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1.
Phytomedicine ; 80: 153394, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33130472

RESUMO

BACKGROUND: Programmed death-ligand 1 (PD-L1), which can be induced by interferon-gamma (IFN-γ) in the tumor microenvironment, is a critical immune checkpoint in cancer immunotherapy. Natural products which reduce IFN-γ-induced PD-L1 might be exert immunotherapy effect. Licochalcone A (LCA), a natural compound derived from the root of Glycyrrhiza inflata Batalin. (Fabaceae), was found to interfere IFN-γ-induced PD-L1. PURPOSE: The aim of this study is to further clarify the effect and the mechanism of LCA on inhibiting IFN-γ-induced PD-L1 in lung cancer cells. METHODS: The expression levels of PD-L1 were evaluated by flow cytometry, western blot and qRT-PCR. Click-iT protein synthesis assay and luciferase assay were used to identify the effect of LCA on protein synthesis. Jurkat T cell proliferation and apoptosis in the co-culture system were detected by flow cytometry. Flow cytometry was also applied to evaluate reactive oxygen species (ROS) generation. RESULTS: LCA downregulated IFN-γ-induced PD-L1 protein expression and membrane localization in human lung cancer cells, regardless of inhibiting PD-L1 mRNA level or promoting its protein degradation. LCA decreased apoptosis and proliferative inhibition of Jurkat T cells caused by IFN-γ-induced PD-L1-expressing in A549 cells in the co-culture system. Strikingly, LCA was verified as a protein synthesis inhibitor, which reduced both cap-dependent and -independent translation. LCA inhibited PD-L1 translation, likely due to inhibition of 4EBP1 phosphorylation (Ser 65) and activation of PERK-eIF2α pathway. Furthermore, LCA induced ROS generation in a time-dependent manner in lung cancer cells. N-acetyl-L-cysteine (NAC) not only revered ROS generation triggered by LCA but also restored IFN-γ-induced expression of PD-L1. Both the inhibition of 4EBP1 phosphorylation (Ser 65) and activation of PERK-eIF2α axis triggered by LCA was restored by co-treatment with NAC. CONCLUSION: LCA abrogated IFN-γ-induced PD-L1 expression via ROS generation to abolish the protein translation, indicating that LCA has the potential to be applied in cancer immunotherapy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antígeno B7-H1/metabolismo , Chalconas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/efeitos dos fármacos , Antígeno B7-H1/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Interferon gama/metabolismo , Interferon gama/farmacologia , Células Jurkat , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
2.
Pest Manag Sci ; 77(1): 325-334, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32729190

RESUMO

BACKGROUND: The expansion of Aedes aegypti (Diptera: Culicidae) population has increased the number of cases of arboviruses, in part due to the inefficiency and toxicity of the chemical control methods available to control this vector. We synthesized 19 chalcone derivatives and examined their activity against Ae. aegypti larvae in order to select larvicidal compounds that are non-toxic to other organisms. RESULTS: Seven chalcone derivatives (3a, 3e, 3f, 6a, 6c, 6d, and 6f) had lethal concentrations of substituted chalcones capable of killing 50% (LC50 ) values lower than 100 mg mL-1 at 24 h post-treatment, which is the dose that the World Health Organization recommends for the selection of promising larvicides. The type of substituent added to (E)-1,3-diphenylprop-2-en-1-one (3a) markedly affected the larvicidal activity. Addition of chlorine, bromine and methoxy groups to the aromatic rings reduced the larvicidal activity, while replacement of the B-ring (phenyl) by a furan ring significantly increased the larvicidal activity. The furan-chalcone (E)-3-(4-bromophenyl)-1-(furan-2-yl)prop-2-en-1-one (6c) killed Ae. aegypti larvae (LC50 = 6.66 mg mL-1 ; LC90 = 9.97 mg mL-1 ) more effectively than the non-substituted chalcone (3a) (LC50 = 14.43 mg mL-1 ; LC90 = 20.96 mg mL-1 ), and was not toxic to the insect Galleria mellonella, to the protozoan Tetrahymena pyriformis, and to the algae Chorella vulgaris. CONCLUSIONS: The substitution pattern of chalcones influenced their larvicidal activity. In the set of compounds tested, (E)-3-(4-bromophenyl)-1-(furan-2-yl)prop-2-en-1-one (6c) was the most effective larvicide against Ae. aegypti, with no clear signs of toxicity to other animal models. Its mechanism of action and effectiveness under field conditions remain to be determined.


