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1.
Acta Virol ; 63(3): 278-285, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507193

RESUMO

Dengue virus (DENV) infection is one of the most widely-spread flavivirus infections with no effective antiviral drugs available. Peptide inhibitors have been considered as one of the best drug candidates due to their high specificity, selectivity in their interactions and minimum side effects. In this study, we employed computational studies using YASARA, HADDOCK server and PyMOL software to generate short and linear peptides based on a reference peptide, CP5-46A, to block DENV NS2B-NS3 protease. The inhibition potencies of the peptides were evaluated using in-house DENV2 serine protease and fluorogenic peptide substrates. In vitro analyses were performed to determine the peptides cytotoxicity and the inhibitory effects against DENV2 replication in WRL-68 cells. Our computational analyses revealed that the docking energy of AYA3, a 16 amino acid (aa) (-81.2 ± 10.6 kcal/mol) and AYA9, a 15 aa peptide (-83.8 ± 6.8 kcal/mol) to DENV NS2B-NS3 protease were much lower than the reference peptide (46 aa; -70.9 ± 7.8 kcal/mol) and the standard protease inhibitor, aprotinin (58 aa; -48.2 ± 10.6 kcal/mol). Both peptides showed significant inhibition against DENV2 NS2B-NS3 protease activity with IC50 values of 24 µM and 23 µM, respectively. AYA3 and AYA9 peptides also demonstrated approximately 68% and 83% of viral plaque reduction without significantly affecting cell viability at 50 µM concentration. In short, we generated short linear peptides with lower cytotoxic effect and substantial antiviral activities against DENV2. Further studies are required to investigate the inhibitory effects of these peptides in vivo. Keywords: peptide inhibitors; dengue virus; NS2B-NS3 protease; plaque reduction.


Assuntos
Antivirais , Vírus da Dengue , Peptídeos , Inibidores de Proteases , Replicação Viral , Antivirais/farmacologia , Biologia Computacional , Vírus da Dengue/enzimologia , Ativação Enzimática/efeitos dos fármacos , Humanos , Peptídeos/síntese química , Peptídeos/farmacologia , Inibidores de Proteases/farmacologia , Replicação Viral/efeitos dos fármacos
2.
Pestic Biochem Physiol ; 158: 156-165, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31378352

RESUMO

Culex pipiens is a main vector for Bancroftian filariasis, Rift Valley Fever and diseases caused by other viruses, leaving several peoples with disabilities. In recent years, plant derived compounds have received much attention as potential alternatives to synthetic chemicals due to their low toxicity to mammals and environmental persistence. Twenty-one monoterpenes from different chemical groups (hydrocarbons and oxygenated products) were evaluated against Culex pipiens larvae. In addition, in vivo biochemical studies including effects on acetylcholine esterase (AChE), acid and alkaline phosphatases (ACP and ALP), total adenosine triphosphatase (ATPase) and gamma-aminobutyric acid transaminase (GABA-T) were investigated. Furthermore, in silico studies including pharmacophore elucidation, ADMET analysis and molecular docking of these compounds were performed. Among all tested monoterpenes, hydrocarbons [p-cymene, (R)-(+)-limonene and (+)-α-pinene], acetates (cinnamyl acetate, citronellyl acetate, eugenyl acetate and terpinyl acetate), alcohols [(±)-ß-citronellol and terpineol], aldehydes [citral and (1R)-(-)-myrtenal] and ketone [(R)-(+)-pulegone] exhibited the highest larval toxicity with LC50 = 14.88, 27.97, 26.13, 2.62, 3.81, 2.74, 21.65, 1.64, 21.70, 21.76, 1.68 and 1.90 mg/L after 48 h of exposure, respectively. The compounds proved a significant inhibition of all tested enzymes except total ATPase. The biochemical and molecular docking studies proved that AChE and GABA-T were the main targets for the tested monoterpenes.


