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1.
Nat Prod Res ; : 1-5, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31359780

RESUMO

The aerial portions of Cynara scolymus commonly have been eaten as vegetables or functional foods by the people lived in Mediterranean region. In preliminary antioxidant screening, the rhizome portions (CSR) of this species showed better potential than leaves ones. However, neither phytochemical nor pharmacology studies of CSR have been reported to date. The purpose of this research was to identify the active components from CSR through bioassay-guided fractionation. The antioxidant properties of secondary metabolites 1-9 were evaluated in this investigation. Compounds 4-6, 8, and 9 showed antioxidant activities based on DPPH free radical scavenging activity with IC50 values of 22.91-147.21 µM. Besides, compound 8 significantly and dose-dependently reduced H2O2-induced ROS levels in keratinocyte HaCaT cells without cytotoxicity toward HaCaT. Overall, our studies demonstrated the rhizome of C. scolymus could be used as a new natural antioxidant like the edible aerial portions and phenolic compounds are the active components.

2.
Mol Oncol ; 13(8): 1744-1762, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31152681

RESUMO

Alternative splicing (AS) is a process that enables the generation of multiple protein isoforms with different biological properties from a single mRNA. Cancer cells often use the maneuverability conferred by AS to produce proteins that contribute to growth and survival. In our previous studies, we identified that amiloride modulates AS in cancer cells. However, the effective concentration of amiloride required to modulate AS is too high for use in cancer treatment. In this study, we used computational algorithms to screen potential amiloride derivatives for their ability to regulate AS in cancer cells. We found that 3,5-diamino-6-chloro-N-(N-(2,6-dichlorobenzoyl)carbamimidoyl)pyrazine-2-carboxamide (BS008) can regulate AS of apoptotic gene transcripts, including HIPK3, SMAC, and BCL-X, at a lower concentration than amiloride. This splicing regulation involved various splicing factors, and it was accompanied by a change in the phosphorylation state of serine/arginine-rich proteins (SR proteins). RNA sequencing was performed to reveal that AS of many other apoptotic gene transcripts, such as AATF, ATM, AIFM1, NFKB1, and API5, was also modulated by BS008. In vivo experiments further indicated that treatment of tumor-bearing mice with BS008 resulted in a marked decrease in tumor size. BS008 also had inhibitory effects in vitro, either alone or in a synergistic combination with the cytotoxic chemotherapeutic agents sorafenib and nilotinib. BS008 enabled sorafenib dose reduction without compromising antitumor activity. These findings suggest that BS008 may possess therapeutic potential for cancer treatment.

3.
Int J Mol Sci ; 20(8)2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010164

RESUMO

Rosa cymosa Tratt is a Chinese herbal remedy that is used in the treatment of diarrhea, burns, rheumatoid arthritis, and hemorrhage. Despite its use in Asian folk medicine, there are limited reports on the biological activity of R. cymosa fruits. This study focused on the investigation of the antitumor effect of the antioxidative ethanolic extract of R. cymosa fruits (RCE) along with its underlying mechanism of action. RCE showed a potent cytotoxic effect against Sup-T1 and Molt-4 lymphoblastic leukemia cells. In the xenograft animal model, the tumor size was significantly reduced to about 59.42% in the RCE-treated group in comparison with the control group. The use of RCE (37.5, 75, or 150 µg/mL) triggered apoptosis by 26.52-83.49%, disrupted mitochondrial membrane potential (MMP) by 10.44-58.60%, and promoted calcium release by 1.29-, 1.44-, and 1.71-fold compared with the control group. The extract induced redox oxygen species (ROS) generation through the elimination of Nrf2/Keap1/P62-mediated oxidative stress response. The loss of phosphatase and tensin homolog (PTEN) activation by RCE impaired PI3K/Akt/Foxo and Jak/Stat activation pathways, which contributed to tumorigenesis. These multiple targets of R. cymosa against hematologic cancer cells suggested its potential application as an antileukemic dietary supplement.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Etanol/química , PTEN Fosfo-Hidrolase/metabolismo , Extratos Vegetais/farmacologia , Rosa/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos SCID , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Phytochemistry ; 162: 39-46, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30852259

