RESUMO
Selected gold complexes have been regarded as promising anti-cancer agents because they can bind with protein targets containing thiol or selenol moieties, but their clinical applications were hindered by the unbiased binding towards off-target thiol-proteins. Recently, a novel gold(III)-hydride complex (abbreviated as 1) with visible light-induced thiol reactivity has been reported as potent photo-activated anticancer agents (Angew. Chem. Int. Ed., 2020, 132, 11139). To explore new strategies to stimuli this potential antitumor drug, the effect of oriented external electric fields (OEEFs) on its geometric structure, electronic properties, and chemical reactivity was systematically investigated. Results reveal that imposing external electric fields along the Au-H bond of 1 can effectively activate this bond, which is conducive to its dissociation and the binding of Au site to potential targets. Hence, this study provides a new OEEF-strategy to activate this reported gold(III)-hydride, revealing its potential application in electrochemical therapy. We anticipate this work could promote the development of more electric field-activated anticancer agents. However, further experimental research should be conducted to verify the conclusions obtained in this work.
Assuntos
Antineoplásicos , Ouro , Ouro/química , Antineoplásicos/química , Eletricidade , Compostos de SulfidrilaRESUMO
Developing novel nanoscale carriers for drug delivery is of great significance for improving treatment efficiency and reducing side effects of antitumor drugs. In view of the good biocompatibility and special affinity of porphyrin (PP) molecule to cancer cells, it was used to construct a series of metal-doped M@PP (M = Ca â¼ Zn) materials for the delivery of anticancer drug 5-fluorouracil (5-Fu) in this work. Our results reveal that 5-Fu is tightly adsorbed on M@PP (M = Ca â¼ V, Mn â¼ Co, and Zn) by chemisorption, but is physically adsorbed by M@PP (M = Cr, Ni, and Cu). The calculated electronic properties show that all these 5-Fu@[M@PP] (M = Ca â¼ Zn) complexes have both high stability and solubility. Among these 5-Fu@[M@PP] complexes, the chemical bond formed between 5-Fu and Ti@PP has the strongest covalent characteristic, resulting in the largest adsorption energy of -19.93 kcal/mol for 5-Fu@[Ti@PP]. In particular, 5-Fu@[Ti@PP] has the proper recovery time under the near-infrared light at body temperature, which further suggests that Ti@PP is the best drug carrier for 5-Fu. This study not only reveals the interaction strength and nature between 5-Fu and M@PP, but also confirmed the intriguing potential of Ti@PP as nano-carrier for drug delivery. However, further experimental research should be conducted to verify the conclusion obtained in this work.
Assuntos
Antineoplásicos , Metaloporfirinas , Portadores de Fármacos , Fluoruracila/farmacologia , Sistemas de Liberação de MedicamentosRESUMO
BACKGROUND: The adaption of brain region is fundamental to the development and maintenance of nervous system disorders. The prelimbic cortex (PrL) participates in the affective components of the pain sensation. However, whether and how the adaptation of PrL contributes to the comorbidity of neuropathic pain and depression are unknown. METHODS: Using resting-state functional magnetic resonance imaging (rs-fMRI), genetic knockdown or overexpression, we systematically investigated the activity of PrL region in the pathogenesis of neuropathic pain/depression comorbid using the combined approaches of immunohistochemistry, electrophysiology, and behavior. RESULTS: The activity of PrL and the excitability of pyramidal neurons were decreased, and the osteoclastic tartrate-resistant acid phosphatase 5 (Acp5) expression in PrL neurons was upregulated following the acquisition of spared nerve injury (SNI)-induced comorbidity. Genetic knockdown of Acp5 in pyramidal neurons, but not parvalbumin (PV) neurons or somatostatin (SST) neurons, attenuated the decrease of spike number, depression-like behavior and mechanical allodynia in comorbidity rats. Overexpression of Acp5 in PrL pyramidal neurons decreased the spike number and induced the comorbid-like behavior in naïve rats. Moreover, the expression of interleukin-6 (IL-6), phosphorylated STAT3 (p-STAT3) and acetylated histone H3 (Ac-H3) were significantly increased following the acquisition of comorbidity in rats. Increased binding of STAT3 to the Acp5 gene promoter and the interaction between STAT3 and p300 enhanced acetylation of histone H3 and facilitated the transcription of Acp5 in PrL in the modeled rodents. Inhibition of IL-6/STAT3 pathway prevented the Acp5 upregulation and attenuated the comorbid-like behaviors in rats. CONCLUSIONS: These data suggest that the adaptation of PrL mediated by IL-6/STAT3/Acp5 pathway contributed to the comorbidity of neuropathic pain/depression induced by SNI.
