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Introduction: Immunotherapies targeting T cells in solid cancers are revolutionizing clinical treatment. Novel immunotherapies have had extremely limited benefit for acute myeloid leukemia (AML). Here, we characterized the immune microenvironment of t(8;21) AML patients to determine how immune cell infiltration status influenced prognosis. Methods: Through multi-omics studies of primary and longitudinal t(8;21) AML samples, we characterized the heterogeneous immune cell infiltration in the tumor microenvironment and their immune checkpoint gene expression. Further external cohorts were also included in this research. Results: CD8+ T cells were enriched and HAVCR2 and TIGIT were upregulated in the CD34+CD117dim%-High group; these features are known to be associated with immune exhaustion. Data integration analysis of single-cell dynamics revealed that a subset of T cells (cluster_2) (highly expressing GZMB, NKG7, PRF1 and GNLY) evolved and expanded markedly in the drug-resistant stage after relapse. External cohort analysis confirmed that the cluster_2 T-cell signature could be utilized to stratify patients by overall survival outcome. Discussion: In conclusion, we discovered a distinct T-cell signature by scRNA-seq that was correlated with disease progression and drug resistance. Our research provides a novel system for classifying patients based on their immune microenvironment.
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Cromosomas Humanos Par 8 , Leucemia Mieloide Aguda , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Análisis de la Célula Individual/métodos , Pronóstico , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Cromosomas Humanos Par 8/genética , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Femenino , Translocación Genética , Cromosomas Humanos Par 21/genética , Linfocitos T CD8-positivos/inmunología , Adulto , Persona de Mediana Edad , Biomarcadores de Tumor/genéticaRESUMEN
OBJECTIVES: To report our initial experience of one-stage flexible ureteroscopic lithotripsy(FURL) with 11/13Fr suctioning ureteral access sheath(UAS) and 8.55Fr single-use digital flexible ureteroscope(SDFU) in upper ureteral or renal calculi. MATERIALS AND METHODS: We retrospectively collected the clinical data of 900 adult patients with upper ureteral or renal calculi treated by FURL with 11/13Fr suctioning UAS and 8.55Fr SDFU from January 2022 to April 2024. Demographics, peri- and postoperative outcomes were assessed. RESULTS: In all, 40 of 940 cases(4.26%) failed to introduce UAS and required second-stage FURL because of ureterostenosis and were excluded. Mean stones size of the remaining 900 eligible cases was 1.68 ± 0.58 cm in greatest diameter. There were 228 cases of upper ureteral stone, 456 cases of renal stone and 216 cases of concomitant ureteral and renal calculi. The mean operation time was 52.20 ± 20.21 min and the postoperative hospital stay was 2.87 ± 1.37 days. The stone-free rate of 1 month postoperatively was 89.56% and only 2.44% of patients with residue underwent additional reoperation. The rate of postoperative fever, postoperative pain needing analgesic and slight ureteral mucosal injury were 5.11%, 8.22% and 7.78%, respectively. None of patient suffered from severe complications, such as sepsis or ureteral perforation. CONCLUSION: It's practical and suitable for the vast majority of adult patients to undergo FURL in single session with 11/13Fr suctioning UAS without preoperative stenting. FURL with 11/13Fr suctioning UAS and 8.55Fr SDFU is feasible, reliable, safe, and efficient in the management of renal stone and upper ureteral stone.
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Cálculos Renales , Litotricia , Cálculos Ureterales , Ureteroscopios , Ureteroscopía , Humanos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Litotricia/métodos , Litotricia/instrumentación , Litotricia/efectos adversos , Adulto , Cálculos Renales/cirugía , Cálculos Renales/terapia , Succión/instrumentación , Succión/métodos , Ureteroscopía/instrumentación , Ureteroscopía/efectos adversos , Ureteroscopía/métodos , Cálculos Ureterales/cirugía , Cálculos Ureterales/terapia , Diseño de Equipo , Resultado del Tratamiento , Anciano , Uréter/cirugía , Tempo OperativoRESUMEN
Despite the emergence of various treatment strategies for rectal cancer based on neoadjuvant chemoradiotherapy, there is currently a lack of reliable biomarkers to determine which patients will respond well to neoadjuvant chemoradiotherapy. Through collecting hematological and biochemical parameters data of patients prior to receiving neoadjuvant chemoradiotherapy, we evaluated the predictive value of systemic inflammatory indices for pathological response and prognosis in rectal cancer patients. We found that baseline GRIm-Score was an independent predictor for MPR in rectal cancer patients. However, no association was observed between several commonly systemic inflammation indices and long-term outcome.
