Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.045
Filtrar
1.
J Agric Food Chem ; 70(2): 554-566, 2022 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-35007076

RESUMO

Dihydro-ß-agarofuran-type sesquiterpenoids are characteristic metabolites of Celastraceae plants, and the extracts of these plants have been developed into botanical pesticides. In the course of our efforts to find novel natural biologically active products, eight new dihydro-ß-agarofuran-type sesquiterpenoids (1-8) were identified from the stems of Celastrus monospermus Roxb. Their structures were elucidated by extensive spectroscopic analysis, single crystal X-ray crystallography, and electronic circular dichroism (ECD) calculations. In consideration of the efficacy of certain Celastrus plants for the treatment of arthritis and arthralgia in folk medicine, the isolates were evaluated for their inhibitory activities against osteoclastogenesis. As a result, compounds 4, 6, and 7 were found to restrain osteoclastogenesis induced by receptor activator of nuclear factor-κB ligand (RANKL) with IC50 values of 0.58, 1.2, and 6.1 µM, respectively. Furthermore, compound 4 was found to inhibit osteoclastogenesis-related gene (c-Fos, MMP-9, CTSK, TRAP) expression and block c-Fos protein expression and inhibited bone resorption of mature osteoclasts induced by M-CSF and RANKL in a dose dependent manner. This is the first report of dihydro-ß-agarofuran-type sesquiterpenoid for their potential medical applications in bone metabolic diseases.


Assuntos
Reabsorção Óssea , Sesquiterpenos , Diferenciação Celular , Humanos , Osteoclastos , Osteogênese , Ligante RANK/genética , Sesquiterpenos/farmacologia
2.
Oncol Rep ; 47(1)2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34738622

RESUMO

Due to drug resistance and disease recurrence, lung cancer remains one of the primary cancer­related causes of death in both men and women worldwide. In addition, lung cancer is clinically silent and thus most patients are at an advanced stage at the time of diagnosis. The limited efficiency of current conventional chemotherapies necessitates the search for novel effective anticancer agents. The present study demonstrated the anti­proliferative effect and apoptosis­inducing activity of three sesquiterpene lactones isolated from Gymnanthemum extensum, vernodalin (VDa), vernolepin (VLe) and vernolide (VLi), on A549 human lung cancer cells. Treatment with sub­cytotoxic doses (cell viability remaining >75%) of VDa, VLe and VLi, arrested progression of the A549 cell cycle at the G0/G1 phase, while cytotoxic doses of the three compounds induced G2/M phase arrest and apoptosis. Mechanistic studies revealed that VDa, VLe and VLi may exert their anti­tumor activity through the JAK2/STAT3 pathway. Molecular docking analysis confirmed that VDa, VLe and VLi formed hydrogen bonds with the FERM domain of JAK2 protein. Overall, the present study highlighted the potential therapeutic value of VDa, VLe and VLi to be further developed as anticancer agents for the treatment of lung cancer.


Assuntos
Carcinoma/tratamento farmacológico , Janus Quinase 2/metabolismo , Lactonas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Extratos Vegetais/farmacologia , Fator de Transcrição STAT3/metabolismo , Sesquiterpenos/farmacologia , Células A549 , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Citostáticos/farmacologia , Humanos , Simulação de Acoplamento Molecular
3.
Food Chem ; 373(Pt A): 131392, 2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-34742043

RESUMO

A sesquiterpene quinone, ilimaquinone, was accessed for its cellular antioxidant efficacy and possible antimicrobial mechanism of action against foodborne pathogens (Staphylococcus aureus and Escherichia coli) in vitro and in vivo. Ilimaquinone was found to be protective against H2O2-induced oxidative stress as validated by the reduction in the ROS levels, including increasing expression of SOD1 and SOD2 enzymes. Furthermore, ilimaquinone evoked MIC against S. aureus and E. coli within the range of 125-250 µg/mL. Ilimaquinone established its antimicrobial mode of action against both tested pathogens as evident by bacterial membrane depolarization, loss of nuclear genetic material, potassium ion, and release of extracellular ATP, as well as compromised membrane permeabilization and cellular component damage. Also, ilimaquinone showed no teratogenic effect against zebrafish, suggesting its nontoxic nature. Moreover, ilimaquinone significantly reduced the S. aureus count without affecting the sensory properties and color values of cold-storaged ground chicken meat even under temperature abuse condition.