RESUMO

Qing Dai (Naturalis Indigo) is a traditional Chinese medicine (TCM) used as a topical agent in moderate psoriasis, targeting interleukin-17 (IL-17). In this study, it was prepared from the aerial parts of Strobilanthes cusia. Three undescribed indole alkaloid derivatives, indigodoles A-C, along with seven known compounds were isolated from this preparation of Qing Dai and their structures were elucidated from spectroscopic data, including NMR, MS, UV, IR, optical rotation, and CD. As well, most compounds were tested against IL-17. Indigodole C and tryptanthrin could significantly inhibit IL-17 production of Th17 cells. In addition, indigodole A and indirubin showed notably anti-IL-17 gene expression in dose-dependent effects without cytotoxicities toward Th17 and Jurkat cells, respectively. Overall, our studies indicate that the aforementioned indole alkaloids could contribute to anti-IL 17 properties of Qing Dai.


Assuntos
Acanthaceae/química , Medicamentos de Ervas Chinesas/química , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Interleucina-17/antagonistas & inibidores , Medicina Tradicional Chinesa , Componentes Aéreos da Planta/química , Animais , Interleucina-17/biossíntese , Camundongos , Modelos Moleculares , Conformação Molecular , Células Th17/efeitos dos fármacos , Células Th17/metabolismo
5.
Int J Mol Sci ; 20(4)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30769922

RESUMO

Reported cases of breast cancer have skyrocketed in the last decades with recent advances in examination techniques. Brest cancer has become the second leading cause of mortality among women worldwide, urging the scientific community to develop or find new drugs from natural sources with potent activity and a reasonable safety profile to tackle this ailment. Antrodia cinnamomea (AC) is a treasured medicinal fungus which has attracted attention due to its potent hepatoprotective and cytotoxic activities. We evaluated the antiproliferative activity of the ethanol extract of artificially cultured AC (EEAC) on breast cancer cells (T47D cells) in vivo and in vitro. Ethanol extract of artificially cultured AC inhibited T47D cells' proliferation mediated by cell cycle arrest at G1 phase as well induced autophagy. Immunoblotting assay confirmed that EEAC not only decreased the expression of the cell-cycle-related proteins but also increased the expression of transcription factor FOXO1, autophagic marker LC3 II, and p62. Ethanol extract of artificially cultured AC mediated endoplasmic reticulum stress by promoting the expression of IRE1 (inositol-requiring enzyme 1α), GRP78/Bip (glucose regulating protein 78), and CHOP (C/EBP homologous protein). Apart from previous studies, HDACs (histone deacetylases) activity was inhibited as demonstrated by a cell-free system, immunoblotting, and immunofluorescence assays following EEAC treatment. The in vivo studies demonstrated that EEAC decreased tumor volume and inhibited tumor growth without any significant side effects. High performance liquid chromatography profile demonstrated similar triterpenoids compared to the profile of wild AC ethanol extract. The multiple targets of EEAC on breast cancer cells suggested that this extract may be developed as a potential dietary supplement targeting this debilitating disease.


Assuntos
Antrodia/química , Neoplasias da Mama/tratamento farmacológico , Carpóforos/química , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Agaricales/química , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Humanos , Proteínas Associadas aos Microtúbulos/genética , Extratos Vegetais/química , Fator de Transcrição CHOP/genética
6.
EBioMedicine ; 40: 528-540, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30709770