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Terapia Neoadyuvante , Neoplasias del Recto , Humanos , Neoplasias del Recto/patología , Neoplasias del Recto/terapia , Neoplasias del Recto/inmunología , Masculino , Femenino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Anciano , Quimioembolización Terapéutica/métodos , Pronóstico , Resultado del Tratamiento , Adulto , Quimioradioterapia/métodosRESUMEN
Introduction: Chronic hepatitis B (CHB) is a worldwide infectious disease caused by hepatitis B virus (HBV). Optimizing antiviral treatment strategies could improve the functional cure (FC) rate of patients with CHB. This study aims to systematically review the FC rate of the de novo combination of nucleos(t)ide analogs (NAs) and pegylated interferon α (PEG-IFNα) versus that of PEG-IFNα monotherapy for CHB. Methods: Databases were searched until 31 December 2023. Selected studies included randomized controlled trials on the de novo combination of NAs and PEG-IFNα versus PEG-IFNα monotherapy for 48 weeks in patients with CHB to achieve FC, which was defined as hepatitis B surface antigen (HBsAg) loss and/or HBsAg seroconversion. Meta-analysis was conducted in accordance with the efficacy at the end of treatment and different time points during follow-up. Results: A total of 10 studies, encompassing 2,339 patients in total, were included. Subgroup analysis was conducted in accordance with whether first-line NAs were used. It found no statistically significant difference between HBsAg loss and HBsAg seroconversion at the end of treatment. Serum HBV DNA <500 copies/mL significantly differed between the two groups at the end of treatment and did not significantly differ during follow-up. Meanwhile, HBsAg loss and HBsAg seroconversion showed statistically significant differences at 24 weeks of follow-up. By contrast, no statistically significant difference was found in HBsAg loss at 48 weeks of follow-up. Discussion: Without distinguishing the eligible preponderant population, the efficacy of the de novo combination of NAs and PEG-IFNα in treating patients with CHB was not superior to that of PEG-IFNα monotherapy. Systematic Review Registration: PROSPERO, identifier CRD42022325239.
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The clinical demand for occlusal reconstruction increases rapidly with increasing number of patients who have lost their normal occlusion because of tooth wear and dentition defects. Occlusal reconstruction is a special type of restoration defined as a comprehensive restoration of the function of the stomatognathic system by reestablishing a uniform and stable occlusal relationship between the upper and lower dentitions. Occlusal function analysis is an important part of occlusal reconstruction to achieve accurate restoration design and adjustment. Digital occlusal function analysis was conducted to monitor the movement of the mandible and obtain related data for the parameter design of occlusal reconstruction. Preoperative design, intraoperative adjustment, and postoperative verification were achieved, thereby improving the efficiency and accuracy of occlusal reconstruction.
