonin administration significantly reduced myocardial injury and improved cardiac function after MI/R Mechanistically, melatonin treatment suppressed MI/R-initiated myocardial oxidative stress and nitrative stress, alleviated endoplasmic reticulum stress and mitochondrial injury, and inhibited myocardial apoptosis. These beneficial actions of melatonin were absent in MT2-silenced heart, but not the MT1 subtype. Furthermore, AAV9-mediated cardiomyocyte-specific overexpression of MT2, but not MT1, mitigated MI/R injury and improved cardiac dysfunction, which was accompanied by significant amelioration of oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction. Mechanistically, MT2 protected primary cardiomyocytes against hypoxia/reoxygenation injury via MT2/Notch1/Hes1/RORα signaling. Our study presents the first direct evidence that the MT2 subtype, but not MT1, is a novel endogenous cardiac protective receptor against MI/R injury. Medications specifically targeting MT2 may hold promise in fighting ischemic heart disease.
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Apoptosis , Daño por Reperfusión Miocárdica , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Receptor de Melatonina MT2 , Transducción de Señal , Animales , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico/genética , Humanos , Masculino , Ratones , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/patología , Miocitos Cardíacos/patología , Estrés Oxidativo/genética , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/genética , Receptor de Melatonina MT2/metabolismoRESUMEN
BACKGROUND Periodontal ligament stem cells (PDLSCs) possess characteristics of multi-potential differentiation and immuno-modulation, and PDLSCs-mediated periodontal tissue regeneration is regarded as a hopeful method for periodontitis treatment. Recent studies demonstrated that RIP3 and caspase8 regulate bacteria-induced innate immune response and programmed necrosis, which is also called necroptosis. This study aimed to determine the role of the RIP3/Caspase8 signal pathway on necroptosis of PDLSCs under the inflammatory microenvironment, both [i]in vitro[/i] and [i]in vivo[/i]. MATERIAL AND METHODS PDLSCs were cultured, and transmission electron microscopy and flow cytometry were used to detect necroptosis. PCR, ALP, and Alizarin Red S staining were used to assess the effect of necroptosis on osteogenesis differentiation of PDLSCs [i]in vitro[/i], while HE and Masson staining were taken after the nude mouse subcutaneous transplant experiment. RESULTS Our research indicates that RIP3/caspase8 can regulate the immune response of PDLSCs, and blockade of RIP3/caspase8 can protect the biological characteristics of the PDLSCs, effectively promoting periodontal tissue regeneration in the inflammatory microenvironment. CONCLUSIONS Inhibiting RIP3/caspase8 can effectively promote periodontal tissue regeneration in the inflammatory microenvironment.
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Caspasa 8/fisiología , Periodontitis/terapia , Proteína Serina-Treonina Quinasas de Interacción con Receptores/fisiología , Animales , Caspasa 8/metabolismo , Diferenciación Celular/fisiología , China , Femenino , Humanos , Masculino , Células Madre Mesenquimatosas/citología , Ratones , Necrosis/fisiopatología , Osteogénesis/efectos de los fármacos , Ligamento Periodontal/citología , Ligamento Periodontal/fisiología , Periodontitis/fisiopatología , Cultivo Primario de Células , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Regeneración/fisiología , Transducción de Señal/fisiología , Nicho de Células Madre/fisiología , Células Madre/citología , Células Madre/fisiologíaRESUMEN
Mesenchymal stem cells (MSCs)-based therapy provides a promising therapy for the ischemic heart disease (IHD). However, engrafted MSCs are subjected to acute cell death in the ischemic microenvironment, characterized by excessive inflammation and oxidative stress in the host's infarcted myocardium. Melatonin, an indole, which is produced by many organs including pineal gland, has been shown to protect bone marrow MSCs against apoptosis although the mechanism of action remains elusive. Using a murine model of myocardial infarction (MI), this study was designed to evaluate the impact of melatonin on adipose-derived mesenchymal stem cells (AD-MSCs)-based therapy for MI and the underlying mechanism involved with a focus on silent information regulator 1(SIRT1) signaling. Our results demonstrated that melatonin promoted functional survival of AD-MSCs in infarcted heart and provoked a synergetic effect with AD-MSCs to restore heart function. This in vivo effect of melatonin was associated with alleviated inflammation, apoptosis, and oxidative stress in infarcted heart. In vitro studies revealed that melatonin exert cytoprotective effects on AD-MSCs against hypoxia/serum deprivation (H/SD) injury via attenuating inflammation, apoptosis, and oxidative stress. Mechanistically, melatonin enhanced SIRT1 signaling, which was accompanied with the increased expression of anti-apoptotic protein Bcl2, and decreased the expression of Ac-FoxO1, Ac-p53, Ac-NF-ΚB, and Bax. Taken together, our findings indicated that melatonin facilitated AD-MSCs-based therapy in MI, possibly through promoting survival of AD-MSCs via SIRT1 signaling. Our data support the promise of melatonin as a novel strategy to improve MSC-based therapy for IHD, possibly through SIRT1 signaling evocation.
