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Melanoma is known to aggressively metastasize and is one of the prominent causes of skin cancer mortality. This study was designed to assess the molecular mechanism of decursinol angelate (DA) against murine melanoma cell line (B16F10 cells). Treatment of DA resulted in growth inhibition and cell cycle arrest at G0/G1 (p < 0.001) phase, evaluated through immunoblotting. Moreover, autophagy-related proteins such as ATG-5 (p < 0.0001), ATG-7 (p < 0.0001), beclin-1 (p < 0.0001) and transition of LC3-I to LC3-II (p < 0.0001) were markedly decreased, indicating autophagosome inhibition. Additionally, DA treatment triggered apoptotic events which were corroborated by the occurrence of distorted nuclei, elevated reactive oxygen species (ROS) levels and reduction in the mitochondrial membrane potential. Subsequently, there was an increase in the expression of pro-apoptotic protein Bax in a dose-dependent manner, with the corresponding downregulation of Bcl-2 expression and cytochrome C expression following 24 h DA treatment in A375.SM and B16F10 cells. We substantiated our results for apoptotic occurrence through flow cytometry in B16F10 cells. Furthermore, we treated B16F10 cells with N-acetyl-L-cysteine (NAC). NAC treatment upregulated ATG-5 (p < 0.0001), beclin-1 (p < 0.0001) and LC3-I to LC3-II (p < 0.0001) conversion, which was inhibited in the DA treatment group. We also noticed a systematic upregulation of important markers for progression of G1 cell phase such as CDK-2 (p < 0.029), CDK-4 (p < 0.036), cyclin D1 (p < 0.0003) and cyclin E (p < 0.020) upon NAC treatment. In addition, we also observed a significant fold reduction (p < 0.05) in ROS fluorescent intensity and the expression of Bax (p < 0.0001), cytochrome C (p < 0.0001), cleaved caspase-9 (p > 0.010) and cleaved caspase-3 (p < 0.0001). NAC treatment was able to ameliorate DA-induced apoptosis and cell cycle arrest to support our finding. Our in vivo xenograft model also revealed similar findings, such as downregulation of CDK-2 (p < 0.0001) and CDK-4 (p < 0.0142) and upregulation of Bax (p < 0.0001), cytochrome C (p < 0.0001), cleaved caspase 3 (p < 0.0001) and cleaved caspase 9 (p < 0.0001). In summary, our study revealed that DA is an effective treatment against B16F10 melanoma cells and xenograft mice model.
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Apoptose , Benzopiranos/farmacologia , Butiratos/farmacologia , Melanoma/patologia , Neoplasias Cutâneas/patologia , Acetilcisteína/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Benzopiranos/toxicidade , Butiratos/toxicidade , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Melanoma Experimental/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Modelos Biológicos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Polymethoxyflavanoids (PMFs) have exhibited a vast array of therapeutic biological properties. 5-O-Demethylnobiletin (5-DN) is one such PMF having anti-inflammatory activity, yet its role in hepatoprotection has not been studied before. Results from in vitro study revealed that 5-DN did not exert a high level of cytotoxicity on HepG2 cells at 40 µM, and it was able to rescue HepG2 cell death induced by carbon tetrachloride (CCl4). Subsequently, we investigated acute liver injury on BALB/c mice induced by CCl4 through the intraperitoneal injection of 1 mL/kg CCl4 and co-administration of 5-DN at (1 and 2 mg/kg) by oral gavage for 15 days. The results illustrated that treatment with 5-DN attenuated CCl4-induced elevated serum aminotransferase (AST)/alanine aminotransferase (ALT) ratio and significantly ameliorated severe hepatic damage such as inflammation and fibrosis evidenced through lesser aberrations in the liver histology of 5-DN dose groups. Additionally, 5-DN efficiently counteracted and equilibrated the production of ROS accelerated by CCl4 and dramatically downregulated the expression of CYP2E1 vitally involved in converting CCl4 to toxic free radicals and also enhanced the antioxidant enzymes. 5-DN treatment also inhibited cell proliferation and inflammatory pathway abnormally regulated by CCl4 treatment. Furthermore, the apoptotic response induced by CCl4 treatment was remarkably reduced by enhanced Bcl-2 expression and noticeable reduction in Bax, Bid, cleaved caspase 3, caspase 9, and apaf-1 expression. 5-DN treatment also induced the conversion of LC3 and promoted the autophagic flux. Conclusively, 5-DN exhibited hepatoprotective effects in vitro and in vivo and prevented liver fibrosis induced by CCl4.