Assuntos
Galinhas , Sesquiterpenos , Animais , Antibacterianos , Antioxidantes/farmacologia , Escherichia coli/genética , Peróxido de Hidrogênio , Testes de Sensibilidade Microbiana , Quinonas , Sesquiterpenos/farmacologia , Staphylococcus aureus , Temperatura , Peixe-Zebra
4.
Phytochemistry ; 193: 113001, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34763221

RESUMO

Twelve undescribed sesquiterpenoids, named chlomultiols A-L, involving three lindenane sesquiterpenoid dimers, three eudesmane sesquiterpenoids, three guaiane sesquiterpenoids, and three cadinane sesquiterpenoids, along with four known compounds, were obtained from the whole plant of Chloranthus multistachys. Their structures were determined through spectroscopic techniques (HRESIMS, 1D and 2D NMR). In addition, the absolute and relative configurations of the undescribed compounds were established by using single crystal X-ray crystallography, NOESY and CD spectroscopy. The inhibitory effects of chlomultiols A-M on the production of nitric oxide in RAW 264.7 cells induced by lipopolysaccharide were evaluated. Chlomultiols A-C, and chlomultiols K-L showed moderate anti-inflammatory activities with IC50 values of 3.34 ± 0.73, 15.06 ± 1.08, 13.13 ± 3.99, 6.63 ± 1.11, and 16.16 ± 1.88 µM, respectively.


Assuntos
Magnoliopsida , Sesquiterpenos , Animais , Anti-Inflamatórios/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico , Células RAW 264.7 , Sesquiterpenos/farmacologia
5.
Phytochemistry ; 193: 112999, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34768186

RESUMO

Eight undescribed sesquiterpenoids, including two eudesmane glycosides dobinosides A and B, five eudesmane aglycones dobinins Q-U, and one germacrane dobinin P, were isolated from the 80% ethanol extract of roots of Dobinea delavayi. Their structures were elucidated by extensive spectroscopic data (1D and 2D NMR, HR-ESI-MS) and single-crystal X-ray diffraction analysis. Dobinoside A, dobinins Q and R, as well as six reported eudesmane sesquiterpenoids, were evaluated for their in vivo antimalarial activities against Plasmodium yoelii BY265RFP in mice. A summary of preliminary structure-activity relationship of eudesmane sesquiterpenoids for in vivo antimalarial activity was described.


Assuntos
Anacardiaceae , Antimaláricos , Sesquiterpenos de Eudesmano , Sesquiterpenos , Animais , Glicosídeos/farmacologia , Camundongos , Estrutura Molecular , Sesquiterpenos/farmacologia , Sesquiterpenos de Eudesmano/farmacologia
6.
Bioorg Chem ; 118: 105478, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34800885

RESUMO

Linderane (LDR) is a main furan-containing sesquiterpenoid of the common herbal medicine Lindera aggregata (Sims) Kosterm. Our early study indicated that LDR led to mechanism-based inactivation (MBI) of CYP2C9 in vitro, implying possible drug-drug interactions (DDIs) in clinic. In the present study, influence of LDR on the pharmacokinetics of the corresponding hydroxylated metabolites of CYP2C9 substrates in rats was investigated. Pharmacokinetic studies revealed that pretreatment with LDR at 20 mg/kg for 15 days inhibited the metabolism of both tolbutamide and warfarin catalyzed by CYP2C9. As for 4-hydroxytolbutamide, the Cmax was decreased, the t1/2z was prolonged, and the Vz/F was increased, all with significant difference. As for 7-hydroxywarfarin, the AUC0-t/AUC0-∞ and CLz/F were significantly decreased and increased, respectively. Furthermore, the underlying molecular mechanisms based on MBI of CYP2C9 by LDR were revealed. Two reactive metabolites of LDR, furanoepoxide and γ-ketoenal intermediates were identified in CYP2C9 recombinant enzyme incubation systems. Correspondingly, covalent modifications of lysine and cysteine residues of CYP2C9 protein were discovered in the CYP2C9 incubation system treated with LDR. The formation of protein adducts exhibited obvious time- and dose-dependence, which is consistent with the trend of enzyme inhibition caused by LDR in vitro. In addition to the apoprotein of CYP2C9, the heme content was significantly reduced after co-incubation with LDR. These data revealed that modification of both apoprotein and heme of CYP2C9 by reactive metabolites of LDR led to MBI of CYP2C9, therefore resulting in the inhibition of biotransformation of CYP2C9 substrates to their corresponding metabolites in vivo.