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Oclusión Dental , Humanos , MandíbulaRESUMEN
Extracellular vesicles (EVs) produced from MSCs were currently considered as a novel therapeutic agent for skin tissue regeneration and repair. Preconditioning stem cells may activate more molecular pathways and release more bioactive agents. In this study, we obtained EVs from normal (N-EVs) and serum- and glucose-deprived (SGD-EVs) human umbilical cord mesenchymal stem cells (HUCMSCs), and showed that SGD-EVs promoted the migration, proliferation, and tube formation of HUVECs in vitro. In vivo experiments utilizing a rat model show that both N-EVs and SGD-EVs boosted angiogenesis of skin defects and accelerated skin wound healing, while treating wounds with SGD-EVs led to faster skin healing and enhanced angiogenesis. miRNA sequencing showed that miR-29a-3p was abundant in SGD-EVs, and overexpressing miR-29a-3p enhanced the angiogenic ability of HUVECs, while inhibiting miR-29a-3p presented the opposite effect. Further studies demonstrated that miR-29a-3p directly targeted CTNNBIP1, which mediated angiogenesis of HUCMSCs-derived EVs through inhibiting CTNNBIP1 to activate Wnt/ß-catenin signaling pathway. Taken together, these findings suggested that SGD-EVs promote angiogenesis via transferring miR-29a-3p, and activation of Wnt/ß-catenin signaling pathway played a crucial role in SGD-EVs-induced VEGFA production during wound angiogenesis. Our results offered a new avenue for modifying EVs to enhance tissue angiogenesis and augment its role in skin repair.
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Vascular dementia (VaD) is a cognitive disorder characterized by a decline in cognitive function resulting from cerebrovascular disease. The hippocampus is particularly susceptible to ischemic insults, leading to memory deficits in VaD. Astaxanthin (AST) has shown potential therapeutic effects in neurodegenerative diseases. However, the mechanisms underlying its protective effects in VaD and against hippocampal neuronal death remain unclear. In this study, We used the bilateral common carotid artery occlusion (BCCAO) method to establish a chronic cerebral hypoperfusion (CCH) rat model of VaD and administered a gastric infusion of AST at 25 mg/kg per day for 4 weeks to explore its therapeutic effects. Memory impairments were assessed using Y-maze and Morris water maze tests. We also performed biochemical analyses to evaluate levels of hippocampal neuronal death and apoptosis-related proteins, as well as the impact of astaxanthin on the PI3K/Akt/mTOR pathway and oxidative stress. Our results demonstrated that AST significantly rescued memory impairments in VaD rats. Furthermore, astaxanthin treatment protected against hippocampal neuronal death and attenuated apoptosis. We also observed that AST modulated the PI3K/Akt/mTOR pathway, suggesting its involvement in promoting neuronal survival and synaptic plasticity. Additionally, AST exhibited antioxidant properties, mitigating oxidative stress in the hippocampus. These findings provide valuable insights into the potential therapeutic effects of AST in VaD. By elucidating the mechanisms underlying the actions of AST, this study highlights the importance of protecting hippocampal neurons and suggests potential targets for intervention in VaD. There are still some unanswered questions include long-term effects and optimal dosage of the use in human. Further research is warranted to fully understand the therapeutic potential of AST and its application in the clinical treatment of VaD.
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Apoptosis , Demencia Vascular , Hipocampo , Trastornos de la Memoria , Neuronas , Fármacos Neuroprotectores , Estrés Oxidativo , Ratas Sprague-Dawley , Xantófilas , Animales , Xantófilas/uso terapéutico , Xantófilas/farmacología , Hipocampo/efectos de los fármacos , Demencia Vascular/tratamiento farmacológico , Ratas , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , Estrés Oxidativo/efectos de los fármacos , Neuronas/efectos de los fármacos , Apoptosis/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Modelos Animales de Enfermedad , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Muerte Celular/efectos de los fármacos , Antioxidantes/uso terapéutico , Antioxidantes/farmacología , Prueba del Laberinto Acuático de Morris/efectos de los fármacosRESUMEN
As an increasingly well-known derivative of coumarin, daphnetin (7,8-dithydroxycoumarin) has demonstrated various pharmacological activities, including anti-inflammation, anti-cancer, anti-autoimmune diseases, antibacterial, organ protection, and neuroprotection properties. Various studies have been conducted to explore the action mechanisms and synthetic methods of daphnetin, given its therapeutic potential in clinical. Despite these initial insights, the precise mechanisms underlying the pharmacological activities of daphnetin remain largely unknown. In order to address this knowledge gap, we explore the molecular effects from the perspectives of signaling pathways, NOD-like receptor protein 3 (NLRP3) inflammasome and inflammatory factors; and try to find out how these mechanisms can be utilized to inform new combined therapeutic strategies.
