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1.
Pharmaceutics ; 13(10)2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34683980

RESUMO

The combination of natural products is an alternative approach to achieving chemopreventive potential. Accordingly, citrus hesperidin exhibits numerous biological activities, including anticarcinogenic activities, while the sesamin in sesame exhibits potent anticancer activities and lipid-lowering effects. We investigated the cancer chemopreventive effects of mixed sesame and orange seed extract (MSO) containing hesperidin and sesamin in diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Rats were injected with DEN once a week for 3 weeks to induce hepatocarcinogenesis. Rats were fed with MSO and various compositions that included sesame extract (SE) and hesperidin. The 10-week administration of MSO more effectively inhibited the number and size of hepatic GST-P-positive foci than hesperidin in DEN-initiated rats. MSO and hesperidin decreased the number of PCNA-positive hepatocytes but increased the apoptotic cells in DEN-induced rats. Furthermore, MSO and its constituents suppressed hepatic triglyceride content concurrently along with the expression of fatty acid synthase. Although the 5-week administration of MSO or hesperidin did not alter hepatic, preneoplastic lesion formation in DEN-initiated rats, it alleviated DEN-induced hepatotoxicity. MSO and its applied compositions did not impact upon the cytochrome P450 system. In conclusion, sesame extract promoted the chemopreventive effect of hesperidin on DEN-induced early stage of hepatocarcinogenesis in rats. The inhibitory mechanisms are likely involved with the induction of cell apoptosis, suppression of cell proliferation and modulation of hepatic lipogenesis. This study may provide revelations in the development of alternative treatments against hepatocellular carcinoma.

2.
Molecules ; 26(17)2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34500779

RESUMO

Up-regulated expression of programmed death-ligand 1 (PD-L1) by interferon-gamma (IFN-γ) has been associated with promotion of cancer cell survival and tumor cell escape from anti-tumor immunity. Therefore, a blockade of PD-L1 expression can potentially be used as a molecular target for cancer therapy. The aim of this study was to investigate whether suppression of IFN-γ induced PD-L1 expression in two oral cancer cell lines, HN6 and HN15, by hesperidin effectively decreased cell proliferation and migration. Further, our objective was to elucidate the involvement of the signal transducer and activator of transcription 1 (STAT1) and STAT3 in the inhibition of induced PD-L1 expression by hesperidin. Our findings indicate that IFN-γ induced expression of PD-L1 protein in HN6 and HN15 via phosphorylation of STAT1 and STAT3 and that hesperidin significantly reduced that induction through suppression of phosphorylated STAT1 and STAT3 in both cell lines. Moreover, hesperidin also significantly decreased the viability, proliferation, migration, and invasion of both cell lines. In conclusion, hesperidin exerted anticancer effects against oral cancer cells through the suppression of PD-L1 expression via inactivation of the STAT1 and STAT3 signaling molecules. The findings of this study support the use of hesperidin as a potential adjunctive treatment for oral cancer.

3.
Front Endocrinol (Lausanne) ; 12: 726182, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512554

RESUMO

Preclinical studies have found impaired osteogenic differentiation to be associated with type 2 diabetes (T2DM), which is related to skeletal accumulation of advanced glycation end products (AGEs). Our previous study also showed impaired osteogenic differentiation in peripheral blood-derived mononuclear cells (PBMC) isolated from patients with long-standing T2DM, which is conceivably due to the overexpression of receptor of advance glycation end products (RAGE) and the enhancement of cellular apoptosis. However, the existence of RAGE overexpression in earlier stages of diabetes remains unclear, as do the factors influencing that RAGE overexpression. This cross-sectional study enrolled 40 patients with T2DM treated with metformin monotherapy and 30 age-matched non-diabetic controls (NDM) to investigate the overexpression of RAGE in PBMC derived from patients with earlier stage diabetes, as well as to explore its determining factors. Almost all (90%) PBMC-isolated from NDM (NDM-pD) expressed osteoblast-specific genes including ALPL, BGLAP, COL1A1, and RUNX2/PPAR while only 40% of PBMC-derived from diabetic patients (DM-pD) expressed those genes. By using age- and pentosidine-matched NDM-pD as a reference, AGER and BAX/BCL2 expression in PBMC isolated from diabetic patients showing impaired osteoblast-specific gene expression (DM-iD) were 6.6 and 5 folds higher than the reference while AGER and BAX/BCL2 expression in DM-pD were comparable to the reference. AGER expression showed a significant positive correlation with age (r=0.470, p=0.003). The multivariate analysis demonstrated that both age and AGER expression correlated with the potential for osteogenic differentiation in the PBMC isolated from patients with diabetes. In conclusion, this study showed osteogenic differentiation impairment in approximately half of PBMC derived from type 2 diabetic patients receiving metformin monotherapy. Both AGER and BAX/BCL2 overexpression were demonstrated only in PBMC-isolated from diabetic patients with poor osteogenic differentiation. Therefore, this study not only illustrated the existence of RAGE overexpression in PBMC derived from patients with early stages of T2DM but also strengthened the linkage between that RAGE overexpression and the retardation of osteogenic differentiation. Age was also shown to be a positive influencing factor for RAGE overexpression. Furthermore, both age and RAGE overexpression were demonstrated as independent risk factors for determining osteogenic differentiation potential of the PBMC-isolated from T2DM.