Assuntos
Culex/virologia , Inseticidas/farmacologia , Monoterpenos/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Culex/patogenicidade , Filariose Linfática/transmissão , Ativação Enzimática/efeitos dos fármacos , Esterases/metabolismo , Simulação de Acoplamento Molecular , Transaminases/metabolismo
3.
J Enzyme Inhib Med Chem ; 34(1): 1178-1185, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31282230

RESUMO

The activation of the ß-class carbonic anhydrases (CAs, EC 4.2.1.1) from the bacteria Brucella suis and Francisella tularensis with amine and amino acids was investigated. BsuCA 1 was sensitive to activation with amino acids and amines, whereas FtuCA was not. The most effective BsuCA 1 activators were L-adrenaline and D-Tyr (KAs of 0.70-0.95 µM). L-His, L-/D-Phe, L-/D-DOPA, L-Trp, L-Tyr, 4-amino-L-Phe, dopamine, 2-pyridyl-methylamine, D-Glu and L-Gln showed activation constants in the range of 0.70-3.21 µM. FtuCA was sensitive to activation with L-Glu (KA of 9.13 µM). Most of the investigated compounds showed a weak activating effect against FtuCA (KAs of 30.5-78.3 µM). Many of the investigated amino acid and amines are present in high concentrations in many tissues in vertebrates, and their role in the pathogenicity of the two bacteria is poorly understood. Our study may bring insights in processes connected with invasion and pathogenic effects of intracellular bacteria.


Assuntos
Aminas/farmacologia , Aminoácidos/farmacologia , Brucella suis/enzimologia , Anidrases Carbônicas/metabolismo , Ativação Enzimática/efeitos dos fármacos , Francisella tularensis/enzimologia , Aminas/química , Aminoácidos/química , Anidrases Carbônicas/genética , Relação Estrutura-Atividade
4.
Cytogenet Genome Res ; 158(1): 17-24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31261155

RESUMO

Osteoarthritis (OA) is a degenerative disease characterized by progressive articular cartilage destruction and joint marginal osteophyte formation with different degrees of synovitis. Docosahexaenoic acid (DHA) is an unsaturated fatty acid with anti-inflammatory, antioxidant, and antiapoptotic functions. In this study, the human chondrosarcoma cell line SW1353 was cultured in vitro, and an OA cell model was constructed with inflammatory factor IL-1ß stimulation. After cells were treated with DHA, cell apoptosis was measured. Western blot assay was used to detect protein expression of apoptosis-related factors (Bax, Bcl-2, and cleaved caspase-3) and mitogen-activated protein kinase (MAPK) signaling pathway family members, including extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), and p38 MAPK. Our results show that IL-1ß promotes the apoptosis of SW1353 cells, increases the expression of Bax and cleaved caspase-3, and activates the MAPK signaling pathway. In contrast, DHA inhibits the expression of IL-1ß, inhibits IL-1ß-induced cell apoptosis, and has a certain inhibitory effect on the activation of the MAPK signaling pathway. When the MAPK signaling pathway is inhibited by its inhibitors, the effects of DHA on SW1353 cells are weakened. Thus, DHA enhances the apoptosis of SW1353 cells through the MAPK signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Ósseas/patologia , Condrossarcoma/patologia , Ácidos Docosa-Hexaenoicos/farmacologia , Interleucina-1beta/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Butadienos/farmacologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Interleucina-1beta/farmacologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Nitrilos/farmacologia , Inibidores de Proteínas Quinases/farmacologia
5.
Pestic Biochem Physiol ; 157: 60-68, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31153478

RESUMO

A series of novel substituted oxazole isoxazole carboxamides derivatives were designed on the basis of active subunit combination. Forty-four novel compounds were synthesized by an efficient one-pot procedure under microwave irradiation. The bioactivity was evaluated as herbicide safener against the injury of chlorsulfuron. It was found that most of the synthesized compounds displayed remarkable protection against chlorsulfuron via enhanced glutathione content and glutathione S transferase activity. Especially compound I-11 exhibited better bioactivity than the safeners isoxadifen-ethyl and R-28725. Molecular docking simulations suggested that the target compounds could compete with chlorsulfuron in the active site of acetolactate synthase, which could explain the protective effects of safeners. The present work demonstrates that the target compounds containing oxazole isoxazole groups could be considered as potential candidates for developing novel safeners in the future.