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Viral communities exist in a variety of ecosystems and play significant roles in mediating biogeochemical processes, whereas viruses inhabiting strongly alkaline geochemical systems remain underexplored. In this study, the viral diversity, potential functionalities, and virus-host interactions in a strongly alkaline environment (pH = 10.4-12.4) exposed to the leachates derived from the serpentinization-like reactions of smelting slags were investigated. The viral populations (e.g., Herelleviridae, Queuovirinae, and Inoviridae) were closely associated with the dominating prokaryotic hosts (e.g., Meiothermus, Trueperaceae, and Serpentinomonas) in this ultrabasic environment. Auxiliary metabolic genes (AMGs) suggested that viruses may enhance hosts' fitness by facilitating cofactor biosynthesis, hydrogen metabolism, and carbon cycling. To evaluate the activity of synthesis of essential cofactor vitamin B9 by the viruses, a viral folA (vfolA) gene encoding dihydrofolate reductase (DHFR) was introduced into a thymidine-auxotrophic strain Escherichia coli MG1655 ΔfolA mutant, which restored the growth of the latter in the absence of thymidine. Notably, the homologs of the validated vDHFR were globally distributed in the viromes across various ecosystems. The present study sheds new light on the unique viral communities in hyperalkaline ecosystems and their potential beneficial impacts on the coexisting microbial consortia by supplying essential cofactors. IMPORTANCE: This study presents a comprehensive investigation into the diversity, potential functionalities, and virus-microbe interactions in an artificially induced strongly alkaline environment. Functional validation of the detected viral folA genes encoding dihydrofolate reductase substantiated the synthesis of essential cofactors by viruses, which may be ubiquitous, considering the broad distribution of the viral genes associated with folate cycling.
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Microbiota , Concentración de Iones de Hidrógeno , Viroma/genética , Virus/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Tetrahidrofolato Deshidrogenasa/genética , Tetrahidrofolato Deshidrogenasa/metabolismo , Bacterias/genética , Bacterias/metabolismo , Bacterias/clasificaciónRESUMEN
OBJECTIVES: Periodontitis is a common oral disease that is aggravated by occlusal trauma. Fibrin is a protein that participates in blood clotting and is involved in several human diseases. The deposition of fibrin in periodontal tissues can induce periodontitis, while mechanical forces may regulate the degradation of fibrin. Our study investigated how occlusal trauma aggravating periodontitis through regulating the plasminogen/plasmin system and fibrin deposition. MATERIALS AND METHODS: This study included 84 C57BL/6 mice in which periodontitis was induced with or without occlusal trauma. Micro-computed tomography was used to assess bone resorption. Fibrin, fibrinogen, plasminogen, plasmin, tissue plasminogen activator (t-PA), and urokinase plasminogen activator (u-PA) levels were measured using Frazer-Lendrum staining, quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, immunofluorescence staining, and immunohistochemistry staining. RESULTS: Occlusal trauma aggravated inflammation and bone resorption. The periodontitis group showed significant fibrin deposition. Occlusal trauma increased fibrin deposition and neutrophil aggregation. The periodontitis with occlusal trauma group had decreased fibrinogen, t-PA, and u-PA expression and plasmin and fibrin degradation product levels, as well as increased plasminogen levels. CONCLUSION: Occlusal trauma promotes excessive fibrin deposition by suppressing the plasminogen/plasmin system, thus exacerbating periodontitis.
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The Liangfu formula, as described in 'Liangfang Jiye', is well-known for its efficacy in treating stomach pain, abdominal pain, and dysmenorrhea. This research aimed to investigate the pharmacokinetics and tissue distribution of 5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-phenyl-3-heptanone (DPHA), Galangin, Kaempferide, 5-Hydroxy-1,7-diphenyl-3-heptanone (DPHC), α-Cyperone, and Nootkatone in vivo using an LC-MS/MS method. The method successfully separated the six active components and internal standards (Chrysin and Yakuchinone-A) on an XB-C18 column with a mobile phase of 0.2⯠formic acid water-acetonitrile. It demonstrated good linearity with a correlation coefficient (r2) ≥ 0.9911 and a lower limit of quantification (LLOQ) of 5-80â¯ng/mL for the different components. Precision, accuracy, matrix effects, and recovery rates were within acceptable ranges. Pharmacokinetic analysis revealed significant differences in parameters between primary dysmenorrhea (PD) and normal rats (especially AUC, Tmax, and CLz/F). Tissue distribution showed that the six active components of the herbal pair Alpinia officinarum Hance-Cyperus rotundus L. (HPAC) extract was primarily distributed in the liver, lung, and kidney. This study offers valuable insights into the potential mechanisms of action and drug development for treating PD.