Assuntos
Aedes , Chalcona , Chalconas , Inseticidas , Animais , Chalconas/farmacologia , Inseticidas/farmacologia , Larva , Mosquitos Vetores , Extratos Vegetais
3.
Chem Biol Interact ; 333: 109315, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33171134

RESUMO

Neutrophil infiltration, pro-inflammatory cytokines, and reactive oxygen species (ROS) production have been implicated in development and progression of ulcerative colitis (UC), an inflammatory bowel disease (IBD) characterized by ulcerating inflammation of the mucosal layer generally restricted to the colon. The side effects, safety and human intolerance are limitations of the currently approved treatments for UC. Hesperidin methyl chalcone (HMC) is a flavonoid used to treat chronic venous disease, which shows anti-inflammatory, analgesic, and antioxidant properties in pre-clinical studies, however, its effects on colitis have never been described. Therefore, we aimed to evaluate the protective effects of HMC in a mouse model of acetic acid-induced colitis. Treatment with HMC significantly reduced neutrophil infiltration, edema, colon shortening, macro and microscopic damages induced by intracolonic administration of acetic acid. The improvement of colitis after HMC treatment is related to the increase in colon antioxidant status, and the inhibition of pro-inflammatory cytokines TNF-α, IL-6, IL-1ß, and IL-33 in the colon. We observed, moreover, that HMC inhibited NF-κB activation in the colon, which might explain the reduction of the cytokines we observed. Finally, these results demonstrate a novel applicability of HMC to increase antioxidant response and reduce inflammation during acetic acid-induced colitis suggesting it as a promising therapeutic approach for the treatment of ulcerative colitis.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Chalconas/farmacologia , Colite Ulcerativa/tratamento farmacológico , Hesperidina/análogos & derivados , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Chalconas/uso terapêutico , Colite Ulcerativa/complicações , Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Colo/efeitos dos fármacos , Colo/patologia , Citocinas/biossíntese , Modelos Animais de Doenças , Edema/complicações , Hesperidina/farmacologia , Hesperidina/uso terapêutico , Masculino , Camundongos , NF-kappa B/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
4.
Phytomedicine ; 80: 153373, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33096451

RESUMO

BACKGROUND: Hepatocellular Carcinoma (HCC) is extremely aggressive and presents low rates of response to the available chemotherapeutic agents. Many studies have focused on the search for alternative low-cost natural compounds with antiproliferative potential that selectively respond to liver cancer cells. PURPOSE: This study assessed the in vitro direct action of trans-chalcone (TC) on cells of the human HCC HuH7.5 cell line. METHODS: We subjected the HuH7.5 tumor cells to TC treatment at increasing concentrations (12.5-100 µM) for 24 and 48 h. Cell viability was verified through MTT and 50% inhibitory concentration of cells (IC50 23.66 µM) was determined within 48 h. We quantified trypan blue proliferation and light microscopy, ROS production, mitochondrial depolarization and autophagy, cell cycle analysis, and apoptosis using Muse® cell analyzer and immunocytochemical markings of p53 and ß-catenin. RESULTS: Data showed an effective dose- and time-dependent TC-cytotoxic action at low micromolar concentrations without causing toxicity to non-cancerous cells, such as erythrocytes. TC-treatment caused mitochondrial membrane damage and cell cycle G0/G1 phase arrest, increasing the presence of the p53 protein and decreasing ß-catenin, in addition, to inducing cell death by autophagy. Additionally, TC decreased the metastatic capacity of HuH7.5, which affected the migration/invasion of this type of cell. CONCLUSION: In vitro TC activity in the human HCC HuH7.5 tumor cell line is shown to be a potential molecule to develop new therapies to repair the p53 pathway and prevent the overexpression of Wnt/ß-catenin tumor development inducing autophagy cell death and decreasing metastatic capacity of HuH7.5 cell line.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Chalcona/farmacologia , Chalconas/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , beta Catenina/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Regulação para Cima/efeitos dos fármacos
5.
Sci Rep ; 10(1): 19963, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203926

RESUMO

Since December 2019, the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused severe pneumonia, a disease named COVID-19, that became pandemic and created an acute threat to public health. The effective therapeutics are in urgent need. Here, we developed a high-content screening for the antiviral candidates using fluorescence-based SARS-CoV-2 nucleoprotein detection in Vero E6 cells coupled with plaque reduction assay. Among 122 Thai natural products, we found that Boesenbergia rotunda extract and its phytochemical compound, panduratin A, exhibited the potent anti-SARS-CoV-2 activity. Treatment with B. rotunda extract and panduratin A after viral infection drastically suppressed SARS-CoV-2 infectivity in Vero E6 cells with IC50 of 3.62 µg/mL (CC50 = 28.06 µg/mL) and 0.81 µΜ (CC50 = 14.71 µM), respectively. Also, the treatment of panduratin A at the pre-entry phase inhibited SARS-CoV-2 infection with IC50 of 5.30 µM (CC50 = 43.47 µM). Our study demonstrated, for the first time, that panduratin A exerts the inhibitory effect against SARS-CoV-2 infection at both pre-entry and post-infection phases. Apart from Vero E6 cells, treatment with this compound was able to suppress viral infectivity in human airway epithelial cells. This result confirmed the potential of panduratin A as the anti-SARS-CoV-2 agent in the major target cells in human. Since B. rotunda is a culinary herb generally grown in China and Southeast Asia, its extract and the purified panduratin A may serve as the promising candidates for therapeutic purposes with economic advantage during COVID-19 situation.