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Apoptose , Autofagia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Flavonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Tetracloreto de Carbono , Colágeno/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Células Hep G2 , Humanos , Inflamação/patologia , Peroxidação de Lipídeos , Fígado/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Tamanho do Órgão , Estresse Oxidativo/efeitos dos fármacosRESUMO
Two-spotted cricket Gryllus bimaculatus is one of many cricket species, and it is widely used as a food source for insectivorous animals. Moreover, this species is one of the edible insects approved by the Korea Food and Drug Administration (KFDA). (±)-Kituramides A (1) and B (2), which are pairs of novel enantiomeric dopamine dimers possessing a formamide group, were isolated from the two-spotted cricket, together with four other known biosynthetically related compounds (3-6). The chemical structures of 1 and 2 were elucidated using a combination of 1D and 2D NMR spectroscopic experiments and HR-ESIMS data. Compounds 1 and 2 were identified as racemic mixtures; the enantiomers (+)-1/2 and (-)-1/2 were successfully separated by utilizing a chiral HPLC column. The absolute configurations of (±)-1 and (±)-2 were unambiguously delineated by the application of quantum chemical ECD calculations. Further, these insect-derived substances were evaluated to understand their effects on cytokine expression in adipocytes. Treatment with (-)-1, (+)-2, and (-)-2 during adipocyte differentiation significantly promoted the expression of Leptin and IL-6, which resembles the actions of dopamine.
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Dopamina/análogos & derivados , Gryllidae/metabolismo , Animais , Cromatografia Líquida de Alta Pressão/métodos , Dimerização , Dopamina/química , Estrutura Molecular , EstereoisomerismoRESUMO
Microbial biofilms are associated with persistent infections because of their high tolerance to antimicrobial agents and host defenses. The effects of centipede oil from Scolopendra subspinipes mutilans and its main components were investigated to identify non-toxic biofilm inhibitors. Centipede oil and linoleic acid at 20 µg ml-1 markedly inhibited biofilm formation by two fluconazole-resistant Candida albicans strains and three Staphylococcus aureus strains without affecting their planktonic cell growth. Also, both centipede oil and linoleic acid inhibited hyphal growth and cell aggregation by C. albicans. In addition, centipede oil and linoleic acid showed anti-biofilm activities against mixed C. albicans and S. aureus biofilms. Transcriptomic analysis showed that centipede oil and linoleic acid downregulated the expressions of several hypha/biofilm-related genes in C. albicans and α-hemolysin in S. aureus. Furthermore, both compounds effectively reduced C. albicans virulence in a nematode infection model with minimal toxicity.
