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1.
Artigo em Inglês | MEDLINE | ID: mdl-39113923

RESUMO

Introduction: Posterior tibial slope (PTS) plays a vital role in knee stability. PTS of more than 12° may be considered with increased strain on the native anterior cruciate ligament (ACL) fibers. To handle the instability caused by changes in PTS degree, Proximal Tibial Anterior Closing Wedge Osteotomy (PT-ACWO) is adopted by surgeons. Methods: Between October 2015 and October 2019, our department conducted a retrospective analysis of patients who experienced anterior cruciate ligament reconstruction (ACLR) graft failures, with a particular focus on pathological PTS. The time from initial ACLR to revision ranged from 1 to 10 years, with a mean of 2.5 years. Radiological assessments of PTS were conducted, and outcomes were quantified using the International Knee Documentation Committee (IKDC) score, Lysholm score, and Tegner activity scale. The surgical technique and the use of 3D Patient-Specific Instrumentation (PSI) were outlined. Preoperative imaging included the use of Kirschner wires to establish tibial plateau reference points, and 3D-PSI was employed to guide the location and depth of the tibial osteotomy, which was performed obliquely. In a notable instance, a novel tibial tunnel was mapped out, and ortho-bridge system (OBS) fixation was utilized to ensure adequate space for the new tunnel. Results: In a cohort of seven patients with a mean follow-up of 28.1 months, a significant reduction in PTS was noted postoperatively (median [interquartile range, IQR], from 15.27° [13.46°, 16.60°] to 6.25° [5.89°, 6.78°]; P = 0.002). IKDC score improved to 85.10 (80.25, 88.10), P < 0.001; the Lysholm score to 88.00 (73.00, 90.50), P < 0.001; and the Tegner score to 8.00 (7.20, 8.05), P = 0.025 at final follow-up. Skin incision healing delays occurred in two instances, yet achieved closure by six weeks. Radiographs at three months demonstrated faster bone healing in oblique osteotomies than transverse ones. Knee joint stability was maintained, with no additional complications or evidence of instability noted. Magnetic resonance imaging (MRI) confirmed graft integrity in all patients, without signs of enlargement or mispositioning at last observation. Conclusion: An augmented PTS angle exceeding 12 may constitute a potential etiology for the failure of ACLR grafts. In such patients, the implementation of ACLR combined with PT-ACWO could mitigate the risk of surgical failure during initial ACLR or subsequent revision procedures.

2.
Ear Nose Throat J ; : 1455613241270505, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39120003

RESUMO

A bronchogenic cyst (BC) is a rare congenital cystic lesion, especially when located in the suprahyoid region of the anterior cervical front. We report a case of a male child who was misdiagnosed with a thyroglossal duct cyst due to the clinical presentation of a mass located near the anterior midline of the neck, in the region above the hyoid bone, which moved up and down with swallowing, characteristics consistent with a thyroglossal duct cyst. We excised the lesion under general anesthesia. Histopathological analysis revealed cartilage tissue, pseudostratified columnar epithelium of the cyst wall with cilia and mucous glands, finally diagnosing it as BC. BC should be considered in the differential diagnosis of neck masses.

3.
Neurourol Urodyn ; 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38973545

RESUMO

PURPOSE: The purpose of this study was to examine the association between blood lead levels and the prevalence of nocturia in American adults. METHODS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2020, focusing on individuals aged 20 years or older (n = 11,919). Blood lead levels were categorized into two groups (<2 µg/dL and ≥2 µg/dL), and the presence of nocturia was assessed based on questionnaire responses. We used multivariable logistic regression models to explore the association between blood lead levels and nocturia while adjusting for various covariates, including sex, ratio of family income to poverty (RIP), lipid profile, age, body mass index (BMI), race, citizenship, sleep trouble, diabetes, and hypertension. To verify whether certain covariates influence blood lead levels and the risk of nocturia, we conducted subgroup analyses. RESULTS: Of the study participants, 31.70% reported experiencing nocturia. Individuals with higher blood lead levels (≥2 µg/dL) exhibited a higher likelihood of experiencing nocturia compared to those with lower levels (<2 µg/dL) in all three models (Model 1: OR 1.46, 95% CI 1.29-1.66, p < 0.0001; Model 2: OR 1.25, 95% CI 1.09-1.44, p = 0.002; Model 3: OR 1.22, 95%CI 1.06-1.41, p = 0.01). Subgroup analyses revealed that factors such as age, sex, sleep trouble, diabetes, hypertension, BMI, RIP, and race did not affect the association between blood lead levels and the risk of nocturia (P for interaction >0.05). CONCLUSIONS: This study reported the correlation between blood lead levels and nocturia. We found that compared to blood lead levels below 2 µg/dL, when lead levels reached or exceeded 2 µg/dL, the risk of nocturia occurrence increased by 22%. CLINICAL TRIAL REGISTRATION: This study is based on existing data from a public database and not from a specific clinical trial; hence, clinical registration information is not provided.

