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1.
Cell ; 172(4): 881-887.e7, 2018 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-29395327

RESUMEN

Generation of genetically uniform non-human primates may help to establish animal models for primate biology and biomedical research. In this study, we have successfully cloned cynomolgus monkeys (Macaca fascicularis) by somatic cell nuclear transfer (SCNT). We found that injection of H3K9me3 demethylase Kdm4d mRNA and treatment with histone deacetylase inhibitor trichostatin A at one-cell stage following SCNT greatly improved blastocyst development and pregnancy rate of transplanted SCNT embryos in surrogate monkeys. For SCNT using fetal monkey fibroblasts, 6 pregnancies were confirmed in 21 surrogates and yielded 2 healthy babies. For SCNT using adult monkey cumulus cells, 22 pregnancies were confirmed in 42 surrogates and yielded 2 babies that were short-lived. In both cases, genetic analyses confirmed that the nuclear DNA and mitochondria DNA of the monkey offspring originated from the nucleus donor cell and the oocyte donor monkey, respectively. Thus, cloning macaque monkeys by SCNT is feasible using fetal fibroblasts.


Asunto(s)
Clonación de Organismos , Técnicas de Transferencia Nuclear , Animales , Blastocisto/citología , Blastocisto/metabolismo , Femenino , Ácidos Hidroxámicos/farmacología , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Histona Demetilasas con Dominio de Jumonji/metabolismo , Macaca fascicularis , Embarazo
3.
PLoS Biol ; 21(12): e3002433, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38091366

RESUMEN

The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1, threatens human health. Expression of the MCR-1 protein affects bacterial fitness and this cost correlates with lipid A perturbation. However, the exact molecular mechanism remains unclear. Here, we identified the MCR-1 M6 variant carrying two-point mutations that conferred co-resistance to ß-lactam antibiotics. Compared to wild-type (WT) MCR-1, this variant caused severe disturbance in lipid A, resulting in up-regulation of L, D-transpeptidases (LDTs) pathway, which explains co-resistance to ß-lactams. Moreover, we show that a lipid A loading pocket is localized at the linker domain of MCR-1 where these 2 mutations are located. This pocket governs colistin resistance and bacterial membrane permeability, and the mutated pocket in M6 enhances the binding affinity towards lipid A. Based on this new information, we also designed synthetic peptides derived from M6 that exhibit broad-spectrum antimicrobial activity, exposing a potential vulnerability that could be exploited for future antimicrobial drug design.


Asunto(s)
Colistina , Proteínas de Escherichia coli , Humanos , Colistina/farmacología , Antibacterianos/farmacología , Antibióticos Betalactámicos , Lípido A , Péptidos Antimicrobianos , Monobactamas , Plásmidos , Farmacorresistencia Bacteriana/genética , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Pruebas de Sensibilidad Microbiana
4.
Curr Issues Mol Biol ; 46(3): 1886-1903, 2024 Feb 29.
Artículo en Inglés | MEDLINE | ID: mdl-38534739

RESUMEN

Kidney renal papillary cell carcinoma (KIRP) is a highly heterogeneous type of kidney cancer, resulting in limited effective prognostic targets for KIRP patients. Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in the regulation of ferroptosis and iron metabolism, making them potential targets for the treatment and prognosis of KIRP. In this study, we constructed a ferroptosis-related lncRNA risk score model (FRM) based on the TCGA-KIRP dataset, which represents a novel subtype of KIRP not previously reported. The model demonstrated promising diagnostic accuracy and holds potential for clinical translation. We observed significant differences in metabolic activities, immune microenvironment, mutation landscape, ferroptosis sensitivity, and drug sensitivity between different risk groups. The high-risk groups exhibit significantly higher fractions of cancer-associated fibroblasts (CAFs), hematopoietic stem cells (HSC), and pericytes. Drugs (IC50) analysis provided a range of medication options based on different FRM typing. Additionally, we employed single-cell transcriptomics to further analyze the impact of immune invasion on the occurrence and development of KIRP. Overall, we have developed an accurate prognostic model based on the expression patterns of ferroptosis-related lncRNAs for KIRP. This model has the potential to contribute to the evaluation of patient prognosis, molecular characteristics, and treatment modalities, and can be further translated into clinical applications.

