RESUMO
The five-year survival rate for patients with hepatocellular carcinoma (HCC) is only 20â¯%, highlighting the urgent need to identify new therapeutic targets and develop potential therapeutic options to improve patient prognosis. One promising approach is inhibiting autophagy as a strategy for HCC treatment. In this study, we established a virtual docking conformation of the autophagy promoter ULK1 binding XST-14 derivatives. Based on this conformation, we designed and synthesized four series of derivatives. By evaluating their affinity and anti-HCC effects, we confirmed that these compounds exert anti-HCC activity by inhibiting ULK1. The structure-activity relationship was summarized, with derivative A4 showing 10 times higher activity than XST-14 and superior efficacy to sorafenib against HCC. A4 has excellent effect on reducing tumor growth and enhancing sorafenib activity in HepG2 and HCCLM3 cells. Moreover, we verified the therapeutic effect of A4 in sorafenib-resistant HCC cells both in vivo and in vitro. These results suggest that inhibiting ULK1 to regulate autophagy may become a new treatment method for HCC and that A4 will be used as a lead drug for HCC in further research. Overall, A4 shows good drug safety and efficacy, offering hope for prolonging the survival of HCC patients.
RESUMO
Combining rare earth elements with the halide perovskite structure offers valuable insights into designing nonlead (Pb) luminescent materials. However, most of these compositions tend to form zero-dimensional (0D) networks of metal-halide polyhedra, with higher-dimensional (1D, 2D, and 3D) structures receiving relatively less exploration. Herein, we present synthesis and optical properties of Cs3CeCl6·3H2O, characterized by its unique 1D crystal structure. The conduction band minimum of Cs3CeCl6·3H2O becomes less localized as a result of the increased structural dimension, making it possible for the materials to achieve an efficient electrical injection. For both Cs3CeCl6·3H2O single crystals and nanocrystals, we also observed remarkable luminescence with near-unity photoluminescence quantum yield and exceptional phase stability. Cs3CeCl6·3H2O single crystals demonstrate an X-ray scintillation light yield of 31900 photons/MeV, higher than that of commercial LuAG:Ce (22000 photons/MeV); electrically driven light-emitting diodes fabricated with Cs3CeCl6·3H2O nanocrystals yield the characteristic emission of Ce3+, indicating their potential use in next-generation violet-light-emitting devices.
RESUMO
This work presents an accurate and efficient method, for solving a two dimensional time-fractional Oldroyd-B fluid model. The proposed method couples the Laplace transform (LT) with a radial basis functions based local meshless method (LRBFM). The suggested numerical scheme first uses the LT which transform the given equation to an elliptic equation in LT space, and then it utilizes the LRBFM to solve transformed equation in LT space, and then the solution is converted back into the time domain via the improved Talbot's scheme. The local meshless methods are widely recognized for scattered data interpolation and for solving PDEs in complex shaped domains. The adaptability, simplicity, and ease of use are features that have led to the popularity of local meshless methods. The local meshless methods are easy and straightforward, they only requires to solve linear system of equations. The main objective of using the LT is to avoid the computation of costly convolution integral in time-fractional derivative and the effect of time stepping on accuracy and stability of numerical solution. The stability and the convergence of the proposed numerical scheme are discussed. Further, the Ulam-Hyers (UH) stability of the proposed model is discussed. The accuracy and efficiency of the suggested numerical approach have been demonstrated using numerical experiments on five different domains with regular nodes distribution.
RESUMO
Calcium plays a crucial role as a second messenger in neuronal signal transduction pathways. The influx of calcium ions through various physicochemical gating channels activates neuronal calcium signaling. The Endoplasmic Reticulum (ER) is a significant intracellular structure that sequesters calcium and controls signaling through SERCA, IPR, and leak channel mechanisms. Disruption of calcium dynamics can trigger intrinsic dyshomeostasis, cell damage, and apoptosis. The present study articulates a Caputo fractional time derivative in the polar coordinate dimensions to investigate the role of nonlocal calcium-free ions in the neuron through the Orai channel, and ER fluxes, incorporating various physiological parameters. The solution was obtained through the hybrid integral transform technique for analytical form. The closed form was generated using Green's function in terms of Mainardi and Wright's functions. Our simulation uncovered the calcium concentration bandwidth of interaction with different neuronal parameters. Parameters and calcium ion synergy show normal and Alzheimer's disease-impacted interaction through different illustrations. Our simulation reveals that S100B and BAPTA have significant calcium-controlling behavior.
