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1.
Food Chem Toxicol ; : 112629, 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34673182

RESUMO

DON is commonly found in foods and feeds; it presents health risks, especially an increase of growth inhibition in humans, particularly children and infants. However, there are relatively few research studies devoted to the mechanism of DON-mediated growth retardation. Interestingly, our results showed that DON does not cause any significant production of ROS but results in a persistent and significant release of NO with iNOS increasing activity, mitochondrial ultrastructural changes and decreasing ΔΨm. Moreover, the significant decreases in GH production and secretion induced by DON were dose-dependent, accompanied by an increase of caspase 3, 8 and 9, IL-11, IL-lß and GHRH. NO scavenging agent (haemoglobin) and free radical scavenging agent (N-acetylcysteine) partially reversed mitochondrial damage, and Z-VAD-FMK increased the levels of GH and decreased the levels of caspase 3, 8 and 9, while haemoglobin decreased the levels of caspase 3, 8 and 9, indicating that NO is the primary target of DON-mediated inhibition. Present research study firstly demonstrated that NO is a key mediator of DON-induced growth inhibition and plays critical roles in the interference of GH transcription and synthesis. The current research is conducive to future research on the molecular mechanisms of DON-induced growth inhibition in humans, especially children.

2.
Cell Biol Toxicol ; 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34581912

RESUMO

Alimentary toxic aleukia (ATA) is correlated with consuming grains contaminated by Fusarium species, particularly T-2 toxin, which causes serious hurt to human and animal health, chiefly in disorders of the haematopoietic system. However, the mechanism of haematopoietic dysfunction induced by T-2 toxin and the possible target pathway for the treatment of T-2 toxin-induced haematopoietic disorder of ATA remains unclear. In this study, genomes and proteomics were used for the first time to investigate the key differential genes and proteins that inhibit erythroid differentiation of K562 cells caused by T-2 toxin, and it was found that heat shock protein 27 (HSP27) and membrane-spanning 4-domains, subfamily A, member 3 (MS4A3) may play an important role in erythroid differentiation. Meanwhile, MS4A3 interference can inhibit the occurrence of erythroid differentiation of K562 cells and promote the phosphorylation of HSP27. Moreover, the binding of HSP27 to MS4A3 in natural state can activate the phosphorylation site of HSP27 (Ser-83), while T-2 toxin can abolish the activation of phosphorylation site by inhibiting the expression of MS4A3. These findings for the first time demonstrated that the MS4A3-HSP27 pathway may function an efficient therapeutic target pathway for treating T-2 toxin elicited haematopoietic disorders of ATA.

3.
J Phys Chem Lett ; 12(32): 7708-7716, 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34355897

RESUMO

NOx emission heavily affects our environment and human health. Photocatalytic denitrification (deNOx) attracted much attention because it is low-cost and nonpolluting, but undesired nitrite and nitrate were produced in reality, instead of harmless N2. Unveiling the active sites and the photocatalytic mechanism is very important to improve the process. Herein, we have employed a combinational scenario to investigate the reaction mechanism of NO2 and H2O on anatase TiO2(101). On the one hand, a polaron-corrected GGA functional (GGA + Lany-Zunger) was applied to improve the description of electronic states in photoassisted processes. On the other hand, a reaction phase diagram (RPD) was established to understand the (quasi) activity trend over both perfect and defective surfaces. It was found that a perfect surface is more active via the Eley-Rideal mechanism without NO2 adsorption, while the activity on defective surfaces is limited by the sluggish recombinative desorption. A photogenerated hole can weaken the OH* adsorption energies and circumvents the scaling relation of the dark reaction, eventually enhancing the deNOx activity significantly. The insights gained from our work indicate that tuning the reactivity by illumination-induced localized charge and diverse reaction pathways are two methods for improving adsorption, dissociation, and desorption processes to go beyond the conventional activity volcano plot limit of dark conditions.