4.
Colloids Surf B Biointerfaces ; 241: 114068, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38954940

RESUMO

Inspired by glycyrrhizin's strong pharmacological activities and the directed self-assembly into hydrogels, we created a novel carrier-free, injectable hydrogel (CAR@glycygel) by combining glycyrrhizin with carvacrol (CAR), without any other chemical crosslinkers, to promote wound healing on bacteria-infected skin. CAR appeared to readily dissolve and load into CAR@glycygel. CAR@glycygel had a dense, porous, sponge structure and strong antioxidant characteristics. In vitro, it showed better antibacterial ability than free CAR. For methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, and Escherichia coli, the diameter of inhibition zone values of CAR@glycygel were 3.80 ± 0.04, 3.31 ± 0.20 and 3.12 ± 0.24 times greater, respectively, than those of free CAR. The MICs for CAR@glycygel was 156.25 µg/mL while it was 1250.00 µg/mL for free CAR to these three bacteria. Its antibacterial mechanism appeared to involve destruction of the integrity of the bacterial cell wall and biomembrane, leading to a leakage of AKP and inhibition of biofilm formation. In vivo, CAR@glycygel effectively stopped bleeding. When applied to skin wounds on rats infected with MRSA, CAR@glycygel had strong bactericidal activity and improved wound healing. The wound healing rates for CAR@glycygel were 49.59 ± 15.78 %, 93.02 ± 3.09 % and 99.02 ± 0.55 % on day 3, day 7, and day 11, respectively, which were much better than blank control and positive control groups. Mechanisms of CAR@glycygel accelerating wound healing involved facilitating epidermis remolding, promoting the growth of hair follicles, stimulating collagen deposition, mitigating inflammation, and promoting angiogenesis. Overall, CAR@glycygel showed great potential as wound dressing for infected skin wounds.


Assuntos
Antibacterianos , Cimenos , Ácido Glicirrízico , Hidrogéis , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Cicatrização , Cicatrização/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Hidrogéis/química , Hidrogéis/farmacologia , Animais , Ácido Glicirrízico/farmacologia , Ácido Glicirrízico/química , Antibacterianos/farmacologia , Antibacterianos/química , Cimenos/farmacologia , Cimenos/química , Ratos , Ratos Sprague-Dawley , Masculino , Escherichia coli/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia
5.
J Biochem Mol Toxicol ; 38(8): e23772, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39030862

RESUMO

Colorectal cancer (CRC) is the leading cause of cancer-related death globally. Circular RNA circCOL5A1 plays an oncogene function in a variety of tumors. However, the function of circCOL5A1 in CRC is still unknown. Here, we aimed to elucidate the function and mechanism of circCOL5A1 in CRC. The correlation between circCOL5A1 and CRC clinicopathological was assessed through chi-square. The relevance between circCOL5A1 and CRC patient survival time was evaluated by Kaplan-Meier analysis. The expressions of circCOL5A1 in CRC were determined via quantitative real-time PCR. The function of circCOL5A1 in CRC was analyzed with Cell Counting Kit-8, EdU assay, Transwell, detection of reactive oxygen species and Fe2+ levels, and Western blot analysis. Moreover, the mechanism of circCOL5A1 was determined by dual-luciferase reporter assay, RNA immunoprecipitation, and RNA pull-down. Finally, the role of circCOL5A1 in vivo was elucidated through a mouse xenograft model, hematoxylin-eosin staining, and immunohistochemistry. CircCOL5A1 expression was increased in CRC, and increased circCOL5A1 levels were related to TNM stage, lymph node metastasis, distant metastasis, and tumor differentiation in CRC patients, and CRC patients with high circCOL5A1 levels had a low overall survival rate. For the circCOL5A1 function in CRC, we found that circCOL5A1 knockdown weakened CRC cell proliferation and invasion, and enhanced cell ferroptosis. For the circCOL5A1 mechanism in CRC, we further confirmed that circCOL5A1 bound to miR-1287-5p, miR-1287-5p bound to SLC7A11. SLC7A11 was negatively interrelated to miR-1287-5p and was positively interrelated to circCOL5A1 in CRC tissues. Furthermore, interfering circCOL5A1 decreased SLC7A11 expression, and this trend was abolished through miR-1287-5p cotransfection. Rescue assays further demonstrated that circCOL5A1 knockdown alleviated CRC cell malignant phenotype via miR-1287-5p/SLC7A11. Moreover, interference with circCOL5A1 reduced CRC growth in vivo. CircCOL5A1 functioned as an oncogene in CRC via miR-1287-5p/SLC7A11.