5.
Biochem Biophys Res Commun ; 718: 150078, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-38735140

RESUMEN

Among the environmental factors contributing to myopia, the role of correlated color temperature (CCT) of ambient light emerges as a key element warranting in-depth investigation. The choroid, a highly vascularized and dynamic structure, often undergoes thinning during the progression of myopia, though the precise mechanism remains elusive. The retinal pigment epithelium (RPE), the outermost layer of the retina, plays a pivotal role in regulating the transport of ion and fluid between the subretinal space and the choroid. A hypothesis suggests that variations in choroidal thickness (ChT) may be modulated by transepithelial fluid movement across the RPE. Our experimental results demonstrate that high CCT illumination significantly compromised the integrity of tight junctions in the RPE and disrupted chloride ion transport. This functional impairment of the RPE may lead to a reduction in fluid transfer across the RPE, consequently resulting in choroidal thinning and potentially accelerating axial elongation. Our findings provide support for the crucial role of the RPE in regulating ChT. Furthermore, we emphasize the potential hazards posed by high CCT artificial illumination on the RPE, the choroid, and refractive development, underscoring the importance of developing eye-friendly artificial light sources to aid in the prevention and control of myopia.


Asunto(s)
Cloruros , Coroides , Transporte Iónico , Epitelio Pigmentado de la Retina , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/efectos de la radiación , Epitelio Pigmentado de la Retina/patología , Coroides/metabolismo , Coroides/efectos de la radiación , Coroides/patología , Animales , Transporte Iónico/efectos de la radiación , Cloruros/metabolismo , Iluminación/métodos , Temperatura , Color , Uniones Estrechas/metabolismo , Miopía/metabolismo , Miopía/patología , Miopía/etiología
6.
Chemistry ; 30(23): e202304157, 2024 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-38270279

RESUMEN

The environmental impact from the waste disposal has been widely concerned around the world. The conversion of wastes to useful resources is important for the sustainable society. As a typical family of wastes, biomass materials basically composed of collagen, protein and lignin are considered as useful resources for recycle and reuse. In recent years, the development of carbon material derived from biomasses, such as plants, crops, animals and their application in electrochemical energy storage have attracted extensive attention. Through the selection of the appropriate biomass, the optimization of the activation method and the control of the pyrolysis temperatures, carbon materials with desired features, such as high-specific surface area, variable porous framework, and controllable heteroatom-doping have been fabricated. Herein, this review summarized the preparation methods, morphologies, heteroatoms doping in the plant/animal-derived carbonaceous materials, and their application as electrode materials for secondary batteries and supercapacitors, and as electrode support for lithium-sulfur batteries. The challenges and prospects for the controllable synthesis and large-scale application of biomass-derived carbonaceous materials have also been outlooked.

7.
Anal Biochem ; 689: 115499, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38431141

RESUMEN

MicroRNAs (miRNAs) are crucial biomarkers for the early detection and monitoring of disease progression of chronic obstructive pulmonary disease (COPD). Herein, we have devised a method for detecting miRNA using a combination of colorimetric and graphene oxide-based fluorescent techniques. The target miRNA in our design could precisely activate the trans-cleavage activity of the CRISPR-Cas13a system. The activated Cas13a enzyme cuts the "rUrU" section in the P1 probe, generating a nicking site to induce entropy-driven amplification (EDA). One of the available EDA products has the capability to unfold the hairpin probe, thereby initiating the catalytic hairpin assembly, exposing the G-quadruplex structure, facilitating the subsequent color response. The fuel strand labeled with Cy3 successfully established a double-stranded DNA structure with DNA3, and consequently the Cy3 would not be quenched by graphene oxide (GO). The implementation of the dual-mode technique in this method yields greater benefits in terms of improving the precision and consistency of the miRNA measurements. The developed method has the capability to fluorescently measure miRNA-21 levels down to a concentration of 5.8 fM. In addition, the analysis of miRNA targets from clinical samples using this method demonstrates its promising utility in the fields of biomedical research of COPD.


