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1.
Pestic Biochem Physiol ; 170: 104698, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980053

RESUMO

Essential oils and their main compounds, monoterpenoids, are considered as alternative control systems for phytopathogenic fungi, particularly those related to late diseases of fruits and vegetables, like anthracnose caused by Colletotrichum species. In this context, we studied the effect of twenty monoterpenoids on Colletotrichum fructicola and C. acutatum to elucidate their effectiveness and mechanisms of action. Thus, we analyzed mycelial growth and conidial inhibitory concentration, as well as the effect of selected monoterpenoids on membrane integrity and cell vitality, reactive oxygen species (ROS) accumulation, and mitochondrial membrane potential by flow cytometry. The results showed that oxygenated monoterpenoids (alcohols and aldehydes) exhibited higher antifungal activity than their corresponding hydrocarbons, esters, and cyclic counterparts. Indicating that OH- and O- radicals react with cellular components affecting fungal homeostasis. In this sense, selected monoterpenoids (citral, citronellol, geraniol, carvacrol, and thymol) inhibited conidial germination of C. acutatum in a dose-dependent manner. The inhibition of conidial germination is associated with a loss of membrane integrity, a decrease of cell metabolism, and a dose-dependent accumulation of ROS, which was non-directly associated with modifications on mitochondrial membrane potential. Membrane dysfunction and ROS accumulation may be responsible for the necrotic behavior induced by high monoterpenoids concentrations, and possible apoptotic response in sub dosages of these compounds.


Assuntos
Colletotrichum , Antifúngicos/farmacologia , Frutas , Monoterpenos/farmacologia , Esporos Fúngicos
2.
Exp Parasitol ; 216: 107937, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32535114

RESUMO

The chemical composition and acaricidal activity of plant-derived essential oils was assessed against Rhipicephalus microplus ticks. The essential oils of Mentha arvensis, Cymbopogon citratus and C. nardus were assessed for acaricidal activity against Rhipicephalus microplus. Essential oils (EO) of plants were separated by hydrodistillation (three times) and analyzed using gas chromatography - mass spectrometer (GC-MS). For bioassays, engorged females of R. microplus were exposed to C. citratus and C. nardus EO at 2%, 3%, 4% and 5% concentrations; and to M. arvensis EO at 1%, 3%, and 5% for 5 min. The weight egg mass, nutrient index (N.I), egg production index (E.P.I), hatching and control rate were evaluated. Non-feed larvae of R. microplus were exposed to essential oils with 0.25%, 0.5%; 1%; 1.5% and 2% concentrations; the mortality rate was measured after 48 h. Only engorged females presented reduced biological activities (oviposition, E.P.I) after exposure to M. arvensis at 3%, when in comparison to both positive and negative controls. The hatchability of R. microplus larvae ranged from 66.9% (after exposure to C. nardus EO at 5%) to 99.2% (positive control). The nutrition index was lower (46.6%) for the exposure to M. arvensis EO at 5%. M. arvensis at 3% and 5% concentrations was significantly efficient for engorged females when compared to control (53.7% and 47.5%, respectively). C. citratus EO at 1%, 1.5% and 2% concentrations yielded better results in the larval packet test, causing 100% mortality. Nonetheless, C. nardus and M. arvensis EO at 2% yielded 66% and 39% mortality, respectively. The study showed that M. arvensis presented potential for the control of R. microplus engorged females while C. citratus and C. nardus presented potential as a larvicide.


Assuntos
Acaricidas , Cymbopogon/química , Mentha/química , Óleos Voláteis/farmacologia , Óleos Vegetais/farmacologia , Rhipicephalus , Acaricidas/isolamento & purificação , Animais , Bioensaio/veterinária , Bovinos , Doenças dos Bovinos/parasitologia , Destilação/métodos , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Dose Letal Mediana , Monoterpenos/isolamento & purificação , Monoterpenos/farmacologia , Óleos Voláteis/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Óleos Vegetais/isolamento & purificação , Infestações por Carrapato/parasitologia , Infestações por Carrapato/veterinária
3.
J Appl Oral Sci ; 28: e20190519, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348444