Assuntos
Herbicidas/química , Herbicidas/farmacologia , Isoxazóis/química , Oxazóis/química , Sulfonamidas/farmacologia , Triazinas/farmacologia , Acetolactato Sintase/genética , Acetolactato Sintase/metabolismo , Ativação Enzimática/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Relação Estrutura-Atividade , Zea mays/enzimologia
6.
Int J Oncol ; 55(1): 59-68, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180529

RESUMO

The present study investigated the effects of the combined treatment of two peptide nucleic acids (PNAs), directed against microRNAs involved in caspase­3 mRNA regulation (miR­155­5p and miR­221­3p) in the temozolomide (TMZ)­resistant T98G glioma cell line. These PNAs were conjugated with an octaarginine tail in order to obtain an efficient delivery to treated cells. The effects of singularly administered PNAs or a combined treatment with both PNAs were examined on apoptosis, with the aim to determine whether reversion of the drug­resistance phenotype was obtained. Specificity of the PNA­mediated effects was analyzed by reverse transcription­quantitative polymerase­chain reaction, which demonstrated that the effects of R8­PNA­a155 and R8-PNA-a221 anti­miR PNAs were specific. Furthermore, the results obtained confirmed that both PNAs induced apoptosis when used on the temozolomide­resistant T98G glioma cell line. Notably, co­administration of both anti­miR­155 and anti­miR­221 PNAs was associated with an increased proapoptotic activity. In addition, TMZ further increased the induction of apoptosis in T98G cells co­treated with anti­miR­155 and anti­miR­221 PNAs.


Assuntos
Caspase 3/metabolismo , Glioma/tratamento farmacológico , Glioma/genética , MicroRNAs/antagonistas & inibidores , Ácidos Nucleicos Peptídicos/farmacologia , Temozolomida/farmacologia , Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Glioma/enzimologia , Humanos , MicroRNAs/genética , Ácidos Nucleicos Peptídicos/genética
7.
Aquat Toxicol ; 212: 241-246, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31150951

RESUMO

Nowadays, eutrophication is a very popular environmental problem in numerous waters around the world. The main reason of eutrophication is the enrichment of the nutrient, which results in the excessive growth of phytoplankton and some of them are toxic and harmful. Fortunately, some studies have shown that some bivalves can filter the overgrown phytoplankton in water, which may alleviate water eutrophication. However, the physiological effects of toxic cyanobacteria on filter feeding animal have not been clarified very well. In this experiment, digestive enzyme activities in Hyriopsis cumingii exposed to different concentrations of the toxic Microcystis aeruginosa (0, 5 * 105 and 5 *106 cell ml-1) at two dissolved oxygen (DO) levels (6 and 2 mg l-1) for 14 days were investigated. Toxic M. aeruginosa significantly affected all digestive enzyme activities throughout the experiment. At high toxic M. aeruginosa concentration, the activities of cellulase, amylase and lipase in digestive gland and stomach were significantly increased (P<0.05). However, hypoxia reduced the activities of cellulase, amylase and lipase in digestive gland and stomach. Conflicting effects were observed between toxic M. aeruginosa and DO in most digestive enzyme activities during the exposure period. Therefore, it is not conducive for the digestion and absorption of M. aeruginosa in H. cumingii under hypoxic conditions. H. cumingii is tolerant to toxic M. aeruginosa and may remove toxic cyanobacteria from waters under normal DO conditions.


