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1.
Inflammopharmacology ; 32(2): 1575-1592, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38267609

RESUMO

Aquaporins like AQP1, AQP3, and AQP4 are known to be involved in the pathophysiology of inflammation based on earlier reports. This study aimed to evaluate the involvement of Aquaporins as a potential target of inflammation. The study also investigates the efficacy of methanolic extract of Garcinia (GME) and its potent phytocompound (garcinol) against the Aquaporins involved in inflammation. siRNA silencing of AQP3 was carried out in RAW264.7 cells followed by LPS stimulation (1 µg/ml) and assessment of important markers of inflammation including NO, PGE2, TNF-α, IL-6, IL-1ß, CCL20, iNOS and COX-2. To assess the anti-inflammatory potential of Garcinia extract and garcinol, cells were stimulated with 1 µg/ml LPS in the absence and presence of increasing concentrations of GME and garcinol. During the experimental period, extract concentrations (115 µg/ml and 230 µg/ml for RAW264.7; 118 µg/ml and 236 µg/ml for THP-1) and garcinol concentrations (6 µM and 12 µM for RAW264.7; 3 µM and 6 µM for THP-1) were selected based on the IC50. The anti-inflammatory effects were assessed by measuring the levels of TNF-α, IL-1ß, IL-6, and CCL20 in LPS-stimulated cells. The AQP expression was studied at transcriptional and translational levels using qPCR and Western blot analysis respectively. AQP3 knockdown significantly decreased the NO, PGE2, TNF-α, IL-1ß levels along with iNOS and COX-2 mRNA expression. LPS stimulation led to a significant increase in the mRNA and protein level expression AQP1, AQP3, and AQP4 in RAW264.7 cells; and AQP1 and AQP3 in THP-1 cells indicating their role as markers of inflammation. GME and garcinol effectively suppressed the LPS-induced proinflammatory cytokine production in both cell lines. The results indicate that AQP1, AQP3, and AQP4 could play a crucial role as markers of inflammation. Anti-inflammatory agents like Garcinia could potentially decrease the expression of such AQPs, thus inhibiting the inflammatory process.


Assuntos
Aquaporinas , Terpenos , Fator de Necrose Tumoral alfa , Humanos , Fator de Necrose Tumoral alfa/metabolismo , Dinoprostona/metabolismo , Ciclo-Oxigenase 2/metabolismo , Lipopolissacarídeos/farmacologia , Interleucina-6/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , RNA Mensageiro/metabolismo
2.
J Cell Biochem ; 124(5): 731-742, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36966470

RESUMO

The p300/CBP associated factor bromodomain (PCAF Brd) is emerged as one of the promising target proteins for different types of cancers. PCAF is one among the histone acetyltransferase enzymes which involved in the regulation of transcriptase process by modifying the chromatin structure. Anacardic acid, carnosol, garcinol are the experimentally reported inhibitors of PCAF Brd; however, their detailed binding mechanism these inhibitors are not yet known. The intermolecular interaction, binding energy, and the stability of these inhibitors with the active site of PCAF Brd are playing the key role in the binding of these inhibitors with PCAF. The in silico study incorporates the molecular docking and dynamics simulations; these molecular level simulations allow to understand the binding mechanism. In the present study, the induced fit molecular docking and molecular dynamics of anacardic acid, carnosol and garcinol molecules against the PCAF Brd have been performed. The docking score values of these molecules are -5.112 (anacardic acid), -5.141 (carnosol), -5.199 (garcinol) and -3.641 (L45) kcal/mol, respectively. Further, the molecular dynamics simulation was carried out for these docked complexes to understand their conformational their stability and binding energy from the roots means square deviation (RMSD) and root means square of fluctuation (RMSF), and molecular mechanics with the generalized born and surface area solvation (MM/GBSA) binding free energy calculations. The intermolecular interactions and binding free energy values confirm that garcinol forms key interactions and has high binding affinity towards PCAF Brd on compare with the other two inhibitors. Therefore, garcinol may be considered as a potential inhibitor of PCAF Brd.