Assuntos
Citocromo P-450 CYP2C9/metabolismo , Inibidores Enzimáticos/farmacologia , Furanos/farmacologia , Sesquiterpenos/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Inibidores Enzimáticos/química , Furanos/química , Humanos , Lindera/química , Estrutura Molecular , Sesquiterpenos/química , Relação Estrutura-Atividade
7.
Oncol Rep ; 47(2)2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34913067

RESUMO

Vasculogenic mimicry (VM) is the formation of a blood supply system that confers aggressive and metastatic properties to tumors and correlates with a poor prognosis in cancer patients. Thus, the inhibition of VM is considered an effective approach for cancer treatment, although such a mechanism remains poorly described. In the present study, we examined methionine aminopeptidase­2 (MetAP2), a key factor of angiogenesis, and demonstrated that it is pivotal for VM, using pharmacological and genetic approaches. Fumagillin and TNP­470, angiogenesis inhibitors that target MetAP2, significantly suppressed VM in various human cancer cell lines. We established MetAP2­knockout (KO) human fibrosarcoma HT1080 cells using the CRISPR/Cas9 system and found that VM was attenuated in these cells. Furthermore, re­expression of wild­type MetAP2 restored VM in the MetAP2­KO HT1080 cells, but the substitution of D251, a conserved amino acid in MetAP2, failed to rescue the VM. Collectively, our results demonstrate that MetAP2 is critical for VM in human cancer cells and suggest fumagillin and TNP­470 as potent VM­suppressing agents.


Assuntos
Aminopeptidases/efeitos dos fármacos , Inibidores da Angiogênese/farmacologia , Cicloexanos/farmacologia , Ácidos Graxos Insaturados/farmacologia , Metaloendopeptidases/efeitos dos fármacos , Metionil Aminopeptidases/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , O-(Cloroacetilcarbamoil)fumagilol/farmacologia , Aminopeptidases/genética , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Fibrossarcoma/tratamento farmacológico , Técnicas de Silenciamento de Genes , Humanos , Metaloendopeptidases/genética , Metionil Aminopeptidases/genética , Neovascularização Patológica/genética , Sesquiterpenos/farmacologia
8.
Biomolecules ; 11(12)2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34944451

RESUMO

Chemotherapy is an essential strategy for cancer treatment. On the other hand, consistent exposure to chemotherapeutic drugs induces chemo-resistance in cancer cells through a variety of mechanisms. Therefore, it is important to develop a new drug inhibiting chemo-resistance. Although hemistepsin A (HsA) is known to have anti-tumor effects, the molecular mechanisms of HsA-mediated cell death are unclear. Accordingly, this study examined whether HsA could induce apoptosis in aggressive prostate cancer cells, along with its underlying mechanism. Using HsA on two prostate cancer cell lines, PC-3 and LNCaP cells, the cell analysis and in vivo xenograft model were assayed. In this study, HsA induced apoptosis and autophagy in PC-3 cells. HsA-mediated ROS production attenuated HsA-induced apoptosis and autophagy after treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. Moreover, autophagy inhibition by 3-MA or CQ is involved in accelerating the apoptosis induced by HsA. Furthermore, we showed the anti-tumor effects of HsA in mice, as assessed by the reduced growth of the xenografted tumors. In conclusion, HsA induced apoptosis and ROS generation, which were blocked by protective autophagy signaling.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Cloroquina/administração & dosagem , Lactonas/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/administração & dosagem , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lactonas/farmacologia , Masculino , Camundongos , Células PC-3 , Neoplasias da Próstata/metabolismo , Sesquiterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Agric Food Chem ; 69(45): 13557-13567, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34726896

RESUMO

Metabolic reprogramming is critical for tumorigenesis. Pyruvate kinase M2 (PKM2) is overexpressed in lung carcinoma cells and plays a critical role in the Warburg effect, making the enzyme a research hotspot for anticancer drug development. Cynaropicrin (CYN), a natural sesquiterpene lactone compound from artichoke, has received increasing consideration due to its consumable esteem and pharmacological properties. Our data reveal that CYN not only inhibited the purified PKM2 activity but also decreased the cellular PKM2 expression in A549 cells. The inhibition of PKM2 leads to the upregulation of p53 and the downregulation of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP), and subsequently causes the cell cycle arrest. Additionally, CYN inhibits the interaction of PKM2 and Nrf2, resulting in the impairment of cellular antioxidant capacity, induction of oxidative stress, and mitochondrial damages. Overexpression of PKM2 attenuates the CYN-induced DNA damage, mitochondrial fission, and cell viability. Thus, targeting PKM2 provides an original mechanism for understanding the pharmacological impact of CYN and assists in the further development of CYN as an anticancer agent.