RESUMO
Fungal infections account for more than 140 million cases of severe and life-threatening conditions each year, causing approximately 1.7 million deaths annually. Candida albicans and related species are the most common human fungal pathogens, causing both superficial (mucosal and cutaneous) and life-threatening invasive infections (candidemia) with a 40-75% mortality rate. Among many virulence factors of Candida albicans, morphological transition from yeast to hyphae, secretion of hydrolytic enzymes, and formation of biofilms are considered to be crucial for pathogenicity. However, the arsenals for the treatment against these pathogens are restricted to only a few classes of approved drugs, the efficacy of which is being compromised by host toxicity, fungistatic activity, and the emergence of drug resistance. In this study, we have described the development of a molecule, exhibiting excellent antifungal activity (MIC 8 µg/mL), by tailoring acidic sophorolipids with aryl alcohols via enzyme catalysis. This novel derivative, ASLdC3, is a surface-active compound that lowers the surface tension of the air-water interface up to 2-fold before reaching the critical micelle concentration of 25 µg/mL. ASLdC3 exhibits excellent antibiofilm properties against Candida albicans and other nonalbicans Candida species. The molecule primarily exhibits its antifungal activity by perturbing mitochondrial function through the alteration of the mitochondrial membrane potential (MMP) and generation of reactive oxygen species (ROS). The ROS damages fungal cell membrane function and cell wall integrity, eventually leading to cell death. ASLdC3 was found to be nontoxic in in vitro assay and nonhemolytic. Besides, it does not cause toxicity in the C. elegans model. Our study provides a valuable foundation for the potential of acidic sophorolipid as a nontoxic, biodegradable precursor for the design and synthesis of novel molecules for use as antimicrobial drugs as well as for other clinical applications.
RESUMO
This interdisciplinary study critically analyzes current research, establishing a profound connection between sea water, sea ice, sea temperature, and surface temperature through a 4D hyperchaotic Caputo fractional differential equation. Emphasizing the collective impact on climate, focusing on challenges from anthropogenic global warming, the study scrutinizes theoretical aspects, including existence and uniqueness. Two sliding mode controllers manage chaos in this 4D fractional system, assessed amid uncertainties and disruptions. The global stability of these controlled systems is also confirmed, considering both commensurate and non-commensurate 4D fractional order. To demonstrate the intricate chaotic motion within the system, we employ the Lyapunov exponent and Poincare sections. Numerical simulations are conducted by using the predictor-corrector method. The effects of surface temperature on chaotic dynamics are discussed. The crucial role of sea ice reflection in climate stability is highlighted in two scenarios. Correlation graphs, comparing model and observational data using the predictor-corrector method, enhance the proposed 4D hyperchaotic model's credibility. Subsequently, numerical simulations validate theoretical assertions about the controllers' influence. These controllers indicate which variable significantly contributes to controlling the chaos.
RESUMO
Purpose: The present study aimed to develop a lipid nanoplatform, denoted as "BAL-PTX-LN", co-loaded with chiral baicalin derivatives (BAL) and paclitaxel (PTX) to promote the anti-lung cancer efficacy of paclitaxel and reduce the toxicity of chemotherapeutic drugs. Methods: BAL-PTX-LN was optimized through central composite design based on a single-factor experiments. BAL-PTX-LN was evaluated by TEM, particle size, encapsulation efficiency, hemolysis rate, release kinetics and stability. And was evaluated by pharmacokinetics and the antitumor efficacy studied both in vitro and in vivo. The in vivo safety profile of the formulation was assessed using hematoxylin and eosin (HE) staining. Results: BAL-PTX-LN exhibited spherical morphology with a particle size of 134.36 ± 3.18 nm, PDI of 0.24 ± 0.02, and with an encapsulation efficiency exceeding 90%, BAL-PTX-LN remained stable after 180 days storage. In vitro release studies revealed a zero-order kinetic model of PTX from the liposomal formulation. No hemolysis was observed in the preparation group. Pharmacokinetic analysis of PTX in the BAL-PTX-LN group revealed an approximately three-fold higher bioavailability and twice longer t1/2 compared to the bulk drug group. Furthermore, the IC50 of BAL-PTX-LN decreased by 2.35 times (13.48 µg/mL vs 31.722 µg/mL) and the apoptosis rate increased by 1.82 times (29.38% vs 16.13%) at 24 h compared to the PTX group. In tumor-bearing nude mice, the BAL-PTX-LN formulation exhibited a two-fold higher tumor inhibition rate compared to the PTX group (62.83% vs 29.95%), accompanied by a ten-fold decrease in Ki67 expression (4.26% vs 45.88%). Interestingly, HE staining revealed no pathological changes in tissues from the BAL-PTX-LN group, whereas tissues from the PTX group exhibited pathological changes and tumor cell infiltration. Conclusion: BAL-PTX-LN improves the therapeutic effect of poorly soluble chemotherapeutic drugs on lung cancer, which is anticipated to emerge as a viable therapeutic agent for lung cancer in clinical applications.