Asunto(s)
Técnicas Biosensibles , Grafito , MicroARNs , Enfermedad Pulmonar Obstructiva Crónica , Humanos , MicroARNs/genética , Colorimetría/métodos , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Entropía , Técnicas de Amplificación de Ácido Nucleico/métodos , Colorantes
8.
Curr Opin Pulm Med ; 30(1): 68-74, 2024 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-37942820

RESUMEN

PURPOSE OF REVIEW: Chronic bronchitis is a phenotype of chronic obstructive pulmonary disease (COPD), characterized by chronic cough and sputum production, associated with an increased rate of COPD exacerbations and hospital admissions, a more rapid decline in lung function and reduced life expectancy. Despite optimal medical therapy, chronic bronchitis remains difficult to treat. Interventional bronchoscopic procedures offer novel therapeutic approaches to this highly symptomatic condition. RECENT FINDINGS: A characteristic feature of chronic bronchitis is the presence of an abnormal epithelium with excessive mucus producing cells, parasympathetic overactivity, and airway inflammation. Metered cryospray and bronchial rheoplasty are designed to target this abnormal epithelium to reduce mucus production and inflammation. Targeted lung denervation aims to reduce parasympathetic overactivity, which may drive mucus hypersecretion. Here, we review the available evidence to determine the safety and efficacy across the bronchoscopic interventions. SUMMARY: Interventional bronchoscopy is a rapidly expanding field and its application in the treatment of chronic bronchitis has been recognized by the Global initiative for chronic Obstructive Lung Disease (GOLD). The outcomes from the latest clinical trials will guide future treatment approaches in patients with difficult to treat chronic bronchitis.


Asunto(s)
Bronquitis Crónica , Bronquitis , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Bronquitis Crónica/terapia , Enfermedad Pulmonar Obstructiva Crónica/cirugía , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Pulmón , Enfermedad Crónica , Inflamación/complicaciones , Bronquitis/terapia , Bronquitis/complicaciones
9.
J Org Chem ; 89(3): 2064-2067, 2024 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-38240190

RESUMEN

A regioselective olefin hydrofunctionalization reaction of pavettine (4) with various nucleophiles was developed and used as the key step in the total syntheses of ß-carboline natural products manzamine C (3), orthoscuticelline C (5), and quassidine S (6). In the 6-step total synthesis of manzamine C (3), an efficient two-step procedure, comprising a Wittig olefination reaction and a Fukuyama-Mitsunobu reaction, was devised for the synthesis of the N-macrocycle with a Z-olefin.


Asunto(s)
Alcaloides , Productos Biológicos , Carbolinas , Alquenos
10.
Anal Bioanal Chem ; 416(8): 1961-1970, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38349532

RESUMEN

Controlling the spread of pathogen requires an efficient and accurate diagnosis. Compared with nucleic acid and antibody detection, antigen assays are more convenient to meet clinical diagnostic needs. However, antigen detection is often difficult to achieve high sensitivity in a limited time. In this work, a novel aptasensing method was designed for the purpose of SARS-CoV-2 antigen detection, using a dumbbell padlock probe-mediated circle-to-circle amplification (C2CA) approach. A sandwich complex of antibody-antigen-aptamer is first formed on the magnetic beads. Afterwards, the signal is amplified by a C2CA reaction involving two tandem rolling circle amplifications. Without special instruments or nanomaterials, a detection limit of 575 fg/mL for S1 protein can be achieved in less than 2 h. In the case of the spike pseudovirus SARS-CoV-2 in artificial saliva, the detection limit is 272 TU/µL, which is much lower than average viral load in patients. Therefore, our method provides a timely, efficient and accurate approach for the clinical diagnosis of SARS-CoV-2. It also opens up the application of C2CA in aptamer sensing and antigen detection.