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Tejido Adiposo/metabolismo , Melatonina/farmacología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Infarto del Miocardio/terapia , Transducción de Señal , Sirtuina 1/metabolismo , Animales , Femenino , Ratones , Ratones Transgénicos , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Miocardio/metabolismo , Miocardio/patologíaRESUMEN
To research the mechanism of dimercaptosuccinic acid coated-superparamagnetic iron oxide nanoparticles (SPION) with human serum albumin (HSA), the methods of spectroscopy, molecular modeling calculation, and calorimetry were used in this paper. The inner filter effect of the fluorescence intensity was corrected to obtain the accurate results. Ultraviolet-visible absorption and circular dichroism spectra reflect that SPION changed the secondary structure with a loss of α-helix and loosened the protein skeleton of HSA; the activity of the protein was also affected by the increasing exposure of SPION. Fluorescence lifetime measurement indicates that the quenching mechanism type of this system was static quenching. The isothermal titration calorimetry measurement and molecular docking calculations prove that the predominant force of this system was the combination of Van der Waals' force and hydrogen bonds.
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Materiales Biocompatibles Revestidos , Compuestos Férricos/química , Nanopartículas , Albúmina Sérica/química , Succímero/farmacología , Calorimetría , Dicroismo Circular , Humanos , Simulación de Dinámica Molecular , Espectrometría de Fluorescencia , Espectrofotometría Ultravioleta , TermodinámicaRESUMEN
The intervertebral disc (IVD) is the largest avascular structure in the body, and IVD cells reside in vivo in an environment that is considered to be hypoxic. However, the role of oxygen in IVD cell biology remains an issue of debate. By reviewing the available literature about the effect of oxygen tension on regulating the phenotype, energy metabolism, matrix production, and survival of IVD cells, as well as on the expression and function of hypoxia-inducible factor in IVD cells, we conclude that hypoxia is essential in maintaining the physiological function of IVD cells. Modulating the oxygen tension of the IVD or the activity of hypoxia-inducible factor in IVD cells may be a promising strategy for the prevention and treatment of IVD degeneration.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Hipoxia de la Célula/fisiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Degeneración del Disco Intervertebral/patología , Disco Intervertebral/citología , Animales , Bovinos , Supervivencia Celular/fisiología , Matriz Extracelular/metabolismo , Glucólisis/fisiología , Humanos , Disco Intervertebral/irrigación sanguínea , Oxígeno/fisiologíaRESUMEN
BACKGROUND/AIMS: Apoptosis and autophagy are two patterns of programmed cell death which play important roles in the intervertebral disc degeneration. Oxidative stress is an important factor for the induction of programmed cell death. However, the cellular reactions linking autophagy to apoptosis of disc cells under oxidative stress have never been described. This study investigated the responses of autophagy and apoptosis and their interactions in the nucleus pulposus cells (NP cells) under oxidative stress, with the aim to better understand the mechanism of disc degeneration. METHODS: NP cells isolated from rat lumbar discs were subjected to different concentrations of H2O2 for various time periods. Cell viability was determined by CCK-8 assay, and their apoptosis and autophagy responses were evaluated by fluorescent analysis, flow cytometry and western blotting, et al. The interactions of autophagy and apoptosis and the possible signaling pathways were also investigated by using autophagy modulators. RESULTS: H2O2 increased the lysosomal membrane permeability in the NP cells and induced apoptosis through the mitochondrial pathway subsequently. Meanwhile, H2O2 stimulated an early autophagy response through the ERK/m-TOR signaling pathway. Autophagy inhibition significantly decreased the apoptosis incidence in the cells insulted by H2O2. CONCLUSION: These results suggested that controlling the autophagy response in the NP cells under oxidative stress should be beneficial for the survival of the cells and probably delay the process of disc degeneration.