Assuntos
Sistema y+ de Transporte de Aminoácidos , Proliferação de Células , Neoplasias Colorretais , Ferroptose , MicroRNAs , Invasividade Neoplásica , RNA Circular , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo
7.
Heliyon ; 10(12): e32793, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-39022035

RESUMO

In light of the low dissolved oxygen concentration in the deep sea, the corrosion mechanisms of the high entropy alloy (HEA) AlCoCrFeNi in artificial seawater with varying oxygen concentrations (2.0, 4.0, 7.0 mg/L) were studied. As the oxygen concentration decreases, the alloy's free corrosion potential decreases, and at 2.0 mg/L, the corrosion rate is 421 times higher than that at 7.0 mg/L. The corrosion form transforms from pitting to uniform corrosion. The primary reasons for this are the passivation film is thin under low oxygen concentration conditions, as well as the preferential dissolution of the alloy elements Al and Ni due to their high activity and "local acidizing" properties, respectively. In designing a super corrosion-resistant high entropy alloy for use in the deep sea, it is advisable to avoid the use of element Al and to add Ni with caution.

8.
Mitochondrial DNA B Resour ; 9(6): 802-807, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38895507

RESUMO

Meconopsis torquata Prain 1906, a national second-class rare and endangered plant, is reported here for the first time for its complete chloroplast genome. The genome is 153,290 bp in length, comprising a large single-copy region (LSC, 83,918 bp), a small single-copy region (SSC, 17,740 bp), and two inverted repeat sequences (IRa and IRb, each 25,816 bp). The overall GC content is 38.7%, with the IR region having the highest content (43.1%). The genome is annotated with 112 unique genes, including 4 rRNA genes, 29 tRNA genes, and 79 protein-coding genes. Analysis of codon usage bias reveals that codons ending in A/T account for 96.7% of those with a Relative Synonymous Codon Usage (RSCU) value above 1. This predominance of A/T-ending codons might be indicative of M. torquata adaptation to high-altitude environments. Phylogenetic analysis reveals a close kinship between M. torquata and M. pinnatifolia and M. paniculata, indicating that the ancestral groups of these species might have a complex evolutionary history. This study uncovers the genetic characteristics and adaptive evolution of M. torquata, offering a new perspective in understanding the phylogenetic relationships within the genus. The findings not only provide a solid theoretical foundation for the conservation and sustainable use of this rare and endangered species but also offer significant scientific support for the conservation of biodiversity.