RESUMO

BACKGROUND: Acute lung injury (ALI) is a severe life-threatening inflammatory disease. Neutrophil activation is a major pathogenic factor in ALI. Protein kinase B (PKB)/AKT regulates diverse cellular responses, but the significance in neutrophilic inflammation and ALI remains unknown. METHODS: Human neutrophils and neutrophil-like differentiated HL-60 (dHL-60) cells were used to examine the anti-inflammatory effects of 5,7-dimethoxy-1,4-phenanthrenequinone (CLLV-1). The therapeutic potential of CLLV-1 was determined in a mouse model of lipopolysaccharide (LPS)-induced ALI. FINDINGS: CLLV-1 inhibited respiratory burst, degranulation, adhesion, and chemotaxis in human neutrophils and dHL-60 cells. CLLV-1 inhibited the phosphorylation of AKT (Thr308 and Ser473), but not of ERK, JNK, or p38. Furthermore, CLLV-1 blocked AKT activity and covalently reacted with AKT Cys310 in vitro. The AKT309-313 peptide-CLLV-1 adducts were determined by NMR or mass spectrometry assay. The alkylation agent-conjugated AKT (reduced form) level was also inhibited by CLLV-1. Significantly, CLLV-1 ameliorated LPS-induced ALI, neutrophil infiltration, and AKT activation in mice. INTERPRETATION: Our results identify CLLV-1 as a covalent allosteric AKT inhibitor by targeting AKT Cys310. CLLV-1 shows potent anti-inflammatory activity in human neutrophils and LPS-induced mouse ALI. Our findings provide a mechanistic framework for redox modification of AKT that may serve as a novel pharmacological target to alleviate neutrophilic inflammation.


Assuntos
Sítio Alostérico , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Fenantrenos/farmacologia , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/química , Quinonas/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Adesão Celular/efeitos dos fármacos , Quimiotaxia de Leucócito/imunologia , Células HL-60 , Humanos , Modelos Moleculares , Conformação Molecular , Neutrófilos/metabolismo , Fenantrenos/química , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinonas/química , Espécies Reativas de Oxigênio , Relação Estrutura-Atividade
7.
Phytomedicine ; 54: 109-119, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30668360

RESUMO

BACKGROUND: Phytochemical naphtho[1,2-b] furan-4,5­dione (NFD) presenting in Avicennia marina exert anti-cancer effects, but little is known regarding about DNA damage-mediated apoptosis in non-small-cell lung carcinoma (NSCLC). PURPOSE: To examine whether NFD-induced apoptosis of NSCLC cells is correlated with the induction of DNA damage, and to investigate its underlying mechanism. STUDY DESIGN: The anti-proliferative effects of NFD were assessed by MTS Assay Kit FACS assay, and in vivo nude mice xenograft assay. The DNA damage related proteins, the Bcl-2 family and pro-apoptotic factors were examined by immunofluorescence assay, q-PCR, and western blotting. The activity of NF-κB p65 in nuclear extracts was detected using a colorimetric DNA-binding ELISA assay. The inhibitory activity of topoisomerase II (TOPO II) was evaluated by molecular docking and TOPO II catalytic assay. RESULTS: NFD exerted selective cytotoxicity against NSCLC H1299, H1437 and A549 cells rather than normal lung-embryonated cells MRC-5. Remarkably, we found that NFD activated the hull marker and modulator of DNA damage repairs such as γ-H2AX, ATM, ATR, CHK1, and CHK2 probably caused by the accumulation of intracellular reactive oxygen species (ROS) and inhibition of TOPO II activity. Furthermore, the suppression of transcription factor NF-κB by NFD resulted in significantly decreased levels of pro-survival proteins including Bcl-2 family Bcl-2, Bcl-xL and Mcl-1 and the endogenous inhibitors of apoptosis XIAP and survivin in H1299 cells. Moreover, the nude mice xenograft assay further validated the suppression of H1299 growth by NFD, which is the first report for evaluating the anti-cancer effect of NFD in vivo. CONCLUSION: These findings provide a novel mechanism indicating the inhibition of TOPO II activity and NF-κB signaling by NFD, leading to DNA damage and apoptosis of NSCLC tumor cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dano ao DNA/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Furanos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Naftoquinonas/farmacologia , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , DNA Topoisomerases Tipo II/química , Feminino , Furanos/química , Humanos , Neoplasias Pulmonares/genética , Camundongos Nus , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Naftoquinonas/química , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , Proteínas de Ligação a Poli-ADP-Ribose/química , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Phytomedicine ; 57: 30-38, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30668320

