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1.
Sci Rep ; 14(1): 18782, 2024 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-39138327

RESUMO

Infections caused by pathogenic Escherichia coli are a serious threat to human health, while conventional antibiotic susceptibility tests (AST) have a long turn-around time, and rapid antibiotic susceptibility methods are urgently needed to save lives in the clinic, reduce antibiotic misuse and prevent emergence of antibiotic-resistant bacteria. We optimized and validated the feasibility of a novel rapid AST based on SYBR Green I and Propidium Iodide (SGPI-AST) for E. coli drug susceptibility test. A total of 112 clinical isolates of E. coli were collected and four antibiotics (ceftriaxone, cefoxitin, imipenem, meropenem) were selected for testing. Bacterial survival rate of E. coli was remarkably linearly correlated with S value at different OD600 values. After optimizing the antibiotic concentrations, the sensitivity and specificity of SGPI-AST reached 100%/100%, 97.8%/100%, 100%/100% and 98.4%/99% for ceftriaxone, cefoxitin, imipenem and meropenem, respectively, and the corresponding concordances of the SGPI-AST with conventional AST were 1.000, 0.980, 1.000 and 0.979, respectively. The SGPI-AST can rapidly and accurately determine the susceptibility of E. coli clinical isolates to multiple antibiotics in 60 min, and has the potential to be applied to guide the precise selection of antibiotics for clinical management of infections caused by pathogenic E. coli.


Assuntos
Antibacterianos , Benzotiazóis , Diaminas , Escherichia coli , Testes de Sensibilidade Microbiana , Compostos Orgânicos , Propídio , Quinolinas , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Testes de Sensibilidade Microbiana/métodos , Benzotiazóis/farmacologia , Antibacterianos/farmacologia , Humanos , Quinolinas/farmacologia , Compostos Orgânicos/farmacologia , Diaminas/farmacologia , Propídio/análogos & derivados , Propídio/farmacologia , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/tratamento farmacológico
2.
Int J Numer Method Biomed Eng ; : e3862, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39142807

RESUMO

Surgery of jawbones has a high potential risk of causing complications associated with temporomandibular joint disorder (TMD). The objective of this study was to investigate the effects of two drive modeling methods on the biomechanical behavior of the temporomandibular joint (TMJ) including articular disc during mandibular movements. A finite element (FE) model from a healthy human computed tomography was used to evaluate TMJ dynamic using two methods, namely, a conventional spatial-oriented method (displacement-driven) and a compliant muscle-initiated method (masticatory muscle-driven). The same virtual FE model was 3D printed and a custom designed experimental platform was established to validate the accuracy of experimental and theoretical results of the TMJ biomechanics during mandibular movements. The results show that stress distributed to TMJ and articular disc from mandibular movements provided better representation from the muscle-driving approach than those of the displacement-driven modeling. The simulation and experimental data exhibited significant strong correlations during opening, protrusion, and laterotrusion (with canonical correlation coefficients of 0.994, 0.993, and 0.932, respectively). The use of muscle-driven modeling holds promise for more accurate forecasting of stress analysis of TMJ and articular disc during mandibular movements. The compliant approach to analyze TMJ dynamics would potentially contribute to clinic diagnosis and prediction of TMD resulting from occlusal disease and jawbone surgery such as orthognathic surgery or tumor resection.

4.
Eur J Pharmacol ; : 176917, 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39154824

RESUMO

Liver fibrosis is a pathological process that endangers human health, for which effective treatments remain elusive to date. Paeoniflorin (PAE), a pineane-type monoter penoid compound from the traditional Chinese medicine PaeoniaeRubra Radix, and metformin (MET), an oral biguanide hypoglycemic agent, both demonstrate anti-inflammatory and hepatoprotective effects. In current work, we first discovered that the combined treatment of PAE and MET synergistically inhibited the progression of liver fibrosis in two different animal models: therapeutic and preventive. This therapeutic effect is evidenced by a reduction in the expression levels of liver fibrosis markers and an improvement in histopathological characteristics. Mechanistic exploration further revealed that this combination therapy downregulated the expression of TGF-ß1 and p-Smad2, while upregulating Smad7 expression in both models. Importantly, we also found that this combinatorial approach significantly reduced hepatotoxicity and nephrotoxicity in both models. Our findings suggest an effective combination therapy for liver fibrosis and provide the possibility of therapeutic improvement for patients with liver fibrosis.