Assuntos
Piruvato Quinase , Sesquiterpenos , Células A549 , Apoptose , Pontos de Checagem do Ciclo Celular , Dano ao DNA , Humanos , Lactonas/farmacologia , Dinâmica Mitocondrial , Piruvato Quinase/genética , Sesquiterpenos/farmacologia
10.
Phytochemistry ; 192: 112978, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34678625

RESUMO

Chemical epigenetic manipulation of a deep-sea-derived Eutypella sp. fungus by the co-treatment with a histonedeacetylase inhibitor (suberohydroxamic acid, SBHA) and a DNA methyltransferase inhibitor (5-azacytidine, 5-Aza), resulted in the activation of a sesquiterpene-related biosynthetic gene cluster. Chromatographic separation of the elicitor-treated cultures led the isolation of 21 sesquiterpenes, including 17 undescribed compounds, eutypeterpenes A-Q. Their structures were identified by the extensive analysis of the spectroscopic data, including the single-crystal X-ray diffraction, chemical conversion, and the calculated NMR and ECD data for configurational assignments. Eutypeterpene A is a first bergamotene-type sesquiterpene incorporated with a dioxolanone unit, and eutypeterpenes O-Q with a cyclopentane ring represent an undescribed subtype of sesquiterpenes. The bioassay results showed that most compounds exert inhibitory effects against the lipopolysaccharide (LPS)-induced NO production in RAW 264.7 macrophages, and eutypeterpene N is the most active. This study demonstrates that the epigenetic manipulation is an effective approach to trigger the production of cryptic metabolites from deep-sea derived fungus. The significant inhibition against LPS-induced NO production in vitro suggests eutypeterpenes to be potential for the development as anti-inflammatory agents.


Assuntos
Sesquiterpenos , Xylariales , Epigênese Genética , Lipopolissacarídeos , Estrutura Molecular , Sesquiterpenos/farmacologia
11.
J Clin Invest ; 131(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623325

RESUMO

Mitochondrial electron transport chain complex I (ETCC1) is the essential core of cancer metabolism, yet potent ETCC1 inhibitors capable of safely suppressing tumor growth and metastasis in vivo are limited. From a plant extract screening, we identified petasin (PT) as a highly potent ETCC1 inhibitor with a chemical structure distinct from conventional inhibitors. PT had at least 1700 times higher activity than that of metformin or phenformin and induced cytotoxicity against a broad spectrum of tumor types. PT administration also induced prominent growth inhibition in multiple syngeneic and xenograft mouse models in vivo. Despite its higher potency, it showed no apparent toxicity toward nontumor cells and normal organs. Also, treatment with PT attenuated cellular motility and focal adhesion in vitro as well as lung metastasis in vivo. Metabolome and proteome analyses revealed that PT severely depleted the level of aspartate, disrupted tumor-associated metabolism of nucleotide synthesis and glycosylation, and downregulated major oncoproteins associated with proliferation and metastasis. These findings indicate the promising potential of PT as a potent ETCC1 inhibitor to target the metabolic vulnerability of tumor cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Sesquiterpenos/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Complexo I de Transporte de Elétrons/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Metaboloma/efeitos dos fármacos , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Metástase Neoplásica/prevenção & controle , Neoplasias Experimentais/patologia , Petasites/química , Fenformin/farmacologia , Sesquiterpenos/química , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Agric Food Chem ; 69(40): 11878-11889, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34605647