Assuntos
Antivirais/farmacologia , Chalconas/farmacologia , /efeitos dos fármacos , Animais , Chlorocebus aethiops , Humanos , Plantas Medicinais/química , Células Vero , Replicação Viral , Zingiberaceae/química
6.
Life Sci ; 263: 118601, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33086122

RESUMO

Dimethyl cardamonin (DMC) has been isolated from diverse plants, notably from Cleistocalyx operculatus. We have reviewed the pharmacological properties of this natural product which displays anti-inflammatory, anti-hyperglycemic and anti-cancer properties. The pharmacological activities essentially derive from the capacity of DMC to interact with the protein targets HMGB1 and AMPK. Upon binding to HMGB1, DMC inhibits the nucleocytoplasmic transfer of the protein and its extracellular secretion, thereby blocking its alarmin function. DMC also binds to the AMP site of AMPK to activate phospho-AMPK and then to trigger downstream signals leading to the anti-inflammatory and anti-hyperglycemic effects. AMPK activation by DMC reinforces inhibition of HMGB1, to further reduce the release of the alarmin protein, likely contributing to the anticancer effects. The characterization of a tight control of DMC over the AMPK-HMGB1 axis not only helps to explain the known activities of DMC but also suggests opportunities to use this chalcone to treat other pathological conditions such as the acute respiratory distress syndrome (which affects patients with COVID-19). DMC structural analogues are also evoked.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Chalconas/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , /tratamento farmacológico , Proteína HMGB1/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Transdução de Sinais/efeitos dos fármacos
7.
Phytomedicine ; 78: 153319, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32950951

RESUMO

BACKGROUND: Inflammation and oxidative stress play essential roles in the occurrence and progression of diabetic cardiomyopathy (DCM). Isoliquiritigenin (ISL), a natural chalcone, exhibits strong anti-inflammatory and antioxidant activities. HYPOTHESIS/PURPOSE: In this study, we aimed to investigate the protective effects of ISL on DCM using high glucose (HG)-challenged cultured cardiomyocytes and streptozotocin (STZ)-induced diabetic mice. STUDY DESIGN AND METHODS: Embryonic rat heart-derived H9c2 cells challenged with a high concentration of glucose were used to evaluate the anti-inflammatory and antioxidant effects of ISL. STZ-induced diabetic mice were used to study the effects of ISL in DCM in vivo. Furthermore, cardiac fibrosis, hypertrophy, and apoptosis were explored both in vitro and in vivo. RESULTS: ISL effectively inhibited HG-induced hypertrophy, fibrosis, and apoptosis probably by alleviating the inflammatory response and oxidative stress in H9c2 cells. Results from in vivo experiments showed that ISL exhibited anti-inflammatory and antioxidant stress activities that were characterized by the attenuation of cardiac hypertrophy, fibrosis, and apoptosis, which resulted in the maintenance of cardiac function. The protective effects of ISL against inflammation and oxidative stress were mediated by the inhibition of mitogen-activated protein kinases (MAPKs) and induction of nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway, respectively. CONCLUSION: Our results provided compelling evidence that ISL, by virtue of neutralizing excessive inflammatory response and oxidative stress, could be a promising agent in the treatment of DCM. Targeting the MAPKs and Nrf2 signaling pathway might be an effective therapeutic strategy for the prevention and treatment of DCM.


Assuntos
Antioxidantes/farmacologia , Chalconas/farmacologia , Cardiomiopatias Diabéticas/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/fisiopatologia , Glucose/metabolismo , Glucose/farmacologia , Hiperglicemia/tratamento farmacológico , Hiperglicemia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Estreptozocina
8.
Phytomedicine ; 77: 153214, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32736296

RESUMO

BACKGROUND: Endometriosis is a common gynaecological disease characterized by growth of uterine endometrial tissue, outside the uterine cavity, on the ovaries, oviduct and pelvic peritoneum. Isoliquiritigenin (ISL) is a natural flavonoid isolated from the root of licorice (Glycyrrhiza uralensis) and shallot (Allium cepa). ISL has previously shown antioxidant, anti-inflammatory, anti-proliferation and anti-tumor activities. PURPOSE: This study aimed to investigate the effects of ISL on endometriosis in vivo and in vitro. METHODS: End1/E6E7 endometriosis cells were treated with ISL and ß-estradiol. The MTT assay was used to detect cell viability. Cell migration was evaluated by the wound-healing assay. The expression of epithelial-to-mesenchymal transition (EMT)-related proteins were detected by western blot. Female Balb/c mice, surgically induced to have endometriosis by transplanting uterine tissue into the abdominal cavity, were treated with ISL or vehicle for 4 weeks. Lesion growth was subsequently analyzed by high-resolution ultrasound imaging. Serum and lesion inflammatory cytokines were measured by ELISA. EMT-related proteins and apoptosis-related proteins of endometriotic lesions were detected by western blot. RESULTS: It was observed that ISL treatment inhibited the viability and migration of End1/E6E7. ISL treatment increased the expression of E-cadherin, and decreased the expression of N-cadherin, Slug and Snail. In the animal model, ISL treatment reduced the volume and weight of endometriotic lesions, decreased serum and lesion inflammatory cytokines, inhibited EMT, and induced apoptosis of the lesions. CONCLUSION: ISL inhibited the viability, migration and EMT-related proteins of End1/E6E7 cells, reduced the volume and weight of endometriotic lesions, inhibited inflammatory cytokines and EMT, and induced apoptosis of the lesions to improve endometriosis.