5.
Int Immunopharmacol ; 140: 112885, 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39116496

RESUMO

Acute kidney injury (AKI) is a syndrome characterized by the rapid loss of the renal function and has high morbidity and mortality worldwide, yet there is no satisfactory means of prevention and treatment at present. Dioscin, a natural steroidal saponin, has been found to have antioxidant, anti-inflammatory and anti-apoptotic effects. In this experiment, we pretreated cisplatin-induced AKI rats with dioscin and found that dioscin significantly enhanced renal function and reduced renal pathological injury in AKI rats. We also found that dioscin improved renal antioxidant capacity by suppressing the accumulation of oxides such as ROS, MDA and H2O2, and increasing the levels of antioxidant enzymes SOD and CAT. In addition, dioscin down-regulated the expression of inflammation-related proteins (IL-1ß, TNF-α, NF-κB) and necroptosis-critical proteins RIP1/RIP3, whereas up-regulated Caspase-8 protein levels in the kidney of AKI rats. Mechanistically, dioscin promoted the nuclear transcription of Nrf2 and activated Nrf2/HO-1 signaling axis to play a positive role in the kidney of AKI rats, while the reno-protective effect of dioscin was significantly attenuated after inhibiting Nrf2. In conclusion, our data indicate that dioscin decreases cisplatin-induced renal oxidative stress and thwarts necroptosis induced inflammation via regulating the Nrf2/HO-1pathway. Our study provides more data and theoretical support for the study of natural drugs to improve AKI.

6.
BMC Pharmacol Toxicol ; 25(1): 35, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-39103956

RESUMO

BACKGROUND AND PURPOSES: It is unclear whether the parent Saxagliptin (SAX) in vivo is the same as that in vitro, which is twice that of 5-hydroxy Saxagliptin (5-OH SAX). This study is to construct a Pharmacokinetic-Pharmacodynamic (PK-PD) link model to evaluate the genuine relationship between the concentration of parent SAX in vivo and the effect. METHODS: First, we established a reliable Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS) method and DPP-4 inhibition ratio determination method. Then, the T2DM rats were randomly divided into four groups, intravenous injection of 5-OH SAX (0.5 mg/kg) and saline group, intragastric administration of SAX (10 mg/kg) and Sodium carboxymethyl cellulose (CMC-Na) group. Plasma samples were collected at different time points for subsequent testing. Finally, we used the measured concentrations and inhibition ratios to construct a PK-PD link model for 5-OH SAX and parent SAX. RESULTS: A two-compartment with additive model showed the pharmacokinetic process of SAX and 5-OH SAX, the concentration-effect relationship was represented by a sigmoidal Emax model and sigmoidal Emax with E0 model for SAX and 5-OH SAX, respectively. Fitting parameters showed SAX was rapidly absorbed after administration (Tmax=0.11 h, t1/2, ka=0.07 h), widely distributed in the body (V ≈ 20 L/kg), plasma exposure reached 3282.06 ng*h/mL, and the elimination half-life was 6.13 h. The maximum plasma dipeptidyl peptidase IV (DPP-4) inhibition ratio of parent SAX was 71.47%. According to the final fitting parameter EC50, EC50, 5-OH SAX=0.46EC50, SAX(parent), it was believed that the inhibitory effect of 5-OH SAX was about half of the parent SAX, which is consistent with the literature. CONCLUSIONS: The PK-PD link model of the parent SAX established in this study can predict its pharmacokinetic process in T2DM rats and the strength of the inhibitory effect of DPP-4 based on non-clinical data.