Assuntos
Dióxido de Nitrogênio/química , Titânio/química , Adsorção , Catálise/efeitos da radiação , Cinética , Modelos Químicos , Termodinâmica , Titânio/efeitos da radiação , Raios Ultravioleta , Água/química
4.
Chem Commun (Camb) ; 57(67): 8300-8303, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34318806

RESUMO

Developing synaptic devices with environment-friendly materials is a promising research direction. Here, light-stimulated synaptic transistors based on natural carotene and organic semiconductors were developed. Several important functions similar to biological synapses were realized and an ultra-low power consumption of 3.4 × 10-18 J was achieved.

5.
Food Chem Toxicol ; 152: 112183, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33836209

RESUMO

T-2 toxin, the most virulent toxin produced by the Fusarium genus, is thought to be the main cause of fatal cardiomyopathy known as Keshan disease. However, the mechanisms of T-2 toxin-induced cardiac toxicity and possible targets for its treatment remain unclear. In the present study, male Wistar rats were administered with 2 mg/kg b. w. T-2 toxin (i.g.) and sacrificed on day 7 after exposure. The hematological indices (CK, LDH) and electrocardiogram were significantly abnormal, the ultrastructure of mitochondria in the heart was changed, and the percentage of collagen area was significantly increased in the T-2 toxin-treated group. Meanwhile, T-2 toxin activated the TGF-ß1/Smad2/3 signalling pathway, and also activated PPAR-γ expression in rats and H9C2 cells. Further application of PPAR-γ agonist (pioglitazone) and antagonist (GW9662) in H9C2 cells revealed that the up-regulation of PPAR-γ expression induced by T-2 toxin is a self-preservation phenomenon, and increasing exogenous PPAR-γ can alleviate the increase in TGF-ß1 caused by T-2 toxin, thereby playing a role in relieving cardiac fibrosis. These findings for the first time demonstrate that T-2 toxin can regulate the expression of PPAR-γ and that PPAR-γ has the potential to serve as an effective therapeutic target in T-2 toxin-induced cardiac fibrosis of rats.


Assuntos
Cardiomiopatias/metabolismo , Fibrose/metabolismo , PPAR gama/metabolismo , Toxina T-2/toxicidade , Anilidas/farmacologia , Animais , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/complicações , Cardiomiopatias/patologia , Linhagem Celular , Colágeno/metabolismo , Fibrose/induzido quimicamente , Fibrose/complicações , Fibrose/patologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , PPAR gama/agonistas , PPAR gama/antagonistas & inibidores , Pioglitazona/farmacologia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos
6.
Pharmacol Ther ; 219: 107702, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33022300

RESUMO

Cardiac fibrosis is a pathogenic factor of many cardiovascular diseases (CVD), which seriously affects people's life, and health and causes huge economic losses. Increasing evidence has shown that peroxisome proliferator-activated receptors (PPARs) can regulate the progression of cardiac fibrosis. For the first time, this review systematically summarizes the literature on cardiac fibrosis from the perspective of PPARs from 2010 to 2020. Moreover, the role of each PPARs in cardiac fibrosis was clarified in this scientific revision from the perspectives of pharmacologically active substances, known agonists, natural extract compounds, and nucleic-acid-based drugs in different CVD models. Furthermore, the combination of multiple PPARs on the treatment of cardiac fibrosis is discussed. This scientific review provides new ideas for targeting PPARs in the treatment of cardiac fibrosis and provides strategies for the development of new, safe, and effective pharmacological antagonists against cardiac fibrosis based on PPAR activity.

7.
J Hazard Mater ; 402: 123846, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33254818

RESUMO

Persulfate-based advanced oxidation technology exhibits great potential for hazardous organic pollutant removal from wastewater. Acceleration of pollutant degradation needs to be elucidated, particularly for heterogeneous catalytic systems. In this study, manganese oxide ordered mesoporous carbon composites (MnOx@OMC) were prepared by nano-casting method and used for persulfate activation to degrade phenol. Kinetics analysis indicate that the rate of phenol degradation using MnOx@OMC composites was improved by 34.9 folds relative to that using a mixture of MnOx and OMC. The phenol toxicity towards Caenorhabditis elegans could be totally reduced within 8 min. The different roles of MnOx and OMC in persulfate activation were confirmed to validate their synergistic effect. MnOx provided major active sites for persulfate activation in accordance with the surface Mn3+/Mn4+ cycle to induce SO4•- radicals. The OMC matrix provided the adsorption sites to enrich phenol molecules on the catalytic surface and promote the interfacial electron transfer process for persulfate activation. Moreover, a novel kinetic model with two distinct kinetic stages was established to verify the effects of phenol and persulfate on phenol removal.