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Apoptosis/fisiología , Autofagia/fisiología , Degeneración del Disco Intervertebral/patología , Disco Intervertebral/patología , Estrés Oxidativo/fisiología , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de los fármacos , Permeabilidad de la Membrana Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Peróxido de Hidrógeno/farmacología , Disco Intervertebral/efectos de los fármacos , Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Autophagy and apoptosis are important in maintaining the metabolic homeostasis of intervertebral disc cells, and transforming growth factor-ß1 (TGF-ß1) is able to delay intervertebral disc degeneration. This study determined the effect of TGF-ß1 on the crosstalk between autophagy and apoptosis in the disc cells, with the aim to provide molecular mechanism support for the prevention and treatment of disc degeneration. Annulus fibrosus (AF) cells were isolated and cultured under serum starvation. 10 ng/mL TGF-ß1 reduced the apoptosis incidence in the cells under serum starvation for 48 h, down-regulated the autophagy incidence in the cells pretreated with 3-methyladenine (3-MA) or Bafilomycin A (Baf A), partly rescued the increased apoptosis incidence in the cells pretreated with 3-MA, while further reduced the decreased apoptosis incidence in the cells pretreated with Baf A. Meanwhile, TGF-ß1 down-regulated the expressions of autophagic and apoptotic markers in the cells under starvation, partly down-regulated the expressions of Beclin-1, LC3 II/I and cleaved caspase-3 in the cells pretreated with 3-MA or Baf A, while significantly decreased the expression of Bax/Bcl-2 in the cells pretreated with Baf A. 3-MA blocked the phosphorylation of both AKT and mTOR and partly reduced the inhibitory effect of TGF-ß1 on the expression of LC3 II/I and cleaved caspase-3. TGF-ß1 enhanced the expression of p-ERK1/2 and down-regulated the expressions of LC3 II/I and cleaved caspase-3. U0126 partly reversed this inhibitory effect of TGF-ß1. In conclusion, TGF-ß1 protected against apoptosis of AF cells under starvation through down-regulating excessive autophagy. PI3K-AKT-mTOR and MAPK-ERK1/2 were the possible signaling pathways involved in this process.
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Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Disco Intervertebral/citología , Factor de Crecimiento Transformador beta1/farmacología , Animales , Medio de Cultivo Libre de Suero , Citoprotección/efectos de los fármacos , Técnica del Anticuerpo Fluorescente , Disco Intervertebral/efectos de los fármacos , Disco Intervertebral/ultraestructura , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fagosomas/efectos de los fármacos , Fagosomas/ultraestructura , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: Diagnosis and treatment decisions of cervical instability are made, in part, based on the clinician's assessment of sagittal rotation on flexion and extension radiographs. The objective of this study is to evaluate the intraobserver and interobserver reliability of three measurement techniques in assessing cervical sagittal rotation. METHODS: Fifty lateral radiographs of patients with single-level cervical degenerative disc were selected and measured on two separate occasions by three spine surgeons using three different measurement techniques. Cervical sagittal rotation was measured using three different techniques. RESULTS: Intraclass correlation coefficients were most consistent for Method 2 (ICC 0.93-0.96) followed by Method 1 (ICC 0.88-0.91) and Method 3 (ICC 0.81-0.87). Intraobserver agreement (% of repeated measures within 0.5° of the original measurement) ranged between 76% and 96% for all techniques, with Method 2 showing the best agreement (92%-96%). Paired comparisons between observers varied considerably with interobserver reliability correlation coefficients ranging from 0.54 to 0.89. Method 2 showed the highest interobserver reliability coefficient (0.82, range 0.73-0.88). Method 2 was also more reliable for the classification of "instability". Intraobserver percent agreements ranged from 94 to 98% for Method 2 versus 84% to 90% for Method 1 and 78% to 86% for Method 3, while interobserver percent agreements ranged from 90% to 98% for Method 2 versus 86% to 94% for Method 1 and 74% to 84% for Method 3. CONCLUSIONS: Method 2 (measuring the angle from the inferior endplate of the vertebra above the degenerative disc and the inferior endplate of the vertebra below the degenerative disc) showed the best intraobserver and interobserver reliability overall in assessing cervical sagittal rotation.