Assuntos
Simulação de Dinâmica Molecular , Simulação de Acoplamento Molecular , Ligação Proteica
3.
Int J Mol Sci ; 24(3)2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36769025

RESUMO

The conversion of skeletal muscle fiber from fast-twitch to slow-twitch is crucial for sustained contractile and stretchable events, energy homeostasis, and anti-fatigue ability. The purpose of our study was to explore the mechanism and effects of garcinol on the regulation of skeletal muscle fiber type transformation. Forty 21-day-old male C57/BL6J mice (n = 10/diet) were fed a control diet or a control diet plus garcinol at 100 mg/kg (Low Gar), 300 mg/kg (Mid Gar), or 500 mg/kg (High Gar) for 12 weeks. The tibialis anterior (TA) and soleus muscles were collected for protein and immunoprecipitation analyses. Dietary garcinol significantly downregulated (p < 0.05) fast myosin heavy chain (MyHC) expression and upregulated (p < 0.05) slow MyHC expression in the TA and soleus muscles. Garcinol significantly increased (p < 0.05) the activity of peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) and markedly decreased (p < 0.05) the acetylation of PGC-1α. In vitro and in vivo experiments showed that garcinol decreased (p < 0.05) lactate dehydrogenase activity and increased (p < 0.05) the activities of malate dehydrogenase and succinic dehydrogenase. In addition, the results of C2C12 myotubes showed that garcinol treatment increased (p < 0.05) the transformation of glycolytic muscle fiber to oxidative muscle fiber by 45.9%. Garcinol treatment and p300 interference reduced (p < 0.05) the expression of fast MyHC but increased (p < 0.05) the expression of slow MyHC in vitro. Moreover, the acetylation of PGC-1α was significantly decreased (p < 0.05). Garcinol promotes the transformation of skeletal muscle fibers from the fast-glycolytic type to the slow-oxidative type through the p300/PGC-1α signaling pathway in C2C12 myotubes.


Assuntos
Fibras Musculares Esqueléticas , Fibras Musculares de Contração Lenta , Animais , Masculino , Camundongos , Acetilação , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares de Contração Lenta/metabolismo , Músculo Esquelético/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo
4.
Exp Brain Res ; 240(1): 113-122, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34633467

RESUMO

Although the etiology of Parkinson's disease (PD) is poorly understood, studies in animal models revealed loss of dopamine and the dopaminergic neurons harbouring the neurotransmitter to be the principal cause behind this neuro-motor disorder. Neuroinflammation with glial cell activation is suggested to play a significant role in dopaminergic neurodegeneration. Several biomolecules have been reported to confer dopaminergic neuroprotection in different animal models of PD, owing to their anti-inflammatory potentials. Garcinol is a tri-isoprenylated benzophenone isolated from Garcinia sp. and accumulating evidences suggest that this molecule could provide neuroprotection by modulating oxidative stress and inflammation. However, direct evidence of dopaminergic neuroprotection by garcinol in the pre-clinical model of PD is not yet reported. The present study aims to investigate whether administration of garcinol in the MPTP mouse model of PD may ameliorate the cardinal motor behavioural deficits and prevent the loss of dopaminergic neurons. As expected, garcinol blocked the parkinsonian motor behavioural deficits which include akinesia, catalepsy, and rearing anomalies in the mice model. Most importantly, the degeneration of dopaminergic cell bodies in the substantia nigra region was significantly prevented by garcinol. Furthermore, garcinol reduced the inflammatory marker, glial fibrillary acidic protein, in the substantia nigra region. Since glial hyperactivation-mediated inflammation is inevitably associated with the loss of dopaminergic neurons, our study suggests the anti-inflammatory role of garcinol in facilitating dopaminergic neuroprotection in PD mice. Hence, in the light of the present study, it is suggested that garcinol is an effective anti-parkinsonian agent to block motor behavioural deficits and dopaminergic neurodegeneration in PD.


Assuntos
Doença de Parkinson , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Anti-Inflamatórios , Modelos Animais de Doenças , Dopamina , Neurônios Dopaminérgicos , Camundongos , Camundongos Endogâmicos C57BL , Neuroproteção , Substância Negra , Terpenos
5.
Br J Nutr ; 126(1): 1-8, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32967737