8.
Med Res Rev ; 41(3): 1751-1774, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33368430

RESUMO

Obesity syndromes, characterized by abnormal lipid, cholesterol, and glucose metabolism, are detrimental to human health and cause many diseases, including obesity and type II diabetes. Increasing evidence has shown that long noncoding RNA (lncRNA), transcripts longer than 200 nucleotides that are not translated into proteins, play an important role in regulating abnormal metabolism in obesity syndromes. For the first time, we systematically summarize how lncRNA is involved in complex obesity metabolic syndromes, including the regulation of lipid, cholesterol, and glucose metabolism. Moreover, we discuss lncRNA involvement in food intake that mediates obesity syndromes. Furthermore, this review might shed new light on a lncRNA-based strategy for the prevention and treatment of obesity syndromes. Recent investigations support that lncRNA is a novel molecular target of obesity syndromes and should be emphasized. Namely, lncRNA plays a crucial role in the development of obesity syndrome process. Various lncRNAs are involved in the process of lipid, cholesterol, and glucose metabolism by regulating gene transcription, signaling pathway, and epigenetic modification of metabolism-related genes, proteins, and enzymes. Food intake could also induce abnormal expression of lncRNA associated with obesity syndrome, especially high-fat diet. Notably, some nanomolecules and natural extracts may target lncRNAs, associated with obesity syndrome, as a potential treatment for obesity syndromes.

9.
Med Sci Monit ; 26: e926941, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33175722

RESUMO

BACKGROUND At present, the relationships among COVID-19 disease progression, patient prognosis, and immune status are unclear. This single-center retrospective study evaluated the correlation between serum interleukin-6 (IL-6) levels at admission with the severity of COVID-19 pneumonia, as determined by admission to the intensive Care Unit (ICU). MATERIAL AND METHODS Patients admitted to The First Affiliated Hospital of Bengbu Medical College in Bengbu City, Anhui Province, China, in January and February 2020 for COVID-19 pneumonia were enrolled in this study. COVID-19 infection was confirmed by the detection of SARS-CoV-2 nucleic acid in throat swab samples using real-time fluorescent reverse transcription PCR. Serum IL-6 concentrations at admission were measured by ELISA. Correlations between serum IL-6 concentrations and ICU admission due to the development of severe COVID-19 pneumonia were evaluated. RESULTS This study enrolled 68 patients with novel coronavirus pneumonia. IL-6 concentrations were significantly higher in patients with more severe than less severe COVID-19 pneumonia. Eight of 40 patients with severe COVID-19 pneumonia became critically ill and required ICU admission. IL-6 concentrations were significantly higher in patients with severe COVID-19 pneumonia who were than who were not treated in the ICU. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.816 (P<0.01), indicating that IL-6 was prognostic of disease severity in patients with COVID-19 pneumonia. CONCLUSIONS Serum IL-6 concentration is closely associated with the severity of COVID-19. Continuous monitoring of IL-6 has clinical value in evaluating patient condition.


Assuntos
COVID-19/diagnóstico , Interleucina-6/sangue , SARS-CoV-2/imunologia , Adulto , Idoso , COVID-19/sangue , COVID-19/epidemiologia , COVID-19/imunologia , China/epidemiologia , Estado Terminal/epidemiologia , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pandemias , Admissão do Paciente , Prognóstico , Curva ROC , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação
10.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(7): 930-935, 2020 Jul 30.
Artigo em Chinês | MEDLINE | ID: mdl-32895152