4.
Int J Mol Sci ; 22(16)2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34445462

RESUMO

Liver cancer is the sixth most common cancer worldwide with high morbidity and mortality. Programmed death ligand 1 (PD-L1) is a major ligand of programmed death 1 receptor (PD1), and PD1/PD-L1 checkpoint acts as a negative regulator of the immune system. Cancers evade the host's immune defense via PD-L1 expression. This study aimed to investigate the effects of tumor-related cytokines, interferon gamma (IFNγ), and tumor necrosis factor alpha (TNFα) on PD-L1 expression in human hepatocellular carcinoma cells, HepG2. Furthermore, as atorvastatin, a cholesterol-lowering agent, is documented for its immunomodulatory properties, its effect on PD-L1 expression was investigated. In this study, through real-time RT-PCR, Western blot, and immunocytochemistry methods, PD-L1 expression in both mRNA and protein levels was found to be synergistically upregulated in HepG2 by a combination of IFNγ and TNFα, and STAT1 activation was mainly responsible for that synergistic effect. Next, atorvastatin can inhibit the induction of PD-L1 by either IFNγ alone or IFNγ/TNFα combination treatment in HepG2 cells. In conclusion, in HepG2 cells, expression of PD-L1 was augmented by cytokines in the tumor microenvironment, and the effect of atorvastatin on tumor immune response through inhibition of PD-L1 induction should be taken into consideration in cancer patients who have been prescribed atorvastatin.


Assuntos
Atorvastatina/farmacologia , Antígeno B7-H1/imunologia , Carcinoma Hepatocelular/imunologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/imunologia , Proteínas de Neoplasias/imunologia , Antígeno B7-H1/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteínas de Neoplasias/genética
5.
FASEB J ; 35(5): e21487, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33811705

RESUMO

Chondrosarcoma is a cartilage-forming bone tumor, well known for intrinsic resistance to chemotherapy and radiotherapy. We have designed a targeted chondrosarcoma gene therapy using a bacteriophage (phage) particle to deliver therapeutic genes. Phage has no tropism for mammalian cells, allowing engineered phage to be targeted to specific cell surface receptors in cancer. We modified the phage capsid to display the RGD4C ligand on the pIII minor coat proteins to specifically bind to αvß3 or αvß5 integrin receptors. The endosomal escape peptide, H5WYG, was also displayed on recombinant pVIII major coat proteins to enhance gene delivery. Finally, a human tumor necrosis factor alpha (TNFα) therapeutic transgene expression cassette was incorporated into the phage genome. First, we found that human chondrosarcoma cells (SW1353) have high expression of αvß3, αvß5 integrin receptors, and both TNFα receptors. Targeted particle encoding a luciferase reporter gene efficiently and selectively mediated gene delivery to these cells. When SW1353 cells were treated with the targeted particle encoding a TNFα transgene, significant cell killing was evident and was associated with high expression of TNFα and apoptosis-related genes. In vivo, mice with established human chondrosarcoma showed suppression of tumors upon repetitive intravenous administrations of the targeted phage. These data show that our phage-based particle is a promising, selective, and efficient tool for targeted chondrosarcoma therapy.