Asunto(s)
Técnicas Biosensibles , COVID-19 , Técnicas Biosensibles/métodos , COVID-19/diagnóstico , Técnicas de Amplificación de Ácido Nucleico/métodos , SARS-CoV-2
11.
Cell Mol Biol (Noisy-le-grand) ; 70(2): 217-226, 2024 Feb 29.
Artículo en Inglés | MEDLINE | ID: mdl-38430019

RESUMEN

Osteoarthritis is a prevalent chronic disease. One of its primary pathological processes involves the degeneration of articular cartilage. Platelet-rich plasma (PRP) contains cytokines and growth factors that can stimulate the repair and regeneration of articular cartilage tissues. PRP may also slow the progression of osteoarthritis. The purpose of this experiment is to compare the efficacy of Leukocyte poor (LP) - PRP and Leukocyte rich (LR) - PRP in treating rabbit osteoarthritis and to investigate their mechanisms of action. Analyzing the impact of leukocytes on PRP therapeutic effectiveness will provide a valuable clinical reference for the choice of which PRP is better for the treatment of osteoarthritis. A rabbit osteoarthritis model was established by injecting papain into the knee joint cavity, and LP-PRP and LR-PRP were prepared through different centrifugation methods for injection into the knee joint cavity. Eight weeks after injection, rabbit knee cartilage specimens were observed for gross changes, HE staining, senna O-solid green staining, and immunohistochemistry of type II collagen and were quantitatively compared using Pelletier's score, Mankin's pathology score, and ImageJ image processing software. Injection of papain into the knee joint cavity successfully established a rabbit model of osteoarthritis. All three evaluation indexes differed significantly from those of the blank group (P<0.05). LP-PRP and LR-PRP exhibited therapeutic effects when compared with the model group. The two PRP groups had similar gross tissue appearance and pathology (P>0.05). The LR-PRP group had higher collagen type-II expression (P < 0.05) than the LP-PRP group. Both LP-PRP and LR-PRP proved therapeutic for the rabbit papain osteoarthritis model. The difference in leukocyte content between the two groups did not yield different cartilage morphology or other factors by 8 weeks posttreatment. LR-PRP displayed the ability to release more factors relevant to the metabolism of type II collagen than LP-PRP, enabling the preservation of into cartilage collagen content of type II collagen and delaying osteoarthritis progression.


Asunto(s)
Cartílago Articular , Osteoartritis , Plasma Rico en Plaquetas , Animales , Conejos , Colágeno Tipo II/metabolismo , Papaína/uso terapéutico , Papaína/metabolismo , Osteoartritis/terapia , Osteoartritis/metabolismo , Leucocitos/metabolismo
12.
Dig Dis Sci ; 69(2): 453-462, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38103106

RESUMEN

BACKGROUND: Gliclazide is a potential anti-cancer drug candidate for preventing carcinogenesis. However, the effect of gliclazide on colitis-associated colorectal cancer remains unknown. AIMS: We aimed to evaluate whether gliclazide plays a protective role in colitis-associated colorectal cancer and the underlying molecular mechanism. METHODS: The administration of azoxymethane (AOM) followed by dextran sulfate sodium (DSS) aimed to induce colitis-associated colorectal cancer in mice. C57BL mice were gavaged with gliclazide (6 mg/kg by gavage 5 days a week) for 12 weeks immediately following AOM administration. After sacrificing the mice, colon tissues were measured for tumor number and tumor burden. The proliferation- and inflammation-related molecular mechanisms were explored. RESULTS: The administration of gliclazide significantly reduced the tumor number and tumor burden in mice. Cell proliferation decreased in the gliclazide group compared with the control group, as indicated by reduced Ki-67 expression. Furthermore, gliclazide alleviated colonic inflammation, significantly decreased pro-inflammatory factor TNF-α levels and increased anti-inflammatory factor IL-10 levels in vivo. In vivo and vitro, it was shown that gliclazide increased the level of phospho-AMPK (p-AMPK) and inhibited NF-κB activity. Further studies demonstrated that the inhibition of NF-κB activity induced by gliclazide was mediated by p-AMPK in vitro. CONCLUSIONS: Gliclazide effectively alleviated colonic inflammation and prevented colonic carcinogenesis in an AOM-DSS mouse model by modulating the AMPK-NF-κB signaling pathway. Thus, gliclazide holds potential as a chemopreventive agent for colitis-associated colorectal cancer.