RESUMO

BACKGROUND: Chinese herbal medicine (CHM) is a complementary natural medicine that is used widely for the treatment of hepatic diseases. The aim of this study was to investigate the effects of the long-term use of CHM for the treatment of liver diseases, as prescribed by TCM doctors, on overall mortality and hepatic outcomes in patients with HCV. PATIENTS AND METHODS: We identified 98788 patients with HCV. Of these, 829 and 829 patients who were users and non-users of CHM, respectively, were matched for age, gender, CCI, and comorbidities prior to CHM treatment. The chi-squared test, Cox proportional hazard model, Kaplan--Meier method, and log-rank test were used for comparisons. RESULTS: CHM users had a lower risk of overall mortality than non-users after adjustment for comorbidities by using a multivariate Cox proportional hazard model (p-value < 0.001; HR: 0.12, 95% CI: 0.06-0.26). In addition,the CHM users had a lower risk of liver cirrhosis than non-users after adjustment for comorbidities (p-value = 0.028; HR: 0.29, 95% CI: 0.09-0.88). The 12-year cumulative incidences of overall mortality and liver cirrhosis were lower in the CHM group (p-value < 0.05 for both, log rank test). The CHM co-prescription for Dan-Shen, Bie-Jia, Jia-Wei-Xiao-Yao-San => E-Shu was found to occur most often associated for the specific treatment of HCV infection. CONCLUSION: CHM as adjunctive therapy may reduce the overall mortality and the risk of liver cirrhosis in patients with HCV. The comprehensive list of the herbal medicines that may be used for the treatment of patients with HCV may be useful in future scientific investigations or for future therapeutic interventions to prevent negative hepatic outcomes in patients with HCV.


Assuntos
Antivirais/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Hepatite C/tratamento farmacológico , Hepatite C/mortalidade , Adulto , Feminino , Hepatite C/complicações , Humanos , Estimativa de Kaplan-Meier , Cirrose Hepática/prevenção & controle , Cirrose Hepática/virologia , Masculino , Medicina Tradicional Chinesa/métodos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Taiwan/epidemiologia , Resultado do Tratamento
9.
Phytomedicine ; 53: 213-222, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30668401

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) represents a clinical challenge because it lacks sensitivity to hormone therapy or other available molecule-targeted agents. In addition, TNBC frequently exhibits over-activation of the PI3K/Akt survival pathway that can contribute to chemotherapy resistance. 4ß-Hydroxywithanolide E (4-HW) and withaferin A (WA) are two withanolides from Solanaceae plants that exhibit promising anticancer activity in vitro and in vivo. PURPOSE: The aim of this study is to investigate and compare the effects of 4-HW and WA on TNBC cells and underling mechanisms. STUDY DESIGN/METHODS: The anticancer effects of 4-HW and WA were evaluated by cell viability, cell cycle arrest, and apoptosis assays. PI3K/Akt signaling and the expression of survivin, Bcl-2 family proteins and cyclin-dependent kinase inhibitors were evaluated by Western blot. The role of PI3K/Akt signaling in the withanolides-induced anticancer effects was examined by using a PI3K inhibitor and overexpression of a constitutively active form of Akt. RESULTS: In TNBC MDA-MB-231 cells, 4-HW and WA displayed different kinetic effect on cell availability. Cell cycle analysis revealed that 4-HW induced the G1-phase arrest while WA caused the G2/M-phase block. Both withanolides induced apoptosis, but WA also caused necrosis. 4-HW inhibited the PI3K/Akt pathway and survivin expression as well as up-regulated the cyclin-dependent kinase inhibitors p21 and p27. In contrast, WA is a more potent inhibitor of Hsp90 and elicited Akt activation at low doses but inhibited Akt signaling at higher doses by depleting the Akt protein. The PI3K inhibitor LY294002 mimicked the effects of 4-HW and potentiated the cytotoxic activity of WA. In contrast, overexpressing a constitutively active form of myristoylated Akt rescue cancer cells from 4-HW-induced cell death. CONCLUSION: The withanolides 4-HW and WA potently inhibit the viability of TNBC cells through induction of cell cycle arrest and apoptosis/necrosis. The PI3K/Akt pathway plays distinct roles in cancer cells respond to 4-HW and WA. These results suggest the potential applications of the withanolides for the treatment of TNBC.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Vitanolídeos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Solanaceae/química , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
10.
BMC Complement Altern Med ; 18(1): 299, 2018 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-30413192