RESUMO

Disorder of hepatic glucose metabolism is the characteristic of late-pregnant sows. The purpose of our study was to look into the mechanism of garcinol on the improvement of hepatic gluconeogenic enzyme in late-pregnant sows. Thirty second- and third-parity sows (Duroc × Yorkshire × Landrace, n 10/diet) were fed a basal diet (control) or that diet supplemented with 100 mg/kg (Low Gar) or 500 mg/kg (High Gar) garcinol from day 90 of gestation to the end of farrowing. The livers were processed to measure enzymatic activity. Hepatocytes from pregnant sows were transfected with P300/CBP-associating factor (PCAF) small interfering RNA (siRNA) or treated with garcinol. Dietary garcinol had no effect on average daily feed intake, body weight (BW), backfat and BW gain of late-pregnant sows. Garcinol promoted plasma glucose levels in pregnant sows and newborn piglets. Garcinol up-regulated hepatic gluconeogenic enzyme expression and decreased PCAF activity. Garcinol had no effect on the expression of PPAR-γ co-activator 1α (PGC-1α) and Forkhead box O1 (FOXO1) but significantly increased their activity and decreased their acetylation in late-pregnant sows. Transfection of PCAF siRNA to hepatocytes of pregnant sows increased PGC-1α and FOXO1 activities. Furthermore, in hepatocytes of pregnant sows, garcinol treatment also up-regulated the activities of PGC-1α and FOXO1 and inhibited the acetylation of PGC-1α and FOXO1. Garcinol improves hepatic gluconeogenic enzyme expression in late-pregnant sows, and this may be due to the mechanism of down-regulating the acetylation of PGC-1α and FOXO1 induced by PCAF in isolated hepatocytes.


Assuntos
Gluconeogênese , Fígado , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Terpenos/farmacologia , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Animais , Dieta , Feminino , Proteína Forkhead Box O1/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Gravidez , RNA Interferente Pequeno/metabolismo , Suínos
6.
Arch Pharm (Weinheim) ; 354(9): e2100123, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34008218

RESUMO

The bioactive components of Garcinia indica, garcinol (camboginol), and isogarcinol (cambogin), are suitable drug candidates for the treatment of various human diseases. HIV-1-RNase H assay was used to study the RNase H inhibition by garcinol and isogarcinol. Docking of garcinol into the active site of the enzyme was carried out to rationalize the difference in activities between the two compounds. Garcinol showed higher HIV-1-RNase H inhibition than the known inhibitor RDS1759 and retained full potency against the RNase H of a drug-resistant HIV-1 reverse transcriptase form. Isogarcinol was distinctly less active than garcinol, indicating the importance of the enolizable ß-diketone moiety of garcinol for anti-RNase H activity. Docking calculations confirmed these findings and suggested this moiety to be involved in the chelation of metal ions of the active site. On the basis of its HIV-1 reverse transcriptase-associated RNase H inhibitory activity, garcinol is worth being further explored concerning its potential as a cost-effective treatment for HIV patients.


Assuntos
Garcinia/química , Inibidores da Transcriptase Reversa/farmacologia , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Terpenos/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Simulação de Acoplamento Molecular , Inibidores da Transcriptase Reversa/isolamento & purificação , Terpenos/isolamento & purificação
7.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799504

RESUMO

Garcinol extracted from Garcinia indica fruit peel and leaves is a polyisoprenylated benzophenone. In traditional medicine it was used for its antioxidant and anti-inflammatory properties. Several studies have shown anti-cancer properties of garcinol in cancer cell lines and experimental animal models. Garcinol action in cancer cells is based on its antioxidant and anti-inflammatory properties, but also on its potency to inhibit histone acetyltransferases (HATs). Recent studies indicate that garcinol may also deregulate expression of miRNAs involved in tumour development and progression. This paper focuses on the latest research concerning garcinol as a HAT inhibitor and miRNA deregulator in the development and progression of various cancers. Garcinol may be considered as a candidate for next generation epigenetic drugs, but further studies are needed to establish the precise toxicity, dosages, routes of administration, and safety for patients.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Epigênese Genética/efeitos dos fármacos , Histona Acetiltransferases/genética , MicroRNAs/genética , Neoplasias/tratamento farmacológico , Terpenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Garcinia/química , Regulação Neoplásica da Expressão Gênica , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/metabolismo , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Extratos Vegetais/química
8.
J Nutr ; 150(2): 231-239, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31579921