RESUMO

Natural products have emerged as a rich source of bioactive compounds for adjunctive treatments of many infectious and inflammatory conditions, including periodontitis. Among the monoterpenes with significant biological properties, there is the perillyl alcohol (POH), which can be found in several essential oils and has shown immunomodulatory properties in recent studies, which may be interesting in the treatment of non-neoplastic inflammatory disorders. Objective To determine the antibacterial and immune modulatory activities of the POH. Methodology The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of the POH for two significant Gram-negative periodontal pathogens were determined by macrodilution and subculture, respectively. Cell proliferation and cytotoxicity in RAW 264.7 macrophages were determined by Trypan Blue and mitochondrial enzymatic activity assay. The modulation of reactive oxygen species (ROS) was analyzed by flow cytometry and expression of TNF and arginase-1 by real-time PCR. Results The POH was effective against P. gingivalis (ATCC 33277) and F. nucleatum (ATCC 25586) with MIC= MBC=1600 µM. No cytotoxicity up to 100 µM was observed on macrophages. The cell proliferation was inhibited from 48 hours at 100 µM (p<0.05) and 250 µM (p<0.01). The POH increased ROS production at both 10 µM and 100 µM (p<0.05) in unstimulated cells. The PMA-induced ROS production was not affected by POH, whereas 100 µM significantly reduced lipopolysaccharide-induced (LPS-induced) ROS. The expression of TNF was not affected by POH in unstimulated cells or in cells polarized to M1 phenotype, whereas both concentrations of POH reduced (p<0.05) the expression of arginase-1 in M2-polarized macrophages. Conclusion The POH has antibacterial activity against periodontal pathogens and reduced proliferation of murine macrophages without significant cytotoxicity at concentrations up to 100 µM. In addition, the POH reduced the LPS-induced ROS and the expression of arginase-1 in M2-polarized macrophages.


Assuntos
Antibacterianos/farmacologia , Fusobacterium nucleatum/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Monoterpenos/farmacologia , Porphyromonas/efeitos dos fármacos , Espécies Reativas de Oxigênio/análise , Animais , Arginase/análise , Produtos Biológicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Fusobacterium nucleatum/crescimento & desenvolvimento , Expressão Gênica , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Porphyromonas/crescimento & desenvolvimento , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Fatores de Tempo , Fator de Necrose Tumoral alfa/análise
4.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 32(1): 83-87, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32148237

RESUMO

OBJECTIVE: To investigate the effect and mechanism of paeoniflorin on the permeability of cardiac microvascular endothelial cells (CMECs) in sepsis. METHODS: Primary rat CMECs were isolated and cultured in vitro, and the cells in the logarithmic growth phase were used for experiments. Tetramethylazozolium colorimetry (MTT) was used to screen the safe and effective concentrations of paeoniflorin at 10, 20, and 40 µmol/L. The cells were divided into blank control group, lipopolysaccharide (LPS) group and low, medium and high concentration paeoniflorin pretreatment group. The cells in the blank control group were cultured in complete medium; the cells in the LPS group were challenged with LPS (1 mg/L) in complete medium; and the cells in the paeoniflorin pretreatment groups were pretreated with 10, 20, and 40 µmol/L paeoniflorin at 4 hours before LPS stimulation. The cells in each group were further cultured for 24 hours after LPS stimulation. The horseradish peroxidase (HRP) method was used to detect the permeability of rat CMECs. The enzyme-linked immunosorbent assay (ELISA) was used to detect the CXC chemokine ligand (CXCL1, CXCL2) levels in the cell supernatant. The real-time fluorescence quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was used to detect the mRNA expressions of CXCL1 and CXCL2 in the cells. Western Blot was used to detect phosphorylated Src (p-Src), vascular endothelial-cadherin (VE-cadherin) and phosphorylated mitogen activated protein kinase (p-MAPK). RESULTS: Compared with the blank control group, the permeability of rat CMECs in the LPS group was significantly increased. The cell permeability was improved to some extent after paeoniflorin pretreatment at different concentrations, and the improvement was most obvious in the 40 µmol/L paeoniflorin group, with statistically significant difference as compared with the LPS group (A value: 1.61±0.07 vs. 2.13±0.06, P < 0.01). ELISA results showed that there were moderate amounts of CXCL1 and CXCL2 in the cell supernatant of rat CMECs in the blank control group. However, the secretion of CXCL1 and CXCL2 in the cell supernatant was increased significantly under the induction of LPS. After pretreatment with paeoniflorin at different concentrations, the secretion of CXCL1 and CXCL2 in the cell supernatant was significantly reduced. The most obvious inhibitory effect on CXCL1 was 40 µmol/L paeoniflorin, and the most obvious inhibition on CXCL2 was 20 µmol/L paeoniflorin, the differences were statistically significant as compared with the LPS group [CXCL1 (ng/L): 337.51±68.04 vs. 829.86±65.06, CXCL2 (ng/L): 4.48±0.11 vs. 9.41±0.70, both P < 0.01]. RT-qPCR results showed that the mRNA expressions of CXCL1 and CXCL2 in the rat CMECs were consistent with the ELISA results. LPS could increase mRNA expressions of CXCL1 and CXCL2 in the rat CMECs, and pretreatment with different concentrations of paeoniflorin could significantly reduce the mRNA expressions of CXCL1 and CXCL2. The 40 µmol/L paeoniflorin had the best inhibitory effect on CXCL1 mRNA expression, and the 20 µmol/L paeoniflorin had the best inhibitory effect on CXCL2 mRNA expression, the differences were statistically significant as compared with the LPS group [CXCL1 mRNA (2-ΔΔCt): 0.543±0.004 vs. 0.812±0.089, CXCL2 mRNA (2-ΔΔCt): 10.52±0.71 vs. 17.68±1.09, both P < 0.01]. Western Blot results showed that moderate amounts of p-Src, VE-cadherin and p-MAPK proteins were expressed in the rat CMECs in the blank control group. After LPS stimulation, the expressions of p-Src and p-MAPK proteins were increased significantly, while the expression of VE-cadherin protein was decreased significantly. After pretreatment with different concentrations of paeoniflorin, the expressions of p-Src and p-MAPK proteins in the cells were decreased to varying degrees, while the expression of VE-cadherin protein was increased, and 40 µmol/L paeoniflorin had the most obvious effect, the differences were statistically significant as compared with the LPS group [p-Src protein (p-Src/GAPDH): 1.02±0.09 vs. 1.29±0.05, p-MAPK proteins (p-MAPK/GAPDH): 0.24±0.02 vs. 0.62±0.02, VE-cadherin protein (VE-cadherin/GAPDH): 0.64±0.03 vs. 0.31±0.02, all P < 0.01]. CONCLUSIONS: Paeoniflorin can regulate the Src/VE-cadherin pathway in CMECs, inhibit the expression and secretion of inflammation-related proteins and chemokines, and improve the cell permeability of CMECs induced by LPS.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Glucosídeos/farmacologia , Monoterpenos/farmacologia , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Transdução de Sinais , Animais , Células Cultivadas , Quimiocina CXCL1/análise , Quimiocina CXCL2/análise , Lipopolissacarídeos , Ratos
5.
Chem Pharm Bull (Tokyo) ; 68(3): 244-250, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115531

RESUMO

Aspidosperma alkaloids, a subclass of monoterpenoid indole alkaloids rich in the Apocynaceae plants, possess remarkable antitumor activities, but the underlying mechanisms have rarely been reported. In the current project, 11-methoxytabersonine (11-MT), an aspidosperma-type alkaloid isolated from Tabernaemontana bovina, significantly inhibited the viability of two human lung cancer cell lines A549 and H157, and the molecular mechanisms were thus investigated. The results showed that 11-MT killed lung cancer cells via induction of necroptosis in an apoptosis-independent manner. In addition, 11-MT strongly induced autophagy in the two cell lines, which played a protective role against 11-MT-induced necroptosis. Finally, the autophagy caused by 11-MT was found to be via activation of the AMP activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) and the c-Jun N-terminal kinase (JNK) signaling pathways in both cells. Taken together, 11-MT exhibited an antitumor mechanism different from that of previously reported analogues and could have the potential to serve as a lead compound for the development of new chemotherapy for lung cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Alcaloides Indólicos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Monoterpenos/farmacologia , Necroptose/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Tabernaemontana/química , Células A549 , Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/isolamento & purificação , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Monoterpenos/isolamento & purificação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo
6.
Biol Pharm Bull ; 43(3): 526-532, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115511

RESUMO

Peroxisome proliferator-activated receptor γ (PPARγ), the molecular target for antidiabetic thiazolidinediones (TZDs), is a master regulator of preadipocyte differentiation and lipid metabolism. The adverse side effects of TZDs, arising from their potent agonistic activity, can be minimized by PPARγ partial agonists or PPARγ non-agonists without loss of insulin sensitization. In this study, we reported that WSF-7, a synthetic chemical derived from natural monoterpene α-pinene, is a partial PPARγ agonist. We found that WSF-7 binds directly to PPARγ. Activation of PPARγ by WSF-7 promotes adipogenesis, adiponectin oligomerization and insulin-induced glucose uptake. WSF-7 also inhibits obesity-mediated PPARγ phosphorylation at serine (Ser)273 and improves insulin sensitivity of 3T3-L1 adipocytes. Our study suggested that WSF-7 activates PPARγ transcription by a mechanism different from that of rosiglitazone or luteolin. Therefore, WSF-7 might be a potential therapeutic drug to treat type 2 diabetes.