RESUMO

OBJECTIVE: To assess the effect of neutralizing CD96 on natural killer (NK) cell functions in mice with pulmonary Chlamydia muridarum infection and explore the possible mechanism. METHODS: Male BALB/c mice were randomly divided into infection group (Cm group), anti-CD96 treatment group (anti-CD96 group) and control group (n=5). In the former two groups, C. muridarum was inoculated via intranasal administration to establish mouse models of pulmonary C. muridarum infection, and the mice in the control group received intranasal administration of the inhalation buffer. In anti-CD96 group, the mice were injected with anti-CD96 antibody intraperitoneally at the dose of 250 µg every 3 days after the infection; the mice in Cm group received intraperitoneal injections of saline. The body weight of the mice was recorded daily. The mice were sacrificed 5 days after C. muridarum infection, and CD96 expression was detected by quantitative real-time PCR and Western blotting. HE staining and pathological scores were used to evaluate pneumonia of the mice. The inclusion body forming units (IFUs) were detected in the lung tissue homogenates to assess lung tissue chlamydia load. Flow cytometry and ELISA were used to assess the capacity of the lung NK cells to produce interferon-γ (IFN-γ) and regulate macrophages and Th1 cells. RESULTS: C. muridarum infection inhibited CD96 expression in NK cells of the mice. Compared with those in Cm group, the mice in antiCD96 mice showed significantly milder lung inflammation (P < 0.05) and reduced chlamydia load in the lung tissue (P < 0.05). Neutralizing CD96 with anti-CD96 significantly enhanced IFN-γ secretion by the NK cells (P < 0.05) and augmented the immunoregulatory effect of the NK cells shown by enhanced responses of the lung macrophages (P < 0.05) and Th1 cells (P < 0.05). CONCLUSIONS: Inhibition of CD96 alleviates pneumonia in C. muridarum-infected mice possibly by enhancing IFN-γ secretion by NK cells and augmenting the immunoregulatory effect of the NK cells on innate and adaptive immunity.


Assuntos
Infecções por Chlamydia , Chlamydia muridarum , Células Matadoras Naturais , Lesão Pulmonar , Animais , Antígenos CD , Interferon gama , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
11.
Expert Opin Drug Deliv ; 17(10): 1473-1484, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32749895

RESUMO

BACKGROUND: A novel nanoemulsion (CU/FU-LN) was developed as an oral 5-fluorouracil and curcumin co-delivery system for synergistic efficacy against liver cancer. METHODS: MTT assay, confocal laser scanning microscope, and H&E staining were utilized to establish the efficacy and safety of CU/FU-LN. RESULTS: The AUC(0-t) of CU/FU-LN was 8.85-fold and 8.59-fold greater than those of CU and FU, respectively. The IC50 of CU/FU-LN was 4.6-fold and 4.9-fold lower than those of FU and CU in HepG2 cells, respectively. In vivo anti-tumor trials, the tumor inhibition rate was significantly elevated by CU/FU-LN (49.29%), compared 24.84% and 4.72% for FU and CU, respectively. Ki-67 immunohistochemical analysis revealed that CU/FU-LN had an obvious anti-proliferation effect. The IC50 of CU/FU-LN in L02 cells was 1.51-fold and 2.60-fold higher than those of CU and FU, respectively. Certain vital organs in the mice of the CU/FU-LN group showed markedly fewer lesions than those of the CU, FU, and CU+FU groups. The CU/FU-LN treatment caused no significant change in mouse body weight relative to the control group (P > 0.05). CONCLUSIONS: We successfully prepared a promising co-delivery platform for the synergistic treatment of liver cancer and it has a comparatively enhanced efficacy and mitigated toxicity.


Assuntos
Curcumina/administração & dosagem , Fluoruracila/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Curcumina/farmacologia , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ratos , Ratos Sprague-Dawley
12.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 40(7): 930-935, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32701231