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Anti-Infecciosos/farmacologia , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Ácido Linoleico/farmacologia , Óleos Voláteis/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Animais , Anti-Infecciosos/toxicidade , Artrópodes/química , Biofilmes/crescimento & desenvolvimento , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/microbiologia , Candida albicans/crescimento & desenvolvimento , Candida albicans/patogenicidade , Hifas/crescimento & desenvolvimento , Ácido Linoleico/toxicidade , Testes de Sensibilidade Microbiana , Óleos Voláteis/toxicidade , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/patogenicidade , Virulência/efeitos dos fármacosRESUMO
Phorbol 12-myristate 13-acetate (PMA) is a potent tumor promoter and highly inflammatory in nature. Here, we investigated the toxic effects of PMA on different model system. PMA (10 µg) caused chromosomal aberrations on the Allium cepa root tip and induced mitotic dysfunction. Similarly, PMA caused embryonic and larval deformities and a plummeted survivability rate on zebrafish embryo in a dose-dependent manner. Persistently, PMA treatment on immortalized human keratinocyte human keratinocyte (HaCaT) cells caused massive inflammatory rush at 4 h and a drop in cell survivability at 24 h. Concomitantly, we replicated a cutaneous inflammation similar to human psoriasis induced by PMA. Herein, we used tangeretin (TAN), as an antagonist to counteract the inflammatory response. Results from an in vivo experiment indicated that TAN (10 and 30 mg/kg) significantly inhibited PMA stimulated epidermal hyperplasia and intra-epidermal neutrophilic abscesses. In addition, its treatment effectively neutralized PMA induced elevated reactive oxygen species (ROS) generation on in vitro and in vivo systems, promoting antioxidant response. The association of hypoxia-inducible factor 1-alpha (HIF-1α)-nuclear factor kappa-light-chain-enhancer of activated b cells (NF-κB) crosstalk triggered by PMA enhanced PKCα-ERK1/2-NF-κB pathway; its activation was also significantly counteracted after TAN treatment. Conclusively, we demonstrated TAN inhibited the nuclear translocation of HIF-1α and NF-κB p65. Collectively, TAN treatment ameliorated PMA incited malignant inflammatory response by remodeling the cutaneous microenvironment.
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Flavonas/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acetato de Tetradecanoilforbol/efeitos adversos , Animais , Antioxidantes , Biomarcadores , Linhagem Celular Transformada , Anormalidades Congênitas , Desenvolvimento Embrionário/genética , Epiderme , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Queratinócitos/metabolismo , Peroxidação de Lipídeos , Cebolas/efeitos dos fármacos , Cebolas/genética , Cebolas/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Peixe-ZebraRESUMO
Mulberry, the fruit of white mulberry tree (Morus alba L., Moraceae), is commonly used in traditional Chinese medicines as a sedative, tonic, laxative, and emetic. In our continuing research of the bioactive metabolites from mulberry, chemical analysis of the fruits led to the isolation of five compounds, 1-5. The compounds were identified as butyl pyroglutamate (1), quercetin 3-O-ß-d-glucoside (2), kaempferol 3-O-ß-d-rutinoside (3), rutin (4), and 2-phenylethyl d-rutinoside (5) by spectroscopic data analysis, comparing their nuclear magnetic resonance (NMR) data with those in published literature, and liquid chromatography-mass spectrometry analysis. The isolated compounds 1-5 were evaluated for their effects on anticancer drug-induced side effects by cell-based assays. Compound 1 exerted the highest protective effect against cisplatin-induced kidney cell damage. This effect was found to be mediated through the attenuation of phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, p38, mitogen-activated protein kinase, and caspase-3 in cisplatin-induced kidney cell damage.
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Cisplatino/efeitos adversos , Frutas/química , Rim/citologia , Morus/química , Compostos Fitoquímicos/farmacologia , Animais , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Rim/efeitos dos fármacos , Rim/metabolismo , Células LLC-PK1 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Compostos Fitoquímicos/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , SuínosRESUMO
Diarylheptanoids are a family of plant secondary metabolites with a 7 carbon skeleton possessing two phenyl rings at the 1- and 7-positions. They can be subdivided into acyclic and cyclic diarylheptanoids where the latter are further divided into meta,meta-bridged biphenyls ([7.0]metacyclophanes) and meta,para-bridged diphenyl ether heptanoids (oxa[7.1]metapara-cyclophanes). Since the isolation of curcumin from the rhizomes of turmeric (Curcuma longa) in 1815 which was named curcumin, a variety of diarylheptanoids have been isolated from a number of plant families such as Aceraceae, Actinidiaceae, Betulaceae, Burseraceae, Casuarinaceae, Juglandaceae, Leguminosae, Myricaceae, and Zingiberaceae. Earlier studies on these diarylheptanoids have been summarized on several occasions, of which the main themes only focus on isolation, structure elucidation, and the biological properties of linear types. Only a few have covered cyclic diarylheptanoids and their chemical synthesis has been covered lastly by Zhu et al. in 2000. The present paper has, therefore, covered recent progress in cyclic diarylheptanoids focusing on the isolation, structural and biological features, and chemical synthesis.