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Alpinia , Cyperus , Medicamentos Herbarios Chinos , Dismenorrea , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem , Animales , Dismenorrea/tratamiento farmacológico , Femenino , Ratas , Distribución Tisular , Espectrometría de Masas en Tándem/métodos , Cyperus/química , Alpinia/química , Medicamentos Herbarios Chinos/farmacocinética , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida/métodosRESUMEN
GATM-related Fanconi renotubular syndrome 1 (FRTS1) is a form of renal Fanconi syndrome (RFS), which is a disorder of solute and water reabsorption caused by defects in the function of the entire proximal tubule. Recent findings reveal the molecular basis of FRTS1: Intramitochondrial fiber aggregation triggered by mutant GATM provides a starting point for proximal tubule damage and drives disease progression. As a rare and newly recognized inherited kidney disease, the complex manifestations of FRTS1 are easily underdiagnosed or misdiagnosed. We discuss the complex phenotype of a 26-year-old woman with onset in infancy and a long history of hypophosphatemic rickets. We also identified a novel heterozygous missense variant in the GATM gene in this patient. The novel variant and phenotype we report expand the disease spectrum of FRTS1. We recommend screening for GATM in children with RFS, especially in patients with resistant rickets who have previously had negative genetic testing. In addition, we found pathological deposition of mutant GATM proteins within mitochondria in the patient's urinary sediment cells by a combination of electron microscopy and immunofluorescence. This unique urine cytology experiment has the potential to be a valuable tool for identifying patients with RRTS1.
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Síndrome de Fanconi , Fenotipo , Raquitismo Hipofosfatémico , Humanos , Femenino , Adulto , Síndrome de Fanconi/genética , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/patología , Raquitismo Hipofosfatémico/genética , Raquitismo Hipofosfatémico/diagnóstico , Mutación MissenseRESUMEN
ABSTARCT: Necrozoospermia is a poorly documented condition with a low incidence, and its definition and clinical significance are unclear. Herein, we provide a reference range for necrozoospermia and discuss its possible etiology and impact on male fertility and assisted reproductive outcomes. We extracted relevant information from 650 Chinese male partners of infertile couples and statistically analyzed sperm vitality. Necrozoospermia was present in 3.4% (22/650) of our study population, and the lower cut-off value for sperm vitality was 75.3%. We compared two methods for assessing sperm vitality (eosin-nigrosin head staining and hypo-osmotic swelling test [HOST]), for which the percentage in the eosin-nigrosin group (mean ± standard deviation [s.d.]: 77.5% ± 10.5%) was significantly higher than that in the HOST group (mean ± s.d.: 58.1% ± 6.7% [5-10 min after incubation] and 55.6% ± 8.2% [25-30 min after incubation]; both P < 0.001). The incidence of necrozoospermia increased with age (odds ratio [OR] = 1.116, 95% confidence interval [CI]: 1.048-1.189, P = 0.001), while the percentage of normal sperm morphology and DNA fragmentation index (DFI) were significantly associated with necrozoospermia, with ORs of 0.691 (95% CI: 0.511-0.935, P = 0.017) and 1.281 (95% CI: 1.180-1.390, P < 0.001), respectively. In the following 6 months, we recruited 166 patients in the nonnecrozoospermia group and 87 patients in the necrozoospermia group to compare intracytoplasmic sperm injection (ICSI) and pregnancy outcomes between the two groups. The necrozoospermia group had a significantly lower normal fertilization rate (74.7% vs 78.2%, P = 0.041; OR = 0.822; 95% CI: 0.682-0.992) than that in the nonnecrozoospermia group. This study presents substantial information on necrozoospermia to establish comprehensive and applicable reference values for sperm vitality for spontaneous conception and artificially assisted reproductive management.