RESUMO

Fourteen eremophilane sesquiterpenoids (1-14), including nine new congeners, septoreremophilanes A-I (1-9), together with three known sesquiterpenes (15-17), two known tetralone derivatives (18, 19), and two known cholesterol analogues (20, 21), were isolated from the endophytic fungus Septoria rudbeckiae. Compounds 1-6 and 7a belong to the family of the highly oxygenated eremophilane sesquiterpenoids with a 6/6/5 tricyclic system and bearing a hemiacetal moiety. The inhibitions of all metabolites against eight bacteria were estimated in vitro, and nine new metabolites (1-9) were tested for antineuroinflammatory activity. Notably, the effects of 4 against Pseudomonas syringae pv. actinidae and 20 against Bacillus cereus displayed potent inhibitory, with the MIC values of 6.25 and 6.25 µM, respectively. Further, scanning electron microscopy analyses indicated that 4 and 20 were to change the outer configuration of bacterial cells, respectively, and the investigations demonstrated that 4 and 20 may act as potential structure templates for the development of the agrochemical bactericides. Additionally, compound 6 displayed potent inhibition of NO generation in lipopolysaccharide-induced BV-2 microglial cells (IC50 = 12.0 ± 0.32 µM), and the conceivable anti-inflammatory mechanisms implicated were also investigated by molecular docking. Thus, the bioactive metabolites of the strain S. rudbeckiae may serve as a novel resource to be developed.


Assuntos
Ascomicetos , Sesquiterpenos , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Sesquiterpenos Policíclicos , Sesquiterpenos/farmacologia
13.
Acta Cir Bras ; 36(8): e360802, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34644770

RESUMO

PURPOSE: To evaluate the influence of atractylenolide (Atr) III on sepsis-induced lung damage. METHODS: We constructed a mouse sepsis model through cecal ligation and puncture. These mice were allocated to the normal, sepsis, sepsis + Atr III-L (2 mg/kg), as well as Atr III-H (8 mg/kg) group. Lung injury and pulmonary fibrosis were accessed via hematoxylin-eosin (HE) and Masson's staining. We used terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and flow cytometry for detecting sepsis-induced lung cell apoptosis. The contents of the inflammatory cytokines in lung tissue were measured via enzyme-linked immunosorbent assay (ELISA). RESULTS: Atr III-H did not only reduce sepsis-induced lung injury and apoptosis level, but also curbed the secretion of inflammatory factors. Atr III-H substantially ameliorated lung function and raised Bcl-2 expression. Atr III-H eased the pulmonary fibrosis damage and Bax, caspase-3, Vanin-1 (VNN1), as well as Forkhead Box Protein O1 (FoxO1) expression. CONCLUSIONS: Atr III alleviates sepsis-mediated lung injury via inhibition of FoxO1 and VNN1 protein.


Assuntos
Amidoidrolases/antagonistas & inibidores , Proteína Forkhead Box O1/antagonistas & inibidores , Lesão Pulmonar , Sepse , Sesquiterpenos , Animais , Apoptose , Proteínas Ligadas por GPI/antagonistas & inibidores , Lactonas , Camundongos , Sepse/complicações , Sepse/tratamento farmacológico , Sesquiterpenos/farmacologia
14.
Nutrients ; 13(10)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34684455

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases with no approved treatment. Zonarol, an extract from brown algae, has been proven to have anti-inflammatory and antioxidant effects. In this study, we investigated the role of zonarol in the progression of methionine- and choline-deficiency (MCD) diet-induced NAFLD in mice. After oral treatment with zonarol, a lighter body weight was observed in zonarol group (ZG) mice in comparison to control group (CG) mice. The NAFLD scores of ZG mice were lower than those of CG mice. Hepatic and serum lipid levels were also lower in ZG mice with the reduced expression of lipid metabolism-related factors. Furthermore, ZG mice showed less lipid deposition, less inflammatory cell infiltration and lower inflammatory cytokine levels in comparison to CG mice. Moreover, the numbers of 8-hydroxy-20-deoxyguanosine (8-OHdG)-positive hepatocytes and levels of hepatic and serum thiobarbituric acid reactive substances (TBARS) were significantly lower in comparison to CG mice. The expression levels of nuclear factor erythroid 2 related factor 2 (Nrf2), as well as its upstream and downstream molecules, changed in ZG mice. Zonarol could prevent the progression of NAFLD by decreasing inflammatory responses, oxidative stress and improving lipid metabolism. Meanwhile the Nrf2 pathway may play an important role in these effects.