RESUMO

BACKGROUND: Increased hepatic glycolysis and lipogenesis are characteristic of pregnancy. OBJECTIVES: The present study aimed to investigate the mechanism of garcinol on the amelioration of hepatic pyruvate and triglyceride (TG) accumulation in mid-to-late pregnant rats. METHODS: Forty Sprague-Dawley pregnant rats (aged 9 wk, n = 10/diet) were fed a basal diet (control) or that diet plus garcinol at 100 ppm (Low Gar), 300 ppm (Mid Gar), or 500 ppm (High Gar) for 14 d. The livers were processed for Western blotting analyses and measuring enzymatic activity and pyruvate and TG concentrations. Hepatocytes from other pregnant Sprague Dawley rats were transfected with P300/CBP associating factor (PCAF) short interfering (si)RNAs; hepatocytes from nonpregnant Sprague-Dawley rats with overexpression of PCAF were treated with garcinol (5 µM). The activity and acetylation of upstream stimulatory factor (USF-1) and glycolytic enzymes were analyzed. RESULTS: Dietary garcinol significantly decreased (P < 0.05) concentrations of hepatic and plasma TG (27.1-45.8%) and total cholesterol (25.3-49.5%), plasma free fatty acids (24.4-37.8%), and hepatic pyruvate (31.5-43.5%) and lactate (33.4-65.7%) in mid-to-late pregnant rats. Garcinol promoted (P < 0.05) antioxidant capacity in the liver and plasma by 27.4-32.1%. Garcinol downregulated (P < 0.05) lipid synthesis-related enzyme expression by 30.6-85.3% and decreased (P < 0.05) glycolytic enzyme activities by 22.5-74.6% and PCAF activity by 18.6-55.4%. Transfection of PCAF siRNAs to hepatocytes of pregnant rats decreased USF-1 and glycolytic enzyme activities by PCAF; garcinol treatment downregulated (P < 0.05) the acetylation and activities of USF-1 and glycolytic enzymes by 35.6-83.7%. CONCLUSIONS: Garcinol attenuates hepatic pyruvate and TG accumulation in the liver of mid-to-late pregnant rats, which may be due to downregulating the acetylation of USF-1 and the glycolytic enzymes induced by PCAF in isolated hepatocytes.


Assuntos
Dieta , Fígado/metabolismo , Ácido Pirúvico/metabolismo , Terpenos/administração & dosagem , Triglicerídeos/metabolismo , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Acetilação , Animais , Antioxidantes/farmacologia , Peso Corporal/efeitos dos fármacos , Feminino , Glicólise , Ácido Láctico/metabolismo , Lipogênese , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Terpenos/farmacologia , Fatores de Transcrição de p300-CBP/metabolismo
9.
Mol Cell Probes ; 54: 101672, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33186709

RESUMO

Garcinol, a polyisoprenylated benzophenone derivative, is isolated from fruit rind of Garcinia indica. It is known to exert potent anti-inflammatory and anti-oxidative properties. In the present study, we tried to investigate the neuroprotective effects of garcinol on a rat model with middle cerebral artery occlusion/reperfusion (MCAO/R) and a cell model subjected to oxygen glucose deprivation and reperfusion (OGD/R). In vivo, we found that the rats with garcinol treatment showed a lower neurological deficit score and a smaller infarct size compared with the rats with ischemia-reperfusion (I/R) injury alone. We further found that garcinol treatment decreased cerebral I/R-induced inflammatory cytokines and oxidative stress, including inhibiting the production of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α (TNF-α), decreasing the levels of malonaldehyde (MDA) and nitric oxide (NO), and suppressing the decreased superoxide dismutase (SOD) activity. Moreover, the suppression of toll-like receptor (TLR) 4 and nuclear NF-κB (p65) expression by garcinol was found both in vivo and in vitro. In addition, NF-κB activator or TLR4 overexpression was employed to investigate its involvement in the effects of garcinol. The results showed that NF-κB activator or TLR4 overexpression at least in part reversed the anti-inflammatory and anti-oxidative properties of garcinol in vitro. Taken together, the data suggest that garcinol could protect against cerebral I/R injury through attenuating inflammation and oxidative stress, and improving neurological function. The molecular mechanism might be related to its suppression of TLR4/NF-ĸB signal pathway.


Assuntos
Inflamação/patologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo , Traumatismo por Reperfusão/tratamento farmacológico , Terpenos/uso terapêutico , Animais , Citocinas/metabolismo , Glucose/deficiência , Inflamação/complicações , Mediadores da Inflamação/metabolismo , Masculino , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Oxigênio , Células PC12 , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Terpenos/farmacologia
10.
Acta Pharmacol Sin ; 41(1): 82-92, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31371781

RESUMO

Metastasis causes the main lethality in esophageal cancer patient. Garcinol, a natural compound extracted from Gambogic genera, is a histone acetyltransferase (HAT) inhibitor that has shown anticancer activities such as cell cycle arrest and apoptosis induction. In this study, we investigated the effects of garcinol on the metastasis of esophageal cancer in vitro and in vivo. We found that garcinol (5-15 µM) dose-dependently inhibited the migration and invasion of human esophageal cancer cell lines KYSE150 and KYSE450 in wound healing, transwell migration, and Matrigel invasion assays. Furthermore, garcinol treatment dose-dependently decreased the protein levels of p300/CBP (transcriptional cofactors and HATs) and p-Smad2/3 expression in the nucleus, thus impeding tumor cell proliferation and metastasis. Knockdown of p300 could inhibit cell metastasis, but CBP knockdown did not affect the cell mobility. It has been reported that TGF-ß1 stimulated the phosphorylation of Smad2/3, which directly interact with p300/CBP in the nucleus, and upregulating HAT activity of p300. We showed that garcinol treatment dose-dependently suppressed TGF-ß1-activated Smad and non-Smad pathway, inhibiting esophageal cancer cell metastasis. In a tail vein injection pulmonary metastasis mouse model, intraperitoneal administration of garcinol (20 mg/kg) or 5-FU (20 mg/kg) significantly decreased the number of lung tumor nodules and the expression levels of Ki-67, p300, and p-Smad2/3 in lung tissues. In conclusion, our study demonstrates that garcinol inhibits esophageal cancer metastasis in vitro and in vivo, which might be related to the suppression of p300 and TGF-ß1 signaling pathways, suggesting the therapeutic potential of Garcinol for metastatic tumors.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proteína p300 Associada a E1A/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Garcinia/química , Transdução de Sinais/efeitos dos fármacos , Terpenos/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Proteína p300 Associada a E1A/deficiência , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Terpenos/química , Terpenos/isolamento & purificação , Células Tumorais Cultivadas , Cicatrização/efeitos dos fármacos
11.
J Cell Physiol ; 234(5): 7498-7509, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30471112

RESUMO

Osteoclasts (OCs) are multinuclear giant cells responsible for bone resorption, and an excessive bone resorption by OCs plays an important role in osteoporosis. Commonly used drugs for the treatment of osteoporosis have severe side effects. As such, identification of alternative treatments is essential. Garcinol, a polyisoprenylated benzophenone extracted from the fruit of Garcinia indica, has shown a strong antitumor effect through the nuclear factor-κB (NF-κB) and mitogen-associated protein kinases (MAPK) signaling pathways. However, the role of garcinol in the osteoclastogenesis is still unclear. Here, we demonstrated that garcinol can inhibit the receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis, osteoclastogenesis-related gene expression, the f-actin ring, and resorption pit formation. In addition, garcinol abrogated RANKL-induced osteoclastogenesis by attenuating the degradation of the MAPK, NF-κB, and PI3K-AKT signaling pathway as well as downstream factors c-jun, c-fos, and NFATC1. In vivo, suppression of osteoclastogenesis by garcinol was evidenced by marked inhibition of lipopolysaccharide-induced bone resorption. In conclusion, our data demonstrated that garcinol inhibited the RANKL-induced osteoclastogenesis by suppressing the MAPK, NF-κB, and PI3K-AKT signaling pathways and thus has potential as a novel therapeutic option for osteolytic bone diseases.


Assuntos
Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ligante RANK/metabolismo , Terpenos/farmacologia , Animais , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Linhagem Celular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-fos/metabolismo , Transdução de Sinais/efeitos dos fármacos
12.
Chem Biodivers ; 16(9): e1900366, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31386266

RESUMO

The natural polyisoprenylated benzophenone derivatives garcinol and isogarcinol are secondary plant metabolites isolated from various Garcinia species including Garcinia indica. This review takes stock of the recent chemical and biological research into these interesting natural compounds over the last five years. New biological sources and chemical syntheses are discussed followed by new insights into the activity of garcinol and isogarcinol against cancer, pathogenic bacteria, parasite infections and various inflammatory diseases.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antiprotozoários/farmacologia , Neoplasias/tratamento farmacológico , Terpenos/farmacologia , Animais , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Garcinia/química , Humanos , Terpenos/química , Terpenos/isolamento & purificação
13.
Int J Mol Sci ; 20(4)2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30781783

RESUMO

Garcinol, a dietary factor obtained from Garcinia indica, modulates several key cellular signaling pathways as well as the expression of miRNAs. Acquired resistance to standard therapies, such as erlotinib and cisplatin, is a hallmark of non-small cell lung cancer (NSCLC) cells that often involves miRNA-regulated epithelial-to-mesenchymal transition (EMT). We used A549 cells that were exposed to transforming growth factor beta 1 (TGF-ß1), resulting in A549M cells with mesenchymal and drug resistant phenotype, and report that garcinol sensitized resistant cells with mesenchymal phenotype to erlotinib as well as cisplatin with significant decrease in their IC50 values. It also potentiated the apoptosis-inducing activity of erlotinib in A549M and the endogenously mesenchymal H1299 NSCLC cells. Further, garcinol significantly upregulated several key EMT-regulating miRNAs, such as miR-200b, miR-205, miR-218, and let-7c. Antagonizing miRNAs, through anti-miRNA transfections, attenuated the EMT-modulating activity of garcinol, as determined by mRNA expression of EMT markers, E-cadherin, vimentin, and Zinc Finger E-Box Binding Homeobox 1 (ZEB1). This further led to repression of erlotinib as well as cisplatin sensitization, thus establishing the mechanistic role of miRNAs, particularly miR-200c and let-7c, in garcinol-mediated reversal of EMT and the resulting sensitization of NSCLC cells to standard therapies.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Terpenos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Cloridrato de Erlotinib/farmacologia , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/metabolismo , Terpenos/química , Terpenos/uso terapêutico , Fator de Crescimento Transformador beta1/farmacologia
14.
Int J Mol Sci ; 21(1)2019 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-31906096

RESUMO

Metabolic syndrome is a cluster of disorders that increase the risk of cardiovascular disease and diabetes. This study has investigated the responses to rind of yellow mangosteen (Garcinia dulcis), usually discarded as waste, in a rat model of human metabolic syndrome. The rind contains higher concentrations of phytochemicals (such as garcinol, morelloflavone and citric acid) than the pulp. Male Wistar rats aged 8-9 weeks were fed either corn starch diet or high-carbohydrate, high-fat diet for 16 weeks, which were supplemented with 5% freeze-dried G. dulcis fruit rind powder during the last 8 weeks. We characterised metabolic, cardiovascular, liver and gut microbiota parameters. High-carbohydrate, high-fat diet-fed rats developed abdominal obesity, hypertension, increased left ventricular diastolic stiffness, decreased glucose tolerance, fatty liver and reduced Bacteroidia with increased Clostridia in the colonic microbiota. G. dulcis fruit rind powder attenuated these changes, improved cardiovascular and liver structure and function, and attenuated changes in colonic microbiota. G. dulcis fruit rind powder may be effective in metabolic syndrome by appetite suppression, inhibition of inflammatory processes and increased fat metabolism, possibly related to changes in the colonic microbiota. Hence, we propose the use of G. dulcis fruit rind as a functional food to ameliorate symptoms of metabolic syndrome.


Assuntos
Colo , Carboidratos da Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Garcinia/química , Microbioma Gastrointestinal/efeitos dos fármacos , Síndrome Metabólica , Compostos Fitoquímicos , Animais , Bacteroides/classificação , Bacteroides/crescimento & desenvolvimento , Clostridium/classificação , Clostridium/crescimento & desenvolvimento , Colo/metabolismo , Colo/microbiologia , Carboidratos da Dieta/farmacologia , Gorduras na Dieta/farmacologia , Masculino , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Síndrome Metabólica/microbiologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Ratos , Ratos Wistar
15.
J Neural Transm (Vienna) ; 125(9): 1319-1331, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29998409