Asunto(s)
Neoplasias Asociadas a Colitis , Colitis , Neoplasias Colorrectales , Gliclazida , Animales , Ratones , FN-kappa B/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Gliclazida/efectos adversos , Colitis/inducido químicamente , Colitis/complicaciones , Colitis/metabolismo , Ratones Endogámicos C57BL , Inflamación/metabolismo , Transducción de Señal , Carcinogénesis , Azoximetano/toxicidad , Sulfato de Dextran/toxicidad , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/prevención & control , Neoplasias Colorrectales/metabolismo
13.
Lipids Health Dis ; 23(1): 101, 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38600581

RESUMEN

BACKGROUND: The objective was to investigate the efficacy of different doses of levothyroxine therapy among pregnant women exhibiting high-normal thyroid stimulating hormone levels and positive thyroid peroxidase antibodies throughout the first half of pregnancy. METHODS: Pregnant women exhibiting high-normal thyroid stimulating hormone levels and thyroid peroxidase antibodies positivity throughout the initial half of pregnancy were selected from January 2021 to September 2023. Based on the different doses of levothyroxine, the pregnant women were categorized into the nonintervention group (G0, 122 women), 25 µg levothyroxine intervention group (G25, 69 women), and 50 µg levothyroxine intervention group (G50, 58 women). Serum parameters, gastrointestinal symptoms, small intestinal bacterial overgrowth (SIBO), maternal and neonatal outcomes were compared after the intervention among the three groups. RESULTS: After the intervention, in the G25 and G50 groups, the thyroid stimulating hormone, triglyceride and low-density lipoprotein levels were notably less in contrast to those in the G0 group (P < 0.05). The rates of abdominal distension and SIBO in the G25 and G50 groups were notably lower in contrast to the G0 group (P = 0.043 and 0.040, respectively). The G50 group had a lower rate of spontaneous abortion and premature membrane rupture than the G0 group (P = 0.01 and 0.015, respectively). Before 11+ 2 weeks of gestation and at thyroid peroxidase antibodies levels ≥ 117 IU/mL, in contrast to the G0 group, the G50 group experienced a decreased rate of spontaneous abortion (P = 0.008). The G50 group had significantly higher newborn weight than the G0 group (P = 0.014), as well as a notably longer newborn length than the G0 and G25 groups (P = 0.005). CONCLUSIONS: For pregnant women with high-normal thyroid stimulating hormone levels and thyroid peroxidase antibodies positive during the first half of pregnancy, supplementation with 50 µg levothyroxine was more effective in improving their blood lipid status and gastrointestinal symptoms, reducing the incidence of SIBO and premature rupture of membranes, and before 11+2 weeks, TPOAb ≥ 117 IU/mL proved more beneficial in mitigating the risk of spontaneous abortion.


Asunto(s)
Aborto Espontáneo , Tiroxina , Recién Nacido , Femenino , Embarazo , Humanos , Tiroxina/uso terapéutico , Mujeres Embarazadas , Yoduro Peroxidasa , Autoanticuerpos , Tirotropina
14.
Thorac Cardiovasc Surg ; 72(2): 156-161, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37402403