Assuntos
Chalconas/farmacologia , Endometriose/tratamento farmacológico , Endometriose/patologia , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Endometriose/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Estradiol/farmacologia , Feminino , Humanos , Camundongos Endogâmicos BALB C
9.
Eur J Pharmacol ; 886: 173448, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-32768503

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is distinctly infective and there is an ongoing effort to find a cure for this pandemic. Flavonoids exist in many diets as well as in traditional medicine, and their modern subset, indole-chalcones, are effective in fighting various diseases. Hence, these flavonoids and structurally similar indole chalcones derivatives were studied in silico for their pharmacokinetic properties including absorption, distribution, metabolism, excretion, toxicity (ADMET) and anti-SARS-CoV-2 properties against their proteins, namely, RNA dependent RNA polymerase (rdrp), main protease (Mpro) and Spike (S) protein via homology modelling and docking. Interactions were studied with respect to biology and function of SARS-CoV-2 proteins for activity. Functional/structural roles of amino acid residues of SARS-CoV-2 proteins and, the effect of flavonoid and indole chalcone interactions which may cause disease suppression are discussed. The results reveal that out of 23 natural flavonoids and 25 synthetic indole chalcones, 30 compounds are capable of Mpro deactivation as well as potentially lowering the efficiency of Mpro function. Cyanidin may inhibit RNA polymerase function and, Quercetin is found to block interaction sites on the viral spike. These results suggest flavonoids and their modern pharmaceutical cousins, indole chalcones are capable of fighting SARS-CoV-2. The in vitro anti-SARS-CoV-2 activity of these 30 compounds needs to be studied further for complete understanding and confirmation of their inhibitory potential.


Assuntos
Betacoronavirus/efeitos dos fármacos , Chalconas/química , Chalconas/farmacologia , Flavonoides/farmacologia , Indóis/química , Simulação de Acoplamento Molecular , Proteínas Virais/metabolismo , Betacoronavirus/metabolismo , Chalconas/metabolismo , Chalconas/farmacocinética , Simulação por Computador , Flavonoides/metabolismo , Flavonoides/farmacocinética , Conformação Proteica , Segurança , Distribuição Tecidual , Proteínas Virais/química
10.
Acta Biochim Biophys Sin (Shanghai) ; 52(8): 810-820, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32638014

RESUMO

Isoliquiritigenin (ISL), a natural flavonoid derived from the root of liquorice, has been reported to possess anti-inflammatory and antioxidant activities. Previous studies have found that ISL plays a crucial role in anti-fibrosis of adipose tissue and renal tissue; however, its effect on pulmonary fibrogenesis has not been demonstrated. In this study, we aimed to explore the roles and the underlying mechanisms of ISL in TGF-ß1-induced fibrogenesis using human lung fibroblast-derived MRC-5 cells. Cell proliferation and migration were determined by MTT and wound healing assay, respectively. The expression levels of alpha-smooth muscle actin (α-SMA), collagen type I alpha 1 (COLIA1) and fibronectin (FN), microtubule-associated protein light chain 3 (LC3) and related signaling molecules were detected by quantitative real-time PCR, western blot and immunofluorescence assay, correspondingly. EGFP-LC3 transfection was used for autophagy analysis. The results showed that ISL inhibited the TGF-ß1-induced proliferation and migration, and down-regulated the expressions of α-SMA, COLIA1 and FN. ISL treatment led to up-regulation of LC3 in TGF-ß1-treated MRC-5 cells, accompanied by significant decrease in the phosphorylation levels of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In addition, the inhibitory effects of ISL on TGF-ß1-induced fibrogenic features in MRC-5 cells were enhanced by pretreatment with autophagy activator Rapmycin and PI3K/AKT inhibitor LY294002 and reversed by autophagy inhibitor 3-methyladenine and PI3K/AKT activator IGF-1. Taken together, our results demonstrated that ISL could attenuate the fibrogenesis of TGF-ß1-treated MRC-5 cells by activating autophagy via suppressing the PI3K/AKT/mTOR pathway. Therefore, ISL holds a great potential to be developed as a novel therapeutic agent for the treatment of pulmonary fibrosis.


Assuntos
Autofagia/efeitos dos fármacos , Chalconas/farmacologia , Fibroblastos/metabolismo , Pulmão/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Linhagem Celular , Fibroblastos/patologia , Humanos , Pulmão/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Serina-Treonina Quinases TOR/metabolismo
11.
Sci Rep ; 10(1): 11814, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32678233

RESUMO

Hepatocellular carcinoma (HCC) ranks as the fifth most common and the second deadliest cancer worldwide. HCC is extremely resistant to the conventional chemotherapeutics. Hence, it is vital to develop new treatment options. Chalcones were previously shown to have anticancer activities in other cancer types. In this study, 11 chalcones along with quercetin, papaverin, catechin, Sorafenib and 5FU were analyzed for their bioactivities on 6 HCC cell lines and on dental pulp stem cells (DPSC) which differentiates into hepatocytes, and is used as a model for untransformed control cells. 3 of the chalcones (1, 9 and 11) were selected for further investigation due to their high cytotoxicity against liver cancer cells and compared to the other clinically established compounds. Chalcones did not show significant bioactivity ([Formula: see text]) on dental pulp stem cells. Cell cycle analysis revealed that these 3 chalcone-molecules induced SubG1/G1 arrest. Akt protein phosphorylation was inhibited by these molecules in PTEN deficient, drug resistant, mesenchymal like Mahlavu cells leading to the activation of p21 and the inhibition of NF[Formula: see text]B-p65 transcription factor. Hence the chalcones induced apoptotic cell death pathway through NF[Formula: see text]B-p65 inhibition. On the other hand, these molecules triggered p21 dependent activation of Rb protein and thereby inhibition of cell cycle and cell growth in liver cancer cells. Involvement of PI3K/Akt pathway hyperactivation was previously described in survival of liver cancer cells as carcinogenic event. Therefore, our results indicated that these chalcones can be considered as candidates for liver cancer therapeutics particularly when PI3K/Akt pathway involved in tumor development.


Assuntos
Chalconas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos , Humanos , Modelos Biológicos , Estrutura Molecular , Fosforilação/efeitos dos fármacos
12.
Chem Biol Interact ; 327: 109182, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32554038

RESUMO

Nothofagin is a natural 3'-C-ß-D-glucoside of the polyphenol phloretin that is mainly found in Aspalathus linearis, Nothofagus fusca, and Leandra dasytricha. In recent years, nothofagin has been described as a potential therapeutic agent for renal disorders, but the mechanisms that are involved in its renoprotective effects remain unclear. In the present study, perfused rat kidneys were used to test the hypothesis that nothofagin causes the direct relaxation of renal arteries. The molecular mechanisms that underlie these vascular effects were also investigated. The left kidney from Wistar rats was coupled in a perfusion system and continuously perfused with physiological saline solution (PSS). Initially, preparations with and without the endothelium were contracted with phenylephrine and received injections of 1-300 nmol nothofagin. The preparations were then perfused with PSS that contained phenylephrine plus KCl, indomethacin, l-NAME, tetraethylammonium, glibenclamide, 4-aminopyridine, iberiotoxin, charybdotoxin, and apamin. After 15 min under perfusion, nothofagin was injected again. In preparations with an intact endothelium, nothofagin dose-dependently reduced perfusion pressure. Endothelium removal or the inhibition of nitric oxide synthase by l-NAME prevented the vasodilatory effect of nothofagin at all doses tested. Perfusion with PSS that contained KCl or tetraethylammonium chloride also abolished the vasodilatory effect of nothofagin. Treatment with glibenclamide, 4-aminopyridine, and apamin did not affect the vasodilatory effect of nothofagin. Iberiotoxin (selective Ca2+-activated high-conductance K+ channel [KCa1.1] blocker) and charybdotoxin (selective KCa1.1 and Ca2+-activated intermediate-conductance K+ channel [KCa3.1] blocker) application blocked the vasodilatory effect of nothofagin at all doses tested, pointing to a predominant role for KCa1.1 in the action of nothofagin. However, these data cannot exclude a potential contribution of endothelial KCa3.1 channel in the nothofagin-induced vasodilation. Overall, our findings indicate that nothofagin induces vasodilation in renal arteries, an effect that is mediated by Ca2+ -activated high-conductance K+ channels opening and endothelial nitric oxide production.