Assuntos
Bivalves/efeitos dos fármacos , Microcistinas/toxicidade , Microcystis/química , Anaerobiose/fisiologia , Animais , Bivalves/enzimologia , Bivalves/fisiologia , Ativação Enzimática/efeitos dos fármacos , Enzimas/metabolismo , Eutrofização , Oxigênio/metabolismo , Poluentes Químicos da Água/toxicidade
8.
J Vet Sci ; 20(3): e12, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31161735

RESUMO

The effects of CYP1A enzyme on the pharmacokinetics of p-acetaminophen were studied in Bactrian camel. Twelve Bactrian camels were divided into 2 groups, then given a single dose of p-acetaminophen only or with the enzyme inhibitor lomefloxacin. Blood samples were collected after different intervals, and p-acetaminophen concentration was determined by high-performance liquid chromatography. Pharmacokinetic parameters were analyzed by Phoenix WinNonLin v.7.0. The results show that lomefloxacin can significantly inhibit Bactrian camel CYP1A enzyme, as evidenced by the prolonged elimination half-life, increased maximum plasma concentration and area under the curve values and the shortened time to peak concentration for p-acetaminophenol in the substrate with inhibitor group. The results lay a foundation for revealing the particular characteristics of the CYP1A enzyme in Bactrian camels.


Assuntos
Acetaminofen/farmacocinética , Camelus , Citocromo P-450 CYP1A1/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Fluoroquinolonas/farmacologia , Acetaminofen/sangue , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Ativação Enzimática/efeitos dos fármacos , Meia-Vida
9.
Cell Mol Biol Lett ; 24: 32, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31143210

RESUMO

Objective: Peritoneal fibrosis remains a serious complication of long-term peritoneal dialysis (PD) leading to peritoneal membrane ultrafiltration failure. Epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) is a key process of peritoneal fibrosis. Curcumin has been previously shown to inhibit EMT of renal tubular epithelial cells and prevent renal fibrosis. There are only limited reports on inhibition of PMCs-EMT by curcumin. This study aimed to investigate the effect of curcumin on the regulation of EMT and related pathway in PMCs treated with glucose-based PD. Methods: EMT of human peritoneal mesothelial cells (HMrSV5) was induced with glucose-based peritoneal dialysis solutions (PDS). Cells were divided into a control group, PDS group, and PDS group receiving varied concentrations of curcumin. Cell Counting Kit-8 (CCK-8) assay was used to measure cell viability, and a transwell migration assay was used to verify the capacity of curcumin to inhibit EMT in HMrSV5 cells. Real-time quantitative PCR and western blot were used to detect the expression of genes and proteins associated with the EMT. Results: High glucose PDS decreased cell viability and increased migratory capacity. Curcumin reversed growth inhibition and migration capability of human peritoneal mesothelial cells (HPMCs). In HMrSV5 cells, high glucose PDS also decreased expression of epithelial markers, and increased expression of mesenchymal markers, a characteristic of EMT. Real-time RT-PCR and western blot revealed that, compared to the 4.25% Dianeal treated cells, curcumin treatment resulted in increased expression of E-cadherin (epithelial marker), and decreased expression of α-SMA (mesenchymal markers) (P < 0.05). Furthermore, curcumin reduced mRNA expression of two extracellular matrix protein, collagen I and fibronectin. Curcumin also reduced TGF-ß1 mRNA and supernatant TGF-ß1 protein content in the PDS-treated HMrSV5 cells (P < 0.05). Furthermore, it significantly reduced protein expression of p-TAK1, p-JNK and p-p38 in PDS-treated HMrSV5 cells. Conclusions: Our results demonstrate that curcumin showed an obvious protective effect on PDS-induced EMT of HMrSV5 cells and suggest implication of the TAK1, p38 and JNK pathway in mediating the effects of curcumin in EMT of MCs.


Assuntos
Curcumina/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Epitélio/patologia , MAP Quinase Quinase Quinases/metabolismo , Peritônio/patologia , Biomarcadores/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/toxicidade , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Diálise Peritoneal , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 48(1): 44-49, 2019 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-31102357

RESUMO

Rifamycins, a group of bacterial RNA polymerase inhibitors, are the firstline antimicrobial drugs to treat tuberculosis. In light of the emergence of rifamycinresistant bacteria, development of new RNA polymerase inhibitors that kill rifamycinresistant bacteria with high bioavailability is urgent. Structural analysis of bacterial RNA polymerase in complex with inhibitors by crystallography and cryo-EM indicates that RNA polymerase inhibitors function through five distinct molecular mechanisms:inhibition of the extension of short RNA; competition with substrates; inhibition of the conformational change of the'bridge helix'; inhibition of clamp opening;inhibition of clamp closure. This article reviews the research progress of these five groups of RNA polymerase inhibitors to provide references for the modification of existing RNA polymerase inhibitors and the discovery of new RNA polymerase inhibitors.