Assuntos
Interleucina-6 , Neuralgia , Fosfatase Ácida/metabolismo , Animais , Comorbidade , Depressão/metabolismo , Histonas , Interleucina-6/metabolismo , Neuralgia/metabolismo , Ratos , Fator de Transcrição STAT3/metabolismo , Fosfatase Ácida Resistente a Tartarato/metabolismoRESUMO
OBJECTIVE: Spasticity is a frequent complication after spinal cord injury (SCI), but the existing therapies provide only limited relief and are associated with adverse reactions. Therefore, we aimed to develop a novel strategy to ameliorate the spasticity induced by SCI. METHODS: This nonrandomized controlled study used a repeated measurement design. The study involved four monkeys, two of which served as controls and only underwent spinal cord hemisection surgery at the T8 spine level. The other two monkeys underwent transplantation of sural nerve segments into the injured sites and long-term infusion of acidic fibroblast growth factor (aFGF). All monkeys received postoperative exercise training and therapy. RESULTS: The combined therapy substantially reduced the spasticity in leg muscle tone, patella tendon reflex, and fanning of toes. Although all monkeys showed spontaneous recovery of function over time, the recovery in the controls reached a plateau and started to decline after 11 weeks. CONCLUSIONS: The combination of peripheral nerve grafting and aFGF infusion may serve as a complementary approach to reduce the signs of spasticity in patients with SCI.
Assuntos
Fator 1 de Crescimento de Fibroblastos , Traumatismos da Medula Espinal , Animais , Haplorrinos , Humanos , Espasticidade Muscular/tratamento farmacológico , Espasticidade Muscular/etiologia , Regeneração Nervosa , Nervos Periféricos , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológicoRESUMO
Based on density functional theory, the adsorption behavior of 5-fluorouracil (5-Fu) on B40 and its derivatives has been explored. It was observed that 5-Fu prefers to combine with the corner boron atom of the B40 cage via one of its oxygen atoms, forming a strong polar covalent B-O bond. The adsorption energy of 5-Fu on B40 was calculated to be -11.15 kcal mol-1, and thus, it can be duly released from B40 by protonation in the slightly acidic environment of tumor tissue, which makes for reducing the toxic and side effects of this drug. Additionally, the substituent and embedding effect of Mg, Al, Si, Mn, Cu, and Zn atoms on the drug delivery performance of B40 have been also considered. We hope this work could offer some implications for the potential application of boron-based nanomaterials, such as B40 in drug delivery.