Assuntos
Adamantano , Diabetes Mellitus Tipo 2 , Dipeptídeos , Inibidores da Dipeptidil Peptidase IV , Ratos Sprague-Dawley , Animais , Adamantano/análogos & derivados , Adamantano/farmacocinética , Adamantano/farmacologia , Adamantano/sangue , Dipeptídeos/farmacocinética , Dipeptídeos/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Inibidores da Dipeptidil Peptidase IV/farmacologia , Ratos , Modelos Biológicos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/sangue , Espectrometria de Massas em Tandem , Dipeptidil Peptidase 4
7.
Org Lett ; 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-39133549

RESUMO

A 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-catalyzed cascade annulation reaction between p-quinamines and 3-formylchromones was developed, affording a series of benzopyrone-fused hydrobenzo[c,d]indoles in moderate to high yields with excellent diastereoselectivity. This cascade reaction is efficient since two new rings as well as one C-N, one C═C, and two C-C bonds are created in a single step. The scale-up synthesis and versatile transformations of the products further demonstrated the practicality and utility of this approach.

8.
Soft Matter ; 20(32): 6424-6430, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39087847

RESUMO

The self-assembled structure has a significant impact on the performance of ion conductors. We prepared a new type of electrolyte with self-assembled structures from an azobenzene-based liquid crystalline (LC) monomer and its corresponding polymer. By doping different amounts of monomers and lithium salt LiTFSI, the self-assembled nanostructure of the electrolyte was changed from lamellae to double gyroid. The ionic conductivity of the azobenzene-based electrolytes with the double gyroid structure was 1.64 × 10-4 S cm-1, higher than most PEO-based polymer electrolytes. The azobenzene-based system provides a new strategy to design solid electrolytes with self-assembled structures that may be potentially used in solid-state lithium-ion batteries.

9.
Cell Rep ; 43(8): 114586, 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-39137113

RESUMO

Our understanding of human fetal cerebellum development during the late second trimester, a critical period for the generation of astrocytes, oligodendrocytes, and unipolar brush cells (UBCs), remains limited. Here, we performed single-cell RNA sequencing (scRNA-seq) in human fetal cerebellum samples from gestational weeks (GWs) 18-25. We find that proliferating UBC progenitors distribute in the subventricular zone of the rhombic lip (RLSVZ) near white matter (WM), forming a layer structure. We also delineate two trajectories from astrogenic radial glia (ARGs) to Bergmann glial progenitors (BGPs) and recognize oligodendrogenic radial glia (ORGs) as one source of primitive oligodendrocyte progenitor cells (PriOPCs). Additionally, our scRNA-seq analysis of the trisomy 21 fetal cerebellum at this stage reveals abnormal upregulated genes in pathways such as the cell adhesion pathway and focal adhesion pathway, which potentially promote neuronal differentiation. Overall, our research provides valuable insights into normal and abnormal development of the human fetal cerebellum.

10.
Sci Rep ; 14(1): 18063, 2024 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-39117679

RESUMO

In recent years, research on organ-on-a-chip technology has been flourishing, particularly for drug screening and disease model development. Fibroblasts and vascular endothelial cells engage in crosstalk through paracrine signaling and direct cell-cell contact, which is essential for the normal development and function of the heart. Therefore, to faithfully recapitulate cardiac function, it is imperative to incorporate fibroblasts and vascular endothelial cells into a heart-on-a-chip model. Here, we report the development of a human heart-on-a-chip composed of induced pluripotent stem cell (iPSC)-derived cardiomyocytes, fibroblasts, and vascular endothelial cells. Vascular endothelial cells cultured on microfluidic channels responded to the flow of culture medium mimicking blood flow by orienting themselves parallel to the flow direction, akin to in vivo vascular alignment in response to blood flow. Furthermore, the flow of culture medium promoted integrity among vascular endothelial cells, as evidenced by CD31 staining and lower apparent permeability. The tri-culture condition of iPSC-derived cardiomyocytes, fibroblasts, and vascular endothelial cells resulted in higher expression of the ventricular cardiomyocyte marker IRX4 and increased contractility compared to the bi-culture condition with iPSC-derived cardiomyocytes and fibroblasts alone. Such tri-culture-derived cardiac tissues exhibited cardiac responses similar to in vivo hearts, including an increase in heart rate upon noradrenaline administration. In summary, we have achieved the development of a heart-on-a-chip composed of cardiomyocytes, fibroblasts, and vascular endothelial cells that mimics in vivo cardiac behavior.