Assuntos
Neoplasias Pulmonares , Paclitaxel , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Paclitaxel/administração & dosagem , Animais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Humanos , Flavonoides/química , Flavonoides/farmacologia , Flavonoides/farmacocinética , Flavonoides/administração & dosagem , Tamanho da Partícula , Nanopartículas/química , Camundongos , Lipossomos/química , Lipossomos/farmacocinética , Células A549 , Lipídeos/química , Masculino , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Camundongos Nus , Hemólise/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagemRESUMO
Calcium ions are the second messenger playing as regulators for various cellular activities. Its spatiotemporal control is critical for various brain functions, including neuroplasticity, apoptosis, and cell death. The Endoplasmic Reticulum (ER) plays an important role in determining these spatiotemporal calcium dynamics. Stromal interaction molecule (STIM) - Orai channel on the membrane generates additional calcium flow, whereas other membrane fluxes contribute to cytosolic flux. Due to their anomalous character, we used the Caputo fractional differential operator to mimic these interactions in polar coordinates. Solutions were generated using hybrid integral transform methods to control the analytical approach. Using Green's function yielded a closed-form solution for Mittag-Leffler-type functions. This work emphasizes the significant relationship between calcium and various buffer levels in neurons. The differential transition simulation of a time derivative with space across different parameters indicated a decrease in calcium concentration. Anomalously low buffer levels exhibited the impact of Alzheimer's disease on calcium higher concentration, leading to the death of neurons. Additionally, the research introduces a method involving S100B, BAPTA, and calmodulin buffers to uphold optimal calcium levels within the neuronal cytosol. The applicability of this model with different buffer properties and parameters and memory impacts the calcium concentration with the neurological disorder.
RESUMO
Prolonged exposure to polycyclic aromatic hydrocarbons (PAHs) and their derivatives, particularly nitrated polycyclic aromatic hydrocarbons (NPAHs) and oxygenated polycyclic aromatic hydrocarbons (OPAHs), can result in adverse health effects and may carry higher toxicity risks compared to PAHs alone. Various extraction methods have been utilized for PAHs derivatives from food samples. The analytes are then analyzed using gas chromatography/mass spectrometry and high-performance liquid chromatography techniques. PAHs derivatives are increasingly being detected in the environment, prompting scrutiny from numerous researchers. Similarly, their presence in food is becoming a significant concern. The elevated levels of PAH derivatives found in smoked food may result in detrimental dietary exposure and pose potential health hazards. Furthermore, investigating the level of exposure to these contaminants in food is imperative, as their consumption by humans carries inherent risks. Consequently, this review concentrates on the toxicity, analysis, occurrence, and risk evaluation of NPAHs and OPAHs present in food sources.
RESUMO
5-Methoxy-3-(5-methoxyindolin-2-yl)-1H-indole (3), whose structure was unambiguously elucidated by X-ray analysis, was identified as a multi-target compound with potential application in neurodegenerative diseases. It is a low nanomolar inhibitor of QR2 (IC50 = 7.7 nM), with greater potency than melatonin and comparable efficacy to the most potent QR2 inhibitors described to date. Molecular docking studies revealed the potential binding mode of 3 to QR2, which explains its superior potency compared to melatonin. Furthermore, compound 3 inhibits hMAO-A, hMAO-B and hLOX-5 in the low micromolar range and is an excellent ROS scavenger. In phenotypic assays, compound 3 showed neuroprotective activity in a cellular model of oxidative stress damage, it was non-toxic, and was able to activate neurogenesis from neural stem-cell niches of adult mice. These excellent biological properties, together with its both good in silico and in vitro drug-like profile, highlight compound 3 as a promising drug candidate for neurodegenerative diseases.