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Diarileptanoides , Compostos Fitoquímicos , Plantas/química , Diarileptanoides/síntese química , Diarileptanoides/química , Diarileptanoides/isolamento & purificação , Estrutura Molecular , Compostos Fitoquímicos/síntese química , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificaçãoRESUMO
Ulcerative colitis is an inflammatory disease of the large intestine whose effects are bloody diarrhea, cramping and bloating. The disease is usually relapsing and remitting. However, the cause of ulcerative colitis is not yet known. Due to this reason, finding an effective treatment has been a great challenge. The suggested medical treatment is usually composed of two portions; keeping the flare up from happening and treating the flare up when it has happened. Active flare ups are treated with corticosteroids. There are several hypothesis which suggest that ulcerative colitis could be due to the micro flora present in gut. For this reason, several researchers tried to modify the gut microflora with probiotics. However, there is no probiotics found that can induce emission faster than the placebo. The ulcerative colitis patients taking probiotics showed fewer and less severe symptoms during the flare up. This means that even though the probiotics did not end up the flare up faster, it slowed up the severity of the symptoms of the patients.
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Colite Ulcerativa/fisiopatologia , Probióticos , HumanosRESUMO
Bifunctional chelators have been successfully used to construct (64)Cu-labeled radiopharmaceuticals. Previously reported chelators with cross-bridged cyclam backbones have various essential features such as high stability of the copper(II) complex, high efficiency of radiolabeling at room temperature, and good biological inertness of the radiolabeled complex, along with rapid body clearance. Here, we report a new generation propylene-cross-bridged chelator with hybrid acetate/phosphonate pendant groups (PCB-TE1A1P) developed with the aim of combining these key properties in a single chelator. The PCB-TE1A1P was synthesized from cyclam with good overall yield. The Cu(II) complex of our chelator showed good robustness in kinetic stability evaluation experiments, such as acidic decomplexation and cyclic voltammetry studies. The Cu(II) complex of PCB-TE1A1P remained intact under highly acidic conditions (12 M HCl, 90 °C) for 8 d and showed quasi-reversible reduction/oxidation peaks at -0.77 V in electrochemical studies. PCB-TE1A1P was successfully radiolabeled with (64)Cu ions in an acetate buffer at 60 °C within 60 min. The electrophoresis study revealed that the (64)Cu-PCB-TE1A1P complex has net negative charge in aqueous solution. The biodistribution and in vivo stability study profiles of (64)Cu-PCB-TE1A1P indicated that the radioactive complex was stable under physiological conditions and cleared rapidly from the body. A whole body positron emission tomography (PET) imaging study further confirmed high in vivo stability and fast clearance of the complex in mouse models. In conclusion, PCB-TE1A1P has good potential as a bifunctional chelator for (64)Cu-based radiopharmaceuticals, especially those involving peptides.