9.
Ann Biomed Eng ; 2024 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-38880816

RESUMO

Porous nickel-titanium (NiTi) manufactured using metal injection molding (MIM) has emerged as an innovative generation of drug-loaded stent materials. However, an increase in NiTi porosity may compromise its mechanical properties and cytocompatibility. This study aims to explore the potential of porous NiTi as a vascular drug delivery material and evaluate the impact of porosity on its drug loading and release, mechanical properties, and cytocompatibility. MIM, combined with the powder space-holder method, was used to fabricate porous NiTi alloys with three porosity levels. The mechanical properties of porous NiTi were assessed, as well as the surface cell growth capability. Furthermore, by loading rapamycin nanoparticles onto the surface and within the pores of porous NiTi, we evaluated the in vitro drug release behavior, inhibitory effect on cell proliferation, and inhibition of neointimal hyperplasia in vivo. The results demonstrated that an increase in porosity led to a decrease in the mechanical properties of porous NiTi, including hardness, tensile strength, and elastic modulus, and a decrease in the surface cell growth capability, affecting both cell proliferation and morphology. Concurrently, the loading capacity and release duration of rapamycin were extended with increasing porosity, resulting in enhanced inhibitory effects on cell proliferation in vitro and inhibition of neointimal hyperplasia in vivo. In conclusion, porous NiTi holds promise as a desirable vascular drug delivery material, but a balanced consideration of the influence of porosity on both mechanical properties and cytocompatibility is necessary to achieve an optimal balance among drug-loading and release performance, mechanical properties, and cytocompatibility.

10.
Hortic Res ; 11(5): uhae063, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38720933

RESUMO

Broccoli (Brassica oleracea var. italica Plenck) is an important vegetable crop, as it is rich in health-beneficial glucosinolates (GSLs). However, the genetic basis of the GSL diversity in Brassicaceae remains unclear. Here we report a chromosome-level genome assembly of broccoli generated using PacBio HiFi reads and Hi-C technology. The final genome assembly is 613.79 Mb in size, with a contig N50 of 14.70 Mb. The GSL profile and content analysis of different B. oleracea varieties, combined with a phylogenetic tree analysis, sequence alignment, and the construction of a 3D model of the methylthioalkylmalate synthase 1 (MAM1) protein, revealed that the gene copy number and amino acid sequence variation both contributed to the diversity of GSL biosynthesis in B. oleracea. The overexpression of BoMAM1 (BolI0108790) in broccoli resulted in high accumulation and a high ratio of C4-GSLs, demonstrating that BoMAM1 is the key enzyme in C4-GSL biosynthesis. These results provide valuable insights for future genetic studies and nutritive component applications of Brassica crops.

11.
Sci Adv ; 10(20): eadn5098, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38758784

RESUMO

The scalable artificial photosynthesis composed of photovoltaic electrolysis and photothermal catalysis is limited by inefficient photothermal CO2 hydrogenation under weak sunlight irradiation. Herein, NiO nanosheets supported with Ag single atoms [two-dimensional (2D) Ni1Ag0.02O1] are synthesized for photothermal CO2 hydrogenation to achieve 1065 mmol g-1 hour-1 of CO production rate under 1-sun irradiation. This performance is attributed to the coupling effect of Ag-O-Ni sites to enhance the hydrogenation of CO2 and weaken the CO adsorption, resulting in 1434 mmol g-1 hour-1 of CO yield at 300°C. Furthermore, we integrate the 2D Ni1Ag0.02O1-supported photothermal reverse water-gas shift reaction with commercial photovoltaic electrolytic water splitting to construct a 103-m2 scale artificial photosynthesis system (CO2 + H2O → CO + H2 + O2), which achieves more than 22 m3/day of green syngas with an adjustable H2/CO ratio (0.4-3) and a photochemical energy conversion efficiency of >17%. This research charts a promising course for designing practical, natural sunlight-driven artificial photosynthesis systems.

12.
Neurourol Urodyn ; 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38693849

RESUMO

AIMS: This study aimed to investigate the association between diarrhea or constipation and urinary incontinence (UI) in adults. METHODS: Data from the National Health and Nutrition Examination Survey for 2009-2010 was used to include 4686 adults aged 20 and over in the analysis. Stress urinary incontinence (SUI) and urgency urinary incontinence (UUI) were used as outcome variables, with diarrhea and constipation as exposure factors. We first compared the baseline characteristics of those with and without SUI, as well as those with and without UUI. The impact of diarrhea or constipation on SUI and UUI was assessed using multivariate logistic regression models. To ensure the stability of the results, subgroup and stratified analyses were conducted. RESULTS: The prevalence rates of UUI and SUI were 22.49% and 23.39%, respectively. Adjusted multivariate logistic regression analysis revealed that the risk of UUI was increased by either diarrhea (OR 1.66, 95% CI 1.36-2.04) or constipation (OR 1.42, 95% CI 1.11-1.83). The risk of SUI was also elevated by either diarrhea (OR 1.36, 95% CI 1.11-1.67) or constipation (OR 1.32, 95% CI 1.06-1.63). Subgroup analysis revealed no significant differences in the interaction tests between constipation or diarrhea and UI. CONCLUSIONS: This study found that both constipation and diarrhea increase the risk of UUI and SUI.