Assuntos
Deficiência de Colina/complicações , Dieta , Metionina/deficiência , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Substâncias Protetoras/farmacologia , Sesquiterpenos/farmacologia , Animais , Biomarcadores , Dieta/efeitos adversos , Modelos Animais de Doenças , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Imuno-Histoquímica , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Modelos Biológicos , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais
15.
Int J Mol Sci ; 22(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34639036

RESUMO

Considering the current dramatic and fatal situation due to the high spreading of SARS-CoV-2 infection, there is an urgent unmet medical need to identify novel and effective approaches for prevention and treatment of Coronavirus disease (COVID 19) by re-evaluating and repurposing of known drugs. For this, tomatidine and patchouli alcohol have been selected as potential drugs for combating the virus. The hit compounds were subsequently docked into the active site and molecular docking analyses revealed that both drugs can bind the active site of SARS-CoV-2 3CLpro, PLpro, NSP15, COX-2 and PLA2 targets with a number of important binding interactions. To further validate the interactions of promising compound tomatidine, Molecular dynamics study of 100 ns was carried out towards 3CLpro, NSP15 and COX-2. This indicated that the protein-ligand complex was stable throughout the simulation period, and minimal backbone fluctuations have ensued in the system. Post dynamic MM-GBSA analysis of molecular dynamics data showed promising mean binding free energy 47.4633 ± 9.28, 51.8064 ± 8.91 and 54.8918 ± 7.55 kcal/mol, respectively. Likewise, in silico ADMET studies of the selected ligands showed excellent pharmacokinetic properties with good absorption, bioavailability and devoid of toxicity. Therefore, patchouli alcohol and especially, tomatidine may provide prospect treatment options against SARS-CoV-2 infection by potentially inhibiting virus duplication though more research is guaranteed and secured.


Assuntos
Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Endorribonucleases/antagonistas & inibidores , SARS-CoV-2/enzimologia , Sesquiterpenos/farmacologia , Tomatina/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/virologia , Proteases 3C de Coronavírus/metabolismo , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Endorribonucleases/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , SARS-CoV-2/efeitos dos fármacos , Tomatina/farmacologia , Proteínas não Estruturais Virais/metabolismo
16.
Future Microbiol ; 16: 1289-1301, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34689597

RESUMO

COVID-19, caused by the SARS-CoV-2 outbreak, has resulted in a massive global health crisis. Bioactive molecules extracted or synthesized using starting material obtained from marine species, including griffithsin, plitidepsin and fingolimod are in clinical trials to evaluate their anti-SARS-CoV-2 and anti-HIV efficacies. The current review highlights the anti-SARS-CoV-2 potential of marine-derived phytochemicals explored using in silico, in vitro and in vivo models. The current literature suggests that these molecules have the potential to bind with various key drug targets of SARS-CoV-2. In addition, many of these agents have anti-inflammatory and immunomodulatory potentials and thus could play a role in the attenuation of COVID-19 complications. Overall, these agents may play a role in the management of COVID-19, but further preclinical and clinical studies are still required to establish their role in the mitigation of the current viral pandemic.


Assuntos
Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Oceanos e Mares , SARS-CoV-2/efeitos dos fármacos , Alcaloides/farmacologia , Anti-Inflamatórios , Antivirais/química , Depsipeptídeos , Cloridrato de Fingolimode/química , Cloridrato de Fingolimode/farmacologia , Humanos , Lectinas , Biologia Marinha , Simulação de Acoplamento Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Ficocianina/farmacologia , Compostos Fitoquímicos , Lectinas de Plantas/química , Lectinas de Plantas/farmacologia , Polifenóis/farmacologia , Polissacarídeos/farmacologia , Alga Marinha , Sesquiterpenos/farmacologia
17.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638856

RESUMO

Sesquiterpene lactones are of pharmaceutical interest due their cytotoxic and antitumor properties, which are commonly found within plants of several genera from the Asteraceae family such as the Decachaeta genus. From Decachaeta incompta four heliangolide, namely incomptines A-D have been isolated. In this study, cytotoxic properties of incomptine A (IA) were evaluated on four lymphoma cancer cell lines: U-937, Farage, SU-DHL-2, and REC-1. The type of cell death induced by IA and its effects on U-937 cells were analyzed based on its capability to induce apoptosis and produce reactive oxygen species (ROS) through flow cytometry with 4',6-diamidino-2-phenylindole staining, dual annexin V/DAPI staining, and dichlorofluorescein 2',7'-diacetate, respectively. A differential protein expression analysis study was carried out by isobaric tags for relative and absolute quantitation (iTRAQ) through UPLC-MS/MS. Results reveal that IA exhibited cytotoxic activity against the cell line U-937 (CC50 of 0.12 ± 0.02 µM) and the incubation of these cells in presence of IA significantly increased apoptotic population and intracellular ROS levels. In the proteomic approach 1548 proteins were differentially expressed, out of which 587 exhibited a fold-change ≥ 1.5 and 961 a fold-change ≤ 0.67. Most of these differentially regulated proteins are involved in apoptosis, oxidative stress, glycolytic metabolism, or cytoskeleton structuration.