RESUMEN

BACKGROUND: Thoracogastric airway fistula (TGAF) is a fatal complication after esophagectomy. Without active treatment, patients may die of intractable pneumonia, sepsis, massive hemoptysis, or respiratory failure. We determined the clinical value of the two-tube method that involves the precise interventional placement of the nasojejunal tube (NJT) and nasogastric tube (NGT) for TGAF. METHODS: Clinical data of patients with TGAF who had undergone fluoroscopic interventional placement of NJT and NGT were analyzed retrospectively. The paired t-test was used to compare the index values before and after treatment. Statistical significance was set at p < 0.05. RESULTS: In total, 212 patients (177 male and 35 female; mean age, 61.3 ± 7.9 years [47-73]) with TGAF who had undergone the two-tube method were included. Posttreatment chest spiral computed tomography and inflammatory indicators showed significantly improved pulmonary inflammation compared with that before treatment. The patients' general condition remained stable. Of 212 patients, 12 (5.7%) underwent surgical repair, 108 (50.9%) received placement of airway stents, and 92 (43.4%) cases only continued treatment with the two-tube method owing to patients' conditions. In total, 47.8% (44/92) patients died of secondary pulmonary infection, bleeding, and primary tumor progression, whereas 52.2% (48/92) patients survived with both tubes. CONCLUSION: The two-tube method, which involves the precise interventional placement of the NJT and NGT, is simple, safe, and effective for treating TGAF. This method is a bridge for successive treatments or a treatment itself for patients who are unsuitable for surgical repair or stent placement.


Asunto(s)
Fístula , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Resultado del Tratamiento , Intubación Gastrointestinal , Nutrición Enteral
15.
BMC Musculoskelet Disord ; 25(1): 126, 2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38336676

RESUMEN

OBJECTIVE: Evaluation of the accuracy and effectiveness of 3D printed guides to assist femoral tunnel preparation in individualised reconstruction of the anterior cruciate ligament. METHODS: Sixty patients who attended the Affiliated Hospital of Binzhou Medical College for autologous hamstring single bundle reconstruction of the anterior cruciate ligament from October 2018 to October 2020 were selected and randomly divided into two groups, including 31 cases in the 3D printing group (14 males and 17 females, mean age 41.94 ± 10.15 years) and 29 cases in the control group (13 males and 16 females, mean age 37.76 ± 10.34 years). Patients in both groups were assessed for intraoperative femoral tunnel accuracy, the number of intraoperative positioning and the time taken to prepare the femoral tunnel, the length of the anteromedial approach incision, the pre-planned bone tunnel length and intraoperative bone tunnel length in the 3D printed group, IKDC score and Lysholm score preoperatively and at 3, 6 and 12 months postoperatively, the Lachman、pivot-shift test preoperatively and at 6 months postoperatively, gait analysis to assess internal and external rotation in flexion of the knee at 12 months postoperatively and postoperative complications in both groups. RESULTS: There was no statistical difference in functional knee scores and anteromedial approach incision length between the 3D printed and control groups (p > 0.05), while there was a statistical difference in the accuracy of tunnel positioning, the time taken to prepare the femoral bone tunnel and the degree of external rotation of the knee in flexion between the two groups (p < 0.05). There was no statistical difference between the preoperative planning of the bone tunnel length and the intraoperative bone tunnel length (p > 0.05). COMPLICATIONS: One case in the 3D printing group developed intermuscular vein thrombosis in the affected lower limb after surgery, which disappeared after treatment, while three cases in the control group developed intermuscular vein thrombosis in the affected lower limb. No complications such as bone tunnel rupture, deep vein thrombosis in the lower limb and infection occurred in either group. CONCLUSION: 3D printed guides assisted with individualized ACL reconstruction may improve the accuracy of femoral tunnel positioning, which is safe and effective, while reducing the operative time and the number of intraoperative positioning, without increasing the length of incision, and may obtain higher functional scores and rotational stability of the knee joint, which is in line with the concept of individualized ACL reconstruction.


Asunto(s)
Lesiones del Ligamento Cruzado Anterior , Trombosis , Masculino , Femenino , Humanos , Adulto , Persona de Mediana Edad , Ligamento Cruzado Anterior/diagnóstico por imagen , Ligamento Cruzado Anterior/cirugía , Lesiones del Ligamento Cruzado Anterior/cirugía , Resultado del Tratamiento , Articulación de la Rodilla/cirugía , Fémur/diagnóstico por imagen , Fémur/cirugía
16.
Biomed Chromatogr ; : e5924, 2024 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-38922973