Assuntos
Células Endoteliais , Fibroblastos , Células-Tronco Pluripotentes Induzidas , Dispositivos Lab-On-A-Chip , Miócitos Cardíacos , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Fibroblastos/citologia , Fibroblastos/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Diferenciação Celular , Células Cultivadas , Técnicas de Cocultura/métodos , Sistemas Microfisiológicos
11.
Sci Rep ; 14(1): 18088, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-39103438

RESUMO

Earthquake-induced rock landslides in the eastern mountains of the Tibetan Plateau, especially landslides with weak interlayers pose a significant threat to major construction projects. Prestressed anchor cable is one of the main reinforcement methods of rock slopes. This paper combines shaking table model tests and numerical simulation to study the reinforcement effect and dynamic response characteristics of prestressed anchor cables applied to rock slopes with weak interlayers under strong earthquakes. The research results show that prestressed anchor cables can effectively reinforce slopes with weak interlayers. A small cable inclination, a small spacing and a high prestress are recommended in the seismic reinforcement design of prestressed anchor cable. In addition, the characteristics of slope progressive damage and prestress loss under the earthquake are found by the shaking table test. The results have been applied in hazard prevention and control of rock slopes on the Chengdu-Lanzhou Railway at the eastern Qinghai-Tibet Plateau.

12.
Mol Pharm ; 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39163212

RESUMO

The solution viscosity and protein-protein interactions (PPIs) as a function of temperature (4-40 °C) were measured at a series of protein concentrations for a monoclonal antibody (mAb) with different formulation conditions, which include NaCl and sucrose. The flow activation energy (Eη) was extracted from the temperature dependence of solution viscosity using the Arrhenius equation. PPIs were quantified via the protein diffusion interaction parameter (kD) measured by dynamic light scattering, together with the osmotic second virial coefficient and the structure factor obtained through small-angle X-ray scattering. Both viscosity and PPIs were found to vary with the formulation conditions. Adding NaCl introduces an attractive interaction but leads to a significant reduction in the viscosity. However, adding sucrose enhances an overall repulsive effect and leads to a slight decrease in viscosity. Thus, the averaged (attractive or repulsive) PPI information is not a good indicator of viscosity at high protein concentrations for the mAb studied here. Instead, a correlation based on the temperature dependence of viscosity (i.e., Eη) and the temperature sensitivity in PPIs was observed for this specific mAb. When kD is more sensitive to the temperature variation, it corresponds to a larger value of Eη and thus a higher viscosity in concentrated protein solutions. When kD is less sensitive to temperature change, it corresponds to a smaller value of Eη and thus a lower viscosity at high protein concentrations. Rather than the absolute value of PPIs at a given temperature, our results show that the temperature sensitivity of PPIs may be a more useful metric for predicting issues with high viscosity of concentrated solutions. In addition, we also demonstrate that caution is required in choosing a proper protein concentration range to extract kD. In some excipient conditions studied here, the appropriate protein concentration range needs to be less than 4 mg/mL, remarkably lower than the typical concentration range used in the literature.

13.
Front Immunol ; 15: 1444923, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39165358

RESUMO

Histone methylation can affect chromosome structure and binding to other proteins, depending on the type of amino acid being modified and the number of methyl groups added, this modification may promote transcription of genes (H3K4me2, H3K4me3, and H3K79me3) or reduce transcription of genes (H3K9me2, H3K9me3, H3K27me2, H3K27me3, and H4K20me3). In addition, advances in tumor immunotherapy have shown that histone methylation as a type of protein post-translational modification is also involved in the proliferation, activation and metabolic reprogramming of immune cells in the tumor microenvironment. These post-translational modifications of proteins play a crucial role in regulating immune escape from tumors and immunotherapy. Lysine methyltransferases are important components of the post-translational histone methylation modification pathway. Lysine methyltransferase 2C (KMT2C), also known as MLL3, is a member of the lysine methyltransferase family, which mediates the methylation modification of histone 3 lysine 4 (H3K4), participates in the methylation of many histone proteins, and regulates a number of signaling pathways such as EMT, p53, Myc, DNA damage repair and other pathways. Studies of KMT2C have found that it is aberrantly expressed in many diseases, mainly tumors and hematological disorders. It can also inhibit the onset and progression of these diseases. Therefore, KMT2C may serve as a promising target for tumor immunotherapy for certain diseases. Here, we provide an overview of the structure of KMT2C, disease mechanisms, and diseases associated with KMT2C, and discuss related challenges.