RESUMO

OBJECTIVE: To assess the effect of neutralizing CD96 on natural killer (NK) cell functions in mice with pulmonary Chlamydia muridarum infection and explore the possible mechanism. METHODS: Male BALB/c mice were randomly divided into infection group (Cm group), anti-CD96 treatment group (anti-CD96 group) and control group (n=5). In the former two groups, C. muridarum was inoculated via intranasal administration to establish mouse models of pulmonary C. muridarum infection, and the mice in the control group received intranasal administration of the inhalation buffer. In anti-CD96 group, the mice were injected with anti-CD96 antibody intraperitoneally at the dose of 250 µg every 3 days after the infection; the mice in Cm group received intraperitoneal injections of saline. The body weight of the mice was recorded daily. The mice were sacrificed 5 days after C. muridarum infection, and CD96 expression was detected by quantitative real-time PCR and Western blotting. HE staining and pathological scores were used to evaluate pneumonia of the mice. The inclusion body forming units (IFUs) were detected in the lung tissue homogenates to assess lung tissue chlamydia load. Flow cytometry and ELISA were used to assess the capacity of the lung NK cells to produce interferon-γ (IFN-γ) and regulate macrophages and Th1 cells. RESULTS: C. muridarum infection inhibited CD96 expression in NK cells of the mice. Compared with those in Cm group, the mice in antiCD96 mice showed significantly milder lung inflammation (P < 0.05) and reduced chlamydia load in the lung tissue (P < 0.05). Neutralizing CD96 with anti-CD96 significantly enhanced IFN-γ secretion by the NK cells (P < 0.05) and augmented the immunoregulatory effect of the NK cells shown by enhanced responses of the lung macrophages (P < 0.05) and Th1 cells (P < 0.05). CONCLUSIONS: Inhibition of CD96 alleviates pneumonia in C. muridarum-infected mice possibly by enhancing IFN-γ secretion by NK cells and augmenting the immunoregulatory effect of the NK cells on innate and adaptive immunity.


Assuntos
Infecções por Chlamydia , Chlamydia muridarum , Interferon gama , Lesão Pulmonar , Animais , Antígenos CD/metabolismo , Infecções por Chlamydia/complicações , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/fisiopatologia , Interferon gama/genética , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Lesão Pulmonar/etiologia , Lesão Pulmonar/genética , Lesão Pulmonar/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
13.
Food Chem Toxicol ; 140: 111258, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32240701

RESUMO

Although many studies have shown that inflammatory response plays a crucial role in the various toxic effects of T-2 toxin, there are relatively few reports on the mechanism of this phenomenon. Meanwhile, accumulating evidence has shown that miR-155-5p is activated in the inflammatory response. As molecular pathways and mechanisms involved in T-2 toxin-induced inflammatory response are poorly elucidated, we assessed whether miR-155-5p is involved in the inflammation effects mediated by T-2 toxin. Treatment of RAW264.7 cells with T-2 toxin (14 nM and 12 h) resulted in inflammatory response and associated with alteration of the gene expression signature of miR-155-5p. Knockdown or overexpression of miR-155-5p both indicated that miR-155-5p positively regulated the expression of the inflammation factors. Moreover, bioinformatics prediction and luciferase assay indicated that atg3 and rheb are targets of miR-155-5p. However, atg3 and SOCS1 play positive roles in the inflammatory response regulated by miR-155-5p, while rheb plays a negative role. In addition, the in vivo study showed that single administration of T-2 toxin in mice enhances spleen immune response, which was accompanied by an overexpression of miR-155-5p. These findings indicate that miR-155-5p might have an important role associated with the inflammatory response induced by T-2 toxin. In conclusion, a dual character of miR-155-5p in inflammation response was revealed, which might exist in other reactions in which miR-155-5p is involved.


Assuntos
Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , MicroRNAs/metabolismo , Animais , Camundongos , Células RAW 264.7 , Transdução de Sinais , Toxina T-2 , Regulação para Cima
14.
J Chem Phys ; 152(12): 124705, 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32241134

RESUMO

Photocatalysis induced by sunlight is one of the most promising approaches to environmental protection, solar energy conversion, and sustainable production of fuels. The computational modeling of photocatalysis is a rapidly expanding field that requires to adapt and to further develop the available theoretical tools. The coupled transfer of protons and electrons is an important reaction during photocatalysis. In this work, we present the first step of our methodology development in which we apply the existing kinetic theory of such coupled transfer to a model system, namely, methanol photodissociation on the rutile TiO2(110) surface, with the help of high-level first-principles calculations. Moreover, we adapt the Stuchebrukhov-Hammes-Schiffer kinetic theory, where we use the Georgievskii-Stuchebrukhova vibronic coupling to calculate the rate constant of the proton coupled electron transfer reaction for a particular pathway. In particular, we propose a modified expression to calculate the rate constant, which enforces the near-resonance condition for the vibrational wave function during proton tunneling.