Assuntos
RNA Polimerases Dirigidas por DNA , Descoberta de Drogas , RNA Bacteriano , Antituberculosos/uso terapêutico , Bactérias/efeitos dos fármacos , Bactérias/enzimologia , RNA Polimerases Dirigidas por DNA/metabolismo , Descoberta de Drogas/tendências , Farmacorresistência Bacteriana , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Tuberculose/tratamento farmacológico , Tuberculose/enzimologia
11.
Cell Physiol Biochem ; 52(6): 1517-1534, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120230

RESUMO

BACKGROUND/AIMS: Cadmium (Cd) is a heavy metal contaminant whose toxicity is associated with colorectal cancer (CRC). However, the underlying molecular mechanisms of Cd-induced CRC malignancy remain obscure. METHODS: A monolayer scratch assay was employed to assess the migration of HT-29 human adenocarcinoma cells. Luciferase reporter assay was used to determine cyclooxygenase-2 (COX-2) transcriptional activity, and Western blotting was used to detect p38 Mitogen Activated Protein Kinase (MAPK) and Akt phosphorylation as well as COX-2 expression. Prostaglandin E2 (PGE2) levels were measured using Enzyme Linked Immunosorbent Assay (ELISA) and reactive oxygen species (ROS) formation was assessed using dihydroethidium (DHE) stain. RESULTS: Here, we show that Cd potentiates the migratory capacity of HT-29 CRC cells. Cd caused a time-dependent increase in COX-2 expression. Celecoxib, a COX-2 selective inhibitor, significantly reduced Cd-induced migration. Cd also increased levels of ROS and phosphorylated p38. Importantly, Cd-induced COX-2 expression and migration were significantly abolished by N-Acetyl-Cysteine (NAC), a ROS scavenger, or SB202190, a specific p38 inhibitor. Furthermore, Cd-induced p38 phosphorylation was inhibited by NAC. Cd (100 nM) also increased PGE2 levels, which was abrogated by NAC, SB202190, or celecoxib. Exogenous PGE2 significantly potentiated cell migration. Cd caused a significant increase in Akt phosphorylation in a ROS-mediated pathway. Moreover, Cd-induced migration was significantly attenuated by LY294 002, a phosphatidylinositol-3-kinase inhibitor. CONCLUSION: Taken together, our results suggest that exposure to low levels of Cd promotes a more migratory cancer phenotype in a ROS-p38-COX-2-PGE2 pathway as well as ROS-Akt pathway. Therefore, COX-2, PGE2 receptors or Akt represent potential targets in the treatment of CRC, particularly in patients exposed to Cd.


Assuntos
Adenocarcinoma/induzido quimicamente , Cádmio/toxicidade , Neoplasias do Colo/induzido quimicamente , Ciclo-Oxigenase 2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2/genética , Ativação Enzimática/efeitos dos fármacos , Células HT29 , Humanos , Ativação Transcricional/efeitos dos fármacos
12.
Aquat Toxicol ; 212: 138-145, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31125791

RESUMO

Multiple antibiotics are simultaneously detected in aquatic environment, so it is extremely important to study the combined effects of their mixtures. In this study, we investigated the toxic effects of erythromycin (ERY) and enrofloxacin (ENR), added individually or in combination, on Chlorella vulgaris and explored the toxic mechanisms. Results showed that the 96 h-EC50 values of ERY, ENR and ERY-ENR mixture to C. vulgaris were 85.7, 124.5 and 39.9 µg L-1 respectively, and combined toxicity assessment found that joint effect of the two antibiotics was synergism, which was proven by the chlorophyll content in algae. Antioxidant defense system and photosynthesis were involved in toxic mechanisms and the results revealed that both the activities of antioxidant enzymes, and the malondialdehyde (MDA) and glutathione (GSH) contents increased in antibiotic treatments. In addition, the increase was more significant in joint exposure treatment, which implied that the antioxidant defense system was synergistically affected. RT-PCR showed that ERY and ENR upregulated the transcript abundance of psaB, psbC and chlB at low concentrations and the transcription abundance was synergistically increased in combined treatment. Therefore, the risk of the toxicity of antibiotics to aquatic organisms in real environment both at organismal and molecular level increases as a result of their combined presence.