Assuntos
Neoplasias , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Metilação , Processamento de Proteína Pós-Traducional , Animais , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histonas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Microambiente Tumoral/imunologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Proteínas de Neoplasias/metabolismo , Regulação Neoplásica da Expressão Gênica
14.
Cancer Lett ; 601: 217154, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39121902

RESUMO

Spinal cord astrocytoma is a rare and highly debilitating tumor, yet our knowledge of its clinical characteristics, molecular features, and pathogenesis remains limited compared to that of its counterparts in the brain. Current diagnostic and therapeutic approaches for spinal cord astrocytomas are primarily based on established guidelines for brain astrocytomas. However, recent studies have revealed unique clinical and pathological attributes that distinguish spinal cord astrocytomas from their corresponding brain counterparts. These findings underscore the inadequacy of directly applying the clinical guidelines developed for brain astrocytomas to spinal astrocytomas. In this review, we provided an up-to-date overview of the advancements in understanding spinal cord astrocytomas. We also discussed the challenges and future research prospects in this field with the aim of improving the precision of diagnosis and therapy for these tumors. Specifically, we emphasized the importance of enhancing our understanding of the molecular heterogeneity, immune characteristics, and clinical trials of spinal cord astrocytomas.

15.
Adv Sci (Weinh) ; : e2404483, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39119840

RESUMO

Novel phase of nano materials that break the traditional structural constraints are highly desirable, particularly in the field of mechanocatalysis, offering versatile applications ranging from energy to medical diagnosis and treatment. In this work, a distinct layered barium dititanate (BaTi2O5) nanocrystals using a pH-modulated hydrothermal method is successfully synthesized. These nanocrystals exhibit outstanding hydrogen generation capability (1160 µmol g-1 h-1 in pure water) and demonstrate remarkable performance in organic dye degradation using ultrasonication. The crystal structure of this newly discovered BaTi2O5 phase, is determined by a combination of synchrotron Powder Diffraction refinement and X-ray adsorption techniques, including X-ray Absorption Near Edge Structure (XANES) and Extended X-ray Absorption Fine Structure (EXAFS). Density Functional Theory calculations revealed that the newly-discovered BaTi2O5 phase demonstrates dipole moments along the z-axis, distributed in an antiparallel direction within a single unit cell. These inherent dipoles induce a surface polarization and a ferroelectric-flexoelectric response under mechanical stimuli when the materials go to nano dimension. With a band alignment well-suitable for hydrogen and reactive oxygen species generation, this BaTi2O5 phase demonstrates promising potential for Mechanocatalysis. The discovery of this distinct phase not only enriches the material candidates for mechanocatalysis but also provides valuable insights.

16.
Eur J Med Chem ; 276: 116678, 2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-39029337

RESUMO

Focal adhesion kinase (FAK) is considered as a pivotal intracellular non-receptor tyrosine kinase, and has garnered significant attention as a promising target for anticancer drug development. As of early 2024, a total of 12 drugs targeting FAK have been approved for clinical or preclinical studies worldwide, including three PROTAC degraders. In recent three years (2021-2023), significant progress has been made in designing targeted FAK anticancer agents, including the development of a novel benzenesulfofurazan type NO-releasing FAK inhibitor and the first-in-class dual-target inhibitors simultaneously targeting FAK and HDACs. Given the pivotal role of FAK in the discovery of anticancer drugs, as well as the notable advancements achieved in FAK inhibitors and PROTAC degraders in recent years, this review is underbaked to present a comprehensive overview of the function and structure of FAK. Additionally, the latest findings on the inhibitors and PROTAC degraders of FAK from the past three years, along with their optimization strategies and anticancer activities, were summarized, which might help to provide novel insights for the development of novel targeted FAK agents with promising anticancer potential and favorable pharmacological profiles.