RESUMO
Non-centrifugal raw cane sugar (NRCS) is a minimally processed product from sugarcane (Saccharum officinarum L). This product contains phytochemical and nutritional compounds that benefit human health. Despite these advantages, NRCS commercialization is hindered by a lack of knowledge about its composition and, consequently, the absence of quality standards. Studies associating the nutritional composition of sugarcane varieties and their genuine products have not yet been found in the literature, and understanding this relationship can help establish quality standards for this product. Therefore, this study evaluated the mineral nutritional composition of genuine derivative NRCS produced from two sugarcane varieties obtained under different agronomic conditions at two stages of maturation to verify the relationships between raw material and the product. The obtained sugarcanes, juices, and bagasse, as well as the produced sugars, were analyzed for mineral content, such as calcium, magnesium, potassium, phosphorus, sulfur, iron, manganese, copper, and zinc, using inductively coupled plasma optical emission spectrometry. Most mineral constituents of sugarcane are in the juice in direct proportions to those in raw sugarcane. Thus, minimally processed food derivatives have nutritional characteristics equivalent to the raw materials. Consumption of NRCS contributes to meeting daily requirements for essential nutrients such as magnesium, copper, potassium, and manganese. For manganese, 25 g of NRCS, like the one produced in this study, can fulfill 22 to 76 % of an adult male's daily mineral requirements. The variation observed in the four NRCS samples, obtained from the same sugarcane variety under different maturation and agronomic conditions, was 250 %. This variation makes establishing quality parameters for mineral or ash content difficult. Therefore, setting mineral content levels for NRCS is inappropriate, as this parameter naturally depends on the raw material.
Assuntos
Minerais , Valor Nutritivo , Saccharum , Saccharum/química , Minerais/análise , Celulose/análise , Celulose/química , Manipulação de Alimentos/métodosRESUMO
Designing an efficient modification molecule to mitigate non-radiative recombination at the NiOx/perovskite interface and improve perovskite quality represents a challenging yet crucial endeavor for achieving high-performance inverted perovskite solar cells (PSCs). Herein, we synthesized a novel fullerene-based hole transport molecule, designated as FHTM, by integrating C60 with 12 carbazole-based moieties, and applied it as a modification molecule at the NiOx/perovskite interface. The in-situ self-doping effect, triggered by electron transfer between carbazole-based moiety and C60 within the FHTM molecule, along with the extended π conjugated moiety of carbazole groups, significantly enhances FHTM's hole mobility. Coupled with optimized energy level alignment and enhanced interface interactions, the FHTM significantly enhances hole extraction and transport in corresponding devices. Additionally, the introduced FHTM efficiently promotes homogeneous nucleation of perovskite, resulting in high-quality perovskite films. These combined improvements led to the FHTM-based PSCs yielding a champion efficiency of 25.58% (Certified: 25.04%), notably surpassing that of the control device (20.91%). Furthermore, the unencapsulated device maintained 93% of its initial efficiency after 1000 hours of maximum power point tracking under continuous one-sun illumination. This study highlights the potential of functionalized fullerenes as hole transport materials, opening up new avenues for their application in the field of PSCs.
RESUMO
AIM: To construct a novel liposomal drug delivery system co-modified with SP94 and BR2 ligands, encapsulating both the bitter ginseng derivative B21 and doxorubicin (DOX), to achieve superior anti-tumour efficacy and reduced toxic side effects. METHODS: Liposomes were prepared using an organic phase reaction method, with B21 encapsulated in the lipid phase and DOX in the aqueous phase. The liposomes were further modified with SP94 and BR2 peptides. The characterisations, cytotoxicity, and in vitro targeting effects were assessed through various methods including ultraviolet spectrophotometry, high-performance liquid chromatography, nano-size analysis, ultrafiltration centrifugation, dialysis, transmission electron microscopy, flow cytometry, Methylthiazolyldiphenyl-tetrazolium bromide assay, confocal laser scanning microscopy, transwell assay, and tumorsphere assay. RESULTS: SP94/BR2-B21/DOX-LP liposomes were spherical with an average diameter of 120.87 ± 1.00 nm, a polydispersity index (PDI) of 0.223 ± 0.006, and a surface charge of -23.1 ± 1.27 mV. The encapsulation efficiencies for B21 and DOX were greater than 85% and 97% (mg/mg), respectively. The results indicated that SP94/BR2-B21/DOX-LP exhibited enhanced targeting and cytotoxicity compared to single-ligand modified and unmodified liposomes, with the combined encapsulation of B21 and DOX showing synergistic anti-hepatocarcinogenic effects. CONCLUSION: SP94/BR2-B21/DOX-LP liposomes represent a promising targeted drug delivery system for hepatocellular carcinoma, offering improved membrane penetration, enhanced therapeutic efficacy, and reduced systemic toxicity.