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Quelantes/química , Radioisótopos de Cobre/química , Compostos Organometálicos/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Animais , Quelantes/síntese química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Estrutura Molecular , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/química , Distribuição TecidualRESUMO
BACKGROUND: Ginseng is a traditional herbal medicine used for thousands of years in Southeast Asian countries because of its medicinal properties. Ginsenosides Rg1 and Rg3 have demonstrated therapeutic properties against a broad spectrum of diseases. PURPOSE: Here in this study, we investigated the therapeutic efficacy of Rg1 and Rg3 in alleviating glycerol-induced acute kidney injury, also known as rhabdomyolysis-induced acute kidney injury (RAKI). METHODS: AKI was induced in male Wistar rats through intramuscular injection of 10 mL/kg glycerol and simultaneous oral treatment of ginsenosides Rg1 and Rg3 for 3 days. We also evaluated the therapeutic potential of Rg1 and Rg3 on human embryonic kidney epithelial (HEK-293). Cell viability and LDH assay were performed on HEK-293 cells to evaluate the toxicity of Rg1 and Rg3. Evaluation of important kidney damage markers such as creatinine and blood urea nitrogen (BUN) was carried out at different time points from the rat serum. Histopathological analysis was performed on kidney tissues. We also performed experiments such as ELISA assay, immunohistochemistry, immunofluorescence staining, COMET assay, western blotting, TUNEL assay, and flow cytometry to obtain results. RESULTS: Rg1 and Rg3 significantly downregulated the expression of kidney damage markers such as creatinine and BUN in a dose-dependent manner. Histopathological analysis revealed damage across the glomerulus, tubules, and collecting duct rendering the kidney dysfunctional in glycerol treatment groups. However, Rg1 and Rg3 treated groups showed a significant reduction in tubular necrosis at both 10 and 20 mg/kg. There was also a sharp downregulation of oxidative and ER stress markers. Additionally, we observed nuclear translocation of Nrf2 which were more prominent in kidney tissues. Rg1 and Rg3 were also able to mitigate apoptotic cell death in vitro and in vivo evaluated through immunofluorescence staining for p53, TUNEL assay, flow cytometry, and immunoblotting for intrinsic apoptosis markers. CONCLUSION: In summary, we conclude that Rg1 and Rg3 exhibited natural therapeutic remedy against AKI.
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Injúria Renal Aguda , Ginsenosídeos , Ratos , Humanos , Masculino , Animais , Ginsenosídeos/uso terapêutico , Ginsenosídeos/farmacologia , Ratos Wistar , Glicerol , Células HEK293 , Creatinina , Apoptose , Injúria Renal Aguda/tratamento farmacológicoRESUMO
Chronic neurodegenerative diseases are typically associated with oxidative stress conditions leading to neuronal cell death. We aimed to investigate the neuroprotective effect of three pyranocoumarins (decursin, decursinol angelate, and decursinol) targeting oxidative stress factors. Decursin (also known as dehydro-8-prenylnaringenin) is a prenylated coumarin compound consisting of a coumarin ring system with a prenyl group attached to one of the carbons in the ring. As a secondary metabolite of plants, pyranocoumarin decursin from Angelica gigas Nakai presented protective effects against glutamate-induced oxidative stress in HT22, a murine hippocampal neuronal cell line. Decursinol (DOH) is a metabolite of decursin, sharing same coumarin ring system but a slightly different chemical structure with the prenyl group replaced by a hydroxyl group (-OH). In our findings, DOH was ineffective while decursin was, suggesting that this prenyl structure may be important for compound absorption and neuroprotection. By diminishing the accumulation of intracellular reactive oxygen species as well as stimulating the expression of HO-1, decursin triggers the self-protection system in neuronal cells. Additionally, decursin also revealed an anti-apoptotic effect by inhibiting chromatin condensation and reducing the forming of annexin-V-positive cells.
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BACKGROUND: Moringa oleifera (M. oleifera) is cultivated throughout the world and it is known by numerous regional names and is consumed as medication for various diseases such as hypertension, diabetes, HIV and is potential source of nutrients and natural antioxidants making it among the most useful trees. METHODS: We evaluated the therapeutic potential of M. oleifera on ethanol-induced fatty liver. The mice were treated with 30% ethanol (EtOH) alone or in combination with different concentration of M. oleifera extracts (100, 200 and 400 mg/kg). We performed biochemical estimation for the serum of important liver damage markers such as aspartate aminotransferase (AST), alanine aminotransferase (ALT) and triglyceride (TG). We performed histopathological analysis from the liver tissues of different mice groups. We also performed ELISA assay, western blotting analysis and SPECT imaging to obtain our results. RESULTS: The results for serum (AST, p < 0.0001), (ALT, p < 0.0006) and triglyceride (TG, p < 0.0003) were found to be significantly reduced in all doses of M. oleifera extract treatment groups in comparison with the ethanol group. H&E staining analysis and scoring revealed a significant reduction in lipid droplet accumulation and a significant reduction of liver steatosis (p < 0.0001), lobular inflammation (p < 0.0013), ballooning (p < 0.0004) and immunohistochemistry for TNF-α. M. oleifera also ameliorated ethanol-induced oxidative stress evaluated through MDA (p < 0.0001), H2DCFDA, JC-1 staining and a significant down-regulation of CYP2E1 enzyme (p < 0.0001) in the 200 and 400 mg/kg groups in comparison with EtOH groups. M. oleifera extract also boosted the antioxidant response evaluated through total GSH assay (p < 0.0001) and nuclear translocation of Nrf2. Furthermore, we performed SPECT imaging and evaluated the liver uptake value (LUV) to assess the extent of liver damage. LUV was observed to be lower in the ethanol group, whereas LUV was higher in control and M. olifera treated groups. CONCLUSION: In summary, from this experiment we conclude that M. oleifera extract has the potential to ameliorate ethanol-induced liver damage.