Assuntos
Bacteriófagos/genética , Neoplasias Ósseas/terapia , Condrossarcoma/terapia , Técnicas de Transferência de Genes , Terapia Genética , Terapia por Fagos/métodos , Fator de Necrose Tumoral alfa/genética , Adulto , Animais , Apoptose , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Proliferação de Células , Condrossarcoma/genética , Condrossarcoma/patologia , Vetores Genéticos/administração & dosagem , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Brain Res Bull ; 172: 190-202, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33894297

RESUMO

Neuroinflammation-mediated microglial reactivity is a major process, which explains the increased risk of Alzheimer's disease (AD) development in patients with Type 2 diabetes mellitus (T2DM). Advanced glycation end products (AGEs), formed by hyperglycemic condition in diabetes, is characterized as an intermediary of brain injury with diabetes through induction of microglial reactivity. Here, we explored the effect of AGEs on microglial reactivity using BV2 as a model. The NF-κB, p38 and JNK pathways were found to be important mechanism in AGEs-induced BV2 microglial reactivity. NF-κB inhibitor (BAY-11-7082), p38 inhibitor (SB203580) and JNK inhibitor (SP600125) exhibited the potential inhibition of AGEs-induced NO production. We also found that the sesamin, a major lignan found in sesame seed oils, exerts an anti-inflammatory effect under AGEs-induced microglial reactivity via suppressing the phosphorylation of NF-κB, p38 and JNK pathways. Moreover, sesamin also ameliorated AGEs-induced-receptor for advanced glycation end products (RAGE) expression. Taken together, sesamin may be a promising phytochemical compound to delay inflammatory progress by AGEs microglia function. Similarly, inhibition of AGEs-induced microglial reactivity might be potential therapeutic targets of neuroinflammation-based mechanisms in T2DM link progressive AD.

7.
Molecules ; 26(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670094

RESUMO

Unapproved ingredients included in herbal medicines and dietary supplements have been detected as adulterated synthetic drugs used for erectile dysfunction. Extraction from a dietary supplement was performed to isolate the compounds by HPLC analysis. The structural characterization was confirmed using mass spectrometry (ESI-TOF/MS and LC-MS/MS), 1H NMR, and 13C NMR spectroscopy techniques. Results identified the thus-obtained compound to be sulfoaildenafil, a thioketone analogue of sildenafil. The biological activities of this active compound have been focused for the first time by the experimental point of view performance in vitro. The results revealed that sulfoaildenafil can affect the therapeutic level of nitric oxide through the upregulation of nitric oxide synthase and phosphodiesterase type 5 (PDE5) gene expressions. This bulk material, which displays structural similarity to sildenafil, was analyzed for the presence of a PDE5 inhibitor using a theoretical calculation. These unique features of the potential activity of PDE5 protein and its inhibitors, sildenafil and sulfoaildenafil, may play a key consideration for understanding the mode of actions and predicting the biological activities of PDE5 inhibitors.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Suplementos Nutricionais , Disfunção Erétil/tratamento farmacológico , Inibidores da Fosfodiesterase 5/química , Cromatografia Líquida de Alta Pressão , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/efeitos dos fármacos , Disfunção Erétil/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Medicina Herbária , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Modelos Moleculares , Estrutura Molecular , Inibidores da Fosfodiesterase 5/uso terapêutico , Piperazinas/química , Piperazinas/uso terapêutico , Citrato de Sildenafila/química , Citrato de Sildenafila/uso terapêutico , Sulfonas/química , Sulfonas/uso terapêutico
8.
Sci Rep ; 11(1): 1895, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479339

RESUMO

Formation of advanced glycation end products (AGEs), which are associated with diabetes mellitus, contributes to prominent features of osteoarthritis, i.e., inflammation-mediated destruction of articular cartilage. Among the phytochemicals which play a role in anti-inflammatory effects, anthocyanins have also been demonstrated to have anti-diabetic properties. Purple corn is a source of three major anthocyanins: cyanidin-3-O-glucoside, pelargonidin-3-O-glucoside and peonidin-3-O-glucoside. Purple corn anthocyanins have been demonstrated to be involved in the reduction of diabetes-associated inflammation, suggesting that they may have a beneficial effect on diabetes-mediated inflammation of cartilage. This investigation of the chondroprotective effects of purple corn extract on cartilage degradation found a reduction in glycosaminoglycans released from AGEs induced cartilage explants, corresponding with diminishing of uronic acid loss of the cartilage matrix. Investigation of the molecular mechanisms in human articular chondrocytes showed the anti-inflammatory effect of purple corn anthocyanins and the metabolite, protocatechuic acid (PCA) on AGEs induced human articular chondrocytes via inactivation of the NFκb and MAPK signaling pathways. This finding suggests that purple corn anthocyanins and PCA may help ameliorate AGEs mediated inflammation and diabetes-mediated cartilage degradation.


Assuntos
Antocianinas/farmacologia , Complicações do Diabetes/tratamento farmacológico , Produtos Finais de Glicação Avançada/genética , Inflamação/tratamento farmacológico , Antocianinas/química , Cartilagem/efeitos dos fármacos , Cartilagem/patologia , Linhagem Celular , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Complicações do Diabetes/genética , Complicações do Diabetes/patologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Glucosídeos/química , Glucosídeos/farmacologia , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Glicosaminoglicanos/genética , Humanos , Hidroxibenzoatos/toxicidade , Inflamação/complicações , Inflamação/genética , Inflamação/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/genética , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Osteoartrite/genética , Osteoartrite/patologia , Zea mays/química
9.
J Mol Graph Model ; 101: 107717, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32861974

RESUMO

The widespread problem of a 2019-novel coronavirus (SARS-CoV-2) strain outbreak in Wuhan, China has prompted a search for new drugs to protect against and treat this disease. It is necessary to immediately investigate this due to the mutation of the viral genome and there being no current protective vaccines or therapeutic drugs. Molecular modelling and molecular docking based on in silico screening strategies were employed to determine the potential activities of seven HIV protease (HIV-PR) inhibitors, two flu drugs, and eight natural compounds. The computational approach was carried out to discover the structural modes with a high binding affinity for these drugs on the homology structure of the Wuhan coronavirus protease (SARS-CoV-2 PR). From the theoretical calculations, all the drugs and natural compounds demonstrated various favorable binding affinities. An interesting finding was that the natural compounds tested had a higher potential binding activity with the pocket sites of SARS-CoV-2 PR compared to the groups of HIV-PR inhibitors. The binding modes of each complex illustrated between the drugs and compounds interacted with the functional group of amino acids in the binding pocket via hydrophilic, hydrophobic, and hydrogen bond interactions using the molecular dynamics simulation technique. This result supports the idea that existing protease inhibitors and natural compounds could be used to treat the new coronavirus. This report sought to provide fundamental knowledge as preliminary experimental data to propose an existing nutraceutical material against viral infection. Collectively, it is suggested that molecular modelling and molecular docking are suitable tools to search and screen for new drugs and natural compounds that can be used as future treatments for viral diseases.


Assuntos
Antivirais/farmacologia , Cisteína Endopeptidases/química , Suplementos Nutricionais , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Antivirais/química , Sítios de Ligação , Proteases 3C de Coronavírus , Cisteína Endopeptidases/metabolismo , Dioxóis/química , Dioxóis/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Ligação de Hidrogênio , Lignanas/química , Lignanas/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Conformação Proteica , Proteínas não Estruturais Virais/metabolismo
10.
Int Immunopharmacol ; 86: 106759, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32663768

RESUMO

Programmed death ligand 1 (PD-L1) is overexpressed in some metastatic breast cancer subtypes, specifically triple-negative breast cancer (TNBC). This feature can assist in the eradication of anti-tumor immunity, thereby enhancing the survival of the tumor. This study aims to explore how sesamin affects PD-L1 expression in breast cancer cells and its related molecular mechanisms. We found high levels of expression of PD-L1 in both mRNA and protein levels in the TNBC cell line, MDA-MB231, but not in the luminal type-breast cancer cell line, MCF-7. We then demonstrated the tumor suppressive effect of sesamin, which induced the inhibition of cell proliferation in MDA-MB231 cells. Additionally, sesamin triggered PD-L1 downregulation (both mRNA and protein) through the inhibition of AKT, NF-κB and JAK/Stat signaling in MDA-MB231 cells. Moreover, the migration ability of MDA-MB231 cells was effectively diminished by sesamin via inhibition of the activation of MMP-9 and MMP-2. In summary, this study demonstrated that sesamin suppresses MDA-MB231 breast cancer cells' proliferation and migration; and decreases the expression of PD-L1 via the downregulation of AKT, NF-κB, and JAK/Stat signaling. Therefore, sesamin may be an effective alternative and novel therapeutic option for immunotherapy in breast cancer cells with high PD-L1 expression.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Dioxóis/farmacologia , Lignanas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Proliferação de Células , Feminino , Humanos , Janus Quinases/metabolismo , Células MCF-7 , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Regulação para Cima
11.
Artigo em Inglês | MEDLINE | ID: mdl-32308720

RESUMO

The promotion of neurogenesis can be a promising strategy to improve and restore neuronal function in neurodegenerative diseases. Nerve growth factor (NGF) plays a key role in neurite outgrowth and synaptic formation during brain repair stage. Nowadays, there are several studies on the developing methods to enhance the endogenous NGF activity for treatment and restore the neuronal function. In this study, the potentiating effect of sesamin, a major lignan in sesame seeds (Sesamum indicum) and oil, on NGF-induced neurogenesis and its involved mechanisms were firstly reported. Sesamin effectively enhanced the PC12 neuron-like cell differentiation and neurite length under insufficient conditions of NGF. The neuronal markers including synaptophysin and growth-associated protein-43 along with the synaptic connections were significantly increased in combination treatment between sesamin and NGF. Moreover, sesamin also increased the level of phospho-ERK1/2 and SIRT1 protein, an important regulatory protein of the neurogenesis process. The neurogenesis was blocked by the specific SIRT1 inhibitor, JGB1741, suggesting that the neuritogenic effect of sesamin was associated with SIRT1 protein modulation. Taken together, the potentiating effect of sesamin on NGF-induced neurogenesis in this finding could be used for alternative treatment in neurodegenerative diseases, including Alzheimer's disease.

12.
J Neuroimmunol ; 341: 577164, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32007785

RESUMO

SIRT1 exhibits inhibitory effects on microglial activation-induced neurodegeneration. Regulating SIRT1 may become a novel approach for curing neurodegenerative diseases. Protocatechuic acid (PA), a phenolic acid, has anti-neuroinflammatory effects. The effect of PA on SIRT1 in activated microglia remains unknown. Here, we examined whether PA has anti-inflammatory effects against microglial activation-induced neuronal cell death via regulating SIRT1 in microglia. We found that PA inhibited the release of inflammatory mediators in LPS-activated BV2 microglia via the SIRT1/NF-κB pathway and thereby attenuated microglial activation-induced PC12 cell apoptosis. This suggests that SIRT1 mediates the anti-neuroinflammatory effects of PA to ameliorate microglial activation-induced neuron death.


Assuntos
Anti-Inflamatórios/farmacologia , Hidroxibenzoatos/farmacologia , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Apoptose/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/metabolismo , Microglia/ultraestrutura , NF-kappa B/fisiologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia , Óxido Nítrico/metabolismo , Células PC12 , Ratos , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/fisiologia
13.
Molecules ; 25(2)2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31936263

RESUMO

Programmed death ligand 1 (PD-L1) is overexpressed in the most aggressive breast cancer subtype, triple-negative breast cancer (TNBC), assisting the eradication of antitumor immunity, and thereby enhancing the survival of the tumor. This study explored how hesperidin affects PD-L1 expression, and thereby cancer progression in breast cancer cells. We found that MDA-MB231, the triple-negative breast adenocarcinoma cancer cell line, (high aggressiveness) has higher expression, in both mRNA and protein, of PD-L1 than that of the other breast cancer cell line, MCF-7 (low aggressiveness). Hesperidin inhibited cell proliferation in MDA-MB231 cells. Additionally, high expression of PD-L1 (both mRNA and protein) in aggressive cancer cells was strongly inhibited by hesperidin through inhibition of Akt and NF-κB signaling. Moreover, hesperidin treatment, by inhibiting activation of matrix metalloproteinases such as MMP-9 and MMP-2, suppressed the metastatic phenotype and cell migration in the PD-L1 high-expressing MDA-MB231 cells. In summary, hesperidin inhibits breast cancer cell growth through the inhibition of the expression of PD-L1 via downregulation of Akt and NF-κB signaling in TNBC. Moreover, hesperidin significantly suppresses cell migration of MDA-MB231 cells. Our findings reveal fresh insights into the anticancer effects of hesperidin which might have potential clinical implications.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Hesperidina/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Hesperidina/química , Humanos , Metaloproteinases da Matriz/metabolismo , Modelos Biológicos , NF-kappa B/metabolismo , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo
14.
Neurotox Res ; 37(1): 111-125, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31485933