15.
Phytother Res ; 34(10): 2438-2458, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32255545

RESUMO

Malignant tumor endangers seriously the health of all mankind. Multidrug resistance (MDR) is one of the main causes of clinical tumor chemotherapy failure. Curcumin (CUR) has not only antitumor activity but also reversing tumor MDR effect. CUR reverses tumor MDR via regulating related signal pathways or corresponding expressed proteins or gene. When combined with chemotherapeutic agents, CUR can be a chemotherapeutic sensitive agent to enhance chemotherapy efficacy and weaken tumor MDR. On the other hand, to improve the MDR reversal effect of CUR, its derivatives have been extensively studied. Therefore, this article mainly focuses on reviewing the application of CUR and its derivatives in MDR and its mechanism of reversing MDR.


Assuntos
Curcumina/análogos & derivados , Curcumina/uso terapêutico , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Curcumina/farmacologia , Humanos , Neoplasias/patologia , Fitoterapia , Transdução de Sinais/efeitos dos fármacos
16.
J Cancer ; 11(13): 3955-3964, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32328199

RESUMO

Curcumin (CU) has shown broad anti-cancer effects. 5-fluorouracil (5-FU) has been a conventional chemotherapeutic agent for hepatocellular carcinoma. Unfortunately, the nonspecific cytotoxicity and multidrug resistance caused by long-term use limited the clinical efficacy of 5-FU. This study was aimed to investigate whether the combination of CU and 5-FU could generate synergistic effect in inhibiting the human hepatocellular carcinoma. The results of cytotoxicity test showed that compared with applying single drugs, the combination of CU and 5-FU (1:1, 1:2, 1:4, 2:1 and 4:1, mol/mol) presented stronger cytotoxicity in SMMC-7721, Bel-7402, HepG-2 and MHCC97H cells, while the combination groups are relatively insensitive to normal hepatocytes (L02). Among them, the molar ratio of 2:1 combination group showed strong synergistic effect in SMMC-7721cells. Then, western blotting assay further verified that the mechanism of the synergistic effect may be related to the inhibition of the expression of NF-κB (overall) and COX-2 protein. In addition, the synergistic effect was also validated in the xenograft mice in vivo. This research not only provides a novel and effective combination strategy for the therapy of hepatocellular carcinoma but also provides an experimental basis for the development of CU and 5-FU compound preparation.

17.
Biochemistry ; 59(18): 1756-1768, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32293884

RESUMO

The majority of current drugs against diseases, such as cancer, can bind to one or more sites in a protein and inhibit its activity. There are, however, well-known limits on the number of druggable proteins, and complementary current drugs with compounds that could selectively target DNA or RNA would greatly enhance the availability of cellular probes and therapeutic progress. We are focusing on the design of sequence-specific DNA minor groove binders that, for example, target the promoter sites of transcription factors involved in a disease. We have started with AT-specific minor groove binders that are known to enter human cells and have entered clinical trials. To broaden the sequence-specific recognition of these compounds, several modules that have H-bond acceptors that strongly and specifically recognize G·C base pairs were identified. A lead module is a thiophene-N-alkyl-benzimidazole σ-hole-based system with terminal phenyl-amidines that have excellent affinity and selectivity for a G·C base pair in the minor groove. Efforts are now focused on optimizing this module. In this work, we are evaluating modifications to the compound aromatic system with the goal of improving GC selectivity and affinity. The lead compounds retain the thiophene-N-alkyl-BI module but have halogen substituents adjacent to an amidine group on the terminal phenyl-amidine. The optimum compounds must have strong affinity and specificity with a residence time of at least 100 s.


Assuntos
Amidinas/química , Benzimidazóis/química , DNA/análise , DNA/química , Tiofenos/química , Pareamento de Bases , Humanos , Estrutura Molecular
18.
Expert Opin Drug Deliv ; 17(5): 665-675, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32149539

RESUMO

Introduction: Many active ingredients from natural plants (AINPs) have been revealed to possess remarkable anticancer properties. Combination chemotherapy of chemo-drugs and AINPs has also proven to be more advantageous than individual chemo-drug treatment with respect to enhancing efficiency, alleviating toxicity, and controlling the development of multidrug resistance (MDR). Co-delivery is considered a promising method to effectively achieve and manage combination chemotherapy of chemo-drugs and AINPs, and various distinctive and functional co-delivery systems have been designed for these purposes to date.Areas covered: This review focuses on recent preclinical investigations of co-delivery systems for chemo-drugs and AINPs as new cancer treatment modalities. We particularly emphasize the apparent treatment advantages of these approaches, including augmenting efficiency, reducing toxicity, and controlling MDR.Expert opinion: There has already been notable progress in the application of combination chemotherapy with co-delivery systems loaded with chemo-drugs and AINPs based on results with cellular and animal models. The main challenge is to translate these successes into new anticancer compound preparations and promote their clinical application in practice. Nevertheless, continuous efforts with new designs of co-delivery systems remain essential, providing a foundation for future clinical research and development of new anticancer drugs.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Animais , Resistência a Múltiplos Medicamentos , Humanos , Preparações de Plantas/administração & dosagem
19.
Chemistry ; 26(20): 4539-4551, 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-31884714

RESUMO

A series of small diamidines with thiophene and modified N-alkylbenzimidazole σ-hole module represent specific binding to single G⋅C base pair (bp) DNA sequence. The variation of N-alkyl or aromatic rings were sensitive to microstructures of the DNA minor groove. Thirteen new compounds were synthesized to test their binding affinity and selectivity. The dicyanobenzimidazoles needed to synthesize the target diamidines were made via condensation/cyclization reactions of different aldehydes with different 3-amino-4-(alkyl- or phenyl-amino) benzonitriles. The final diamidines were synthesized using lithium bis-trimethylsilylamide (LiN[Si(CH3 )3 ]2 ) or Pinner methods. The newly synthesized compounds showed strong binding and selectivity to AAAGTTT compared to similar sequences AAATTT and AAAGCTTT investigated by several biophysical methods including biosensor-SPR, fluorescence spectroscopy, DNA thermal melting, ESI-MS spectrometry, circular dichroism, and molecular dynamics. The binding affinity results determined by fluorescence spectroscopy are in accordance with those obtained by biosensor-SPR. These small size single G⋅C bp highly specific binders extend the compound database for future biological applications.


Assuntos
DNA/química , Pentamidina/química , Tiofenos/química , Pareamento de Bases , Técnicas Biossensoriais/métodos , Dicroísmo Circular , Espectrometria de Fluorescência
20.
Bioorg Med Chem Lett ; 30(1): 126725, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732409

RESUMO

Cyanine compounds have previously shown excellent in vitro and promising in vivo antileishmanial efficacy, but the potential toxicity of these agents is a concern. A series of 22 analogs of thiazole orange ((Z)-1-methyl-4-((3-methylbenzo[d]thiazol-2(3H)-ylidene)methyl)quinolin-1-ium salt), a commercial cyanine dye with antileishmanial activity, were synthesized in an effort to increase the selectivity of such compounds while maintaining efficacy. Cyanines possessing substitutions on the quinolinium ring system displayed potency against Leishmania donovani axenic amastigotes that differed little from the parent compound (IC50 12-42 nM), while ring disjunction analogs were both less potent and less toxic. Changes in DNA melting temperature were modest when synthetic oligonucleotides were incubated with selected analogs (ΔTm ≤ 5 °C), with ring disjunction analogs showing the least effect on this parameter. Despite the high antileishmanial potency of the target compounds, their toxicity and relatively flat SAR suggests that further information regarding the target(s) of these molecules is needed to aid their development as antileishmanials.


Assuntos
Benzotiazóis/síntese química , Leishmaniose Visceral/metabolismo , Quinolinas/síntese química , Animais , Descoberta de Drogas
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