Assuntos
Apoptose/efeitos dos fármacos , Linfoma não Hodgkin/metabolismo , Proteoma/metabolismo , Proteômica/métodos , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/farmacologia , Asteraceae/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida/métodos , Humanos , Linfoma não Hodgkin/patologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Espectrometria de Massas em Tandem/métodos , Células U937
18.
Molecules ; 26(19)2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34641334

RESUMO

Malignant tumors are life-threatening, and chemotherapy is one of the common treatment methods. However, there are often many factors that contribute to the failure of chemotherapy. The multidrug resistance of cancer cells during chemotherapy has been reported, since tumor cells' sensitivity decreases over time. To overcome these problems, extensive studies have been conducted to reverse drug resistance in tumor cells. Elemene, an extract of the natural drug Curcuma wenyujin, has been found to reverse drug resistance and sensitize cancer cells to chemotherapy. Mechanisms by which elemene reverses tumor resistance include inhibiting the efflux of ATP binding cassette subfamily B member 1(ABCB1) transporter, reducing the transmission of exosomes, inducing apoptosis and autophagy, regulating the expression of key genes and proteins in various signaling pathways, blocking the cell cycle, inhibiting stemness, epithelial-mesenchymal transition, and so on. In this paper, the mechanisms of elemene's reversal of drug resistance are comprehensively reviewed.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Sesquiterpenos/farmacologia , Antineoplásicos/uso terapêutico , Autofagia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Exossomos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias/metabolismo , Sesquiterpenos/uso terapêutico
19.
Molecules ; 26(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34641542

RESUMO

Cancer is the second leading cause of death in the world. Chemotherapy and radiotherapy (RT) are the common cancer treatments. In addition to these limitations, the development of adverse effects from chemotherapy and RT reduces the quality of life for cancer patients. Cellular radiosensitivity, or the ability to resist and overcome cell damage caused by ionizing radiation (IR), is directly related to cancer cells' response to RT. Therefore, radiobiological research is emphasizing chemical compounds 'radiosensitization of cancer cells so that they are more reactive in the IR spectrum. Recent years researchers have seen an increase in interest in natural products that have antitumor effects with minimal side effects. Natural products, on the other hand, are easy to recover and therefore less expensive. There have been several scientific studies done based on these compounds that have tested their ability in vitro and in vivo to induce tumor radiosensitization. The role of natural products in RT, as well as their usefulness and potential applications, is the goal of this current review.


Assuntos
Produtos Biológicos/farmacologia , Radioterapia/efeitos adversos , Berberina/farmacologia , Curcumina/farmacologia , Emodina/farmacologia , Genisteína/farmacologia , Humanos , Neoplasias/radioterapia , Triterpenos Pentacíclicos/farmacologia , Protetores contra Radiação/farmacologia , Radiossensibilizantes/farmacologia , Resveratrol/farmacologia , Sesquiterpenos/farmacologia , Triterpenos/farmacologia , Vitamina D/farmacologia , Vitanolídeos/farmacologia
20.
Arch Biochem Biophys ; 711: 109028, 2021 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-34509463

RESUMO

Elevated expression of thioredoxin reductase (TrxR) is associated with the tumorigenesis and resistance to cancer chemoradiotherapy, highlighting the potential of TrxR inhibitors as anticancer drugs. Deoxyelephantopin (DET) is the major active ingredient of Elephantopus scaber and reveals potent anticancer activity. However, the potential mechanism of action and the cellular target of DET are still unknown. Here, we found that DET primarily targets the Sec residue of TrxR and irreversibly prohibits enzyme activity. Suppression of TrxR by DET leads to accumulation of reactive oxygen species and dysregulation in intracellular redox balance, eventually inducing cancer cell apoptosis mediated by oxidative stress. Noticeably, down-regulation of TrxR1 by shRNA increases cell sensitivity to DET. Collectively, targeting of TrxR1 by DET uncovers a novel mechanism of action in DET and deepens the understanding of developing DET as a potential chemotherapeutic agent for treating cancers.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Animais , Antineoplásicos Fitogênicos/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/metabolismo , Células HeLa , Humanos , Lactonas/metabolismo , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica , Ratos , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/metabolismo , Tiorredoxina Dissulfeto Redutase/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA