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1.
Chem Biol Interact ; 315: 108911, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31786185

RESUMO

Over the years, the attention of researchers in the field of modern drug discovery and development has become further intense on the identification of active compounds from plant sources and traditional remedies, as they exhibit higher therapeutic efficacies and improved toxicological profiles. Among the large diversity of plant extracts that have been discovered and explored for their potential therapeutic benefits, asperuloside, an iridoid glycoside, has been proven to provide promising effects as a therapeutic agent for several diseases. Although, this potent substance exists in several genera, it is primarily found in plants belonging to the genus Eucommia. Recent decades have seen a surge in the research on Asperuloside, making it one of the most studied natural products in the field of medicine and pharmacology. In this review, we have attempted to study the various reported mechanisms of asperuloside that form the basis of its wide spectrum of pharmacological activities.


Assuntos
/farmacologia , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Iridoides/farmacologia , Iridoides/uso terapêutico , Piranos/farmacologia , Piranos/uso terapêutico , Animais , Eucommiaceae/química , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
2.
J Agric Food Chem ; 67(45): 12558-12564, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31609622

RESUMO

All four stereoisomers of naturally occurring 6-(2-hydroxy-6-phenylhex-1-yl)-5,6-dihydro-2H-pyran-2-one (1) were synthesized by employing yeast-reduction products with high optical purity [from 95% enantiomeric excess (ee) to more than 99% ee], and then their phytotoxicities against lettuce and Italian ryegrass were evaluated. In the Italian ryegrass seedlings test, (6S,2'R)-1 showed the most potent and stereospecific activity against the shoots (IC50 = 260 µM) and roots (IC50 = 43.2 µM), with a significant difference from other stereoisomers. The highest seed germination inhibitory activity against Italian ryegrass seed was also observed in (6S,2'R)-1, showing a 53% germination ratio from the control at 1000 µM. This advantageous (6S,2'R) stereochemistry was employed in the syntheses of α,ß-dihydro, 2'-dehydroxy, and 2'-methoxy derivatives 13-15. By the test using these derivatives, the importance of the α,ß-unsaturated double bond and hydroxy group bonding to a chiral center on the 6-alkyl chain of 5,6-dihydro-α-pyrone for phytotoxicity was determined. In the test against lettuce, the 6S configuration and (6S,2'S) configuration were necessary for growth inhibition (IC50 = ca. 60 µM) and germination inhibition (63% germination ratio at 1000 µM), respectively.


Assuntos
Carbono/química , Herbicidas/farmacologia , Piranos/química , Carbono/farmacologia , Germinação/efeitos dos fármacos , Herbicidas/síntese química , Herbicidas/química , Alface/efeitos dos fármacos , Alface/crescimento & desenvolvimento , Lolium/efeitos dos fármacos , Lolium/crescimento & desenvolvimento , Estrutura Molecular , Piranos/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
3.
Environ Sci Pollut Res Int ; 26(32): 33304-33310, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520384

RESUMO

In this study, we present experimental data on the effects of meso-2,3-dimercaptosuccinic acid (DMSA) and tetraethylammonium salt of salinomycinic acid (Sal) on cadmium-induced spleen dysfunction and altered essential metal balance in mice. Sixty-day-old male mice (ICR line) were randomly divided into four groups: untreated control group (Ctrl)-obtained distilled water for 28 days, toxic control group (Cd)-exposed to cadmium acetate dihydrate at average daily dose of 20mg/kg body weight (BW) for 14 days, Cd + DMSA group-obtained cadmium acetate dihydrate as the toxic control group followed by treatment with 20mg/kg BW DMSA for 2 weeks, and Cd + Sal group-mice exposed to cadmium acetate dihydrate at average daily dose of 20mg/kg BW for 2 weeks followed by administration of Sal at an average daily dose of 20mg/kg BW for 2 weeks. The compounds were administered orally via the drinking water of the animals. We found that cadmium exposure caused splenomegaly and reduced the hemoglobin and hematocrit levels and total red blood cell count compared with untreated controls. Cadmium intoxication of mice induced accumulation of the toxic metal ion in the blood and spleen. Alterations in the endogenous levels of calcium (Ca) and iron (Fe) in the spleen of cadmium-exposed mice compared with those in untreated controls were observed. Treatment of cadmium-exposed mice with DMSA or Sal recovered the spleen weight and hematological parameters to normal control values, decreased cadmium concentration in the blood and spleen, and improved splenic architecture. The results prove that Sal is a potential antidote for treatment of Cd-induced spleen dysfunction.


Assuntos
Substâncias Protetoras/farmacologia , Piranos/farmacologia , Baço/efeitos dos fármacos , Succímero/farmacologia , Poluentes Químicos da Água/toxicidade , Acetatos , Animais , Cádmio/toxicidade , Cálcio , Água Potável , Ferro , Masculino , Camundongos , Camundongos Endogâmicos ICR , Baço/fisiologia
4.
BioDrugs ; 33(5): 539-553, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31392631

RESUMO

MYC is a master transcriptional regulator that controls almost all cellular processes. Over the last several decades, researchers have strived to define the context-dependent transcriptional gene programs that are controlled by MYC, as well as the mechanisms that regulate MYC function, in an effort to better understand the contribution of this oncoprotein to cancer progression. There are a wealth of data indicating that deregulation of MYC activity occurs in a large number of cancers and significantly contributes to disease progression, metastatic potential, and therapeutic resistance. Although the therapeutic targeting of MYC in cancer is highly desirable, there remain substantial structural and functional challenges that have impeded direct MYC-targeted drug development and efficacy. While efforts to drug the 'undruggable' may seem futile given these challenges and considering the broad reach of MYC, significant strides have been made to identify points of regulation that can be exploited for therapeutic purposes. These include targeting the deregulation of MYC transcription in cancer through small-molecule inhibitors that induce epigenetic silencing or that regulate the G-quadruplex structures within the MYC promoter. Alternatively, compounds that disrupt the DNA-binding activities of MYC have been the long-standing focus of many research groups, since this method would prevent downstream MYC oncogenic activities regardless of upstream alterations. Finally, proteins involved in the post-translational regulation of MYC have been identified as important surrogate targets to reduce MYC activity downstream of aberrant cell stimulatory signals. Given the complex regulation of the MYC signaling pathway, a combination of these approaches may provide the most durable response, but this has yet to be shown. Here, we provide a comprehensive overview of the different therapeutic strategies being employed to target oncogenic MYC function, with a focus on post-translational mechanisms.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica , Genes myc , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Animais , Humanos , Morfolinas/farmacologia , Neoplasias/genética , Fosforilação , Multimerização Proteica/efeitos dos fármacos , Proteína Fosfatase 2/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Piranos/farmacologia , Serina/metabolismo
5.
Chem Biodivers ; 16(9): e1900266, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31298476

RESUMO

Two new spliceostatin analogs, designed as spliceostatins J and K (1 and 2), were isolated and identified from the culture of Pseudomonas sp., along with two known ones, FR901464 (3) and spliceostatin E (4). Their structures were elucidated by detailed interpretation of their spectroscopic data, especially 2D-NMR and HR-ESI-MS. Spliceostatin J (1) represented the first example of spliceostatins bearing an unusual hexahydrofuro[3,4-b]furan moiety. Biological assay showed all the isolated compounds except 1 displayed potent cytotoxic activities against two cancer cell lines (MDA-MB-231 and A-549). Structure-activity-relationship studies revealed that the tetrahydropyran ring in spliceostatin analogs was necessary for their bioactive retention.


Assuntos
Antineoplásicos/farmacologia , Furanos/farmacologia , Lactonas/farmacologia , Pseudomonas/química , Pironas/farmacologia , Células A549 , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/química , Furanos/isolamento & purificação , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Estrutura Molecular , Piranos/química , Piranos/isolamento & purificação , Piranos/farmacologia , Pironas/química , Pironas/isolamento & purificação , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
6.
J Pharm Pharmacol ; 71(9): 1393-1399, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31218683

RESUMO

OBJECTIVE: To evaluate the pharmacological characteristics of SU-011, a novel sodium-dependent glucose co-transporter 2 (SGLT2) inhibitor. METHODS: The in vitro activities of SU-011 were investigated in cell-based assays. The urinary glucose excretion, glucose tolerance and the risk of hypoglycaemia were evaluated in mice. Moreover, the dose-response relationship and chronic pharmacological studies of SU-011 were assessed in streptozotocin (STZ)-induced diabetic model, a STZ-treated model with impaired insulin secretion. KEY FINDINGS: SU-011 is a potential SGLT2 inhibitor with 5.6 nm inhibitory activity for SGLT2 and 1137-fold selectivity for SGLT1. In healthy mice, SU-011 improves the tolerance to a glucose load and promotes the urinary glucose excretion. Besides, SU-011 (10 mg/kg) still exhibited less risk of hypoglycaemia. During chronic treatment, SU-011 exhibited sustained glucose-lowering effect without the side effect of weight gain in STZ-induced diabetic mice. The levels of non-fasting and fasting plasma glucose, glycosylated haemoglobin, food and water intake were significantly decreased in SU-011-treated group. Moreover, SU-011 decreases the plasma levels of interleukin-1ß, tumour necrosis factor-α and C-reactive protein even better than that of dapagliflozin. CONCLUSIONS: All of these results indicated that SU-011 may be effective for the management of diabetes.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Piranos/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Animais , Compostos Benzidrílicos/química , Compostos Benzidrílicos/farmacologia , Proteína C-Reativa , Diabetes Mellitus Experimental/sangue , Glucosídeos/química , Glucosídeos/farmacologia , Células HEK293 , Humanos , Interleucina-1beta/sangue , Masculino , Camundongos , Fragmentos de Peptídeos/sangue , Piranos/química , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Estreptozocina , Fator de Necrose Tumoral alfa/sangue
7.
Chem Biol Interact ; 309: 108718, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31211952

RESUMO

We have previously reported the isolation of four compounds, caffeoyloxy-5,6-dihydro-4-methyl-(2H)-pyran-2-one (CDMP), olinioside, caffeic acid and 3-hydroxylup-12-en-28-oic acid, from the leaves of Olinia usambarensis. Here, we evaluated the inhibitory effects of these compounds on lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) in RAW 264.7 macrophages, and found that CDMP is the most potent of these two pro-inflammatory mediators (IC50; 12.12 µM and 10.78 µM, respectively). Consistent with these results, CDMP also down-regulated inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and interleukin 6 (IL-6) at the protein and mRNA levels in LPS-treated RAW 264.7 macrophages. Furthermore, CDMP suppressed LPS-induced nuclear factor κB (NF-κB) activation by decreasing p65 nuclear translocation through the phosphorylation and degradation of the inhibitory κBα (IκBα). CDMP also attenuated LPS-induced transcriptional and DNA-binding activities of activator protein 1 (AP-1) by suppressing the phosphorylation and expression of c-Fos and c-Jun. Finally, CDMP considerably suppressed the LPS-induced phosphorylation of c-Jun N-terminal kinase (JNK), but did not affect the phosphorylation of p38 or extracellular signal-regulated kinase (ERK). Taken together, our data suggest that CDMP down-regulates genes encoding pro-inflammatory mediators and cytokines, such as iNOS, COX-2, TNF-α, IL-1ß, and IL-6 via NF-κB and JNK/AP-1 inactivation in LPS-induced RAW 264.7 macrophages.


Assuntos
Mediadores da Inflamação/metabolismo , Myrtales/química , NF-kappa B/antagonistas & inibidores , Piranos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição AP-1/antagonistas & inibidores , Animais , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Citocinas/genética , Citocinas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Myrtales/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Folhas de Planta/química , Folhas de Planta/metabolismo , Piranos/química , Células RAW 264.7 , Fator de Transcrição AP-1/metabolismo
8.
Anticancer Res ; 39(6): 2821-2827, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177119

RESUMO

BACKGROUND/AIM: Tumour cells of the profile CD44+/CD24low/- have a high tumorigenic potential. Salinomycin can specifically inhibit the growth of these cells. Herein, we investigated the effects of salinomycin on the viability and migration of triple negative breast cancer cells. MATERIALS AND METHODS: We analysed two cell lines: i) triple-negative MDA-MB 231 breast cancer cells and ii) a cytokeratin 18-transfected, re-differentiated subclone of the MDA-MB 231 cell line. The viability was determined using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test, and the migration was determined using 24-h videography. The expression of oestrogen receptor was determined using immunohistochemistry. RESULTS: Salinomycin reduces all migration parameters in MDA-MB 231 cells. A significant correlation was found between increasing salinomycin concentrations and loss of cell viability, which was significantly less noticeable in the transfected control cells. CONCLUSION: With salinomycin there is a specific inhibition of MDA-MB 231 cells. Since MDA-MB 231 has over 90% cells with the profile CD44+/CD24low/-, these might represent a possible point of attack for salinomycin.


Assuntos
Queratina-18/genética , Piranos/farmacologia , Receptores Estrogênicos/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Queratina-18/metabolismo , Transfecção , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética
9.
Crit Rev Oncol Hematol ; 140: 17-27, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154235

RESUMO

Metastasis leads to poor prognosis and reduced disease-free survival in breast cancer patients, particularly in those with triple-negative breast cancer (TNBC) which is resistant to common treatments. Anoikis is a type of apoptosis commenced by the detachment of cells from the native extracellular matrix and prohibits the attachment of detached cells to other body organs. Resistance to anoikis is a critical culprit in the development and progression of tumours. It is therefore important to understand the anoikis-related molecular pathways in order to design effective therapies for TNBC. Several compounds have been shown to possess the potential to regulate anoikis in breast cancer cells such as DSF, AEB071, nanoencapsulated doxorubicin, berberine, salinomycin, PEM POL5551, AL10, 5-azacytidine, synthesized flavonoid derivative GL-V9, Tubeimoside V (TBMS-V) and HPW-RX40. We reviewed the molecular basis of anoikis regulation, its potential role as an important target to inhibit metastasis in TNBC, and potential anoikis modulators that could serve as drug candidates.


Assuntos
Anoikis , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/fisiopatologia , Berberina/farmacologia , Berberina/uso terapêutico , Clorobenzoatos/farmacologia , Clorobenzoatos/uso terapêutico , Feminino , Humanos , Piranos/farmacologia , Piranos/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Saponinas/farmacologia , Saponinas/uso terapêutico , Estirenos/farmacologia , Estirenos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
10.
Eur J Med Chem ; 176: 208-227, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103901

RESUMO

The history of drug development clearly shows the scale of painstaking effort leading to a finished product - a highly biologically active agent that would be at the same time no or little toxic to human organism. Moreover, the aim of modern drug discovery can move from "one-molecule one-target" concept to more promising "one-molecule multiple-targets" one, particularly in the context of effective fight against cancer and other complex diseases. Gratifyingly, natural compounds are excellent source of potential drug leads. One of such promising naturally-occurring drug candidates is a polyether ionophore - salinomycin (SAL). This compound should be identified as multi-target agent for two reasons. Firstly, SAL combines a broad spectrum of bioactivity, including antibacterial, antifungal, antiviral, antiparasitic and anticancer activity, with high selectivity of action, proving its significant therapeutic potential. Secondly, the multimodal mechanism of action of SAL has been shown to be related to its interactions with multiple molecular targets and signalling pathways that are synergistic for achieving a therapeutic anticancer effect. On the other hand, according to the Paul Ehrlich's "magic bullet" concept, invariably inspiring the scientists working on design of novel target-selective molecules, a very interesting direction of research is rational chemical modification of SAL. Importantly, many of SAL derivatives have been found to be more promising as chemotherapeutics than the native structure. This concise review article is focused both on the possible role of SAL and its selected analogues in future antimicrobial and/or cancer therapy, and on the potential use of SAL as a new class of multiple-targeted "magic bullet" because of its multimodal mechanism of action.


Assuntos
Anti-Infecciosos/uso terapêutico , Antineoplásicos/uso terapêutico , Piranos/uso terapêutico , Animais , Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Piranos/farmacologia , Transdução de Sinais/efeitos dos fármacos
11.
Shanghai Kou Qiang Yi Xue ; 28(1): 20-24, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-31080994

RESUMO

PURPOSE: To investigate the effects of salinomycin on proliferative, migratory and invasive properties of tongue squamous cell carcinoma cells, and to explore its possible mechanism. METHODS: CCK8 assay was used to detect the effect of salicamycin and cisplatin on proliferative abilities of CAL-27 cells and EA.hy926 cells. The invasive and migratory ability was detected by Transwell assay. The protein expressions of E-cadherin, vimentin and ß-catenin was evaluated by Western blot. SPSS20.0 software package was used to analyze the data. RESULTS: Salicamycin can effectively inhibit proliferation of CAL-27 cells, and the inhibitive ability of salicamycin on the proliferation was stronger than that of cisplatin. CAL-27 cells were treated by salinomycin (4 µmol/L) before invasive and migratory abilities were examined. Compared with control group, the number of invasive and migratory cells in the salinomycin-treated group was significantly decreased (P<0.05). Western blot analysis showed that the protein expression of vimentin and ß-catenin was significantly down-regulated. The expression of E-cadherin was significantly increased with the increase of salicamycin concentration. CONCLUSIONS: The proliferative, invasive and migratory ability of CAL-27 cells can be inhibited by salinomycin, which may be related to the inhibition of epithelial-mesenchymal transitions.


Assuntos
Antineoplásicos , Neoplasias de Células Escamosas , Piranos , Neoplasias da Língua , Antineoplásicos/farmacologia , Caderinas , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Humanos , Neoplasias de Células Escamosas/tratamento farmacológico , Piranos/farmacologia , Neoplasias da Língua/tratamento farmacológico
12.
Biomolecules ; 9(5)2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100934

RESUMO

4-oxo-4H-pyran-2.6-dicarboxylic acid (chelidonic acid, ChA) in the native state and in the complex with calcium [Ca(ChA)(H2O)3], named saucalchelin (CaChA), was isolated from the extract of Saussurea controversa leaves for the first time for the Asteraceae family. The structure of ChA was determined by NMR, MS and confirmed by X-ray analysis of its monomethyl ester, and CaChA was described by IR, ICP-MS, CHN analysis. The yield of ChA and CaChA was 45 mg/g and 70 mg/g of extract, respectively. The osteogenic activity of ChA, n-monobutyl ester of chelidonic acid, and CaChA has been studied in vitro in a 21-day culture of human adipose-derived multipotent mesenchymal stromal cells (hAMMSCs) in a standard nutrient medium without osteogenic supplements. CaChA significantly stimulated the growth of cell mass and differentiation of hAMMSCs into osteoblasts with subsequent mineralization of the culture and it may be a promising substance for accelerating bone tissue regeneration and engineering.


Assuntos
Diferenciação Celular , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Piranos/farmacologia , Saussurea/química , Células Cultivadas , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/citologia , Osteoblastos/metabolismo , Extratos Vegetais/química , Piranos/química
13.
Microb Pathog ; 132: 369-373, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31075430

RESUMO

Present study evaluates the protective effect of mollugin against Klebsiella pneumonia (KP) and also postulates the possible mechanism of its action. Klebsiella pneumoniae (2.4 × 108 CFU/ml) was used for the induction of KP. PMNs and WBC count was determined in the blood and bronchoalveolar lavage fluid (BALF) of Klebsiella pneumonia rat. Level of inflammatory cytokines in the blood of Klebsiella pneumonia rat was determined by ELISA methods. Moreover effect of mollugin was estimated by Western blot assay and RT-PCR method. Result of the study suggests that water content in lung was reduced in the mollugin treated group compared to pneumonia control group of rats. Count of PMNs and WBC were found to be reduced in mollugin treated group compared to pneumonia control group of rats. Level of inflammatory cytokines was also found to be reduced in the blood of mollugin treated group than pneumonia control group. Moreover treatment with mollugin attenuates the altered expression of p-MAPK, p-JNK and p-ERK protein and mRNA expression of NF-κB in the lung tissues of Klebsiella pneumonia rat. In conclusion, data of the study reveals that treatment with mollugin ameliorates Klebsiella pneumonia rat by reducing the lung inflammation. Inflammation of lung tissue was reduced by regulating the NF-κB/MAPK signaling pathway in mollugin treated group.


Assuntos
Klebsiella pneumoniae/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Piranos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Líquido da Lavagem Broncoalveolar/microbiologia , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Infecções por Klebsiella/sangue , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/patogenicidade , Pulmão/metabolismo , Pulmão/patologia , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Pneumonia/microbiologia , Piranos/uso terapêutico , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
14.
Toxicol In Vitro ; 60: 125-133, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31077746

RESUMO

Cisplatin (cis-diamminedichloro-platinum, CDDP), is a widely used platinum compound for various solid tumors including breast cancer as first line of therapy. However, its positive effects are limited due to acquired drug resistance and severe side effects in non-malignant tissue, especially due to dose-dependent nephro- and/or neuro-toxicity. Salinomycin is an antibiotic with coccidiostat effect and has shown anticancer efficacy against various cancer cells with selectivity in targeting cancer stem cells. In the present study, anticancer efficacy and mechanism of action of salinomycin in CDDP-resistant human breast cancer (MCF7DDP) cells has been examined. Initially, we generated CDDP-resistant cells by a new protocol followed by checking the anticancer efficacy of salinomycin through MTT, clonogenic, annexin-V/PI and sub-G1 assay. Our results demonstrated that salinomycin diminished both cell proliferation and metastatic migration of MCF7DDP cells. Salinomycin also induced mitochondrial dysfunction in CDDP-resistant breast cancer cells. The analysis of nuclear translocation of pro-survival transcription factors by western blotting showed a distinct role of p65 (NF-κB) in CDDP-mediated resistance in breast cancer. Salinomycin abrogated nuclear translocation of NF-κB proteins and also caused a concurrent reduction in NF-κB regulated expression of pro-survival proteins e.g., survivin, XIAP and BCL-2 in CDDP-resistant cells. These results suggest that a follow up treatment of salinomycin may be promising strategy against CDDP resistant breast cancer cells and metastasis and help in reducing CDDP-induced side effects.


Assuntos
Antineoplásicos/farmacologia , Cisplatino , Resistencia a Medicamentos Antineoplásicos , NF-kappa B/metabolismo , Piranos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Células MCF-7
15.
Neurol Res ; 41(9): 780-790, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31092134

RESUMO

Objectives-Elevated protein O-GlcNAcylation could benefit cell survival and promote organ functional recovery. Thiamet-G (O-GlcNAcase inhibitor) could upregulate protein O-GlcNAcylation level to improve dyskinesia in models of neurodegenerative diseases without any obvious detrimental side-effects. Therefore, we conducted this study to investigate the effects of protein O-GlcNAcylation upregulation by Thiamet-G on the spinal cord injury (SCI) in rats. Methods-We randomly assigned 74 rats to three groups: sham-operated group (Sham) with no lesion (n = 22), injured control group (SCI+SS) with saline solution (n = 26), and Thiamet-G treated group (SCI+Thiamet-G) (n = 26). We assessed Locomotor behavior using the Basso, Beattice, and Bresnahan (BBB) scale and evaluated histopathological alterations by morphometry and histochemistry. We also assessed potential inflammatory effects by microglia/macrophages immunohistochemistry, and potential apoptosis effects by caspase-3 western blot. Results-Thiamet-G treatment improved hindlimb motor functional recovery by inducing elevated protein O-GlcNAcylation, and mitigated the severity, reduced the lesion size and promoted the structural recovery of the injured spinal cord. Thiamet-G treatment also inhibited microglia/macrophages infiltration at the injury sites and the caspase-3 mediated apoptosis pathway. Discussion-We conclude that Thiamet-G induced elevated protein O-GlcNAcylation to ameliorate acute SCI, which could provide a potential novel therapeutic approach for SCI treatment.


Assuntos
Atividade Motora/efeitos dos fármacos , Piranos/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/patologia , Tiazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Microglia/efeitos dos fármacos , Ratos Wistar , Recuperação de Função Fisiológica/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/patologia
16.
Chemosphere ; 228: 139-148, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31029959

RESUMO

Lipophilic phycotoxins are secondary metabolites produced by phytoplanktonic species. They accumulate in filtering shellfish and can cause human intoxications. Humans can be exposed to combinations of several phycotoxins. The toxicological effects of phycotoxin mixtures on human health are largely unknown. Published data on phycotoxin co-exposure show that okadaic acid (OA) is simultaneously found with pectenetoxin-2 (PTX-2), 13-desmethylspirolide C (also known as SPX-1), or yessotoxin (YTX). Therefore, the aim of this study was to examine the effects of three binary mixtures, OA/PTX-2, OA/SPX-1 and OA/YTX on human intestinal Caco-2 cells. A multi-parametric approach for cytotoxicity determination was applied using a high-content analysis platform, including markers for cell viability, oxidative stress, inflammation, and DNA damage. Mixtures effects were analyzed using two additivity mathematical models. Our assays revealed that OA induced cytotoxicity, DNA strand breaks and interleukin 8 release. PTX-2 slightly induced DNA strand breaks, whereas SPX-1 and YTX did not affect the investigated endpoints. The combination of OA with another toxin resulted in reduced toxicity at low concentrations, suggesting antagonistic effects, but in increased effects at higher concentrations, suggesting additive or synergistic effects. Taken together, our results demonstrated that the cytotoxic effects of binary mixtures of lipophilic phycotoxins could not be predicted by additivity mathematical models. In conclusion, the present data suggest that combined effects of phycotoxins may occur which might have the potential to impact on risk assessment of these compounds.


Assuntos
Células CACO-2/efeitos dos fármacos , Combinação de Medicamentos , Interações de Medicamentos , Toxinas Marinhas/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Furanos/farmacologia , Humanos , Inflamação , Intestinos/citologia , Toxinas Marinhas/análise , Ácido Okadáico/análise , Ácido Okadáico/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Oxocinas/farmacologia , Piranos/farmacologia , Frutos do Mar/análise , Frutos do Mar/toxicidade , Compostos de Espiro/farmacologia
17.
Phytochemistry ; 163: 187-194, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31014820

RESUMO

Smoke derived karrikinolide and trimethylbutenolide exerted neuroprotective effects against monoamine oxidase and acetylcholinesterase. Synthesis of potent analogs was achieved. Sulphur substitution in the bicyclic ring structure of KAR1 displayed the most encouraging activity returning IC50 values of 13.75 ±â€¯0.001 µM and 0.03 ±â€¯0.02 µM for monoamine oxidase A and B and 0.08 ±â€¯0.006 µM for acetylcholinesterase. Neuroprotective butenolides may be particularly useful in the treatment of depressive disorders, Alzheimer's and Parkinson's diseases.


Assuntos
4-Butirolactona/análogos & derivados , Transtorno Depressivo/tratamento farmacológico , Furanos/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Piranos/farmacologia , 4-Butirolactona/síntese química , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Acetilcolinesterase/metabolismo , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Humanos , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Piranos/síntese química , Piranos/química , Relação Estrutura-Atividade
18.
J Biol Chem ; 294(22): 8973-8990, 2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31010828

RESUMO

Chronic, low-grade inflammation increases the risk for atherosclerosis, cancer, and autoimmunity in diseases such as obesity and diabetes. Levels of CD4+ T helper 17 (Th17) cells, which secrete interleukin 17A (IL-17A), are increased in obesity and contribute to the inflammatory milieu; however, the relationship between signaling events triggered by excess nutrient levels and IL-17A-mediated inflammation is unclear. Here, using cytokine, quantitative real-time PCR, immunoprecipitation, and ChIP assays, along with lipidomics and MS-based approaches, we show that increased levels of the nutrient-responsive, post-translational protein modification, O-GlcNAc, are present in naive CD4+ T cells from a diet-induced obesity murine model and that elevated O-GlcNAc levels increase IL-17A production. We also found that increased binding of the Th17 master transcription factor RAR-related orphan receptor γ t variant (RORγt) at the IL-17 gene promoter and enhancer, as well as significant alterations in the intracellular lipid microenvironment, elevates the production of ligands capable of increasing RORγt transcriptional activity. Importantly, the rate-limiting enzyme of fatty acid biosynthesis, acetyl-CoA carboxylase 1 (ACC1), is O-GlcNAcylated and necessary for production of these RORγt-activating ligands. Our results suggest that increased O-GlcNAcylation of cellular proteins may be a potential link between excess nutrient levels and pathological inflammation.