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Vértebras Cervicales/diagnóstico por imagen , Degeneración del Disco Intervertebral/diagnóstico por imagen , Intensificación de Imagen Radiográfica/normas , Rotación , Cirujanos/normas , Humanos , Variaciones Dependientes del Observador , Intensificación de Imagen Radiográfica/métodos , Reproducibilidad de los ResultadosRESUMEN
The growing interest in utilizing lignin for dye removal has gained momentum, but there is limited information on the intricate relationship between lignin structural characteristics and adsorption efficacy, especially for its biochar derivatives. This study focused on three types of lignin and their corresponding biochar derivatives. Among them, ZnCl2-activated acidic/alkali densified lignin preparation of lignin-derived active carbon exhibited superior adsorption performance, achieving 526.32 mg/g for methylene blue and 2156.77 mg/g for congo red. Its exceptional adsorption capacity was attributed to its unique structural properties, including low alkyl and O-alkyl group content and high aromatic carbon levels. Furthermore, the adsorption mechanisms adhered to pseudo-second-order kinetics and the Langmuir model, signifying a spontaneous process. Intriguingly, lignin-derived active carbon also demonstrated remarkable recovery capabilities. These findings provide valuable insights into the impact of structural attributes on lignin and its biochar's adsorption performance.
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Carbón Orgánico , Lignina , Lignina/química , Adsorción , Carbón Orgánico/química , Cinética , Azul de Metileno/química , Rojo Congo/químicaRESUMEN
Background: Epilepsy's pathogenesis and progression are significantly influenced by neuroinflammation, blood-brain barrier function, and synaptic remodeling function. Matrix metalloproteinase 9 (MMP-9), as a critical factor, may contribute to the development of epilepsy through one or more of the above-mentioned pathways. This study aims to evaluate and quantify the correlation between MMP-9 levels and epilepsy. Methods: We conducted a comprehensive search of Embase, Web of Science, PubMed, Cochrane Library, WanFang DATA, VIP, and the CNKI to identify studies that investigate the potential association between MMP-9 and epilepsy. The data were independently extracted by two researchers and assessed for quality using the Cochrane Collaboration tool. The extracted data were analyzed using Stata 15 and Review Manager 5.4. The study protocol was registered prospectively at PROSPERO, ID: CRD42023468493. Results: Thirteen studies with a total of 756 patients and 611 matched controls met the inclusion criteria. Eight of these studies reported total serum MMP-9 levels, and the other five studies were used for a further subgroup analysis. The meta-analysis indicated that the serum MMP-9 level was higher in epilepsy patients (SMD = 4.18, 95% confidence interval = 2.18-6.17, p < 0.00001) compared with that in the control group. Publication bias was not detected according to Begg's test. The subgroup analysis of country indicated that the epilepsy patients in China, Poland, and Egypt had higher levels of serum MMP-9 than the control group, with the increase being more pronounced in Egypt. The subgroup analysis of the age category demonstrated that the serum MMP-9 levels of the adult patients with epilepsy were significantly higher than those of the matched controls. However, the serum MMP-9 levels did not significantly differ in children with epilepsy. The subgroup analysis of the seizure types demonstrated substantial difference in the MMP-9 levels between patients of seizure-free epilepsy (patients who have been seizure-free for at least 7 days) and the control group. Meanwhile, the serum MMP-9 level in patients with epileptic seizures was significantly higher than that in the control group. The subgroup analysis based on seizure duration in patients showed that the serum MMP-9 levels at 1-3, 24, and 72 h after seizure did not exhibit significant differences between female and male patients with epilepsy when compared with the control group. The serum MMP-9 levels at 1-3 and 24 h were significantly higher than those of the matched controls. Nevertheless, the serum MMP-9 level at 72 h was not significantly different from that in the control group. Conclusion: This meta-analysis presents the first comprehensive summary of the connection between serum MMP-9 level and epilepsy. The MMP-9 levels in epilepsy patients are elevated. Large-scale studies with a high level of evidence are necessary to determine the exact relationship between MMP-9 and epilepsy.