RESUMEN

The co-administration of dapagliflozin (DPF) and sacubitril/valsartan (LCZ696) has emerged as a promising therapeutic approach for managing heart failure. Given that DPF and LCZ696 are substrates for P-glycoprotein, there is a plausible potential for drug-drug interactions when administered concomitantly. To investigate the pharmacokinetic changes when these drugs are co-administered, we have established and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method capable of simultaneously detecting DPF, LBQ657 (the active metabolite of sacubitril) and valsartan in rat plasma. This method has demonstrated selectivity, sensitivity, and accuracy. Drug-drug interactions were examined by the LC-MS/MS method. The mechanisms were investigated using everted intestinal sac models and Caco-2 cells. The results showed that DPF significantly increased the area under the curve (AUC(0-t)) (3,563.3 ± 651.7 vs. 7,146.5 ± 1,714.9 h µg/L) of LBQ657 (the active metabolite of sacubitril) and the AUC(0-t) (24,022.4 ± 6,774.3 vs. 55,728.3 ± 32,446.3 h µg/L) of valsartan after oral co-administration. Dapagliflozin significantly increased the amount of LBQ657 and valsartan in intestinal sacs by 1- and 1.25-fold at 2.25 h. Caco-2 cell uptake studies confirmed that P-glycoprotein is the transporter involved in this interaction. This finding enhances the understanding of drug-drug interactions in the treatment of heart failure and provides a guidence for clinical therapy.

17.
Ecotoxicol Environ Saf ; 273: 116121, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38402792

RESUMEN

In recent years, nanoplastics (NPs) and triclosan (TCS, a pharmaceutical and personal care product) have emerged as environmental pollution issues, and their combined presence has raised widespread concern regarding potential risks to organisms. However, the combined toxicity and mechanisms of NPs and TCS remain unclear. In this study, we investigated the toxic effects of polystyrene NPs and TCS and their mechanisms on KGN cells, a human ovarian granulosa cell line. We exposed KGN cells to NPs (150 µg/mL) and TCS (15 µM) alone or together for 24 hours. Co-exposure significantly reduced cell viability. Compared with exposure to NPs or TCS alone, co-exposure increased reactive oxygen species (ROS) production. Interestingly, co-exposure to NPs and TCS produced synergistic effects. We examined the activity of superoxide dismutase (SOD) and catalase (CAT), two antioxidant enzymes; it was significantly decreased after co-exposure. We also noted an increase in the lipid oxidation product malondialdehyde (MDA) after co-exposure. Furthermore, co-exposure to NPs and TCS had a more detrimental effect on mitochondrial function than the individual treatments. Co-exposure activated the NRF2-KEAP1-HO-1 antioxidant stress pathway. Surprisingly, the expression of SESTRIN2, an antioxidant protein, was inhibited by co-exposure treatments. Co-exposure to NPs and TCS significantly increased the autophagy-related proteins LC3B-II and LC3B-Ⅰ and decreased P62. Moreover, co-exposure enhanced CASPASE-3 expression and inhibited the BCL-2/BAX ratio. In summary, our study revealed the synergistic toxic effects of NPs and TCS in vitro exposure. Our findings provide insight into the toxic mechanisms associated with co-exposure to NPs and TCS to KGN cells by inducing oxidative stress, activations of the NRF2-KEAP1-HO-1 pathway, autophagy, and apoptosis.


Asunto(s)
Triclosán , Femenino , Humanos , Especies Reactivas de Oxígeno/metabolismo , Triclosán/toxicidad , Triclosán/metabolismo , Antioxidantes/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Microplásticos/metabolismo , Poliestirenos/toxicidad , Poliestirenos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Células de la Granulosa/metabolismo
18.
Sheng Li Xue Bao ; 76(1): 89-96, 2024 Feb 25.
Artículo en Zh | MEDLINE | ID: mdl-38444134

RESUMEN

Trace amine-associated receptor 1 (TAAR1) is a classical type of G-protein-coupled receptor, which is widely distributed in the brain of mammals, especially in the limbic system and the region rich in monoaminergic neurons, and it is a highly conserved TAAR subtype in all species. TAAR1 can specifically respond to endogenous trace amines in the central nervous system and peripheral tissues, and plays an important role in the pathophysiological mechanisms involving the dysregulation of monoamine system and glutamate system leading to mental disorders. In addition, TAAR1 modulator can act on inwardly rectifying potassium channels and regulate synaptic transmission and neuronal activity. According to the latest research findings, TAAR1 exerts a series of functions by regulating signal pathways and substrate phosphorylation, which is related to emotion, cognition, fear and addiction. Therefore, we conducted a detailed review of relevant studies on the TAAR1 signaling pathways, aiming at revealing the great potential of TAAR1 as a new target for drug treatment of neuropsychiatric disorders.