RESUMO
Donor-linker-acceptor (D-L-A)-based photoinduced electron transfer (PET) has been frequently used for the construction of versatile fluorescent chemo/biosensors. However, sophisticated and tedious processes are generally required for the synthesis of these probes, which leads to poor design flexibility. In this work, by exploiting a Schiff base as a linker unit, a covalently bound D-L-A system was established and subsequently utilized for the development of a PET sensor. Cysteamine (Cys) and N-acetyl-l-cysteine (NAC) costabilized gold nanoclusters (Cys/NAC-AuNCs) were synthesized and adopted as an electron acceptor, and pyridoxal phosphate (PLP) was selected as an electron donor. PLP can form a Schiff base (an aldimine) with the primary amino group of Cys/NAC-AuNC through its aldehyde group and thereby suppresses the fluorescence of Cys/NAC-AuNC. The Rehm-Weller formula results and a HOMO-LUMO orbital study revealed that a reductive PET mechanism is responsible for the observed fluorescence quenching. Since the pyridoxal (PL) produced by the acid phosphatase (ACP)-catalyzed cleavage of PLP has a weak interaction with Cys/NAC-AuNC, a novel turn-on fluorescent method for selective detection of ACP was successfully realized. To the best of our knowledge, this is the first example of the development of a covalently bound D-L-A system for fluorescent PET sensing of enzyme activity based on AuNC nanoprobes using a Schiff base.
Assuntos
Acetilcisteína/metabolismo , Cisteamina/metabolismo , Ouro/metabolismo , Nanopartículas Metálicas/química , Fosfato de Piridoxal/metabolismo , Acetilcisteína/química , Cisteamina/química , Teoria da Densidade Funcional , Transporte de Elétrons , Ouro/química , Tamanho da Partícula , Processos Fotoquímicos , Fosfato de Piridoxal/química , Bases de Schiff/química , Bases de Schiff/metabolismo , Propriedades de SuperfícieRESUMO
Recently, cancer research microRNA studies have drawn great attention. However, the results of these studies have been inconsistent and variable regarding the availability of circulating miRNAs in gastric cancer (GC) diagnosis. Thus, results should be interpreted cautiously. The purpose of the present study was to assess the diagnostic performance of circulating miRNAs in GC diagnosis. We conducted a systematic and comprehensive approach for the inclusion of studies. The sensitivity, specificity, and diagnostic odds ratio were pooled with random effects models, and a summary of receiver operator characteristic (SROC) curves were plotted. The potential heterogeneity was assessed with Q test and I2 statistics. Subgroup analyses and metaregressions further investigated the sources of heterogeneity. A total of 77 studies from 48 articles were eligible for the metaanalysis. The results revealed a sensitivity of 0.76, a specificity of 0.81, and an AUC of 0.86 for gastric cancer diagnosis with circulating miRNAs. In addition, subgroup analyses indicated that multiple miRNAs assays, nonmicroarray screening approaches, and serumbased miRNA assays exhibited good diagnostic performance in contrast to a single miRNA assay, microarray expression profiling screening, and plasmabased miRNA group analysis. The diagnostic ability of miRNAs in early stage III groups and the high expression group were approximately similar to that in the stage IIV groups and the low expression group. For the circulating miRNAs, our metaanalysis identified a combination of multiple miRNAs, nonmicroarray chip screening, and serumbased miRNA assays were associated with the most effective GC diagnostic performance. However, many unclear molecular mechanisms limited the accuracy of the diagnostic results, and should be interpreted with caution. Further largescale prospective studies are required for validating the diagnostic applicability of circulating miRNAs in gastric cancer patients.
Assuntos
Biomarcadores Tumorais/genética , MicroRNA Circulante/genética , Neoplasias Gástricas/diagnóstico , Humanos , Estadiamento de Neoplasias , Razão de Chances , Estudos Prospectivos , Sensibilidade e Especificidade , Neoplasias Gástricas/genéticaRESUMO
Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), and HBV X protein (HBx) serves an essential role in the development of HCC. However, its mechanism remains to be elucidated. The aim of the present study was to investigate the role and mechanism of the HBx protein in the epithelial-mesenchymal transition (EMT) and metastasis of HCC. The HCCLM3 cell line was transfected with a HBx-expressing vector. The effects of HBx overexpression on proliferation, migration, invasion and EMT capacities of the HCCLM3 cell line were evaluated using MTT, migration and invasion assays, and western blotting, respectively. Furthermore, the impact of High mobility group AT-hook 2 (HMGA2) knockdown on HBx-mediated metastasis was investigated in the HCC cell line HCCLM3. The results demonstrated that HBx significantly upregulated HMGA2 expression, and enhanced the proliferation, EMT, invasion and migration in HCC cells. Furthermore, HMGA2 knockdown almost abolished HBx-induced EMT and metastasis in HCC. The results of the present study suggest that HBx promotes the proliferation, EMT, invasion and migration of HCC cells by targeting HMGA2. HMGB2 may serve as a potential therapeutic target for HBV-associated HCC.