Assuntos
Insulina/metabolismo , Monoterpenos/farmacologia , PPAR gama/agonistas , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adiponectina/metabolismo , Animais , Glucose/metabolismo , Camundongos , Monoterpenos/química , Obesidade/metabolismo
7.
J Med Chem ; 63(4): 1709-1716, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31999455

RESUMO

A hybrid of dearomatized isoprenylated acylphloroglucinol (DIAP) and monoterpenoid, hypatone A (1), together with its biosynthetic analogues 2-4 is characterized from Hypericum patulum. Structurally, 1 possesses an unprecedented spiro[bicyclo[3.2.1]octane-6,1'-cyclohexan]-2',4',6'-trione core as elucidated by extensive spectroscopic and X-ray crystallographic analyses. Biological studies reveal that compounds 1 and 2-4 produce opposite effects on Cav3.1 low voltage-gated Ca2+ channel, with 1 and 4, respectively, being the most potent Cav3.1 agonist and antagonist from natural products. Further studies suggest that compound 1 and its biogenetical precursor, 2, have the same binding site on Cav3.1 and that the rigid cagelike moiety at C-5 and C-6 is a key structural feature responsible for 1 being an agonist. Furthermore, 1 can normalize the pathological gating of a mutant Cav3.1 channel found in spinocerebellar ataxia 42 (SCA42), a hereditary neurodegenerative disorder with no available therapy. Collectively, our findings provide valuable tools for future studies on Cav3.1 physiology and pathophysiology, as well as afford possible leads for developing new drugs against SCA42, epilepsy, and pain.


Assuntos
Agonistas dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Monoterpenos/farmacologia , Floroglucinol/análogos & derivados , Floroglucinol/farmacologia , Animais , Agonistas dos Canais de Cálcio/isolamento & purificação , Canais de Cálcio Tipo T/genética , Células HEK293 , Humanos , Hypericum/química , Ativação do Canal Iônico/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Monoterpenos/isolamento & purificação , Mutação , Floroglucinol/isolamento & purificação
8.
Clin Sci (Lond) ; 134(3): 331-347, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31967309

RESUMO

G protein-coupled receptor kinase 2 (GRK2), a type of cytosolic enzyme, transiently translocates to the plasma membrane upon G protein-coupled receptors (GPCRs) activation, and it also binds to extracellular signal-regulated kinase (ERK) to inhibit the activation of ERK. GRK2 deficiency in endothelial cells (ECs) leads to increased pro-inflammatory signaling and promotes recruitment of leukocytes to activated ECs. However, the role of GRK2 in regulating angiogenesis remains unclear. Here, we show that GRK2 is a novel regulatory molecule on migration and tube formation of ECs, vessel sprouting ex vivo and angiogenesis in vivo. We identify that EP4/AC/cAMP/protein kinase A (PKA)-mediated GRK2 translocation to cells membrane decreases the binding of GRK2 and ERK1/2 to inhibit ERK1/2 activation, which promotes prostaglandin E2 (PGE2)-induced angiogenesis. GRK2 small interfering RNA (siRNA) inhibits the increase in PGE2-induced HUVECs migration and tube formation. In vivo, PGE2 increases ECs sprouting from normal murine aortic segments and angiogenesis in mice, but not from GRK2-deficient ones, on Matrigel. Further research found that Lys220 and Ser685 of GRK2 play an important role in angiogenesis by regulating GRK2 translocation. Paeoniflorin-6'-O-benzene sulfonate (CP-25), as a novel ester derivative of paeoniflorin (pae), has therapeutic potential for the treatment of adjuvant arthritis (AA) and collagen-induced arthritis (CIA), but the underlying mechanism of CP-25 on angiogenesis has not been elucidated. In our study, CP-25 inhibits the migration and tube formation of HUVECs, and angiogenesis in mice by down-regulating GRK2 translocation activation without affecting GRK2 total expression. Taken together, the present results revealed that CP-25 down-regulates EP4/AC/cAMP/PKA-mediated GRK2 translocation, restoring the inhibition of GRK2 for ERK1/2, thereby inhibiting PGE2-stimulated angiogenesis.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Dinoprostona/farmacologia , Regulação para Baixo/efeitos dos fármacos , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Glucosídeos/farmacologia , Monoterpenos/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Adenilil Ciclases/metabolismo , Animais , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Membrana Celular/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células HEK293 , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Fenótipo , Transporte Proteico/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia
9.
Org Biomol Chem ; 18(6): 1135-1139, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31967630

RESUMO

Biomimetic total syntheses of baefrutones A-D (1-4), baeckenon B (5), and frutescones A, D-F (6-9), isolated from the leaves of Baeckea frutescens, were achieved in 9, 8, and 5 steps, respectively, in moderate to good yields (72-83%). The synthetic routes feature the Michael addition, oxidative [4 + 2] cycloaddition, and water-promoted Diels-Alder click reactions as the key steps. This study helped gain thorough mechanistic insights into the biosynthetic origins and provided a facile approach for the construction of a library of natural tasmanone-based meroterpenoid analogues. Moreover, compounds 1-9 show potent inhibitory effects against S. paratyphi and/or C. albicans with MIC values of 3.125-25 µg mL-1, and they could be promising lead molecules for the design of new antibiotic agents.