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The inverted hyperplastic polyp (IHP) is known as hyperplastic gastric mucosa growth into submucosa and endoscopically presented as sessile or pedunculated submucosa lesion. It occurs in between 3.1% to 20.1% of cases, while its malignant transformation rate is just 0.02%. A male underwent esophagogastroduodenoscopy (EGD) and discovered a submucosal lesion with a pinhole-like orifice in the fundus. And endoscopic ultrasound (EUS) showed it was a heterogenous hypoechoic lesion located in the submucosa. After endoscopic resection, the pathological findings and immunohistochemical staining revealed it was inverted hyperplastic polyp (IHP) with adenocarcinoma. The measurement of the cancerous IHP depth of invasion is controversial. Thus, how to define the depth of lesion invasion in this patient needs to be seriously considered. To manage IHP with adenocarcinoma better, the depth of lesion invasion cancerous IHP needs to be seriously considered.
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Currently, the successful healing of critical-sized calvarial bone defects remains a considerable challenge. The immune response plays a key role in regulating bone regeneration after material grafting. Previous studies mainly focused on the relationship between macrophages and bone marrow mesenchymal stem cells (BMSCs), while dural cells were recently found to play a vital role in the calvarial bone healing. In this study, a series of 3D elastomers with different proportions of polycaprolactone (PCL) and poly(glycerol sebacate) (PGS) were fabricated, which were further supplemented with polydopamine (PDA) coating. The physicochemical properties of the PCL/PGS and PCL/PGS/PDA grafts were measured, and then they were implanted as filling materials for 8 mm calvarial bone defects. The results showed that a matched and effective PDA interface formed on a well-proportioned elastomer, which effectively modulated the polarization of M2 macrophages and promoted the recruitment of dural cells to achieve full-thickness bone repair through both intramembranous and endochondral ossification. Single-cell RNA sequencing analysis revealed the predominance of dural cells during bone healing and their close relationship with macrophages. The findings illustrated that the crosstalk between dural cells and macrophages determined the vertical full-thickness bone repair for the first time, which may be the new target for designing bone grafts for calvarial bone healing.
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OBJECTIVES: To assess the efficacy and safety of colchicine versus placebo on reducing the risk of subsequent stroke after high risk non-cardioembolic ischaemic stroke or transient ischaemic attack within the first three months of symptom onset (CHANCE-3). DESIGN: Multicentre, double blind, randomised, placebo controlled trial. SETTING: 244 hospitals in China between 11 August 2022 and 13 April 2023. PARTICIPANTS: 8343 patients aged 40 years of age or older with a minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L were enrolled. INTERVENTIONS: Patients were randomly assigned 1:1 within 24 h of symptom onset to receive colchicine (0.5 mg twice daily on days 1-3, followed by 0.5 mg daily thereafter) or placebo for 90 days. MAIN OUTCOME MEASURES: The primary efficacy outcome was any new stroke within 90 days after randomisation. The primary safety outcome was any serious adverse event during the treatment period. All efficacy and safety analyses were by intention to treat. RESULTS: 4176 patients were assigned to the colchicine group and 4167 were assigned to the placebo group. Stroke occurred within 90 days in 264 patients (6.3%) in the colchicine group and 270 patients (6.5%) in the placebo group (hazard ratio 0.98 (95% confidence interval 0.83 to 1.16); P=0.79). Any serious adverse event was observed in 91 (2.2%) patients in the colchicine group and 88 (2.1%) in the placebo group (P=0.83). CONCLUSIONS: The study did not provide evidence that low-dose colchicine could reduce the risk of subsequent stroke within 90 days as compared with placebo among patients with acute non-cardioembolic minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05439356.