RESUMO

BACKGROUND: Brachychiton rupestris and Brachychiton discolor (Malvaceae) are ornamental trees native to Australia. Some members of Brachychiton and its highly related genus, Sterculia, are employed in traditional medicine for itching, dermatitis and other skin diseases. However, scientific studies on these two genera are scarce. Aiming to reveal the scientific basis of the folk medicinal use of these plants, the cytotoxicity, anti-inflammatory and anti-allergic activities of Brachychiton rupestris and Brachychiton discolor leaves extracts and fractions were evaluated. Also, phytochemical investigation of B. rupestris was performed to identify the compounds exerting the biological effect. METHODS: Extracts as well as fractions of Brachychiton rupestris and Brachychiton discolor were tested for their cytotoxicity versus hepatoma HepG2, lung A549, and breast MDA-MB-231 cancer cell lines. Assessment of the anti-allergic activity was done using degranulation assay in RBL-2H3 mast cells. Anti-inflammatory effect was tested by measuring the suppression of superoxide anion production as well as elastase release in fMLF/CB-induced human neutrophils. Phytochemical investigation of the n-hexane, dichloromethane and ethyl acetate fractions of B. rupestris was done using different chromatographic and spectroscopic techniques. RESULTS: The tested samples showed no cytotoxicity towards the tested cell lines. The nonpolar fractions of both B. rupestris and B. discolor showed potent anti-allergic potency by inhibiting the release of ß-hexosaminidase. The dichloromethane fraction of both species exhibited the highest anti-inflammatory activity by suppressing superoxide anion generation and elastase release with IC50 values of 2.99 and 1.98 µg/mL, respectively for B. rupestris, and 0.78 and 1.57 µg/mL, respectively for B. discolor. Phytochemical investigation of various fractions of B. rupestris resulted in the isolation of ß-amyrin acetate (1), ß-sitosterol (2) and stigmasterol (3) from the n-hexane fraction. Scopoletin (4) and ß-sitosterol-3-O-ß-D-glucoside (5) were obtained from the dichloromethane fraction. Dihydrodehydrodiconiferyl alcohol 4-O-ß-D-glucoside (6) and dihydrodehydrodiconiferyl alcohol 9-O-ß-D-glucoside (7) were separated from the ethyl acetate fraction. Scopoletin (4) showed anti-allergic and anti-inflammatory activity. CONCLUSIONS: It was concluded that the nonpolar fractions of both Brachychiton species exhibited anti-allergic and anti-inflammatory activities.

11.
Sci Rep ; 8(1): 15417, 2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30337630

RESUMO

Glaulactams A-C (1-3), which possess a novel skeleton, as well as the known compound daphmanidin B (4), were isolated from the leaves of Daphniphyllum glaucescens and separated using ion-exchange chromatography aided by NMR fingerprinting. Their structures, including their absolute configurations, were elucidated by spectroscopic analyses and time-dependent density-functional-theory-calculated electronic circular dichroism spectra; the data were subsequently analyzed to gain insight into the respective biogenetic relationships between the isolates, which exhibited anti-H1N1 and immunosuppressive activities.