Assuntos
Materiais Biomiméticos/farmacologia , Monoterpenos/farmacologia , Terpenos/farmacologia , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Candida albicans/efeitos dos fármacos , Reação de Cicloadição , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monoterpenos/síntese química , Monoterpenos/química , Oxirredução , Pseudomonas aeruginosa/efeitos dos fármacos , Salmonella/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Terpenos/síntese química , Terpenos/química
10.
Fitoterapia ; 140: 104416, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31704261

RESUMO

Vitiligo is a common depigmentary disease characterized as diagnosis simplicity and cure difficulty in view of the ambiguity of etiology, thus novel and effective treatments are urgently needed. Paeoniflorin, the major active compound extracted from the root of Paeonia lactiflora Pall, a traditional Chinese medicine, has been validated pharmacological properties such as antioxidant stress, a theory participating in the occurrence of vitiligo, but the effect on melanogenesis is still unclear. In this study, melanosythesis effect of paeoniflorin and the potential mechanism were evaluated. We found that treatment with paeoniflorin at the concentration of 10 µg/ml significantly increased melanin content and intracellular tyrosinase activity of human melanocytes, in accordance with the elevation of protein levels of microphthalmia-associated transcription factor (MITF), tyrosinase-related protein 1 (TRP-1). In addition, we also investigated that paeoniflorin promoted phosphorylation of cAMP-response element binding (CREB) and extracellular signal-regulated kinase (ERK) without affecting p38 and c-Jun N-terminal kinase (JNK). These results demonstrated that paeoniflorin had a synergistic effect on normal human melanocytes via ERK/CREB pathway with up-regulation of MITF and TRP-1, enhancing melanin synthesis. Meanwhile, the milder pathological changes in vitiligo mice treat with paeoniflorin also confirmed its potential in treating vitiligo. To sum up, we suggest that paeoniflorin may be a potential medicine of vitiligo treatment in clinical.


Assuntos
Glucosídeos/farmacologia , Melanócitos/efeitos dos fármacos , Monoterpenos/farmacologia , Vitiligo/tratamento farmacológico , Animais , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição Associado à Microftalmia/metabolismo , Oxirredutases/metabolismo , Fosforilação , Distribuição Aleatória
11.
Nat Prod Res ; 34(8): 1074-1079, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30663357

RESUMO

Incorporation of the Beckmann rearrangement into the presented research resulted in the formation of nitrogen-containing terpenoid derivatives originating from naturally occurring compounds. Both starting monoterpenes and obtained derivatives were subjected to estimation of their antibacterial potential. In the presented study, Staphylococcus aureus was the most sensitive to examined compounds. The Minimal Inhibitory Concentration (MIC) experiments performed on S. aureus demonstrated that the (-)-menthone oxime (-)-8 and (+)-pulegone oxime (+)-13 had the best antibacterial activity among the tested derivatives and starting compounds. Their MIC90 value was 100 µg/mL. The obtained derivatives were also evaluated for their inhibitory activity against bacterial urease. Among the tested compounds, three active inhibitors were found - oxime 14 and lactams (-)-15 and 16 limited the activity of Sporosarcina pasteurii urease with Ki values of 174.3 µM, 43.0 µM and 4.6 µM, respectively. To our knowledge, derivative 16 is the most active antiureolytic lactam described to date.


Assuntos
Antibacterianos/síntese química , Monoterpenos/síntese química , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacologia , Monoterpenos Cicloexânicos/farmacologia , Lactamas/farmacologia , Mentol/farmacologia , Testes de Sensibilidade Microbiana , Monoterpenos/farmacologia , Nitrogênio/química , Oximas/farmacologia , Urease/antagonistas & inibidores
12.
Nat Prod Res ; 34(6): 843-846, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30398363

RESUMO

Chemical constitutes and phytotoxic activity of Cuminum cymiunm L. is investigated in the present study. For this means seeds of C. cyminum L. was harvested from Ilkhchi of Iran. The major components of essential oil (EO) with more than 94% were 3-caren-10-al, cuminal, 2-Caren-10-al, γ-Terpinene, (-)-ß-Pinene and p-Cymene. This study found that cumin EO displayed meaningful inhibitory impacts on germination indices and the growth of the seedlings of Amaranthus retroflexus, Lactuca sativa, and Acroptilon repens. The germination indices showed severely concentration-dependent responses. In the case of A. retroflexus and L. sativa germination indices were controlled in the 500 ppm and in the A. repens were inhibited in the 1500 ppm of EO concentration. Overall, this study suggests that EO derived from C. cyminum L. looks to be a promising candidate for its utilization as a natural herbicide in large scale.[Formula: see text].


Assuntos
Cuminum/química , Herbicidas/isolamento & purificação , Monoterpenos/isolamento & purificação , Óleos Voláteis/isolamento & purificação , Oxigênio/química , Plântula , Amaranthus/efeitos dos fármacos , Germinação/efeitos dos fármacos , Herbicidas/toxicidade , Irã (Geográfico) , Monoterpenos/farmacologia , Monoterpenos/toxicidade , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Óleos Voláteis/toxicidade , Plântula/efeitos dos fármacos , Sementes/efeitos dos fármacos
13.
Nat Prod Res ; 34(3): 351-358, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30580601

RESUMO

A new sesquiterpene (1) and a new monoterpene (2), together with thirteen known compounds (3-15) were isolated from an ethanol extract of the roots of Aristolochia debilis Sieb. et Zucc. The structures of compounds 1 and 2 were elucidated using HR-ESI-MS, 1D and 2D NMR spectroscopy. Anti-inflammatory effects of the isolated compounds were evaluated in terms of inhibition of nitric oxide, tumour-necrosis factor-α and interleukin-6 production in lipopolysaccharide-stimulated RAW264.7 cells. Compounds 1-9 and 12-15 significantly inhibited the levels of NO, TNF-α and IL-6 in LPS-induced RAW264.7 cells from concentrations of 3 µM to 30 µM.


Assuntos
Anti-Inflamatórios/isolamento & purificação , Aristolochia/química , Monoterpenos/isolamento & purificação , Raízes de Plantas/química , Sesquiterpenos/isolamento & purificação , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Lipopolissacarídeos , Camundongos , Estrutura Molecular , Monoterpenos/química , Monoterpenos/farmacologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Análise Espectral/métodos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese
14.
Chem Biol Interact ; 315: 108890, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31678597

RESUMO

The monoterpenoid terpinen-4-ol (4TERP) is known to inhibit cell excitability, has low toxicity and important pharmacological activities, which are likely related to neural excitability, such as anti-inflammatory, antiepileptic and antinociceptive effects. However, the pharmacological characteristics and mechanisms underlying the effects of 4TERP on blockade of neural action potential are not completely elucidated. Since Na+ current (INa) through voltage-dependent Na+ channels (NaV) is a major mechanism for excitability, the present study investigated the pharmacological characteristics and mechanisms of the action of 4TERP on INa through NaV. For this aim, dissociated small neurons of dorsal root ganglia of adult rats were used for whole cell patch-clamp recordings. 4TERP concentration-dependently inhibits INa (IC50 0.8 ±â€¯0.3 mM; pharmacological efficacy 42.89 ±â€¯5.54%). 4TERP interfered with INa through a mechanism with various components, which includes predominantly channel pore block and sensitivity to frequency of use. In presence of 4TERP (3 mM), decreasing stimulation from 5 Hz to very low frequency (75 s of quiescence previously to stimulation) induced INa decrease to 65.17 ±â€¯5.86% of control. 4TERP also altered (left shift) voltage sensitivity of the steady state activation of NaV. Data are discussed aiming to interpret the importance of blockade of INa through NaV as participant of 4TERP-induced inhibition of membrane excitability.


Assuntos
Gânglios Espinais/efeitos dos fármacos , Monoterpenos/farmacologia , Neurônios/efeitos dos fármacos , Terpenos/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Canais de Sódio Disparados por Voltagem/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Feminino , Gânglios Espinais/metabolismo , Masculino , Neurônios/metabolismo , Técnicas de Patch-Clamp/métodos , Ratos , Ratos Wistar
15.
J Appl Microbiol ; 128(2): 401-413, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31602708