RESUMO
Oxidative stress and excess hepatic lipid accumulation contribute to nonalcoholic fatty liver disease. Radix Hedysari polysaccharides (RHP) have attracted interest due to their antioxidant properties and immunomodulatory effects. However, the effect of RHP on hepatic lipid metabolism remains to be elucidated. In the present study, the response of SpragueDawley rat livers to a highfat diet and RHP treatment was investigated by evaluating body weight, liver histology, hepatic lipid content, adenosine monophosphateactivated protein kinase (AMPK) activity and lipid metabolism gene transcriptional profiles. The present study demonstrated that RHP ameliorated lipid metabolism disorders, regulated hepatic lipid content, improved liver inflammation and damage, activated AMPK via phosphorylation, upregulated peroxisome proliferatoractivated receptor α and downregulated the mRNA expression of sterol regulatory element binding protein1c in rat livers, which reduced lipogenesis and increased lipolysis. Taken together, these results suggested that RHP effectively ameliorates lipid metabolism disorders in rat livers; thus, RHP may be a potential therapeutic agent in the prevention of hepatic steatosis.
Assuntos
Proteínas Quinases Ativadas por AMP/genética , Aconitum/química , Hipolipemiantes/farmacologia , Lipogênese/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Polissacarídeos/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antioxidantes/farmacologia , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Regulação para Baixo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/genética , PPAR alfa/metabolismo , Extratos Vegetais/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Insulin receptor tyrosine kinase substrate (IRTKS) is closely associated with actin remodelling and membrane protrusion, but its role in the pathogenesis of malignant tumours, including hepatocellular carcinoma (HCC), is still unknown. In this study, we showed that IRTKS was frequently upregulated in HCC samples, and its expression level was significantly associated with tumour size. Enforced expression of IRTKS in human HCC cell lines significantly promoted their proliferation and colony formation in vitro, and their capacity to develop tumour xenografts in vivo, whereas knockdown of IRTKS resulted in the opposite effects. Furthermore, the bromodeoxyuridine (BrdU) incorporation analyses and propidium iodide staining indicated that IRTKS can promote the entry into S phase of cell cycle progression. Significantly, IRTKS can interact with epidermal growth factor receptor (EGFR), results in the phosphorylation of extracellular signal-regulated kinase (ERK). By contrast, inhibition of ERK activation can attenuate the effects of IRTKS overexpression on cellular proliferation. Taken together, these data demonstrate that IRTKS promotes the proliferation of HCC cells by enhancing EGFR-ERK signalling pathway.
Assuntos
Carcinoma Hepatocelular/patologia , Proliferação de Células , Receptores ErbB/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas dos Microfilamentos/fisiologia , Adulto , Idoso , Animais , Ciclo Celular , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Transdução de Sinais , Especificidade por SubstratoRESUMO
The aim of the present study was to investigate the expression changes of three steroidogenic enzymes in the polycystic ovary syndrome (PCOS). Thirty Sprague-Dawley (SD) rats were randomly divided into normal control (NC) group and PCOS group. PCOS rat model was established by DHEA injection. The serum levels of progesterone, estrogen and testosterone were measured by immunoradioassay or enzyme immunoassay. The cellular distributions of 3ß-hydroxy steroid dehydrogenase (3ß-HSD), 17ß-hydroxy steroid dehydrogenase (17ß-HSD) and cytochrome P450 aromatase (P450arom) in ovaries were detected by immunohistochemistry. The expression levels of 3ß-HSD, 17ß-HSD and P450arom were detected by RT-PCR and Western blot. The results showed that the serum levels of estrogen and testosterone of PCOS group were significantly higher than those of the NC group. There was no significant difference of serum progesterone level between the PCOS and NC groups. Compared with the NC group, the PCOS group showed increased mRNA and protein expressions of both 3ß-HSD and 17ß-HSD, as well as reduced P450arom mRNA and protein expressions. These results suggest that 3ß-HSD and 17ß-HSD, but not P450arom, may participate in the ovarian hormonal regulation in the present rat model of PCOS.