Assuntos
Chalconas/farmacologia , Rim/efeitos dos fármacos , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Óxido Nítrico/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Endotélio Vascular/efeitos dos fármacos , Masculino , Perfusão , Ratos Wistar , Artéria Renal/efeitos dos fármacos
13.
Chem Biol Interact ; 327: 109185, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32590072

RESUMO

The present study examined the apoptotic effects and the underlying mechanism of sappanchalcone, a major bioactive compound isolated from Caesalpinia sappan L. on human colon cancer cells. To achieve this, we used two different colon cancer cell lines, namely HCT116 (as wild-type p53 cells) and SW480 (as p53-mutant cells) cells. Our results illustrated that sappanchalcone treatment decreased the proliferation and further promoted apoptosis in HCT116 cells compared with the findings in SW480 cells. Sappanchalcone triggered phosphorylation of p53, which is involved in the activation of caspases and increased expression of Bax in HCT116 cells. Conversely, sappanchalcone-treated SW480 cells displayed no change in p53 phosphorylation or caspase activation. In addition, sappanchalcone further increased reactive oxygen species (ROS) levels and apoptosis-inducing factor (AIF) release in both HCT116 and SW480 cells. These data suggest that sappanchalcone induces apoptosis through caspase-dependent and caspases-independent mechanisms that were characterized by decreased Bcl-2 expression, mitochondrial targeting, and altered ROS production and AIF translocation to the nuclei.


Assuntos
Fator de Indução de Apoptose/metabolismo , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Chalconas/farmacologia , Neoplasias do Colo/metabolismo , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/metabolismo
14.
Life Sci ; 250: 117591, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32224026

RESUMO

Nature's pharmacy has undoubtedly served humans as an affordable and safer health-care regime for a long times. Cardamonin, a chalconoid present in several plants has been known for a longtime to have beneficial properties towards human health. In this review, we aimed to highlight the recent advances achieved in discovering the pharmacological properties of cardamonin. Cardamonin is cardamom-derived chalcone, which plays a role in cancer treatment, immune system modulation, inflammation and pathogens killing. Through the modulation of cellular signaling pathways, cardamonin activates cell death signal to induce apoptosis in malignant cells that results in the inhibition of cancer development. Moreover, cardamonin arrests cell cycle by altering the expression of regulatory proteins during malignant cells division. Due to its relatively selective cytotoxic potential against host malignant cells, cardamonin is emerging as a promising novel experimental anticancer agent. The potential of cardamonin to target various signaling molecules, transcriptional factors, cytokines and enzymes, such as mTOR, NF-κB, Akt, STAT3, Wnt/ß-catenin and COX-2 enhances the opportunity to explore it as a new multi-target therapeutic agent. The pharmacokinetic and biosafety profile of cardamonin favor it as a potentially safe biomolecule for pharmaceutical drug development.


Assuntos
Chalconas/farmacologia , Neoplasias/metabolismo , Transdução de Sinais , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Humanos , Sistema Imunitário , Inflamação , Fígado/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neovascularização Patológica , Fator de Transcrição STAT3/metabolismo
15.
Cardiovasc Ther ; 2020: 1926249, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32328171

RESUMO

Isoliquiritigenin (ISL) is a flavonoid isolated mainly from the licorice plant, a traditional Chinese herb. ISL has shown anticancer, anti-inflammatory, antioxidant, and antidiabetic activities. However, the pharmaceutical effects of ISL on atherosclerosis are seldom explored. In this study, we used apolipoprotein E (ApoE) knockout mouse model and angiotensin II- (Ang II-) stimulated vascular smooth muscle cells (VSMCs) to elucidate the pharmacological mechanism of ISL to inhibit atherosclerosis. We found that in ApoE-/- mice ISL could attenuate atherosclerotic lesion, reduce serum lipid levels, and inhibit TRPC5 expression. In vitro, ISL inhibited Ang II-stimulated proliferation of VSMCs and suppressed Ang II-induced TRPC5 and PCNA expressions in a dose-dependent fashion. In conclusion, our findings provide novel insight into the pharmacological effects of ISL on atherosclerosis and suggest that ISL is beneficial for cardiovascular protection.


Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Chalconas/farmacologia , Placa Aterosclerótica , Canais de Cátion TRPC/antagonistas & inibidores , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Lipídeos/sangue , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Transdução de Sinais , Canais de Cátion TRPC/metabolismo
16.
Chem Biol Interact ; 324: 109084, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32289290

RESUMO

INTRODUCTION: An imbalance between oxidants and antioxidants in favour of oxidants, potentially leading to damage, is termed oxidative stress. Antioxidants (AO), either enzymatic or non-enzymatic, are the ones that can reduce diverse effects of pro-oxidants such as DNA, proteins and lipids damage. Chalcones (1,3-diaryl-2-propen-1-ones) are open chain flavonoids that are widely biosynthesized in plants. Aim of this study was to test antioxidative potency of 15 chalcones (Chs) in in vitro model in serum (native conditions), so as with exogenously induced oxidative stress. MATERIAL AND METHODS: Oxidative stress was induced in serum samples of healthy individuals with 0.25 mmol/L terc-buthyl-hydroperoxide (TBH), and then we monitored the effects of various concentrations of chalcones on oxidative stress parameters: total antioxidative status (TAS), total oxidative status (TOS), total concentration of sulfhydryl group (SHG) and prooxidative-antioxidative balance (PAB), and calculated prooxidative score, antioxidative score, and oxy score (OS). Nonparametric repeated measures ANOVA (Friedman's test) was used for comparison of antioxidative potency of samples with 15 different chalcones, in a native state and upon TBH influence. Spearman's nonparametric correlation analysis was used for estimation of relation between different parameters. RESULTS: Negative Oxy Score (OS) values for Chs11-15 showed significantly stronger antioxidative potency compared to other investigated chalcones (p < 0.05). Ch11, Ch13 and Ch14 remained with negative OS even after TBH addition, whereas OS of Ch12 and Ch15 became positive, with small nominal values. Samples with Ch11 and Ch13 showed significant negative correlation between TAS and TOS (p < 0.05 for both), but in Ch14 sample the negative correlation existed between TAS and PAB (p < 0.05). CONCLUSION: Lower value of OS (i.e. better antioxidative potency) was noticed in samples with Ch11-Ch15. Electron-donor effects of substituent groups as a structural part of these chalcones could explain its antioxidative capability. Phenolic and methyl groups are responsible for antioxidative ability enhancement of five chalcones with the best activity.


Assuntos
Antioxidantes/farmacologia , Sangue/metabolismo , Chalconas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/síntese química , Antioxidantes/química , Sangue/efeitos dos fármacos , Chalconas/síntese química , Chalconas/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , terc-Butil Hidroperóxido/farmacologia
17.
Biochim Biophys Acta Mol Basis Dis ; 1866(7): 165795, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278009

RESUMO

Cisplatin's toxicity in renal tubular epithelial cells limits the therapeutic efficacy of this antineoplastic drug. In cultured human proximal tubular HK-2 cells (PTC) a prostaglandin uptake transporter (PGT)-dependent increase in intracellular prostaglandin E2 (iPGE2) mediates cisplatin's toxicity (i.e. increased cell death and loss of cell proliferation) so that it is prevented by PGT inhibitors. Here we found in cisplatin-treated PTC that 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), a PGT inhibitor, prevented cisplatin's toxicity but not the increase in iPGE2. Because expression of retinoic acid receptor-ß (RAR-ß) is dependent on iPGE2 and because RAR-ß is a regulator of cell survival and proliferation, we hypothesized that RAR-ß might mediate the protective effect of DIDS against cisplatin's toxicity in PTC. Our results confirmed this hypothesis because: i) protection of PTC by DIDS was abolished by RAR-ß antagonist LE-135; ii) DIDS increased the expression of RAR-ß in PTC and prevented its decrease in cisplatin-treated PTC but not in cisplatin-treated human cervical adenocarcinoma HeLa cells in which DIDS failed to prevent cisplatin's toxicity; iii) while RAR-ß expression decreased in cisplatin-treated PTC, RAR-ß over-expression prevented cisplatin's toxicity. RAR-ß agonist CH55 or RAR pan-agonist all-trans retinoic acid did not prevent cisplatin's toxicity, which suggests that RAR-ß does not protect PTC through activation of gene transcription. In conclusion, RAR-ß might be a new player in cisplatin-induced proximal tubular injury and the preservation of its expression in proximal tubules through treatment with DIDS might represent a novel strategy in the prevention of cisplatin's nephrotoxicity without compromising cisplatin's chemotherapeutic effect on cancer cells.


Assuntos
Adenocarcinoma/tratamento farmacológico , Cisplatino/efeitos adversos , Dinoprostona/genética , Receptores do Ácido Retinoico/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Ácido 4,4'-Di-Isotiocianoestilbeno-2,2'-Dissulfônico/farmacologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalconas/farmacologia , Cisplatino/farmacologia , Dibenzazepinas/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Túbulos Renais Proximais/efeitos dos fármacos , Substâncias Protetoras , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
18.
Phytomedicine ; 69: 153210, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32217447

