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1.
Sci Rep ; 14(1): 17664, 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39085290

RESUMO

The utilization of high-risk test cases constitutes an effective approach to enhance the safety testing of autonomous vehicles (AVs) and enhance their efficiency. This research paper presents a derivation of 2052 high-hazard pre-crash scenarios for testing autonomous driving, which were based on 23 high-hazard cut-in accident scenarios from the National Automobile Accident In-Depth Investigation System (NAIS) through combining importance sampling and combined testing methods. Compared to the direct combination of the original distribution after sampling, the proposed method has a 2.92 times higher crash rate of 69.32% for the test case set in this paper. It also has a 5.8 times higher rate of triggering Automatic Emergency Braking (AEB), improving hazardous scenario coverage. Using the proposed method, the generated parameters of the cut-in accident scenario test set were compared with those of the cut-in test scenarios included in existing Chinese autonomous driving test protocols and standards. The velocity of the ego-vehicle obtained using the proposed method matched those in the existing protocols, whereas the velocity, time gap, and time to collision of the target vehicle were significantly lower than those existing protocols indicating scenarios obtained from accident data can enrich the selection of testing scenarios for autonomous driving.

2.
Aesthetic Plast Surg ; 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38995348

RESUMO

BACKGROUND: In Asia, the demand for cosmetic facial treatments has surged due to technological advancements, increased social acceptability, and affordability. Poly-L-lactic acid (PLLA) fillers, known for their biocompatibility and biodegradability, have emerged as a popular choice for facial contouring, yet studies specifically addressing their use in Asian populations are scarce. METHODS: This retrospective study examined 30 Chinese patients who underwent facial contouring with PLLA fillers, focusing on product composition, injection techniques, and safety measures. A comprehensive clinical evaluation was performed, including the Global Aesthetic Improvement Scale (GAIS) and Global Impression of Change Scale (GICS) for effectiveness and patient satisfaction, respectively. RESULTS: No significant difference in GAIS scores was observed between injectors and blinded evaluators over a 12-month period, indicating consistent effectiveness. Patient satisfaction remained high, with GICS scores reflecting positive outcomes. The safety profile was favorable, with no serious adverse events reported. The study highlighted the importance of anatomical knowledge to avoid complications, particularly in areas prone to blindness. CONCLUSIONS: PLLA fillers offer a safe, effective option for facial contour correction in the Asian population, achieving high patient satisfaction and maintaining results over time. The study underscores the need for tailored approaches in cosmetic procedures for Asians, considering their unique facial structures and aesthetic goals. Further research with larger, multicenter cohorts is recommended to validate these findings and explore long-term effects. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

3.
J Am Chem Soc ; 146(33): 23121-23137, 2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-38980064

RESUMO

Addressing the global challenge of bacterial resistance demands innovative approaches, among which multitargeting is a widely used strategy. Current strategies of multitargeting, typically achieved through drug combinations or single agents inherently aiming at multiple targets, face challenges such as stringent pharmacokinetic and pharmacodynamic requirements and cytotoxicity concerns. In this report, we propose a bacterial-specific global disruption approach as a vastly expanded multitargeting strategy that effectively disrupts bacterial subcellular organization. This effect is achieved through a pioneering chemical design of ligand-receptor interaction-induced aggregation of small molecules, i.e., DNA-induced aggregation of a diarginine peptidomimetic within bacterial cells. These intracellular aggregates display affinity toward various proteins and thus substantially interfere with essential bacterial functions and rupture bacterial cell membranes in an "inside-out" manner, leading to robust antibacterial activities and suppression of drug resistance. Additionally, biochemical analysis of macromolecule binding affinity, cytoplasmic localization patterns, and bacterial stress responses suggests that this bacterial-specific intracellular aggregation mechanism is fundamentally different from nonselective classic DNA or membrane binding mechanisms. These mechanistic distinctions, along with the peptidomimetic's selective permeation of bacterial membranes, contribute to its favorable biocompatibility and pharmacokinetic properties, enabling its in vivo antimicrobial efficacy in several animal models, including mice-based superficial wound models, subcutaneous abscess models, and septicemia infection models. These results highlight the great promise of ligand-receptor interaction-induced intracellular aggregation in achieving a globally disruptive multitargeting effect, thereby offering potential applications in the treatment of malignant cells, including pathogens, tumor cells, and infected tissues.


Assuntos
Antibacterianos , Ligantes , Animais , Antibacterianos/farmacologia , Antibacterianos/química , Camundongos , Testes de Sensibilidade Microbiana , Farmacorresistência Bacteriana/efeitos dos fármacos , Peptidomiméticos/farmacologia , Peptidomiméticos/química , Separação de Fases
4.
Free Radic Biol Med ; 222: 467-477, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38969272

RESUMO

To investigate the effects of discharge plasma on Agropyron mongolicum seeds, various treatments including direct exposure to discharge plasma, combined treatment with discharge plasma and plasma-activated water (PAW) were applied to the seeds. The changes in germination rate, MDA content, and volatile compound levels of Agropyron mongolicum seeds after different treatments were examined. The results showed that the direct effect of plasma had no significant effect on the MDA content or germination rate of Agropyron mongolicum seeds due to the limited penetration depth. However, the combined effect of plasma and activated water could cause active nitrogen and oxygen particles to enter the seeds and cause oxidative stress damage. After 18 h of combined treatment, the MDA content increased significantly, and the germination rate decreased to below the semilethal dose, which was 33.44 %. After plasma treatment, 55 volatile compounds, mainly alcohols, aldehydes and ketones, were identified from the seeds of Agropyron mongolicum. Due to the oxidation and modification of the plasma, the content of most aldehydes increased with increasing reaction time. After screening, 13 volatile organic compounds could be used as potential markers to distinguish between different treatment methods. These results reveal the mechanism underlying the biological effects of plasma treatment on Agropyron mongolicum seeds.


Assuntos
Agropyron , Germinação , Gases em Plasma , Sementes , Compostos Orgânicos Voláteis , Sementes/crescimento & desenvolvimento , Sementes/metabolismo , Sementes/química , Compostos Orgânicos Voláteis/metabolismo , Gases em Plasma/farmacologia , Agropyron/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Malondialdeído/metabolismo , Malondialdeído/sangue , Aldeídos/metabolismo
5.
Org Lett ; 26(26): 5554-5559, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38912750

RESUMO

A rhodium-catalyzed highly stereoselective formal [2 + 4]-cycloaddition reaction of α-diazo pyrazoleamides and 2-aminophenyl ketones that produces 4-hydroxy-2-quinolinones in good yields with excellent diastereoselectivities has been developed. A pyrazolium ylide species that is generated from α-diazo pyrazoleamides is used as a C2 synthon for this cycloaddition. This protocol offers an efficient approach to a variety of 4-hydroxy-2-quinolinones featuring sequential quaternary centers.

6.
ACS Nano ; 18(24): 15950-15957, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38847327

RESUMO

Resilient ceramic aerogels with a unique combination of lightweight, good high-temperature stability, high specific area, and thermal insulation properties are known for their promising applications in various fields. However, the mechanical properties of traditional ceramic aerogels are often constrained by insufficient interlocking of the building blocks. Here, we report a strategy to largely increase the interlocking degree of the building blocks by depositing a pyrolytic carbon (PyC) coating onto Si3N4 nanowires. The results show that the mechanical performances of the Si3N4 nanowire aerogels are intricately linked to the microstructure of the PyC nodes. The compression resilience of the Si3N4@PyC nanowire aerogels increases with an increase of the interlayer cross-linking in PyC. Additionally, benefiting from the excellent high-temperature stability of PyC, the Si3N4@PyC nanowire aerogels demonstrate significantly superior in situ resilience up to 1400 °C. The integrated mechanical and high-temperature properties of the Si3N4@PyC nanowire aerogels make them highly appealing for applications in harsh conditions. The facile method of manipulating the microstructure of the nodes may offer a perspective for tailoring the mechanical properties of ceramic aerogels.

7.
Heliyon ; 10(11): e32013, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38867994

RESUMO

The aim of this study was to investigate the effects of temporal instability and possible heterogeneity on pedestrian accident severity, 48786 accident data from 2018 to 2021 in the UK STATS database were used as the study object, and accident severity was used as the dependent variable, and 49 accident characteristics were selected as independent variables from 6 characteristics of accident pedestrian, driver, vehicle, road, environment and time to construct the pedestrian accident mean heterogeneity random-parameter logit model and examined its temporal stability. The results of model estimation and likelihood ratio tests indicate that the variables affecting pedestrian injury severity are highly variable and not stable over the years. And further demonstrates the potential of models that address unobserved heterogeneity for significant relationships in pedestrian accident severity analyses.

8.
J Formos Med Assoc ; 2024 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-38910095

RESUMO

INTRODUCTION: Fluid resuscitation reduces mortality and morbidity in acute pancreatitis (AP); however, whether glucose-containing fluids negatively impact AP remains uncertain. We aimed to examine the association between glucose-containing fluids and AP outcomes. METHODS: This multicenter retrospective cohort study included patients diagnosed with AP between January 2015 and December 2018. Glucose density was defined as total glucose content divided by total fluid volume (g/dl) on day 1, and was considered high if the level exceeded the median. Endpoints were early organ failure (OF), including cardiovascular, renal, or respiratory system failure within 7 days; 30-day OF; ICU admission; and AP-related 90-day mortality. Logistic regression models, restricted cubic spline curves, and Cox proportional hazards models were used for statistical analysis. RESULTS: From the database, 1,146 patients with AP were included. Early OF occurred in 8.8% of patients within 7 days. The high glucose-density group (>5 g/dl) had increased risk of early OF (9.7% vs. 8.2%; adjusted odds ratio [aOR], 1.69; 95% confidence interval [CI], 1.03-2.80; P = 0.039), respiratory failure (8.0% vs. 6.2%; aOR, 1.88; 95% CI, 1.09-3.24; P = 0.024), cardiovascular failure (3.4% vs. 2.4%; aOR, 3.59; 95% CI, 1.28-10.0; P = 0.015), and ICU admission (6.8% vs. 5.8%; aOR, 2.06; 95% CI, 1.08-3.94; P = 0.029), with a dose-response effect observed for cardiovascular failure and ICU admission. A significant increase 30-day OF risk (adjusted hazard ratio [aHR], 1.70; 95% CI, 1.19-2.45) was also noted. CONCLUSION: Excess glucose-containing fluid was associated with increased risks of overall, respiratory, and cardiovascular OF and ICU admission in AP.

9.
Traffic Inj Prev ; : 1-8, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38917367

RESUMO

OBJECTIVE: Collisions are a significant cause of injury and fatality among young novice drivers. Using real crash data, this study further explores the multifaceted and complex nature of young novice drivers' crash injury risk by synthesizing different driver attributes and crash scenarios in order to update and validate previous research findings and provide more feasible recommendations for preventive measures. METHODS: Detailed data on traffic crash of young novice drivers were extracted from the National Automobile Accident In-Depth Investigation System (NAIS) in China, and a mixed research methodology using a Random Forest and multinomial logit modeling framework was used in order to explore and study the important influences on traffic crash injuries of young novice drivers in Songjiang District, Shanghai, during the period from 2018 to 2022. RESULTS: The results of the study showed that human, vehicle, road and environmental characteristics contributed 36.83%, 22.65%, 17.07% and 23.45% respectively to the prediction of crash injury level of novice drivers. Among the various single factors, driver negligence was the most important factor affecting the crash injury level of novice drivers. Age of the vehicle, crash location, road signal condition and time of crash all had a significant effect on the crash injury level of young novice drivers (95% of the confidence level). CONCLUSIONS: The study comprehensively analyzed young novice driver crash data to reveal the crash injury risk and its severity faced by young novice drivers in different contexts, and suggested targeted safety improvements. There are similarities and differences with the results of previous studies, in which there are new contributions to understanding the driving risks of young novice drivers in daytime and nighttime.

10.
Commun Chem ; 7(1): 135, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866907

RESUMO

The discovery of selective Nav1.7 inhibitors is a promising approach for developing anti-nociceptive drugs. In this study, we present a novel oxindole-based readily accessible library (OREAL), which is characterized by readily accessibility, unique chemical space, ideal drug-like properties, and structural diversity. We used a scaffold-based approach to screen the OREAL and discovered compound C4 as a potent Nav1.7 inhibitor. The bioactivity characterization of C4 reveals that it is a selective Nav1.7 inhibitor and effectively reverses Paclitaxel-induced neuropathic pain (PINP) in rodent models. Preliminary toxicology study shows C4 is negative to hERG. The consistent results of molecular docking and molecular simulations further support the reasonability of the in-silico screening and show the insight of the binding mode of C4. Our discovery of C4 paves the way for pushing the Nav1.7-based anti-nociceptive drugs forward to the clinic.

11.
Chemistry ; 30(41): e202400971, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-38735847

RESUMO

The quest to explore chemical space is vital for identifying novel disease targets, impacting both the effectiveness and safety profile of therapeutic agents. The tangible chemical space, currently estimated at a conservative 108 synthesized compounds, pales in comparison to the theoretically conceivable diversity of 1060 molecules. To bridge this vast gap, organic chemists are spearheading innovative methodologies that promise to broaden this limited chemical diversity. A beacon of this progressive wave is Asymmetric Carbene Transfer (ACT), a burgeoning strategy that significantly boosts molecular diversity with efficient bond-formation and precise chiral control. This review focuses on the capabilities of ACT in creating pharmaceutically significant molecules, encompassing an array of natural products and bioactive compounds. Through the lens of ACT, we discern its substantial influence on drug discovery, paving the way for novel therapeutic avenues by expanding the boundaries of molecular diversity. This review will shed light on prospective methodological developments of ACT and articulate their conceivable contributions to the medicinal chemistry arena.


Assuntos
Produtos Biológicos , Descoberta de Drogas , Metano , Metano/análogos & derivados , Metano/química , Produtos Biológicos/química , Estereoisomerismo , Química Farmacêutica , Humanos
12.
Nucl Med Biol ; 134-135: 108915, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38723361

RESUMO

BACKGROUND: The polyamine transporter system (PTS), which renders it a promising target for tumor therapy and imaging applications, facilitates the transmembrane transport of polyamines. We reported a novel derivative of spermine labeled with gallium-68 ([68Ga]Ga-NOTA-Spermine) for the imaging of the PTS in mouse models of tumor. RESULTS: The radiochemical yield of [68Ga]Ga-NOTA-Spermine was determined to be 64-69 %, demonstrating exceptional stability and radiochemical purity (>98 %). Cellular uptake experiments revealed that A549 cells exhibited peak uptake of [68Ga]Ga-NOTA-Spermine at 90 min (15.4 % ± 0.68 %). Biodistribution analysis demonstrated significant accumulation of [68Ga]Ga-NOTA-Spermine in kidneys and liver, while exhibiting low uptake levels in muscle, brain, and bones. Furthermore, Micro-PET/CT scans conducted on A549 tumor-bearing mouse models indicated substantial uptake of [68Ga]Ga-NOTA-Spermine, with maximum tumor/muscle (T/M) ratios reaching 3.71. CONCLUSION: These results suggest that [68Ga]Ga-NOTA-Spermine holds potential as a PET imaging agent for tumors with high levels of PTS.


Assuntos
Radioisótopos de Gálio , Espermina , Animais , Radioisótopos de Gálio/química , Camundongos , Espermina/análogos & derivados , Espermina/química , Espermina/síntese química , Espermina/farmacocinética , Humanos , Distribuição Tecidual , Marcação por Isótopo , Técnicas de Química Sintética , Tomografia por Emissão de Pósitrons/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Células A549 , Radioquímica , Transporte Biológico , Compostos Heterocíclicos com 1 Anel
13.
Zhongguo Zhong Yao Za Zhi ; 49(9): 2355-2363, 2024 May.
Artigo em Chinês | MEDLINE | ID: mdl-38812136

RESUMO

This study explored the effects of 4-hydroxy-2(3H)-benzoxazolone(HBOA) on the proliferation and apoptosis of pancreatic cancer cells and its molecular mechanism. The L3.6 cells cultured in vitro were treated with HBOA of 0-1.0 mmol·L~(-1). The cell viability was detected by the cell counting kit-8(CCK-8) method, and the half inhibitory concentration(IC_(50)) was analyzed to determine the drug concentration and time. The cell morphology was observed under an inverted microscope and by acridine orange(AO) staining. The ability of proliferation and self-renewal were evaluated through live cell counting and colony formation experiments. The cell cycle progression and cell apoptosis rate were detected by flow cytometry. The morphology of cell apoptosis was observed by scanning electron microscopy. The mRNA expression of proliferating cell nuclear antigen(PCNA), cyclinA1, cyclinA2, cyclin dependent kinase 2(CDK2), and cyclin dependent kinase inhibitor 1A(P21) were determined by qPCR. The level of reactive oxygen species(ROS), lipid peroxide, and mitochondrial membrane potential were measured by flow cytometry. The activity of protein kinase B(Akt)/mammalian target of rapamycin(mTOR) signaling pathway was detected by Western blot. Compared with the control group, the cells treated with HBOA exhibited a significant decrease in viability. Then the optimal concentration and intervention time of HBOA were determined to be 0.4 mmol·L~(-1), 0.6 mmol·L~(-1), and 48 h. Compared with the control group, groups with HBOA of 0.4 mmol·L~(-1 )and 0.6 mmol·L~(-1) showed a significant suppression in cell proliferation and colony formation ability, down-regulated mRNA of PCNA, cyclinA1, cyclinA2, and CDK2, up-regulated P21 mRNA, S-phase cell cycle arrest, and increased cell apoptosis rate. There was an appearance of apoptotic bodies, increased ROS and lipid peroxide, decreased mitochondrial membrane potential(with a significant decrease in 0.6 mmol·L~(-1) group), and down-regulated p-Akt and p-mTOR proteins. The results show that HBOA inhibits the proliferation of pancreatic cancer L3.6 cells and induces cell apoptosis, which may be related to the increase in reactive oxygen species and the inhibition of the Akt/mTOR pathway.


Assuntos
Apoptose , Proliferação de Células , Neoplasias Pancreáticas , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Humanos , Linhagem Celular Tumoral , Benzoxazóis/farmacologia , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ciclo Celular/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
15.
Diagn Pathol ; 19(1): 66, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730456

RESUMO

BACKGROUND: TFEB/6p21/VEGFA-amplified renal cell carcinoma (RCC) is rare and difficult to diagnose, with diverse histological patterns and immunohistochemical and poorly defined molecular genetic characteristics. CASE PRESENTATION: We report a case of a 63-year-old male admitted in 2017 with complex histomorphology, three morphological features of clear cell, eosinophilic and papillary RCC and resembling areas of glomerular and tubular formation. The immunophenotype also showed a mixture of CD10 and P504s. RCC with a high suspicion of collision tumors was indicated according to the 2014 WHO classification system; no precise diagnosis was possible. The patient was diagnosed at a different hospital with poorly differentiated lung squamous cell carcinoma one year after RCC surgery. We exploited molecular technology advances to retrospectively investigate the patient's molecular genetic alterations by whole-exome sequencing. The results revealed a 6p21 amplification in VEGFA and TFEB gene acquisition absent in other RCC subtypes. Clear cell, papillary, chromophobe, TFE3-translocation, eosinophilic solid and cystic RCC were excluded. Strong TFEB and Melan-A protein positivity prompted rediagnosis as TFEB/6p21/VEGFA-amplified RCC as per 2022 WHO classification. TMB-L (low tumor mutational load), CCND3 gene acquisition and MRE11A and ATM gene deletion mutations indicated sensitivity to PD-1/PD-L1 inhibitor combinations and the FDA-approved targeted agents Niraparib (Grade C), Olaparib (Grade C), Rucaparib (Grade C) and Talazoparib (Class C). GO (Gene Ontology) and KEGG enrichment analyses revealed major mutations and abnormal CNVs in genes involved in biological processes such as the TGF-ß, Hippo, E-cadherin, lysosomal biogenesis and autophagy signaling pathways, biofilm synthesis cell adhesion substance metabolism regulation and others. We compared TFEB/6p21/VEGFA-amplified with TFEB-translocated RCC; significant differences in disease onset age, histological patterns, pathological stages, clinical prognoses, and genetic characteristics were revealed. CONCLUSION: We clarified the patient's challenging diagnosis and discussed the clinicopathology, immunophenotype, differential diagnosis, and molecular genetic information regarding TFEB/6p21/VEGFA-amplified RCC via exome analysis and a literature review.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Carcinoma de Células Renais , Sequenciamento do Exoma , Neoplasias Renais , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Neoplasias Renais/genética , Neoplasias Renais/patologia , Biomarcadores Tumorais/genética
16.
Mol Divers ; 2024 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-38762686

RESUMO

Monomethyl auristatin F (MMAF), a synthetic analogue of the natural compound dolastatin 10, has garnered significant attention in cancer research due to its high potency in vitro. While previous studies have focused on modifying the N-terminal extension of the amino group and the C-terminal modification of the carboxyl group, there has been limited exploration into modifying the P1 and P5 side chains. In this study, we substituted the valine residue at the P1 position with various natural or unnatural amino acids and introduced triazole functional groups at the P5 side chain. Compounds 11k and 18d exhibited excellent inhibition on tubulin. Additionally, compound 18d demonstrated enhanced cytotoxicity against HCT116 cells compared to the parent compound MMAF, suggesting its potential as a cytotoxic payload for further antibody-drug conjugates (ADCs) development.

17.
Int J Nanomedicine ; 19: 3275-3293, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38601348

RESUMO

Purpose: This study aims to explore a novel scaffold for osteotendinous junction regeneration and to preliminarily verify its osteogenic and tenogenic abilities in vitro. Methods: A polycaprolactone (PCL) scaffold with aligned and orthogonal fibers was created using melt electrowriting (MEW) and fused deposition modeling (FDM). The scaffold was coated with Type I collagen, and hydroxyapatite was carefully added to separate the regions intended for bone and tendon regeneration, before being rolled into a cylindrical shape. Human adipose-derived stem cells (hADSCs) were seeded to evaluate viability and differentiation. Scaffold characterization was performed with Scanning Electron Microscope (SEM). Osteogenesis was assessed by alkaline phosphatase (ALP) and Alizarin red staining, while immunostaining and transcription-quantitative polymerase chain reaction (RT-qPCR) evaluated osteogenic and tendogenic markers. Results: Scaffolds were developed in four variations: aligned (A), collagen-coated aligned (A+C), orthogonal (O), and mineral-coated orthogonal (O+M). SEM analysis confirmed surface morphology and energy-dispersive X-ray spectroscopy (EDS) verified mineral coating on O+M types. Hydrophilicity and mechanical properties were optimized in modified scaffolds, with A+C showing increased tensile strength and O+M improved in compression. hADSCs demonstrated good viability and morphology across scaffolds, withO+M scaffolds showing higher cell proliferation and osteogenic potential, and A and A+C scaffolds supporting tenogenic differentiation. Conclusion: This study confirms the potential of a novel PCL scaffold with distinct regions for osteogenic and tenogenic differentiation, supporting the regeneration of osteotendinous junctions in vitro.


Assuntos
Biomimética , Alicerces Teciduais , Humanos , Alicerces Teciduais/química , Osteogênese , Poliésteres/química , Durapatita/farmacologia , Durapatita/química , Impressão Tridimensional , Engenharia Tecidual/métodos , Diferenciação Celular , Regeneração Óssea
18.
Beilstein J Org Chem ; 20: 661-671, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38590540

RESUMO

Herein, we report a visible-light-mediated palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines, affording unsaturated γ- and ε-amino acid derivatives with diverse structures. In this methodology, the diazo compound readily transforms into a hybrid α-ester alkylpalladium radical with the release of dinitrogen. The radical intermediate selectively adds to the double bond of a 1,3-diene or allene, followed by the allylpalladium radical-polar crossover path and selective allylic substitution with the amine substrate, thereby leading to a single unsaturated γ- or ε-amino acid derivative. This approach proceeds under mild and simple reaction conditions and shows high functional group tolerance, especially in the incorporation of various bioactive molecules. The studies on scale-up reactions and diverse derivatizations highlight the practical utility of this multicomponent reaction protocol.

19.
Angew Chem Int Ed Engl ; 63(21): e202401189, 2024 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-38506220

RESUMO

This study introduces a novel approach for synthesizing Benzoxazine-centered Polychiral Polyheterocycles (BPCPHCs) via an innovative asymmetric carbene-alkyne metathesis-triggered cascade. Overcoming challenges associated with intricate stereochemistry and multiple chiral centers, the catalytic asymmetric Carbene Alkyne Metathesis-mediated Cascade (CAMC) is employed using dirhodium catalyst/Brønsted acid co-catalysis, ensuring precise stereo control as validated by X-ray crystallography. Systematic substrate scope evaluation establishes exceptional diastereo- and enantioselectivities, creating a unique library of BPCPHCs. Pharmacological exploration identifies twelve BPCPHCs as potent Nav ion channel blockers, notably compound 8 g. In vivo studies demonstrate that intrathecal injection of 8 g effectively reverses mechanical hyperalgesia associated with chemotherapy-induced peripheral neuropathy (CIPN), suggesting a promising therapeutic avenue. Electrophysiological investigations unveil the inhibitory effects of 8 g on Nav1.7 currents. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) assay provide insights into the stable complex formation and favorable binding free energy of 8 g with C5aR1. This research represents a significant advancement in asymmetric CAMC for BPCPHCs and unveils BPCPHC 8 g as a promising, uniquely acting pain blocker, establishing a C5aR1-Nav1.7 connection in the context of CIPN.


Assuntos
Alcinos , Benzoxazinas , Metano , Metano/análogos & derivados , Metano/química , Metano/farmacologia , Alcinos/química , Benzoxazinas/química , Benzoxazinas/farmacologia , Benzoxazinas/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/síntese química , Humanos , Estereoisomerismo , Analgésicos/química , Analgésicos/farmacologia , Analgésicos/síntese química , Estrutura Molecular , Catálise , Descoberta de Drogas , Animais
20.
Bioact Mater ; 36: 157-167, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38463554

RESUMO

Much effort has been devoted to improving treatment efficiency for osteosarcoma (OS). However, most current approaches result in poor therapeutic responses, thus indicating the need for the development of other therapeutic options. This study developed a multifunctional nanoparticle, PDA-MOF-E-M, an aggregation of OS targeting, programmed death targeting, and near-infrared (NIR)-aided targeting. At the same time, a multifunctional nanoparticle that utilises Fe-MOFs to create a cellular iron-rich environment and erastin as a ferroptosis inducer while ensuring targeted delivery to OS cells through cell membrane encapsulation is presented. The combination of PDA-MOF-E-M and PTT increased intracellular ROS and LPO levels and induced ferroptosis-related protein expression. A PDA-based PTT combined with erastin showed significant synergistic therapeutic improvement in the anti-tumour efficiency of the nanoparticle in vitro and vivo. The multifunctional nanoparticle efficiently prevents the osteoclasia progression of OS xenograft bone tumors in vivo. Finally, this study provides guidance and a point of reference for clinical approaches to treating OS.

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