RESUMO

AIM: To evaluate the antimicrobial effect of paeoniflorin against carbapenem-resistant Klebsiella pneumoniae (CRKP). METHODS AND RESULTS: Minimum inhibitory concentration (MIC) of paeoniflorin against CRKP was determined by agar dilution method. Changes in intracellular ATP concentration, intracellular pH (pHin), cell membrane potential and membrane integrity were investigated to assess the influence of paeoniflorin on cell membrane damage. Additionally, alterations in cell structure of CRKP cells and cell damage within biofilms were examined. The results indicated that paeoniflorin was effective against CRKP at MIC of 1·2 mg ml-1 . Paeoniflorin destroyed the integrity of CRKP cell membrane, as was confirmed by decrease of intracellular ATP, pHin, membrane potential, as well as distinctive alteration in cell morphology, resulting in leakage of CRKP intracellular components. Moreover, paeoniflorin displayed a markedly inhibitory influence on biofilm formation of CRKP and inactivated CRKP cells within biofilms. CONCLUSIONS: Paeoniflorin shows promise as an effective antibiotic against CRKP with the potential to be an alternative therapeutic agent. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides information about the potential use of paeoniflorin to reduce the infection of CRKP in clinical practice and food production.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Carbapenêmicos/farmacologia , Farmacorresistência Bacteriana , Glucosídeos/farmacologia , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/efeitos dos fármacos , Monoterpenos/farmacologia , Humanos , Klebsiella pneumoniae/fisiologia , Testes de Sensibilidade Microbiana
16.
Curr Pharm Biotechnol ; 21(8): 702-709, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31884927

RESUMO

OBJECTIVE: The purpose of this paper was to study the protective effect of paeoniflorin on acute cerebral ischemia. The animal model of cerebral infarction induced by Middle Cerebral Artery Occlusion (MCAO) was blocked by the suture method. Sixty SD rats were randomly divided into the shame group, MCAO group, paeoniflorin (60, 120, 240 mg/kg, respectively) and Nimodipine (NMDP) group (n = 10 per group). METHODS: The rats were intragastrically administered immediately after the operation. After 7 days of gavage, the brains were decapitated at 24 h. Hematoxylin and Eosin (HE) staining was used to observe the degree of cell damage in the cerebral cortex of rats. Immunohistochemistry was used to detect silver plating and to observe changes in nerve cells. Rats in the model group showed obvious symptoms of neurological deficits, such as the ischemic morphological changed, the Malondialdehyde (MDA), Lactate Dehydrogenase (LD) content and lactate dehydrogenase (LDH) activity were significantly increased in the ischemic brain tissue, while the Superoxide Dismutase (SOD) activity was decreased. RESULTS: The decrease in Na+-K+-ATPase activity was significantly lower than that in the sham group. The neurological symptoms and signs of MCAO in the different doses of paeoniflorin group were improved, and the neuronal edema in the cortical area was alleviated. The activities of SOD, LDH and Na+-K+-ATPase were significantly increased, and the contents of MDA and LD were decreased. CONCLUSION: Therefore, paeoniflorin could alleviate the degree of tissue damage in rats with acute cerebral infarction, inhabit the formation of free radicals in the brain tissue after ischemia, and reduce the degree of lipid peroxidation. Thus, the degree of cell damage was reduced greatly and a protective effect was showed on cerebral ischemia.


Assuntos
Infarto Cerebral/prevenção & controle , Glucosídeos/farmacologia , Monoterpenos/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença Aguda , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Infarto Cerebral/metabolismo , Infarto Cerebral/patologia , Modelos Animais de Doenças , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Nimodipina/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , ATPase Trocadora de Sódio-Potássio/metabolismo , Superóxido Dismutase/metabolismo
17.
Phytochemistry ; 170: 112216, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31841782

RESUMO

Hyperelodiones A-C, three undescribed monoterpenoid polyprenylated acylphloroglucinols possessing 6/6/6 fused tricyclic core, were isolated from Hypericum elodeoides Choisy. Their gross structures were elucidated by HRESIMS and NMR data. The absolute configurations of hyperelodiones A-C were assigned by their calculated and compared electronic circular dichroism (ECD) spectra combined with their common biosynthetic origin. A fluorescence quenching assay suggested that hyperelodiones A-C could bind to RXRα-LBD, whereas hyperelodione C showed the strongest interaction with a KD of 12.81 µΜ. In addition, hyperelodiones A-C dose-dependently inhibited RXRα transactivation and the growth of HeLa and MCF-7 cells. Among them, hyperelodione C showed the most potent inhibitory activities and dose-dependent PARP cleavage. Molecular docking results suggested that hyperelodione C showed a different interaction mode compared with hyperelodione A and hyperelodione B. Thus, hyperelodione C can be considered as a promising lead compound for cancer therapy, which can bind to RXRα-LBD and induce HeLa and MCF-7 cell apoptosis.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Hypericum/química , Monoterpenos/farmacologia , Compostos Fitoquímicos/farmacologia , Receptor X Retinoide alfa/antagonistas & inibidores , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Células MCF-7 , Conformação Molecular , Simulação de Acoplamento Molecular , Monoterpenos/química , Monoterpenos/isolamento & purificação , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Receptor X Retinoide alfa/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
18.
Int J Mol Sci ; 21(1)2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31878088