RESUMO

BACKGROUND: More than 80% of advanced prostate cancer (PCa) cases have bone metastasis, with a 5-year survival rate of 25%. Previously, we reported that GRT, a standardized, pharmaceutical-grade aspalathin-rich extract (12.78 g aspalathin/100 g extract), prepared from green rooibos produced from the leaves and fine stems of Aspalathus linearis, inhibits the proliferation of PCa cells, meriting this investigation to determine if GRT can suppress the migration and invasion of castration-resistant prostate cancer (CRPC) cells. PURPOSE: In the present study, we investigated whether GRT extract can interfere with the migration and invasion of human CRPC cells. METHODS: Transwell assays were used to explore the effects of GRT on the migration and invasion of CRPC cells. Micro-Western Array (MWA) and Western blot analysis were carried out to unravel the underlying molecular mechanism(s). RESULTS: Treatment with 25-100 µg/ml GRT suppressed the migration and invasion of LNCaP C4-2B and 22Rv1 CRPC cells. MWA and Western blot analysis indicated that GRT treatment suppressed the protein level of yes-associated protein (YAP), macrophage stimulating 1 protein (MST1), phospho-MST1/phospho-MST2 T183/T180, and paxillin, but increased the abundance of E-cadherin. Over-expression of YAP rescued the suppressive effects of GRT on migration and invasion of CRPC cells. Treatment with the major flavonoid of GRT - the C-glucosyl dihydrochalcone, aspalathin - at a concentration of 75-100 µg/ml also reduced the migration and invasion of CRPC cells, and the inhibition was partially rescued by YAP over-expression. CONCLUSIONS: GRT treatment suppresses the migration and invasion of CRPC cells via inhibition of YAP signaling and paxillin.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Aspalathus/química , Chalconas/farmacologia , Extratos Vegetais/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Masculino , Paxilina/metabolismo , Extratos Vegetais/química , Neoplasias de Próstata Resistentes à Castração/patologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo
19.
Molecules ; 25(6)2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32197426

RESUMO

Background: In order to identify potential activities against periodontal diseases, eighteen dihydrochalcones and structurally related compounds were tested in an established biological in vitro cell model of periodontal inflammation using human gingival fibroblasts (HGF-1 cells). Methods: Subsequently to co-incubation of HGF-1 cells with a bacterial endotoxin (Porphyromonas gingivalis lipopolysaccharide, pgLPS) and each individual dihydrochalcone in a concentration range of 1 µM to 100 µM, gene expression of interleukin-8 (IL-8) was determined by qPCR and cellular interleukin-8 (IL-8) release by ELISA. Results: Structure-activity analysis based on the dihydrochalcone backbone and various substitution patterns at its aromatic ring revealed moieties 2',4,4',6'-tetrahydroxy 3-methoxydihydrochalcone (7) to be the most effective anti-inflammatory compound, reducing the pgLPS-induced IL-8 release concentration between 1 µM and 100 µM up to 94%. In general, a 2,4,6-trihydroxy substitution at the A-ring and concomitant vanilloyl (4-hydroxy-3-methoxy) pattern at the B-ring revealed to be preferable for IL-8 release inhibition. Furthermore, the introduction of an electronegative atom in the A,B-linker chain led to an increased anti-inflammatory activity, shown by the potency of 4-hydroxybenzoic acid N-vanillylamide (13). Conclusions: Our data may be feasible to be used for further lead structure designs for the development of potent anti-inflammatory additives in oral care products.


Assuntos
Anti-Inflamatórios , Chalconas , Fibroblastos/metabolismo , Gengiva/metabolismo , Interleucina-8/biossíntese , Chumbo , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Linhagem Celular , Chalconas/química , Chalconas/farmacologia , Fibroblastos/patologia , Gengiva/patologia , Humanos , Chumbo/química , Chumbo/farmacologia , Lipopolissacarídeos/toxicidade , Doenças Periodontais/induzido quimicamente , Doenças Periodontais/tratamento farmacológico , Doenças Periodontais/metabolismo , Doenças Periodontais/patologia , Porphyromonas gingivalis/química
20.
Food Funct ; 11(3): 2522-2534, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32141447

RESUMO

Pleurisy refers to a pleural disease caused by pathogenic factors that stimulate the pleura associated with pleural inflammation and oxidative stress. Isoliquiritigenin (ISL), a flavonoid from the liquorice compound, possesses antioxidative and anti-inflammatory properties. In the current study, we investigated the protective effects of ISL on carrageenan-induced pleurisy and lung injury in mice. The mice were intraperitoneally injected with ISL (30 mg kg-1) twice (each time interval of 12 h), followed by exposure to Car 1 h after the second dose of ISL. Our results indicated that ISL treatment significantly alleviated carrageenan-induced histopathological damage and increased levels of inflammatory cell exudation, protein leakage, and pro-inflammatory mediators. Meanwhile, ISL inhibited reactive oxygen species (ROS) generation, MDA and MPO formation, and SOD and GSH depletion induced by carrageenan. In addition, it decreased the GSSG level and GSSG-to-GSH ratio. In terms of the mechanism, ISL inhibited NOX2 and NOX4 levels, caused the dissociation of KEAP-1 and Nrf2, and activated the downstream genes HO-1, NQO1, GCLC and GCLM, thus decreasing oxidative stress. In addition, ISL exerts protective effects against inflammation by suppressing the NOD-like receptor protein 3 (NLRP3)/NF-κB pathway and the high levels of iNOS and COX-2. In summary, our results reinforce the hypothesis that ISL exerts protective effects on carrageenan-induced pleurisy and lung injury in a manner that can be attributed to Nrf2-mediated antioxidative activities and NLRP3/NF-κB-mediated anti-inflammatory activities.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Chalconas/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Carragenina/toxicidade , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Pleurisia/induzido quimicamente , Pleurisia/tratamento farmacológico
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