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Fígado Gorduroso , Moringa oleifera , Extratos Vegetais , Animais , Camundongos , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Etanol/efeitos adversos , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Fígado/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Extratos Vegetais/farmacologia , Triglicerídeos/metabolismoRESUMO
Effective treatment choices to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are limited because of the absence of effective target-based therapeutics. The main object of the current research was to estimate the antiviral activity of cannabinoids (CBDs) against the human coronavirus SARS-CoV-2. In the presented research work, we performed in silico and in vitro experiments to aid the sighting of lead CBDs for treating the viral infections of SARS-CoV-2. Virtual screening was carried out for interactions between 32 CBDs and the SARS-CoV-2 Mpro enzyme. Afterward, in vitro antiviral activity was carried out of five CBDs molecules against SARS-CoV-2. Interestingly, among them, two CBDs molecules namely Δ9 -tetrahydrocannabinol (IC50 = 10.25 µM) and cannabidiol (IC50 = 7.91 µM) were observed to be more potent antiviral molecules against SARS-CoV-2 compared to the reference drugs lopinavir, chloroquine, and remdesivir (IC50 ranges of 8.16-13.15 µM). These molecules were found to have stable conformations with the active binding pocket of the SARS-CoV-2 Mpro by molecular dynamic simulation and density functional theory. Our findings suggest cannabidiol and Δ9 -tetrahydrocannabinol are possible drugs against human coronavirus that might be used in combination or with other drug molecules to treat COVID-19 patients.
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Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , COVID-19/virologia , Canabinoides/farmacologia , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , Antivirais/farmacocinética , Canabidiol/química , Canabidiol/farmacocinética , Canabidiol/farmacologia , Canabinoides/química , Canabinoides/farmacocinética , Simulação por Computador , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/efeitos dos fármacos , Dronabinol/química , Dronabinol/farmacocinética , Dronabinol/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Técnicas In Vitro , Ligantes , Modelos Biológicos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , SARS-CoV-2/químicaRESUMO
Synergistic therapy is emerging as a promising strategy for improving the chemotherapeutic efficacy of anticancer drugs. Addition of adjuvants with standard anticancer drugs has shown successful reduction of adverse side effects. The synthetic drug 5-Fluorouracil (5-FU) shows several side effects upon prolonged chemotherapy, thereby restricting its long-term clinical application. Several studies have reported anticancer potential and anti-inflammatory activity of tangeretin (TAN) towards mammalian cells. Therefore, we investigate whether the combination of TAN with 5-FU increases their anticancer potential against colorectal cancer. In this study, we examined the synergistic activity of TAN and 5-FU on the viability of several human cancer and normal cells. Several possible mechanistic pathways were screened, and found that co-exposure of TAN and 5-FU accelerates oxidative-stress and increases endogenous-ROS generation, which sequentially triggers the DNA damage response and activates the apoptotic pathway, by down-regulating autophagy and DNA repair system in HCT-116 cells. TAN and 5-FU co-treatment also remarkably reduces the mitochondrial membrane potential, and sequentially decreases ATPase activity. Collectively, results indicate that combination of TAN and 5-FU significantly accelerates apoptosis via JNK mediated pathway. To our knowledge gained from literature, this study is the first to describe synergistic activity of TAN and 5-FU against colorectal cancer cells.