Assuntos
Antineoplásicos , Proteína-Tirosina Quinases de Adesão Focal , Neoplasias , Inibidores de Proteínas Quinases , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Neoplasias/tratamento farmacológico , Animais , Estrutura Molecular
17.
Int J Biol Macromol ; 275(Pt 1): 133631, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38964688

RESUMO

Controllable heparin-release is of great importance and necessity for the precise anticoagulant regulation. Efforts have been made on designing heparin-releasing systems, while, it remains a great challenge for gaining the external-stimuli responsive heparin-release in either intravenous or catheter delivery. In this study, an azobenzene-containing ammonium surfactant is designed and synthesized for the fabrication of photoresponsive heparin ionic complexes through the electrostatic complexation with heparin. Under the assistance of photoinduced trans-cis isomerization of azobenzene, the obtained heparin materials perform reversible athermal phase transition between ordered crystalline and isotropic liquid state at room temperature. Compared to the ordered state, the formation of isotropic state can effectively improve the dissolving of heparin from ionic materials in aqueous condition, which realizes the photo-modulation on the concentration of free heparin molecules. With good biocompatibility, such a heparin-releasing system addresses photoresponsive anticoagulation in both in vitro and in vivo biological studies, confirming its great potential clinical values. This work provides a new designing strategy for gaining anticoagulant regulation by light, also opening new opportunities for the development of photoresponsive drugs and biomedical materials based on biomolecules.


Assuntos
Anticoagulantes , Heparina , Heparina/química , Heparina/farmacologia , Anticoagulantes/química , Anticoagulantes/farmacologia , Animais , Humanos , Compostos Azo/química , Liberação Controlada de Fármacos , Coagulação Sanguínea/efeitos dos fármacos , Tensoativos/química , Camundongos , Íons/química
18.
Nanoscale ; 16(31): 14831-14843, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39034677

RESUMO

This study reports a fluorescent nanoprobe operated in fluorescence turn-on mode for simultaneously sensing and imaging intracellular GSH and ATP. By using maleimide-derivatives as the ligand, the bimetallic nanoscale metal-organic framework (NMOF) Cu-Mi-UiO-66 has been synthesized for the first time using a straightforward one-step solvothermal approach, serving as a GSH recognition moiety. Subsequently, a Cy5-labeled ATP aptamer was assembled onto Cu-Mi-UiO-66 via strong coordination between phosphate and zirconium, π-π stacking and electrostatic adsorption to develop the dual-responsive fluorescence nanoprobe Cu-Mi-UiO-66/aptamer. Due to the photoinduced electron transfer (PET) effect between maleimide groups and the benzene ring of the ligand and the charge transfer between Cy5 and the Zr(IV)/Cu(II) bimetal center of the NMOF, the Cu-Mi-UiO-66/aptamer exhibits a fluorescence turn-off status. The Michael addition reaction between the thiol group of GSH and the maleimide on the NMOF skeleton results in turning on of the blue fluorescence of Cu-Mi-UiO-66. Meanwhile, upon specific interaction with ATP, the aptamer changes into internal loop structures and detaches from Cu-Mi-UiO-66, resulting in turning on of the red fluorescence of Cy5. The nanoprobe demonstrated an excellent sensing performance with a good linear range (GSH, 5.0-450.0 µM; ATP, 1.0-50.0 µM) and a low detection limit (GSH, 2.17 µM; ATP, 0.635 µM). More importantly, the Cu-Mi-UiO-66/aptamer exhibits good performance for tracing intracellular concentration variations of GSH and ATP in living HepG2 cells under different stimulations. This study highlights the potential of NMOFs for multiplexed analysis and provides a valuable tool for tumor microenvironment research and early cancer diagnosis.