RESUMO

Histone acetylation is a key regulatory factor for gene expression in cells. Modulation of histone acetylation by targeting of histone acetyltransferases (HATs) effectively alters many gene expression profiles and synaptic plasticity in the brain. However, the role of HATs on L-DOPA-induced dyskinesia of Parkinson's disease (PD) has not been reported. Our aim was to determine whether HAT inhibitors such as anacardic acid, garcinol, and curcumin from natural plants reduce severity of L-DOPA-induced dyskinesia using a unilaterally 6-hydroxydopamine (6-OHDA)-lesioned PD mouse model. Anacardic acid 2 mg/kg, garcinol 5 mg/kg, or curcumin 100 mg/kg co-treatment with L-DOPA significantly reduced the axial, limb, and orofacial (ALO) score indicating less dyskinesia with administration of HAT inhibitors in 6-OHDA-lesioned mice. Additionally, L-DOPA's efficacy was not altered by the compounds in the early stage of treatment. The expression levels of c-Fos, Fra-2, and Arc were effectively decreased by administration of HAT inhibitors in the ipsilateral striatum. Our findings indicate that HAT inhibitor co-treatment with L-DOPA may have therapeutic potential for management of L-DOPA-induced dyskinesia in patients with PD.


Assuntos
Ácidos Anacárdicos/uso terapêutico , Antiparkinsonianos/toxicidade , Curcumina/uso terapêutico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Histona Acetiltransferases/antagonistas & inibidores , Levodopa/toxicidade , Transtornos Parkinsonianos/tratamento farmacológico , Terpenos/uso terapêutico , Ácidos Anacárdicos/farmacologia , Animais , Curcumina/farmacologia , Proteínas do Citoesqueleto/biossíntese , Proteínas do Citoesqueleto/genética , Avaliação Pré-Clínica de Medicamentos , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/genética , Inibidores Enzimáticos/farmacologia , Antígeno 2 Relacionado a Fos/biossíntese , Antígeno 2 Relacionado a Fos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Oxidopamina/toxicidade , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Organismos Livres de Patógenos Específicos , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Terpenos/farmacologia
16.
Nutr Cancer ; 70(7): 1075-1087, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30273070

RESUMO

Pancreatic cancer (PC) patients have poor prognosis and survival rate. Gemcitabine, the drug of choice has a dismal 15% response rate. Earlier, we reported that Garcinol alone and in combination with gemcitabine showed a dose-dependent favorable response on PC cell lines. This study probes the in vivo effects of dietary Garcinol on PC progression in transgenic PC mice (KPC; K-ras and p53 conditional mutant). KPC male mice were divided into: KC- Control diet; KGr-0.05% Garcinol diet; KGm-Gemcitabine injected; KGG - Garcinol diet + Gemcitabine injected groups. Changes in tumor progression, toxicity, or cell morphology were monitored by magnetic resonance imaging, Fore-stomach, and blood smear, respectively. Pancreatic Intraepithelial Neoplasia (mPanIN) grading with hematoxylin and eosin (H&E) staining was conducted on pancreas and validated by immunohistochemistry. The KGr group showed improved survival, no observable toxicity with marked reduction in papilloma formation in the fore-stomach, and a higher ratio of NK and NKT cells compared to Non-NK lymphocytes. Additionally, the KGr, KGm, and KGG groups showed reduction in tumor volumes and reduced number of advanced mouse PanIN3. Dietary Garcinol alone and in combination with gemcitabine retarded the progression of PC in transgenic PC mice, arresting the cancer in the earlier stages, improving prognosis and survival.


Assuntos
Neoplasias Pancreáticas/dietoterapia , Terpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Suplementos Nutricionais , Genes p53 , Genes ras , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Proteína Smad4/imunologia , Taxa de Sobrevida , Terpenos/efeitos adversos , Gencitabina
17.
Molecules ; 23(7)2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-30004456

RESUMO

Garcinol is a polyisoprenylated benzophenone derived from the Garcinia indica fruit that possess potential therapeutic effects such as inhibition of inflammation and tumor expansion. Here, we investigated whether garcinol induces TRAIL sensitization in renal carcinoma cells. Single treatment with garcinol or TRAIL did not effect on apoptosis. However, combined treatment with garcinol plus TRAIL significantly induced apoptosis in renal carcinoma (Caki, ACHN and A498), lung carcinoma (A549), and hepatoma (SK-Hep1) cells. In contrast, garcinol plus TRAIL did not alter cell viability in normal cells. Garcinol plus TRAIL induced up-regulation of DR5 and down-regulation of c-FLIP expression at post-translational levels. Furthermore, knock-down of DR5 by siRNA and ectopic expression of c-FLIP blocked apoptotic cell death induced by garcinol plus TRAIL. Overall, our study provides evidence that garcinol can be exploited as a potential TRAIL sensitizer.