12.
Int J Mol Sci ; 19(9)2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30223438

RESUMO

Obesity and diabetes are global health-threatening issues. Interestingly, the mechanism of these pathologies is quite different among individuals. The discovery and development of new categories of medicines from diverse sources are urgently needed for preventing and treating diabetes and other metabolic disorders. Previously, we reported that chalcones are important for preventing biological disorders, such as diabetes. In this study, we demonstrate that the synthetic halogen-containing chalcone derivatives 2-bromo-4'-methoxychalcone (compound 5) and 2-iodo-4'-methoxychalcone (compound 6) can promote glucose consumption and inhibit cellular lipid accumulation via 5'-adenosine-monophosphate-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase 1 (ACC) phosphorylation in 3T3-L1 adipocytes and C2C12 skeletal myotubes. In addition, the two compounds significantly prevented body weight gain and impaired glucose tolerance, hyperinsulinemia, and insulin resistance, which collectively help to delay the progression of hyperglycemia in high-fat-diet-induced obese C57BL/6 mice. These findings indicate that 2-bromo-4'-methoxychalcone and 2-iodo-4'-methoxychalcone could act as AMPK activators, and may serve as lead compounds for a new class of medicines that target obesity and diabetes.

13.
Mar Drugs ; 16(9)2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-30227646

RESUMO

The structures, names, bioactivities, and references of 82 natural products, including 48 new metabolites, purified from the gorgonian corals belonging to the genus Junceella are described in this review. All compounds mentioned in this review were obtained from Junceella fragilis, Junceella gemmacea, Junceella juncea, and Junceella sp., collected from tropical Indo-Pacific Ocean. Some of these compounds exhibited potential biomedical activities.

14.
Front Pharmacol ; 9: 1004, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30233379

RESUMO

Antiretroviral (ART) drugs has previously been associated with lipodystrophic syndrome, metabolic consequences, and neuropsychiatric complications. ART drugs include three main classes of protease inhibitors (PIs), nucleoside analog reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our previous work demonstrated that a high risk of hyperlipidemia was observed in HIV-1-infected patients who received ART drugs in Taiwan. Patients receiving ART drugs containing either Abacavir/Lamivudine (Aba/Lam; NRTI/NRTI), Lamivudine/Zidovudine (Lam/Zido; NRTI/NRTI), or Lopinavir/Ritonavir (Lop/Rit; PI) have the highest risk of hyperlipidemia. The aim of this study was to investigate the effects of Aba/Lam (NRTI/NRTI), Lam/Zido (NRTI/NRTI), and Lop/Rit (PI) on metabolic and neurologic functions in mice. Groups of C57BL/6 mice were administered Aba/Lam, Lam/Zido, or Lop/Rit, orally, once daily for a period of 4 weeks. The mice were then extensively tested for metabolic and neurologic parameters. In addition, the effect of Aba/Lam, Lam/Zido, and Lop/Rit on lipid metabolism was assessed in HepG2 hepatocytes and during the 3T3-L1 preadipocyte differentiation. Administration with Aba/Lam caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in leptin serum levels. Administration with Lop/Rit also caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in serum levels of total cholesterol, and HDL-c. Treatment of mice with Aba/Lam and Lop/Rit enhanced the lipid accumulation in the liver, and the decrease in AMP-activated protein kinase (AMPK) phosphorylation and/or its downstream target acetyl-CoA carboxylase (ACC) protein expression. In HepG2 hepatocytes, Aba/Lam, Lam/Zido, and Lop/Rit also enhanced the lipid accumulation and decreased phosphorylated AMPK and ACC proteins. In 3T3-L1 pre-adipocyte differentiation, Aba/Lam and Lop/Rit reduced adipogenesis by decreasing expression of transcription factor CEBPb, implicating the lipodystrophic syndrome. Our results demonstrate that daily oral administration of Aba/Lam and Lop/Rit may produce cognitive, motor, and metabolic impairments in mice, regardless of HIV-1 infection.