RESUMO
The electron extraction from perovskite/C60 interface plays a crucial role in influencing the photovoltaic performance of inverted perovskite solar cells (PSCs). Here, we develop a one-stone-for-three-birds strategy via employing a novel fullerene derivative bearing triple methyl acrylate groups (denoted as C60-TMA) as a multifunctional interfacial layer to optimize electron extraction at the perovskite/C60 interface. It is found that the C60-TMA not only passivates surface defects of perovskite via coordination interactions between C=O groups and Pb2+ cations but also bridge electron transfer between perovskite and C60. Moreover, it effectively induces the secondary grain growth of the perovskite film through strong bonding effect, and this phenomenon has never been observed in prior art reports on fullerene related studies. The combination of the above three upgrades enables improved perovskite film quality with increased grain size and enhanced crystallinity. With these advantages, C60-TMA treated PSC devices exhibit a much higher power conversion efficiency (PCE) of 24.89% than the control devices (23.66%). Besides, C60-TMA benefits improved thermal stability of PSC devices, retaining over 90% of its initial efficiency after aging at 85 °C for 1200 h, primarily due to the reinforced interfacial interactions and improved perovskite film quality.
RESUMO
Chitosan is a potentially suitable material for wound dressing, but is undesirably water-insoluble. Although chitosan can be modified to produce water-soluble derivatives, the best chitosan derivative for wound dressings remains unclear. The present study introduced three water-soluble chitosan derivatives, namely, carboxymethyl chitosan, quaternized chitosan (QCS), and carboxymethyl quaternized chitosan, and explored the physical properties, biochemical properties, and wound care effectiveness of films of these derivatives. The QCS-based film exhibited higher absorption ability, mechanical properties, water-vapor permeability, electroconductivity, and antioxidant capacity than the other films. Most importantly, the cationic quaternary ammonium groups facilitated the antibacterial activity (>95â¯%) and blood coagulant capacity of the QCS-based film. As this film also promoted wound healing, it presented as an ideal candidate for wound dressings.
RESUMO
The isothiourea derivative NT-1505 is known as a neuroprotector and cognition enhancer in animal models of neurodegenerative diseases. Bearing in mind possible relation of the NT-1505-mediated neuroprotection to mitochondrial uncoupling activity, here, we examine NT-1505 effects on mitochondria functioning. At concentrations starting from 10 µM, NT-1505 prevented Ca2+-induced mitochondrial swelling, similar to common uncouplers. Alongside the inhibition of the mitochondrial permeability transition, NT-1505 caused a decrease in mitochondrial membrane potential and an increase in respiration rate in both isolated mammalian mitochondria and cell cultures, which resulted in the reduction of energy-dependent Ca2+ uptake by mitochondria. Based on the oppositely directed effects of bovine serum albumin and palmitate, we suggest the involvement of fatty acids in the NT-1505-mediated mitochondrial uncoupling. In addition, we measured the induction of electrical current across planar bilayer lipid membrane upon the addition of NT-1505 to the bathing solution. Importantly, introduction of the palmitic acid into the lipid bilayer composition led to weak proton selectivity of the NT-1505-mediated BLM current. Thus, the present study revealed an ability of NT-1505 to cause moderate protonophoric uncoupling of mitochondria, which could contribute to the neuroprotective effect of this compound.
RESUMO
Complexes [Cu(PI)2(H2O)](NO3)2 (1), [Cu(PBI)2(NO3)]NO3 (2), [Cu(TBI)2(NO3)]NO3 (3), [Cu(BBIP)2](ClO4)2 (4) and [Cu(BBIP)(CH3OH)(ClO4)2] (5) were synthesized from the reactions of Cu(II) salts with 2-(2'-pyridyl)imidazole (PI), (2-(2'-pyridyl)benzimidazole (PBI), 2-(4'-thiazolyl)-benzimidazole (TBI), 2,6-bis(benzimidazol-2-yl)-pyridine (BBIP), respectively. Their compositions and crystal structures were determined. Their in-vitro antitumor activities were screened on four cancer cell lines and one normal cell line (HL-7702) using cisplatin as the positive control. Complexes 2 and 4 show higher cytotoxicity than the other three complexes. The cytotoxicity of complex 2 are comparable to those for cisplatin, and the cytotoxicity for 4 are much higher than those for cisplatin. From a viewpoint of antitumor, 2 might be a nice choice on the tumor cell line of T24 because its IC50 values on T24 and HL-7702 are 15.03 ± 1.10 and 21.34 ± 0.35, respectively. Thus, a mechanistic study for complexes 2 and 4 on T24 cells was conducted. It revealed that they can reduce mitochondrial membrane potential and increase mitochondrial membrane permeability, resulting in increased intracellular ROS levels, Ca2+ inward flow, dysfunctional mitochondria and the eventual cell apoptosis. In conclusion, they can induce cell apoptosis through mitochondrial dysfunction. These findings could be useful in the development of new antitumor agents.