Assuntos
Apoptose/efeitos dos fármacos , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Regulação para Baixo/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Terpenos/farmacologia , Regulação para Cima/efeitos dos fármacos , Células A549 , Animais , Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , RNA Interferente Pequeno/metabolismo
18.
Neurobiol Learn Mem ; 142(Pt A): 162-171, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27838441

RESUMO

Interfering with memory reconsolidation has valuable potential to be used as a treatment for maladaptive memories and psychiatric disorders. Numerous studies suggest that reconsolidation-based therapies may benefit psychiatric populations, but much remains unanswered. After reviewing the literature in clinical and healthy human populations, we discuss some of the major limitations to reconsolidation studies and clinical application. Finally, we provide recommendations for developing improved reconsolidation-based treatments, namely exploiting known boundary conditions and focusing on a novel unconditioned stimulus-retrieval paradigm.


Assuntos
Consolidação da Memória/fisiologia , Transtornos Mentais/terapia , Psicoterapia/métodos , Humanos , Transtornos Mentais/psicologia
19.
Bioorg Chem ; 71: 74-80, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28169002

RESUMO

Garcinol from the fruit rind of Garcinia indica shows anti-carcinogenic and anti-inflammatory properties, but its mechanism and key functional groups were still need to be identified. Our previous computer modeling suggested that the C8 side chain of Garcinol is so large that it may influence the bioactivity of the compound. 8-Me Garcinol, a derivative of Garcinol in which the bulky side chain at the C8 position of Garcinol is replaced with a much smaller methyl group, was synthesized through a 12-step procedure starting from 1,3-cyclohexanedione. The antitumor activity of Garcinol and 8-Me Garcinol was evaluated in vitro by MTT, cell cycle and cell apoptosis assays. The results showed that 8-Me Garcinol had weaker inhibitory activity on cells proliferation, and little effects on cell cycle and apoptosis in oral cancer cell line SCC15 cells when compared with Garcinol. All of the results indicated 8-Me Garcinol exerts weaker antitumor activity than Garcinol, and the C8 side chain might be an important active site in Garcinol. Changing the C8 side chain will affect the inhibitory effect of Garcinol.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Garcinia/química , Neoplasias Bucais/tratamento farmacológico , Terpenos/química , Terpenos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cicloexanonas/química , Frutas/química , Humanos , Metilação
20.
Biotechnol Appl Biochem ; 64(2): 165-173, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26400206

RESUMO

Pancreatic cancer represents one of the most aggressive types of malignancy due to its high resistance toward most clinically available treatments. The presence of pancreatic cancer stem-like cells (CSCs) has been attributed to the intrinsically high resistance and highly metastatic potential of this disease. Here, we identified and isolated pancreatic CSCs using the side population (SP) method from human pancreatic cancer cell line, PANC-1. We then compared the SP and non-SP PANC-1 cells genetically. PANC-1 SP cells exhibited CSC properties including enhanced self-renewal ability, increased metastatic potential, and resistance toward gemcitabine treatment. These cancer stem-like phenotypes were supported by their enhanced expression of ABCG2, Oct4, and CD44. A traditional plant-derived antioxidant, garcinol, has been implicated for its anticancer properties. Here, we found that garcinol treatment to PANC-1 SP cells significantly suppressed the stem-like properties of PANC-1 SP cells and metastatic potential by downregulating the expression of Mcl-1, EZH2, ABCG2, Gli-1, and Notch1. More importantly, garcinol treatment led to the upregulation of several tumor suppressor microRNAs, and miR-200c increased by garcinol treatment was found to target and downregulate Notch1. Thus, PANC-1 SP cells may serve as a model for studying drug-resistant pancreatic CSCs, and garcinol has the potential as an antagonist against pancreatic CSCs.


Assuntos
Biomarcadores Tumorais/genética , MicroRNAs/genética , Neoplasias Pancreáticas/tratamento farmacológico , Receptor Notch1/genética , Terpenos/administração & dosagem , Biomarcadores Tumorais/biossíntese , Linhagem Celular Tumoral , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/biossíntese , MicroRNAs/biossíntese , Proteínas de Neoplasias/biossíntese , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Receptor Notch1/biossíntese , Transdução de Sinais/efeitos dos fármacos
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