13.
Ear Nose Throat J ; : 1455613241256520, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38808678

RESUMO

Malignant melanoma originating from the sphenoid sinus is an extremely rare but aggressive tumor of the head and neck. A 57-year-old man had a 1 month history of headache, right trigeminal paresthesias, and upper lid ptosis. Magnetic resonance imaging showed a large mass in the right sphenoid sinus and an invasion of the right cavernous sinus and clivus. The patient underwent endoscopic endonasal transsphenoidal surgery, and pathologically revealed malignant melanoma. One month after the operation, the patient was treated with radiation therapy. Unfortunately, the patient died of distant metastasis 2 years later. Due to its rarity, there is still no effective treatment strategy and no way to assess the progression of malignant melanoma.

14.
Int J Biol Macromol ; 270(Pt 2): 132476, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38777016

RESUMO

Gasdermin (GSDM) proteins are executioners of pyroptosis in many species. Gasdermin proteins can be cleaved at their linker region between the amino domain (NT) and carboxyl domain (CT) by enzymes. The released GSDM-NTs bind cell membrane and form pores, thereby leading to the release of cellular components and lytic cell death. GSDM-mediated pyroptosis is considered to play important role in immune responses. However, little is known about the GSDM proteins and GSDM-mediated pyroptosis in birds. In the current study, genes encoding chicken gasdermin A (chGSDMA) and chGSDME were cloned. The cleavage of chGSDMA and chGSDME by chicken caspase-1 (chCASP1), chCASP3 and chCASP7 and the cleavage sites were determined. The chGSDMA-NT obtained form chCASP1-mediated cleavage and chGSDME-NT obtained from chCASP3/chCASP7-mediated cleavage could bind and damage cell membrane and lead to cell death of HEK293 cells. chGSDMA-NT also strongly localized to and formed puncta in nucleus. Besides, both chGSDMA-NT and chGSDME-NT showed growth inhibition and bactericidal activity to bacteria. In chickens challenged with Pasteurella multocida and Salmonella typhimurium, the expression of chGSDMA and chGSDME was upregulated and the activation of chCASP3 and the cleavage of chGSDME were observed. The work provides essential information for expanding our knowledge on pyroptosis in birds.


Assuntos
Caspases , Galinhas , Piroptose , Animais , Humanos , Células HEK293 , Caspases/metabolismo , Pasteurella multocida , Proteólise , Proteínas Aviárias/metabolismo , Proteínas Aviárias/genética , Sequência de Aminoácidos , Gasderminas
15.
Cell Metab ; 36(7): 1586-1597.e7, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38703762

RESUMO

The mitochondrial genome transcribes 13 mRNAs coding for well-known proteins essential for oxidative phosphorylation. We demonstrate here that cytochrome b (CYTB), the only mitochondrial-DNA-encoded transcript among complex III, also encodes an unrecognized 187-amino-acid-long protein, CYTB-187AA, using the standard genetic code of cytosolic ribosomes rather than the mitochondrial genetic code. After validating the existence of this mtDNA-encoded protein arising from cytosolic translation (mPACT) using mass spectrometry and antibodies, we show that CYTB-187AA is mainly localized in the mitochondrial matrix and promotes the pluripotent state in primed-to-naive transition by interacting with solute carrier family 25 member 3 (SLC25A3) to modulate ATP production. We further generated a transgenic knockin mouse model of CYTB-187AA silencing and found that reduction of CYTB-187AA impairs females' fertility by decreasing the number of ovarian follicles. For the first time, we uncovered the novel mPACT pattern of a mitochondrial mRNA and demonstrated the physiological function of this 14th protein encoded by mtDNA.