RESUMO
In this study, we introduce a novel iterative method combined with the Elzaki transformation to address a system of partial differential equations involving the Caputo derivative. The Elzaki transformation, known for its effectiveness in solving differential equations, is incorporated into the proposed iterative approach to enhance its efficiency. The system of partial differential equations under consideration is characterized by the presence of Caputo derivatives, which capture fractional order dynamics. The developed method aims to provide accurate and efficient solutions to this complex mathematical system, contributing to the broader understanding of fractional calculus applications in the context of partial differential equations. Through numerical experiments and comparisons, we demonstrate the efficacy of the proposed Elzaki-transform-based iterative method in handling the intricate dynamics inherent in the given system. The study not only showcases the versatility of the Elzaki transformation but also highlights the potential of the developed iterative technique for addressing similar problems in various scientific and engineering domains.
RESUMO
Blood-brain barrier (BBB) disruption is a major pathophysiological event of ischemic stroke. Brain microvascular endothelial cells are critical to maintain homeostasis between central nervous system and periphery. Resveratrol protects against ischemic stroke. 3,3',4,5'-tetramethoxy-trans-stilbene (3,3',4,5'-TMS) and 3,4',5-trimethoxy-trans-stilbene (3,4',5-TMS) are resveratrol derivatives with addition of methoxy groups, showing better pharmacokinetic performance. We aimed to explore their protective effects and underlying mechanisms. Oxygen-glucose deprivation (OGD) model was applied in bEnd.3 cell line, mouse brain microvascular endothelium to mimic ischemia. The cells were pre-treated with 3,3',4,5'-TMS or 3,4',5-TMS (1 and 5 µM, 24 h) and then subjected to 2-h OGD injury. Cell viability, levels of proinflammatory cytokines and reactive oxygen species (ROS), and protein expressions were measured by molecular assays and fluorescence staining. OGD injury triggered cell death, inflammatory responses, ROS production and nuclear factor-kappa B (NF-κB) signalling pathway. These impairments were remarkably attenuated by the two stilbenes, 3,3',4,5'-TMS and 3,4',5-TMS. They also alleviated endothelial barrier injuries through upregulating the expression of tight junction proteins. Moreover, 3,3',4,5'-TMS and 3,4',5-TMS activated 5' adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS). Overall, 3,3',4,5'-TMS and 3,4',5-TMS exert protective effects against OGD damage through suppressing cell death, inflammatory responses, oxidative stress, as well as BBB disruption on bEnd.3 cells.
Assuntos
Encéfalo , Sobrevivência Celular , Células Endoteliais , Glucose , Oxigênio , Espécies Reativas de Oxigênio , Estilbenos , Estilbenos/farmacologia , Animais , Glucose/metabolismo , Camundongos , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Oxigênio/metabolismo , Linhagem Celular , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Sobrevivência Celular/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Citocinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacosRESUMO
Formaldehyde (FA) is a carcinogen that is not only widespread in the environment, but is also produced endogenously by metabolic processes. In organisms, FA is converted to formic acid in a glutathione (GSH)-dependent manner by alcohol dehydrogenase 5 (ADH5). The abnormal accumulation of FA in the body can cause a variety of diseases, especially cognitive impairment leading to Alzheimer's disease (AD). In this study, melatonin derivative 6a (MD6a) markedly improved the survival and chemotactic performance of wild-type Caenorhabditis elegans exposed to high concentrations of FA. MD6a lowered FA levels in the nematodes by enhancing the release of covalently-bound GSH from S-hydroxymethyl-GSH in an adh-5-dependent manner. In addition, MD6a protected against mitochondrial dysfunction and cognitive impairment in beta-amyloid protein (Aß) transgenic nematodes by lowering endogenous FA levels and reducing Aß aggregation in an adh-5-dependent manner. Our findings suggest that MD6a detoxifies FA via ADH5 and protects against Aß toxicity by reducing endogenous FA levels in the C. elegans AD models. Thus, ADH5 might be a potential therapeutic target for FA toxicity and AD.