Assuntos
Antioxidantes , Chlorella vulgaris/efeitos dos fármacos , Enrofloxacina/toxicidade , Eritromicina/toxicidade , Transcrição Genética/efeitos dos fármacos , Antibacterianos/farmacologia , Chlorella vulgaris/enzimologia , Chlorella vulgaris/genética , Clorofila/metabolismo , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Glutationa/metabolismo , Malondialdeído , Fotossíntese/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade
13.
Aquat Toxicol ; 212: 146-153, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31128415

RESUMO

Although aquatic organisms are increasingly exposed to pollutants and abnormally high temperatures as a consequence of climate change, interactive effects between those stressors remain poorly assessed. Especially in ectotherms, such as fish, increases in ambient temperature are expected to affect fitness-related traits and physiology. We used the turquoise killifish Nothobranchius furzeri to study the effects of a range of 3,4-dichloroaniline concentrations (0, 50, 100 µg/L) in combination with two temperature conditions (control and control +4 °C) during four months of exposure. As part of an integrated multi-level approach, we quantified effects on classic life history traits (size, maturation time, body mass, fecundity), critical thermal maximum and physiology (energy reserves and stress-associated enzymatic activity). While no interactive effects of 3,4-DCA exposure and increased temperature emerged, our results do show a negative effect of 3,4-DCA on thermal tolerance. This finding is of particular relevance in light of increasing temperatures under climate change. Due to increases in pest species and faster degradation of 3,4-DCA under higher temperatures, increased use of the pesticide is expected under climate change which, in turn, could result in a decreased tolerance of aquatic organisms to high temperatures.


Assuntos
Fundulidae/fisiologia , Praguicidas/toxicidade , Temperatura Ambiente , Poluentes Químicos da Água/toxicidade , Animais , Tamanho Corporal/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Fertilidade/efeitos dos fármacos , Crescimento/efeitos dos fármacos
14.
Aquat Toxicol ; 212: 214-221, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31132739

RESUMO

Beta-N-methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid produced by several cyanobacteria species. It is considered to be a potent neurotoxin. Although its neurotoxic effects are well studied, other negative effects of BMAA have not yet been completely elucidated. In the present study, we studied the cytotoxic effects of a wide range of concentrations of BMAA (0.25-2.0 mM) on a stable fish immune cell line (CLC) obtained from carp monocytes. The cells exposed to higher concentrations of BMAA exhibited an altered morphology, changed ATP levels, and reduced proliferation. On the basis of toxic effects of BMAA on lysosomes, mitochondrial dehydrogenases activity, and cell membrane integrity, we determined its cytotoxic concentrations. We also investigated effects of the toxin at non-cytotoxic concentrations on the basic functions of CLC cells. BMAA did not affect the production and release of IL-1ß or phagocytic activity of the cells. However, higher non-toxic BMAA concentrations altered the levels of extracellular and intracellular total proteins compared to those in control cells.