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Colchicina , Ataque Isquémico Transitorio , Accidente Cerebrovascular Isquémico , Humanos , Colchicina/administración & dosificación , Colchicina/uso terapéutico , Colchicina/efectos adversos , Masculino , Femenino , Método Doble Ciego , Persona de Mediana Edad , Ataque Isquémico Transitorio/tratamiento farmacológico , Anciano , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/prevención & control , Resultado del Tratamiento , China , Proteína C-Reactiva/análisis , AdultoRESUMEN
BACKGROUND: The purpose of this study was to investigate the photoprotection effect of peroxiredoxin 1 (PRDX1) protein in ultraviolet B (UVB) irradiation-induced damage of retinal pigment epithelium (RPE) and its possible molecular mechanism. METHODS: ARPE-19 cell viability and apoptosis were assessed by MTT assay and flow cytometry, respectively. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the PRDX1 expression. The corresponding kits were employed to measure the levels or activities of lactate dehydrogenase (LDH), 8-hydroxy-2-deoxyguanosine (8-OHdG), reactive oxygen species (ROS), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD). Western blotting was applied to examine PRDX1 expression and mitogen-activated protein kinase (MAPK) signaling pathway-related proteins. RESULTS: After exposure to 20 mJ/cm2 intensity of UVB irradiation for 24 h, ARPE-19 cells viability was decreased, the leakage degree of LDH and 8-OHdG were increased, and cell apoptosis was elevated. The expression of PRDX1 was significantly down-regulated in UVB-induced ARPE-19 cells. The low expression of PRDX1 was involved in high irradiation intensity. Overexpression of PRDX1 increased cell activity, decreased cell apoptosis, and LDH as well as 8-OHdG leakage in UVB-induced ARPE-19 cells. In addition to alleviating UVB-induced cell damage, PRDX1 overexpression also inhibited UVB-induced oxidative stress (down-regulation of ROS and MDA levels, up-regulation of GSH-Px and SOD activities) and the activation of MAPK signaling pathway in ARPE-19 cells. CONCLUSION: PRDX1 exerts a photoprotection effect on RPE by attenuating UVB-induced cell damage and inhibiting oxidative stress, which can be attributed to the inhibition of MAPK signaling pathway activation.
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Apoptosis , Supervivencia Celular , Estrés Oxidativo , Peroxirredoxinas , Especies Reactivas de Oxígeno , Epitelio Pigmentado de la Retina , Rayos Ultravioleta , Humanos , Epitelio Pigmentado de la Retina/efectos de la radiación , Epitelio Pigmentado de la Retina/metabolismo , Peroxirredoxinas/metabolismo , Rayos Ultravioleta/efectos adversos , Especies Reactivas de Oxígeno/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Línea Celular , Western Blotting , Células Cultivadas , 8-Hidroxi-2'-Desoxicoguanosina/metabolismo , Transducción de SeñalRESUMEN
Background: The current dilemma of osteosarcoma treatment is the resistance of chemotherapeutic drugs after long-term usage, which also introduces life-threatening side effects. Methods and results: To minimize chemoresistance in osteosarcoma patients, the authors applied shock waves (SWs) to human osteosarcoma MNNG/HOS cells, then evaluated the cell viability and extracellular ATP levels, and further investigated the effect of SWs on cisplatin (DDP) cytotoxicity in MNNG/HOS cells. The authors' results showed that 400 SW pulses at 0.21 mJ/mm2 exhibited little influence on the MNNG/HOS cell viability. In addition, this SW condition significantly promoted the extracellular ATP release in MNNG/HOS cells. Importantly, low-energy SWs obviously increased Akt and mammalian target of rapamycin (mTOR) phosphorylation and activation in MNNG/HOS cells, which could be partially reversed in the presence of P2X7 siRNA. The authors also found that low-energy SWs strongly increased the DDP sensitivity of MNNG/HOS cells in the absence of P2X7. Conclusions: For the first time, the authors found that SW therapy reduced the DDP resistance of MNNG/HOS osteosarcoma cells when the ATP receptor P2X7 was downregulated. SW therapy may provide a novel treatment strategy for chemoresistant human osteosarcoma.