15.
Phytomedicine ; 46: 184-192, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30097117

RESUMO

BACKGROUND: Pancreatic cancer (PC) remains the leading cause of cancer mortality, with limited therapeutic targets, and alterations in endoplasmic reticulum (ER)-related proteostasis may be a potential target for therapy. The root bark of Paeonia suffruticosa has been shown to inhibit cancer growth and metastasis, although its impact on PC is unknown. PURPOSE: To ascertain the anti-cancer effects of P. suffruticosa on oncogenic functions of PC and determine the detailed molecular mechanisms. STUDY DESIGN: Efficacy assessment of extracts, in vitro using PC cells as a model system and in vivo in mouse xenograft tumors. METHODS: P. suffruticosa aqueous extracts (PS) were prepared and assessed using liquid chromatography-tandem mass spectrometry. Cell viability, proteins, and cell components were measured using MTT assay, western blotting, and immunofluorescence. Cell apoptosis, cell cycle, and migration were assessed using colorimetric assays, fluorescence activated cell sorting, and transwell migration. Reactive oxygen species (ROS) were evaluated with a commercial 2'-7'-dichlorofluorescin diacetate kit. For the xenograft model, AsPC1 cells were inoculated subcutaneously into immunocompromised mice and PS (oral) was administered over 3 weeks with or without gemcitabine (GEM, intraperitoneal), a first-line advanced/metastatic PC therapy. RESULTS: PS stimulated ER stress and affected mitochondrial membrane potential to increase autophagosome numbers and block their degradation, followed by autophagy induction and finally cell apoptosis. Additionally, PS-mediated proteostasis impairment resulted in altered dynamics of the actin cytoskeleton, cell motility impairment, and cell cycle progression inhibition. Conversely, a ROS scavenger partially reversed PS-mediated degradation of peptidyl-prolyl cis-trans isomerase B (PPIB), an ER protein important for protein folding, suggesting that ROS generation by PS may be the upstream of PS-triggering of mitophagy and final cell apoptosis. Nevertheless, oral administration of PS, alone or in combination with GEM, delayed tumor growth in a xenograft model without affecting body weight. CONCLUSION: These findings indicate that PS may constitute a potential new alternative or complementary medicine for PC.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Paeonia/química , Neoplasias Pancreáticas/tratamento farmacológico , Extratos Vegetais/farmacologia , Proteostase/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Potencial da Membrana Mitocondrial , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Pharm Biomed Anal ; 159: 548-566, 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-30077947

RESUMO

In current work, targeted and non-targeted analysis of alkaloids and acetogenins from methanolic extracts of Asimina, Annona species and dietary supplements have been performed using UHPLC-QToF in positive ion mode. Thirty-five standard compounds (twelve alkaloids and twenty-three acetogenins) were used for the analysis. The fragment ions produced by collision induced dissociation (CID) revealed the characteristic cleavage and provided structural information. Aporphine alkaloids and acetogenins are the major groups found in Asimina and Annona species. An untargeted analysis based on high-resolution mass spectrometry was carried out to profile the alkaloids and acetogenins from Asimina species (As. triloba, As. parviflora). Magnoflorine, being a major alkaloid from twigs of As. triloba samples, was used as an example to discuss the fragmentation patterns. In (+)-ESI-MS, magnoflorine gave [M]+ ions at m/z 342.1705. The fragment ions at m/z 297.1127 [M-(CH3)2NH]+, 282.0886 [M-(CH3)3NH]+, 265.0865 [M-(CH3)2NH-CH3OH]+, 237.0916 [M-(CH3)2NH-CH3OH-CO]+, and 222.0681 [M-(CH3)2NH-CH3OH-CO-CH3]+ resulted from the [M]+ molecular ion. One dietary supplement claiming to contain paw paw (As. triloba) was also analyzed and showed a similar profile to twigs of As. triloba. A total of 131 compounds including standard compounds were identified from the different parts of As. triloba and As. parviflora samples. These compounds can be used to distinguish Asimina species. However, for definite identification of these unknown components, further investigation is required. This may provide a model for the rapid screening and structural characterization of bioactive constituents from plant extracts in a single analysis.

17.
J Nat Prod ; 81(7): 1534-1539, 2018 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-29975532

RESUMO

Five new compounds named buxifoximes A-C (1-3), buxifobenzoate (4), and 7- O-(7'-peroxygeranyl) coumarin (5), together with 25 known compounds, were identified from the twigs of Atalantia buxifolia. Compounds 1-3 are unique secondary metabolites with the aldoxime functionality. The structures of the isolates were determined on the basis of spectroscopic data analyses, and the structure of 1 was confirmed by an X-ray single-crystallographic analysis. With respect to bioactivity, antidengue virus, anti-inflammatory, and cytotoxic activities of all purified compounds were tested and evaluated. Compound 1 showed a significant anti-inflammatory effect by inhibiting superoxide anion generation with an IC50 value of 4.8 ± 0.7 µM. Among the acridone alkaloids, 5-hydroxy- N-methylseverifoline (23) exhibited antidengue activity (IC50 = 5.3 ± 0.4 µM), and atalaphyllinine (20) demonstrated cytotoxicity (IC50 = 6.5 ± 0.0 µM) against the human liver cancer cell line, HepG2.