Assuntos
Diamino Aminoácidos/toxicidade , Peixes , Animais , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cianobactérias/química , Ativação Enzimática/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Oxirredutases/metabolismo , Poluentes Químicos da Água/toxicidade
15.
Artif Cells Nanomed Biotechnol ; 47(1): 1839-1845, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31066305

RESUMO

Atherosclerosis is the chronic inflammatory disease, and inflammation-elicited endothelial activation is an early event in the development of atherosclerosis. The P2Y11 receptor is a purinergic receptor and a member of the P2 family of G coupled protein which has been shown to modulate vascular function. Progress in the study of purine receptors has been tremendous and these receptors have become pharmacological targets for various diseases. In this study, we show that the P2Y11R antagonist NF157 can mitigate oxidized LDL (ox-LDL)-induced endothelial inflammation. Our study demonstrates that P2Y11R is expressed to a fair degree in human aortic endothelial cells and is induced by treatment with ox-LDL. Blockage of P2Y11R by its selective antagonist NF157 ameliorates ox-LDL-induced adhesion of THP-1 monocytes to endothelial cells. NF157 inhibits ox-LDL-induced expression of adhesion molecules including E-selectin and VCAM-1. NF157 also suppresses ox-LDL-associated ROS production and induction of the NADPH oxidase subunit NOX-4. Moreover, NF157 has an inhibitory effect on the production of major cytokines including IL-6 and TNF-α. Mechanistically, we show that NF157 mitigates ox-LDL-induced phosphorylation of MAPK kinase p38 and NF-κB activation. Our findings indicate that blockage of P2Y11R signalling by its antagonist NF157 may protect endothelial cells from ox-LDL-induced endothelial inflammation. Therefore, NF157 may have therapeutic implications in the modulation of atherosclerosis-associated inflammation.


Assuntos
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , Receptores Purinérgicos P2/metabolismo , Suramina/análogos & derivados , Adesão Celular/efeitos dos fármacos , Selectina E/genética , Ativação Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Inflamação/tratamento farmacológico , Interleucina-6/biossíntese , Monócitos/citologia , Monócitos/efeitos dos fármacos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Suramina/farmacologia , Suramina/uso terapêutico , Fator de Necrose Tumoral alfa/biossíntese , Molécula 1 de Adesão de Célula Vascular/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Mar Drugs ; 17(5)2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31121891

RESUMO

Hizikia fusiformis (Harvey) Okamura is an edible marine alga that has been widely used in Korea, China, and Japan as a rich source of dietary fiber and essential minerals. In our previous study, we observed that the methanol extract of H. fusiformis and its non-polar fractions showed potent protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase inhibition. Therefore, the aim of the present study was to identify the active ingredient in the methanol extract of H. fusiformis. We isolated a new glycerol fatty acid (13) and 20 known compounds including 9 fatty acids (1-3, 7-12), mixture of 24R and 24S-saringosterol (4), fucosterol (5), mixture of 24R,28R and 24S,28R-epoxy-24-ethylcholesterol (6), cedrusin (14), 1-(4-hydroxy-3-methoxyphenyl)-2-[2-hydroxy -4-(3-hydroxypropyl)phenoxy]-1,3-propanediol (15), benzyl alcohol alloside (16), madhusic acid A (17), glycyrrhizin (18), glycyrrhizin-6'-methyl ester (19), apo-9'-fucoxanthinone (20) and tyramine (21) from the non-polar fraction of H. fusiformis. New glycerol fatty acid 13 was identified as 2-(7'- (2″-hydroxy-3″-((5Z,8Z,11Z)-icosatrienoyloxy)propoxy)-7'-oxoheptanoyl)oxymethylpropenoic acid by spectroscopic analysis using NMR, IR, and HR-ESI-MS. We investigated the effect of the 21 isolated compounds and metabolites (22 and 23) of 18 against the inhibition of PTP1B and α-glucosidase enzymes. All fatty acids showed potent PTP1B inhibition at low concentrations. In particular, new compound 13 and fucosterol epoxide (6) showed noncompetitive inhibitory activity against PTP1B. Metabolites of glycyrrhizin, 22 and 23, exhibited competitive inhibition against PTP1B. These findings suggest that H. fusiformis, a widely consumed seafood, may be effective as a dietary supplement for the management of diabetes through the inhibition of PTP1B.