RESUMO

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme in humans, and a current and promising inhibition target for the development of new chemosensitizing agents due to its ability to remove DNA damage caused by topoisomerase 1 (Top1) poisons such as topotecan and irinotecan. Herein, we report our work on the synthesis and characterization of new Tdp1 inhibitors that combine the arylcoumarin (neoflavonoid) and monoterpenoid moieties. Our results showed that they are potent Tdp1 inhibitors with IC50 values in the submicromolar range. In vivo experiments with mice revealed that compound 3ba (IC50 0.62 µM) induced a significant increase in the antitumor effect of topotecan on the Krebs-2 ascites tumor model. Our results further strengthen the argument that Tdp1 is a druggable target with the potential to be developed into a clinically-potent adjunct therapy in conjunction with Top1 poisons.


Assuntos
Carcinoma Krebs 2/tratamento farmacológico , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Monoterpenos , Proteínas de Neoplasias , Inibidores de Fosfodiesterase , Diester Fosfórico Hidrolases/metabolismo , Animais , Carcinoma Krebs 2/enzimologia , Carcinoma Krebs 2/patologia , Carcinoma Pulmonar de Lewis/enzimologia , Carcinoma Pulmonar de Lewis/patologia , Feminino , Humanos , Células MCF-7 , Masculino , Camundongos , Monoterpenos/síntese química , Monoterpenos/química , Monoterpenos/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Relação Estrutura-Atividade
19.
Neurochem Res ; 44(12): 2821-2831, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31728857

RESUMO

Paeoniflorin (PF) has been reported to possess neuroprotective influences on cognitive dysfunction illness. In current research, we attempted to probe into the protective influences of PF against H2O2-induced damage and the underlying regulating mechanisms on hippocampal HT-22 cells. HT-22 cells were pretreated with PF, and then induced by H2O2. Afterwards, the influences of PF pretreatment were examined using CCK-8 assay, apoptosis assay, western blot and ROS assay, respectively. In addition, the expression of microRNA-135a (miR-135a) was analyzed and altered by qRT-PCR and cell transfection, respectively. After overexpression of miR-135a, the effects of miR-135a mimic on cell functions were detected again. Moreover, influences of H2O2, PF and miR-135a overexpression on JAK2/STAT3 and ERK1/2 signal pathways were further investigated. Further experiments verified that PF pretreatment alleviated H2O2-induced oxidative stress through increasing cell viability, inhibiting cell apoptosis, reducing ROS generation and activating JAK2/STAT3 and ERK1/2 pathways. Besides, expression of miR-135a was declined by PF pretreatment. Whereas, miR-135a mimic abrogated the protective effects triggered by PF pretreatment. These results indicated that PF can alleviate H2O2-induced oxidative stress by down-regulation of miR-135a via activation of JAK2/STAT3 and ERK1/2 pathways.


Assuntos
Regulação para Baixo , Glucosídeos/farmacologia , MicroRNAs/metabolismo , Monoterpenos/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Janus Quinase 2/metabolismo , Janus Quinase 3/metabolismo , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Exp Parasitol ; 207: 107774, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31614118

RESUMO

The acaricidal activity of combinations of thymol, carvacrol and eugenol was evaluated on larvae and engorged females of the cattle tick Rhipicephalus microplus. The first step assessed the compounds separately, in concentrations of 3.125, 6.25, 12.5 and 25 mg/mL. Then tests were performed with the compounds combined in the ratio of 1:1 at concentrations of 3.125 and 6.25 mg/mL, along with the control group treated with the solvent (3% DMSO). In the second step, combinations were tested incorporated in a formulation at the concentration de 6.25 mg/mL, using the larval packet and adult immersion tests. The associations carvacrol + thymol (3.125 mg/mL), carvacrol + eugenol and thymol + eugenol (6.25 mg/mL) presented synergism, while the other associations had an additive effect. In the experiments with formulation, all combinations caused 100% larval mortality, but the efficacy was under 15% against engorged females. Therefore, the combinations of thymol + carvacrol (3.125 mg/mL) as well as carvacrol + eugenol and eugenol + thymol (6.25 mg/mL) had a synergistic effect on engorged females, but when incorporated in the formulation, the acaricide activity was strong against larvae but weak against engorged females.


Assuntos
Acaricidas/farmacologia , Eugenol/farmacologia , Monoterpenos/farmacologia , Rhipicephalus/efeitos dos fármacos , Timol/farmacologia , Animais , Cimenos , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Larva/efeitos dos fármacos
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