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Apoptose/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Flavonas/farmacologia , Fluoruracila/farmacologia , MAP Quinase Quinase 4/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sobrevivência Celular , Fragmentação do DNA , Regulação para Baixo , Sinergismo Farmacológico , Flavonas/administração & dosagem , Fluoruracila/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , MAP Quinase Quinase 4/genéticaRESUMO
Parasite death via ion channel activations is the hallmark of anthelmintic and antiparasitic drugs. Glutamate gated chloride channel (GluCl) is a prominent targets for drug selection and design in parasitology. We report several iodine-fluorine based lead activators of GluCl by computational studies and structure-activity relationship analysis. 5-Fluoro-4-iodo-1H-pyrrolo [2, 3-b] pyridine and 5-iodoindole were bioactive hits that displayed in vitro anthelmintic and insecticidal activities against Bursaphelenchus xylophilus, Meloidogyne incognita, and Tenebrio molitor. Two important findings stood out: (i) 5F4IPP induced parasite death, and interacted proficiently with Gln219 amino acid of pentameric GluCl in docking analysis, and (ii) 5-iodoindole appeared to act by forming giant vacuoles in nematodes, which led to a form of non-apoptotic death known as methuosis. The study suggests halogenated-indoles and 1H-pyrrolo [2, 3-b] pyridine derivatives be regarded potential biocides for plant-parasitic nematodes and insects, and warrants further research on the mode of actions, and field investigations.
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Antinematódeos/química , Halogenação , Indóis/química , Inseticidas/química , Avaliação Pré-Clínica de MedicamentosRESUMO
Rheum undulatum L. (R. undulatum) is a medicinal plant used for the treatment of inflammatory diseases in East Asian countries. Numerous stilbenes isolated from R. undulatum have been revealed to possess anticancer effects. The aim of the present study was to evaluate the effect of extracts and compounds isolated from R. undulatum on human gastric cancer cell viability and to elucidate their molecular mechanism of action on the apoptosis pathway. The results demonstrated that aloe-emodin and chrysophanol 1-O-ß-D-glucopyranoside, isolated from the methanolic extract of dried rhizomes of R. undulatum, exhibited anti-proliferative effects on the human gastric carcinoma cell line AGS, with IC50 values of 84.66±0.44 and 68.28±0.29 µM, respectively. The percentage of apoptotic cells increased significantly following treatment with each compound at a concentration of 100 µM, compared with that in the non-treated group in the image-based cytometry assay. Western blot analysis revealed that these compounds activated the caspase cascade and inhibited B-cell lymphoma-2, an anti-apoptotic protein.
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Decursinol angelate (DA) is a pyranocoumarin purified from the roots of Angelica gigas. Here, we synthesized DA and determined its anti-inflammatory potential on TPA-induced mice ear inflammation. First, we evaluated the non-toxic behaviour of DA on HaCaT cells. Additionally, we observed the free radical scavenging potential of DA at 60⯵M to be 50%. This finding was further supported by nitric oxide assay, malondialdehyde assay, H2DCFDA staining and western blotting analysis of antioxidant enzymes. DA also suppressed the activation and polarization of macrophage phagocytic activity on RAW 264.7â¯cells. We further evaluated the expression of ICAM-1, MCP-1, MIP-2 and MIP-1ß on in-vivo model system. Consequently, DA significantly reduced the production of NF-κB and COX-2 induced proinflammatory cytokine levels on TPA induced ear edema. Inhibition of MAPK and transcriptional factor NF-κB was also validated by western blotting analysis of p-ERK, p-p38, IKKα, IKKγ, IκBα, NF-κB-p65. Immunohistochemistry and immunofluorescence staining of NFκB-p65, TNF-α and IL-1ß were also performed to support the findings. Conclusively, these results suggest that topical administration of DA significantly inhibited the expression of pro-inflammatory cytokines by blocking the canonical NF-κB and MAPK pathway. Therefore, we suggest DA as a potent therapeutic compound against skin inflammation related diseases.