Assuntos
17-Hidroxiesteroide Desidrogenases/metabolismo , 3-Hidroxiesteroide Desidrogenases/metabolismo , Aromatase/metabolismo , Síndrome do Ovário Policístico/enzimologia , Animais , Modelos Animais de Doenças , Estrogênios/sangue , Feminino , Progesterona/sangue , Ratos , Ratos Sprague-Dawley , Testosterona/sangueRESUMO
The lowest-energy structures of the Al(n)Be (n = 1-13) clusters are obtained and compared with the corresponding Al(n+1) and Al(n+1)(+) (n = 2-13) as well as Al(n)Mg clusters at the B3LYP/aug-cc-pVDZ level. The configurations of Al(n)Be show strong resemblances to those of pure Al(n+1) clusters, and the first three-dimensional ground state in the Al(n)Be clusters occurs for Al(3)Be. Various properties of the Al(n)Be clusters are systematically investigated using the CCSD(T) method and their thermodynamic properties are also compared with those of corresponding Al(n+1)(+) clusters. The evolution of the energetic and electronic properties with the size of the clusters shows the unique stability of the 20-valence electron systems Al(6)Be and Al(7)(+), which can be understood from the spherical jellium model (SJM). However, different from Al(7)(+) with 1s(2)1p(6)1d(10)2s(2) shell occupation, the electronic-shell structure of 1s(2)1p(6)1d(6)2s(2)1d(4) for the Al(6)Be cluster demonstrates that the impurity atom makes the molecular orbital distribution of doped clusters much more complex than that of pure metal clusters.
RESUMO
DNA damage to peripheral blood lymphocytes of patients with Graves' disease (GD) was studied in vitro before and after treatment with antioxidants, melatonin, quercetin, N-acetylcysteine (NAC) and vitamin C. DNA damage (comet %) was remarkably higher in patients (23.7 +/- 5.5%) than that in healthy persons (9.8 +/- 3.2%, p < 0.01). Plasma malondialdehyde (MDA) content (7.90 +/- 1.77 microM) of patients was significantly higher than that of healthy persons (4.71 +/- 1.19 microM, p < 0.01). Also, the plasma total antioxidant capacity (TAC) (7.53 +/- 1.35 U/ml) in GD patients was significantly lower than that in healthy persons (10.56 +/- 2.21 U/ml, p < 0.01). Negative correlations were observed between plasma TAC and DNA damage in lymphocytes (r = -0.599, p < 0.01), and between plasma TAC and MDA (r = -0.40, p < 0.05) in GD patients. After treatment with 100 microM melatonin, quercetin or NAC for 4 h in vitro, DNA damage in lymphocytes in GD patients declined significantly (from 23.8 +/- 4.4% to 14.4 +/- 4.0%, p < 0.001 for melatonin, from 23.4 +/- 4.7% to 18.1 +/- 4.3%, p < 0.01 for quercetin, from 23.7 +/- 4.0% to 18.7 +/- 5.7%, p < 0.05 for NAC), while there was little change with concentrations of 1-100 microM of vitamin C. However, 1000 microM vitamin C enhanced DNA damage significantly (from 23.8 +/- 2.3% to 30.3 +/- 3.9%, p < 0.05). Our results showed that oxidative stress existed in GD patients and the antioxidants melatonin, quercetin and NAC are beneficial for DNA damage in lymphocytes of GD patients in vitro.