Assuntos
Trifosfato de Adenosina , Cobre , Corantes Fluorescentes , Glutationa , Estruturas Metalorgânicas , Glutationa/análise , Glutationa/química , Trifosfato de Adenosina/análise , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Humanos , Corantes Fluorescentes/química , Cobre/química , Estruturas Metalorgânicas/química , Aptâmeros de Nucleotídeos/química , Zircônio/química , Carbocianinas/química , Espectrometria de Fluorescência , Ácidos Ftálicos
19.
Int J Mol Sci ; 25(13)2024 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-39000568

RESUMO

Osteoarthritis (OA) is the most common joint disease, causing symptoms such as joint pain, swelling, and deformity, which severely affect patients' quality of life. Despite advances in medical treatment, OA management remains challenging, necessitating the development of safe and effective drugs. Quercetin (QUE), a natural flavonoid widely found in fruits and vegetables, shows promise due to its broad range of pharmacological effects, particularly in various degenerative diseases. However, its role in preventing OA progression and its underlying mechanisms remain unclear. In this study, we demonstrated that QUE has a protective effect against OA development both in vivo and in vitro, and we elucidated the underlying molecular mechanisms. In vitro, QUE inhibited the expression of IL-1ß-induced chondrocyte matrix metalloproteinases (MMP3 and MMP13) and inflammatory mediators such as INOS and COX-2. It also promoted the expression of collagen II, thereby preventing the extracellular matrix (ECM). Mechanistically, QUE exerts its protective effect on chondrocytes by activating the SIRT1/Nrf-2/HO-1 and inhibiting chondrocyte ferroptosis. Similarly, in an OA rat model induced by anterior cruciate ligament transection (ACLT), QUE treatment improved articular cartilage damage, reduced joint pain, and normalized abnormal subchondral bone remodeling. QUE also reduced serum IL-1ß, TNF-α, MMP3, CTX-II, and COMP, thereby slowing the progression of OA. QUE exerts chondroprotective effects by inhibiting chondrocyte oxidative damage and ferroptosis through the SIRT1/Nrf-2/HO-1 pathway, effectively alleviating OA progression in rats.


Assuntos
Cartilagem Articular , Condrócitos , Modelos Animais de Doenças , Ferroptose , Fator 2 Relacionado a NF-E2 , Osteoartrite , Quercetina , Sirtuína 1 , Animais , Sirtuína 1/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Osteoartrite/patologia , Ratos , Quercetina/farmacologia , Quercetina/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Ferroptose/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Cartilagem Articular/metabolismo , Masculino , Transdução de Sinais/efeitos dos fármacos , Ratos Sprague-Dawley , Interleucina-1beta/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo
20.
J Hazard Mater ; 476: 135098, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38970977

RESUMO

Next-generation sequencing (NGS) has revolutionized taxa identification within contaminant-degrading communities. However, uncovering a core degrading microbiome in diverse polluted environments and understanding its associated microbial interactions remains challenging. In this study, we isolated two distinct microbial consortia, namely MA-S and Cl-G, from separate environmental samples using 1,4-dioxane as a target pollutant. Both consortia exhibited a persistent prevalence of the phylum Proteobacteria, especially within the order Rhizobiales. Extensive analysis confirmed that Rhizobiales as the dominant microbial population (> 90 %) across successive degradation cycles, constituting the core degrading microbiome. Co-occurrence network analysis highlighted synergistic interactions within Rhizobiales, especially within the Shinella and Xanthobacter genera, facilitating efficient 1,4-dioxane degradation. The enrichment of Rhizobiales correlated with an increased abundance of essential genes such as PobA, HpaB, ADH, and ALDH. Shinella yambaruensis emerged as a key degrader in both consortia, identified through whole-genome sequencing and RNA-seq analysis, revealing genes implicated in 1,4-dioxane degradation pathways, such as PobA and HpaB. Direct and indirect co-cultivation experiments confirmed synergistic interaction between Shinella sp. and Xanthobacter sp., enhancing the degradation of 1,4-dioxane within the core microbiome Rhizobiales. Our findings advocate for integrating the core microbiome concept into engineered consortia to optimize 1,4-dioxane bioremediation strategies.


Assuntos
Biodegradação Ambiental , Dioxanos , Microbiota , Dioxanos/metabolismo , Consórcios Microbianos/genética , Proteobactérias/genética , Proteobactérias/metabolismo
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