Assuntos
Citocromos b , Animais , Citocromos b/genética , Citocromos b/metabolismo , Camundongos , Feminino , Camundongos Transgênicos , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Humanos , Camundongos Endogâmicos C57BL , Genes Mitocondriais , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Masculino
16.
Angew Chem Int Ed Engl ; 63(28): e202404328, 2024 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-38804831

RESUMO

The inner mitochondrial membrane (IMM) undergoes dynamic morphological changes, which are crucial for the maintenance of mitochondrial functions as well as cell survival. As the dynamics of the membrane are governed by its lipid components, a fluorescent probe that can sense spatiotemporal alterations in the lipid properties of the IMM over long periods of time is required to understand mitochondrial physiological functions in detail. Herein, we report a red-emissive IMM-labeling reagent with excellent photostability and sensitivity to its environment, which enables the visualization of the IMM ultrastructure using super-resolution microscopy as well as of the lipid heterogeneity based on the fluorescence lifetime at the single mitochondrion level. Combining the probe and fluorescence lifetime imaging microscopy (FLIM) showed that peroxidation of unsaturated lipids in the IMM by reactive oxygen species caused an increase in the membrane order, which took place prior to mitochondrial swelling.


Assuntos
Corantes Fluorescentes , Membranas Mitocondriais , Imagem Óptica , Corantes Fluorescentes/química , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/química , Humanos , Lipídeos/química , Microscopia de Fluorescência , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/análise , Células HeLa , Mitocôndrias/metabolismo , Mitocôndrias/química
17.
Bioorg Chem ; 149: 107477, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38820938

RESUMO

Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis targeting chimeras (PROTACs) emerge as a promising approach to overcome the limitations of FLT3 inhibitors, while the development of orally bioavailable FLT3-PROTACs faces great challenges. Here, we report the rational design and evaluation of a series of Gilteritinib-based FLT3-PROTACs. Among them, B3-2 exhibited the strongest antiproliferative activity against FLT3-ITD mutant AML cells, and significantly induced FLT3-ITD protein degradation. Mechanistic investigations demonstrated that B3-2 induced FLT3-ITD degradation in a ubiquitin-proteasome-dependent manner. More importantly, B3-2 exhibited an oral bioavailability of 5.65%, and oral administration of B3-2 showed good antitumor activity in MV-4-11 xenograft models. Furthermore, B3-2 showed strong antiproliferative activity against FLT3 resistant mutations, highlighting its potential in overcoming drug resistance.


Assuntos
Antineoplásicos , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Leucemia Mieloide Aguda , Inibidores de Proteínas Quinases , Pirazinas , Tirosina Quinase 3 Semelhante a fms , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Pirazinas/química , Pirazinas/farmacologia , Pirazinas/síntese química , Proliferação de Células/efeitos dos fármacos , Animais , Relação Estrutura-Atividade , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Camundongos , Descoberta de Drogas , Tiofenos/química , Tiofenos/farmacologia , Tiofenos/síntese química , Proteólise/efeitos dos fármacos , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Compostos de Anilina/síntese química , Linhagem Celular Tumoral , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Experimentais/metabolismo
18.
Planta ; 260(1): 5, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38777878

RESUMO

MAIN CONCLUSION: Trace amounts of epibrassinolide (EpiBL) could partially rescue wheat root length inhibition in salt-stressed situation by scavenging ROS, and ectopic expression of TaDWF4 or TaBAK1 enhances root salt tolerance in Arabidopsis by balancing ROS level. Salt stress often leads to ion toxicity and oxidative stress, causing cell structure damage and root development inhibition in plants. While prior research indicated the involvement of exogenous brassinosteroid (BR) in plant responses to salt stress, the precise cytological role and the function of BR in wheat root development under salt stress remain elusive. Our study demonstrates that 100 mM NaCl solution inhibits wheat root development, but 5 nM EpiBL partially rescues root length inhibition by decreasing H2O2 content, oxygen free radical (OFR) content, along with increasing the peroxidase (POD) and catalase (CAT) activities in salt-stressed roots. The qRT-PCR experiment also shows that expression of the ROS-scavenging genes (GPX2 and CAT2) increased in roots after applying BR, especially during salt stress situation. Transcriptional analysis reveals decreased expression of BR synthesis and root meristem development genes under salt stress in wheat roots. Differential expression gene (DEG) enrichment analysis highlights the significant impact of salt stress on various biological processes, particularly "hydrogen peroxide catabolic process" and "response to oxidative stress". Additionally, the BR biosynthesis pathway is enriched under salt stress conditions. Therefore, we investigated the involvement of wheat BR synthesis gene TaDWF4 and BR signaling gene TaBAK1 in salt stress responses in roots. Our results demonstrate that ectopic expression of TaDWF4 or TaBAK1 enhances salt tolerance in Arabidopsis by balancing ROS (Reactive oxygen species) levels in roots.