18.
Cancer Med ; 7(8): 3743-3754, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29923327

RESUMO

Sphingosine-1-phosphate (S1P) is a bioactive lipid that exerts various pathophysiological functions through binding to its receptor family (S1PRs). Since first report of the breast cancer (BCA) promoting function by S1P production (through the function of sphingosine kinases) and S1P/S1PR signaling, their antagonists have never been successfully progress to clinics after three decades. Taking advantage of bioinformatics linking to gene expression to disease prognosis, we examined the impact of associated genes in BCA patients. We found high gene expressions involved in S1P anabolism suppressed disease progression of patients who are basal cell type BCA or receiving adjuvant therapy. In addition, S1PRs expression also suppressed disease progress of multiple categories of BCA patient progression. This result is contradictory to tumor promoter role of S1P/S1PRs which revealed in the literature. Further examination by directly adding S1P in BCA cells found a cell growth suppression function, which act via the expression of S1PR1. In conclusion, our study is the first evidence claiming a survival benefit function of S1P/S1PR signaling in BCA patients, which might explain the obstacle of relative antagonist apply in clinics.

19.
Molecules ; 23(7)2018 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-29932137

RESUMO

Two new briarane metabolites—fragilides K (1) and L (2)—along with five known analogues—gemmacolide X, praelolide, juncins P and ZI, and gemmacolide V (3⁻7)—were extracted and purified from Junceella fragilis, a gorgonian coral. Based on data obtained via spectroscopic techniques, the structures of new briaranes 1 and 2 were determined and the cyclohexane rings in 1 and 2 were found to exist in chair and twist boat conformation, respectively. Additionally, anti-inflammatory analysis showed that briaranes 2, 3, and 6 inhibited pro-inflammatory inducible nitric oxide synthase protein expression and briaranes 3 and 7 suppressed the cyclooxygenase-2 level, in LPS-stimulated murine macrophage-like RAW264.7 cells.


Assuntos
Antozoários/química , Anti-Inflamatórios/química , Diterpenos/química , Expressão Gênica/efeitos dos fármacos , Animais , Antozoários/metabolismo , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Configuração de Carboidratos , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/isolamento & purificação , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Lactonas/química , Lactonas/isolamento & purificação , Lactonas/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas de Plantas/química , Proteínas de Plantas/isolamento & purificação , Proteínas de Plantas/farmacologia , Células RAW 264.7
20.
Mar Drugs ; 16(6)2018 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-29903990

RESUMO

Six new polyoxygenated cembrane-based diterpenoids, stellatumolides A⁻C (1⁻3), stellatumonins A and B (4 and 5), and stellatumonone (6), were isolated together with ten known related compounds (7⁻16) from the ethyl acetate (EtOAc) extract of soft coral Sarcophyton stellatum. The structures of the new compounds were established by extensive spectroscopic analyses, including 1D and 2D nuclear magnetic resonance (NMR) spectroscopy and data comparison with related structures. Compounds 8 and 14 were isolated from a natural source for the first time. The isolated metabolites were shown to be not cytotoxic against a limited panel of cancer cells. Compound 9 showed anti-inflammatory activity by reducing the expression of proinflammatory cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proteins in lipopolysaccharide (LPS)-stimulated mouse leukaemic monocyte macrophage (RAW 264.7) cells.


Assuntos
Antozoários/química , Inibidores de Ciclo-Oxigenase 2/química , Diterpenos/química , Animais , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Inibidores de Ciclo-Oxigenase 2/farmacologia , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo
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