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BACKGROUND: Haemodynamics plays an important role in the development of vascular disease. There is currently a lack of studies evaluating the characteristics and affecting factors of the iliac vein haemodynamics in clinical practice. OBJECTIVE: The goal of this study was to use 4D flow MRI to explore the haemodynamic characteristics of iliac veins and its affecting factors in an asymptomatic population. METHODS: Thirty consecutive volunteers without venous-related symptoms or signs underwent four-dimensional postprocessing of their MRI images. Relevant parameters, the demographic data, common iliac vein-inferior vena cava angle, iliac vein area, tortuosity, iliac vein mean flow, mean velocity was computed and analysed. T tests and Spearman's tests were used for analysing. A P value of 0.05 or less was considered significant. RESULTS: Height and iliac vein area were positively correlated with flow, while degree of stenosis, and common iliac-inferior vena cava angle were negatively correlated with that. Degree of stenosis was positively correlated with velocity, but the common iliac-inferior vena cava angle and iliac vein tortuosity were negatively correlated with that. The mean flow and velocity of iliac veins in females were lower than males. The mean flow and velocity of the left iliac veins were lower than those of the right. CONCLUSION: The height, gender, tortuosity, degree of stenosis, common iliac vein-inferior vena cava angle of the iliac vein are important factors that affect flow and velocity of the iliac veins. There were differences in haemodynamic parameters of the bilateral iliac veins.
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Prior studies have revealed an increased susceptibility to epilepsy in hyperthyroid individuals, but the genetic basis of the hyperthyroidism-epilepsy relationship is not fully comprehended, prompting this study to explore this potential association. We conducted a two-sample Mendelian randomization (TSMR) study to explore the relationship between hyperthyroidism and epilepsy by utilizing aggregated statistics from Genome-Wide Association Studies (GWAS). Data for hyperthyroidism were derived from a GWAS encompassing 462,933 participants, while epilepsy data were sourced from the International League Against Epilepsy (ILAE) consortium. Five distinct methods were employed for TSMR analysis, which included the inverse variance weighting method, MR Egger method, weighted median method, simple model, and weighted model. In our sensitivity analysis, we employed the MR Egger and MR PRESSO methods to assess pleiotropy, and inverse variance weighting and MR Egger in Cochran's Q statistics to assess heterogeneity. In the IEU database, utilizing the MR-Egger method, we obtained an odds ratio (OR) of 2.631 (95% CI 0.608, 9.796) with a p-value of 0.122. Meanwhile, employing the Weighted Median method yielded an OR of 1.813 (95% CI 0.786, 4.181) with a p-value of 0.163. The IVW method exhibited an OR of 1.986 (95% CI 1.127, 3.502) with a p-value of 0.018. In the assessment of heterogeneity, the MR-Egger method produced a Q statistic of 65.205, accompanied by a p-value of 0.087, while the IVW method recorded a Q statistic of 66.668 with a p-value of 0.083. The multifactorial analysis results showed an intercept term with a standard error (SE) value of 0.009 and a p-value of 0.291. In the FinnGen database, employing the MR-Egger method for all epilepsy data, we observed an OR of 0.952 (95% CI 0.831, 1.093) with a p-value of 0.539. Simultaneously, the Weighted Median method produced an OR of 0.986 (95% CI 0.953, 1.021) with a p-value of 0.423. The IVW method indicated an OR of 0.992 (95% CI 0.965, 1.019) with a p-value of 0.541. The MR-Egger method's assessment of heterogeneity resulted in a Q statistic of 2.671, associated with a p-value of 0.445, while the IVW method generated a Q statistic of 3.011 with a p-value of 0.556. The multifactorial analysis results displayed an intercept term with a SE-value of 0.019 and a p-value of 0.601. Sensitivity analysis found no evidence of horizontal pleiotropy or heterogeneity. Hyperthyroidism was found to be causally related to all epilepsy but had no effect on other types of epilepsy.
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Epilepsia , Hipertiroidismo , Humanos , Epilepsia/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización MendelianaRESUMEN
An efficient protocol for the asymmetric synthesis of fluorenols has been developed through an enantioconvergent process enabled by Pd(ii)/chiral norbornene cooperative catalysis. This approach allows facile access to diverse functionalized chiral fluorenols with constantly excellent enantioselectivities, applying readily available racemic secondary ortho-bromobenzyl alcohols and aryl iodides as the starting materials.