Assuntos
Brassinosteroides , Homeostase , Raízes de Plantas , Espécies Reativas de Oxigênio , Tolerância ao Sal , Esteroides Heterocíclicos , Triticum , Triticum/genética , Triticum/fisiologia , Triticum/metabolismo , Triticum/crescimento & desenvolvimento , Triticum/efeitos dos fármacos , Brassinosteroides/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/fisiologia , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tolerância ao Sal/genética , Esteroides Heterocíclicos/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Estresse Salino , Estresse Oxidativo , Arabidopsis/genética , Arabidopsis/fisiologia , Arabidopsis/efeitos dos fármacos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Catalase/metabolismo
19.
Neurourol Urodyn ; 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38634519

RESUMO

BACKGROUND: The relationship between waist circumference and nocturia has not been previously studied. This study investigated the association between waist circumference and the occurrence of nocturia in adults. METHODS: We analyzed data from the National Health and Nutrition Examination Survey covering 2005-2020, encompassing 6287 adults aged ≥20. Nocturia was defined as the need to urinate two or more times during the night. First, we compared baseline characteristics between the nocturia and non-nocturia groups. Subsequently, we used multivariate logistic regression analysis to investigate the relationship between waist circumference and nocturia prevalence. We also employed restricted cubic spline analysis to study the potential nonlinear correlation between waist circumference and the prevalence of nocturia. Recognizing the baseline data's heterogeneity based on nocturia prevalence, we conducted subgroup analyses according to age, sex, body mass index (BMI), and ethnicity. RESULTS: Our findings indicated that females, individuals aged ≥50, citizens, Non-Hispanic Black, those with lower education levels (high school or less), higher BMIs, lower family income-to-poverty ratios, higher waist circumference, hypertension, and diabetes were more likely to experience nocturia. Compared with individuals in the lowest waist circumference quartile (Q1), those in the higher quartiles (Q4) exhibited an increased risk of nocturia in Model 1 (Q4, OR:2.00, 95% CI:1.64, 2.45, p < 0.0001). These results remained consistent after adjusting for covariates in models 2 and 3. A restricted cubic spline analysis suggested a linear association between waist circumference and nocturia (P for nonlinearity = 0.066). Subgroup analyses based on age, sex, BMI, and ethnicity revealed no significant differences in the interaction tests between waist circumference and nocturia (P for interaction = 0.437, 0.331, 0.121, and 0.889, respectively), indicating that these baseline characteristics did not influence the association. CONCLUSIONS: Our findings indicated an association between increased waist circumference and a higher prevalence of nocturia. Knowledge of this association reinforces the importance of lifestyle modifications in maintaining a healthy waist circumference and informs public health strategies to address other potential risk factors for nocturia.

20.
Sensors (Basel) ; 24(8)2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38676222

RESUMO

The performance of the extended state observer (ESO) in an Active Disturbance Rejection Control (ADRC) is limited by the operational load in stepper motor control, which has high real-time requirements and may cause delays. Additionally, the complexity of parameter tuning, especially in high-order systems, further limits the ESO's performance. This paper proposes a composite ADRC (LTDRO-ADRC) based on a load torque dimensionality reduction observer (LTDRO). Firstly, the LTDRO is designed to estimate abrupt load disturbances that are difficult to compensate for using the ESO. Secondly, the transfer function under the double-closed loop is deduced. Additionally, the LTDRO uses a magnetic encoder to gather the system state and calculate the load torque. It then outputs a compensating current feedforward to the current loop input. This method reduces the delay and complexity of the ESO, improving the response speed of the ADRC speed ring and the overall response of the system to load changes. Simulation and experimental results demonstrate that it significantly enhances dynamic control performance and steady-state errors. LTDRO-ADRC can stabilize the speed again within 49 ms and 17 ms, respectively, in the face of sudden load increase and sudden load removal. At the same time, in terms of steady-state error, compared with ADRC and CADRC, they have increased by 94% and 88%, respectively. In terms of zero-speed starting motors, the response speed is increased by 58% compared to a traditional ADRC.

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