Asunto(s)
Receptores Acoplados a Proteínas G , Transmisión Sináptica , Animales , Humanos , Encéfalo , Aminas , Mamíferos
19.
J Clin Pediatr Dent ; 48(1): 128-137, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38239165

RESUMEN

To investigate the role of a fully digital process in the surgical treatment of mandibular fractures in children. We analyzed a complete dataset from 22 children with mandibular fractures treated with digital surgical assistance. The patient's treatment process included preoperative thin layer CT (Computed Tomography) scanning, computer-aided design (3D reconstruction, virtual reduction, and internal fixation device determination and shaping), and 3D printing (jaw model, bite plate). We used occlusal and shaping plates during surgery to assist in fracture reduction and fixation. During the follow-up, we observed the occurrence of fracture healing, occlusal relationships, opening degrees, and complications in pediatric patients after surgery. Next, we used the 3D overlay function of MIMICS software to compare the preoperative surgical design with postoperative jaw imaging data to evaluate the overall surgical effect. The postoperative imaging data showed good fracture healing, normal occlusion during follow-up, and significant improvement in opening degrees. The mean preoperative opening degree was 23.59 ± 2.89 mm, and the mean postoperative opening degree was 29.82 ± 1.79 mm; there was a significant difference between these two parameters (p < 0.05). There were no complications such as tooth germ injury, nerve injury or fracture block displacement. The postoperative mandibular imaging data was imported into MIMICS software for 3D overlay visualization, and the postoperative mandibular morphology recovery was well-matched with the preoperative design. We measured the average upper deviation (0.65 ± 0.09) mm and the average lower deviation (-0.57 ± 0.14) mm. The fully digital process has a precise, minimally invasive, and safe effect in the surgical treatment of mandibular fractures in children, and the clinical effect is satisfactory.


Asunto(s)
Fracturas Mandibulares , Humanos , Niño , Fracturas Mandibulares/diagnóstico por imagen , Fracturas Mandibulares/cirugía , Fijación Interna de Fracturas/métodos , Curación de Fractura , Impresión Tridimensional , Diseño Asistido por Computadora
20.
Angew Chem Int Ed Engl ; 63(7): e202317220, 2024 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-38153674

RESUMEN

Modulating the microenvironment of single-atom catalysts (SACs) is critical to optimizing catalytic activity. Herein, we innovatively propose a strategy to improve the local reaction environment of Ru single atoms by precisely switching the crystallinity of the support from high crystalline and low crystalline, which significantly improves the hydrogen evolution reaction (HER) activity. The Ru single-atom catalyst anchored on low-crystalline nickel hydroxide (Ru-LC-Ni(OH)2 ) reconstructs the distribution balance of the interfacial ions due to the activation effect of metal dangling bonds on the support. Single-site Ru with a low oxidation state induces the aggregation of hydronium ions (H3 O+ ), leading to the formation of a local acidic microenvironment in alkaline media, breaking the pH-dependent HER activity. As a comparison, the Ru single-atom catalyst anchored on high-crystalline nickel hydroxide (Ru-HC-Ni(OH)2 ) exhibits a sluggish Volmer step and a conventional local reaction environment. As expected, Ru-LC-Ni(OH)2 requires low overpotentials of 9 and 136 mV at 10 and 1000 mA cm-2 in alkaline conditions and operates stably at 500 mA cm-2 for 500 h in an alkaline seawater anion exchange membrane (AEM) electrolyzer. This study provides a new perspective for constructing highly active single-atom electrocatalysts.

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