Assuntos
Ácidos Graxos/biossíntese , Interleucina-17/metabolismo , Células Th17/metabolismo , Acetil-CoA Carboxilase/metabolismo , Acilação/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Ácidos Graxos/análise , Feminino , Humanos , Interleucina-17/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Regiões Promotoras Genéticas , Ligação Proteica , Piranos/farmacologia , Células Th17/citologia , Tiazóis/farmacologia , Ativação Transcricional/efeitos dos fármacos
19.
Molecules ; 24(7)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934811

RESUMO

Although smoke-isolated karrikins (KAR1) could regulate secondary metabolism in medicinal plants, the signal transduction mechanism has not been reported. This study highlights the influence of KAR1 on tanshinone I (T-I) production in Salvia miltiorrhiza and the involved signal molecules. Results showed KAR1-induced generation of nitric oxide (NO), jasmonic acid (JA) and T-I in S. miltiorrhiza hairy root. KAR1-induced increase of T-I was suppressed by NO-specific scavenger (cPTIO) and NOS inhibitors (PBITU); JA synthesis inhibitor (SHAM) and JA synthesis inhibitor (PrGall), which indicated that NO and JA play essential roles in KAR1-induced T-I. NO inhibitors inhibited KAR1-induced generation of NO and JA, suggesting NO was located upstream of JA signal pathway. NO-induced T-I production was inhibited by SHAM and PrGall, implying JA participated in transmitting signal NO to T-I accumulation. In other words, NO mediated the KAR1-induced T-I production through a JA-dependent signaling pathway. The results helped us understand the signal transduction mechanism involved in KAR1-induced T-I production and provided helpful information for the production of S. miltiorrhiza hairy root.


Assuntos
/biossíntese , Ciclopentanos/metabolismo , Furanos/farmacologia , Óxido Nítrico/metabolismo , Oxilipinas/metabolismo , Piranos/farmacologia , Salvia miltiorrhiza/efeitos dos fármacos , Salvia miltiorrhiza/metabolismo , Fumaça , Análise de Variância , Furanos/isolamento & purificação , Regulação da Expressão Gênica de Plantas , Redes e Vias Metabólicas/efeitos dos fármacos , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Piranos/isolamento & purificação , Salvia miltiorrhiza/genética , Transdução de Sinais/efeitos dos fármacos , Fumaça/análise
20.
Pharm Res ; 36(6): 83, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30989413

RESUMO

PURPOSE: Salinomycin (SAL) is a polyether compound that exhibits strong antimicrobial as well as anticancer activity. Nanomedicine has been at the forefront of drug delivery research with the aim of increasing the efficacy, specificity and reduce toxicity of drugs. There is an intersection between infection and cancer, and cancer patients are prone to bacterial infections. In this study, polymeric micelles were prepared using Pluronic® F127 (PM) to encapsulate SAL (PM_SAL) with the view of enhancing antimicrobial and anticancer activity. METHODS: A Quality by Design (QbD) approach was utilized to synthesize PM_SAL, and nanoformulation activity was determined against bacterial (S. aureus, MRSA and E. coli). Effects on cancer cell line A549, i.e. cell viability, prevention of P-gp efflux, vimentin expression, effects on migratory ability of A549 cells. Anticancer activity was determined by ability to eradicate cancer stem-like cells. RESULTS: PM_SAL demonstrated only efficacy against MRSA, being even higher than that obtained with SAL. In A549 cells, a 15-fold increase in P-gp's expression as well as a significant decrease of the cell's migration, was observed. CONCLUSIONS: PM_SAL can interfere with the oncogenic protein VIM, involved in the crucial mechanisms EMT, downregulating its expression. Altogether data obtained indicates that this antibiotic and the developed polymeric micelle system is a very promising inhibitor of tumor cell growth.


Assuntos
Anti-Infecciosos/química , Antineoplásicos/química , Portadores de Fármacos/química , Poloxâmero/química , Piranos/química , Células A549 , Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Escherichia coli/efeitos dos fármacos , Humanos , Micelas , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Tamanho da Partícula , Piranos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Propriedades de Superfície , Vimentina/genética
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