Assuntos
Benzopiranos/farmacologia , Butiratos/farmacologia , Citocinas/biossíntese , Mediadores da Inflamação/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologia , Animais , Antioxidantes/farmacologia , Linhagem Celular , Orelha , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Pele/efeitos dos fármacos , Pele/metabolismoRESUMO
Candida albicans is an opportunistic pathogen and responsible for candidiasis. C. albicans readily forms biofilms on various biotic and abiotic surfaces, and these biofilms can cause local and systemic infections. C. albicans biofilms are more resistant than its free yeast to antifungal agents and less affected by host immune responses. Transition of yeast cells to hyphal cells is required for biofilm formation and is believed to be a crucial virulence factor. In this study, six components of ginger were investigated for antibiofilm and antivirulence activities against a fluconazole-resistant C. albicans strain. It was found 6-gingerol, 8-gingerol, and 6-shogaol effectively inhibited biofilm formation. In particular, 6-shogaol at 10 µg/ml significantly reduced C. albicans biofilm formation but had no effect on planktonic cell growth. Also, 6-gingerol and 6-shogaol inhibited hyphal growth in embedded colonies and free-living planktonic cells, and prevented cell aggregation. Furthermore, 6-gingerol and 6-shogaol reduced C. albicans virulence in a nematode infection model without causing toxicity at the tested concentrations. Transcriptomic analysis using RNA-seq and qRT-PCR showed 6-gingerol and 6-shogaol induced several transporters (CDR1, CDR2, and RTA3), but repressed the expressions of several hypha/biofilm related genes (ECE1 and HWP1), which supported observed phenotypic changes. These results highlight the antibiofilm and antivirulence activities of the ginger components, 6-gingerol and 6-shogaol, against a drug resistant C. albicans strain.
Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Catecóis/farmacologia , Álcoois Graxos/farmacologia , Hifas/efeitos dos fármacos , Animais , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Biofilmes/crescimento & desenvolvimento , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/microbiologia , Candida albicans/crescimento & desenvolvimento , Candidíase/tratamento farmacológico , Candidíase/patologia , Catecóis/administração & dosagem , Catecóis/efeitos adversos , Catecóis/isolamento & purificação , Modelos Animais de Doenças , Álcoois Graxos/administração & dosagem , Álcoois Graxos/efeitos adversos , Álcoois Graxos/isolamento & purificação , Zingiber officinale/química , Hifas/crescimento & desenvolvimento , Análise de Sobrevida , Virulência/efeitos dos fármacosRESUMO
The seminal discovery of browning of white adipose tissue (WAT) holds great promise for the treatment of obesity and metabolic syndrome. DJ-1 is evolutionarily conserved across species, and mutations in DJ-1 have been identified in Parkinson's disease. Higher levels of DJ-1 are associated with obesity, but the underlying mechanism is less understood. Here, we report the previously unappreciated role of DJ-1 in white adipocyte biology in mature models of obesity. We used DJ-1 knockout (KO) mouse models and wild-type littermates maintained on a normal diet or high-fat diet as well as in vitro cell models to show the direct effects of DJ-1 depletion on adipocyte phenotype, thermogenic capacity, fat metabolism, and microenvironment profile. Global DJ-1 KO mice show increased sympathetic input to WAT and ß3-adrenergic receptor intracellular signaling, leading to a previously unrecognized compensatory mechanism through browning of WAT with associated characteristics, including high mitochondrial contents, reduced lipid accumulation, adequate vascularization and attenuated autophagy. DJ-1 KO mice had normal body weight, energy balance, and adiposity, which were associated with protective effects on healthy WAT expansion by hyperplasia. Our findings revealed that browning of inguinal WAT occurred in DJ-1 KO mice that do not show increased predisposition to obesity and suggest that such potential mechanism may overcome the adverse metabolic consequences of obesity independent of an effect on body weight. Here, we provide the first direct evidence that targeting DJ-1 in adipocyte metabolic health may offer a unique therapeutic strategy for the treatment of obesity.