Assuntos
Extratos Vegetais/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Sargassum/química , alfa-Glucosidases/metabolismo , Suplementos Nutricionais , Ativação Enzimática/efeitos dos fármacos , Ácidos Graxos/química , Ácidos Graxos/isolamento & purificação , Ácidos Graxos/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Metanol/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação
18.
Chem Biol Interact ; 307: 16-20, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31004594

RESUMO

Bispyridinium oximes with one (K865, K866, K867) or two (K868, K869, K870) ortho-positioned chlorine moiety, analogous to previously known K027, K048 and K203 oximes, and potent reactivators of human acetylcholinesterase (AChE) inhibited by nerve agents, were tested in the reactivation of human butyrylcholinesterase (BChE) inhibited by sarin, cyclosarin, VX, and tabun. A previously highlighted AChE reactivator, dichlorinated bispyridinium oxime with propyl linker (K868), was tested in more detail for reactivation of four nerve agent-BChE conjugates. Its BChE reactivation potency was showed to be promising when compared to the standard oximes used in medical practice, asoxime (HI-6) and pralidoxime (2-PAM), especially in case of sarin and tabun. This finding could be used in the pseudo-catalytic scavenging of the most nerve agents due to its cumulative capacity to reactivate both AChE and BChE.


Assuntos
Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/metabolismo , Agentes Neurotóxicos/metabolismo , Oximas/metabolismo , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Ativação Enzimática/efeitos dos fármacos , Halogenação , Humanos , Cinética , Agentes Neurotóxicos/química , Oximas/química , Oximas/farmacologia , Compostos de Piridínio/química , Sarina/química , Sarina/metabolismo
19.
Molecules ; 24(7)2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30934730

RESUMO

Peptidyl-prolyl cis/trans isomerase Pin1 plays a key role in amplifying and translating multiple oncogenic signaling pathways during oncogenesis. The blockade of Pin1 provided a unique way of disrupting multiple oncogenic pathways and inducing apoptosis. Aiming to develop potent Pin1 inhibitors, a series of benzimidazole derivatives were designed and synthesized. Among the derivatives, compounds 6h and 13g showed the most potent Pin1 inhibitory activity with IC50 values of 0.64 and 0.37 µM, respectively. In vitro antiproliferative assay demonstrated that compounds 6d, 6g, 6h, 6n, 6o and 7c exhibited moderate antiproliferative activity against human prostate cancer PC-3 cells. Taken together, these unique benzimidazole derivatives exhibited great potential to be further explored as potent Pin1 inhibitors with improved potency.


Assuntos
Benzimidazóis/química , Desenho de Drogas , Inibidores Enzimáticos/química , Peptidilprolil Isomerase de Interação com NIMA/química , Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Molecular , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Relação Estrutura-Atividade
20.
Environ Toxicol ; 34(7): 853-860, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30983163

RESUMO

Licochalcone A is widely studied in different fields and possesses antiasthmatic, antibacterial, anti-inflammatory, antioxidative, and anticancer properties. Its antimalignancy activity on renal, liver, lung, and oral cancer has been explored. However, limited studies have been conducted on the inhibitory effects of licochalcone A in human nasopharyngeal carcinoma cells. We determined cell viability using MTT assay. Cell cycle distribution and apoptotic cell death were measured via flow cytometry. Caspase activation and mitogen-activated protein kinase-related proteins in nasopharyngeal cancer cells in response to licochalcone A were identified by Western blot analysis. Results indicated that licochalcone A reduces cell viability and induces apoptosis, as evidenced by the upregulation of caspase-8 and caspase-9, caspase-3 activation, and cleaved-poly ADP-ribose polymerase expression. Treatment with licochalcone A significantly increases ERK1/2, p38, and JNK1/2 activation. Co-administration of a JNK inhibitor (JNK-IN-8) or p38 inhibitor (SB203580) abolishes the activation of caspase-9, caspase-8, and caspase-3 protein expression during licochalcone A treatment. These findings indicate that licochalcone A exerts a cytostatic effect through apoptosis by targeting the JNK/p38 pathway in human nasopharyngeal carcinoma cells. Therefore, licochalcone A is a promising therapeutic agent for the treatment of human nasopharyngeal cancer cells.


Assuntos
Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Antineoplásicos/farmacologia , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
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