RESUMO

Neuroinflammation is a major factor in the pathogenesis of various neurodegenerative diseases. Microglia are resident macrophages that act as key mediators of inflammation in the brain. In response to inflammatory stimuli including lipopolysaccharide (LPS), microglial activation occurs immediately. Overproduction of inflammatory mediators released by activated microglia contributes to neuron damage in neurodegenerative disease. Therefore, identification of a compound that has anti-inflammatory activities and inhibits microglial activation may be an alternative therapeutic approach for the treatment of neurodegenerative diseases. Cyanidin-3-O-glucoside (C3G), a type of anthocyanin, possesses powerful anti-inflammatory activities. In this study, the anti-inflammatory effects of C3G were investigated in LPS-stimulated BV2 microglia. The results indicate that pretreatment with C3G significantly suppresses microglial activation and the production of neurotoxic mediators including nitric oxide (NO), prostaglandin E2 (PGE2), and pro-inflammatory cytokines such as interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in LPS-activated BV2 cells. Moreover, C3G downregulates the gene expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines via the suppression of NF-κB and p38 MAPK signaling pathways. Furthermore, a co-culture system to determine the indirect neuroprotective effects of C3G was used. Results demonstrated that conditioned medium (CM) from LPS-stimulated BV2 cells can promote the apoptosis of differentiated pheochromocytoma (PC12) cells through the activation of caspase-3, while C3G pretreatment in BV2 microglia can protect differentiated PC12 cells from microglial activation-induced apoptosis. Therefore, C3G may be a potential therapeutic agent for the treatment and prevention of neurodegenerative diseases associated with microglial activation.


Assuntos
Antocianinas/farmacologia , Apoptose/efeitos dos fármacos , Glucosídeos/farmacologia , Microglia/efeitos dos fármacos , Animais , Caspase 3/metabolismo , Técnicas de Cocultura , Meios de Cultivo Condicionados/farmacologia , Ciclo-Oxigenase 2/biossíntese , Dinoprostona/metabolismo , Regulação para Baixo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Camundongos , Microglia/metabolismo , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Células PC12 , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Matrix Biol ; 87: 77-93, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31669737

RESUMO

Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan in the extracellular matrix, and is expressed at high levels in tissues during development and remodeling in pathological conditions. Its core protein is cleaved at a region close to the N-terminal end of CSß domain by several members of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, i.e., ADAMTS-1, 4, 5, 9, 15, and 20. Here, using a CRISPR/Cas9 system, we generated knock-in mice (V1R), which express an ADAMTS cleavage-resistant versican. Some V1R homozygote mice, termed R/R, exhibit syndactyly and organ hemorrhage. In wound healing experiments, R/R wound shows accumulation of versican and activated TGFß-signaling in the early stage, leading to faster healing than wild type wound. Immunostaining for Ki67, CD31, smooth muscle α-actin, periostin demonstrates higher levels of overall cell proliferation and an increased number of endothelial cells and myofibroblasts. Immunostaining for CD11b and qRT-PCR for macrophage markers revealed increased levels of inflammatory cell infiltration, especially those of M1 macrophages. Cultured R/R dermal fibroblasts revealed increased deposition of versican, type I and III collagens, and hyaluronan, and upregulation of Smad2/3 signaling. Taken together, these results demonstrate that the cleavage site determines versican turnover and that versican plays a central role in the provisional matrix during the wound repair.


Assuntos
Proteínas ADAMTS/metabolismo , Hemorragia/genética , Sindactilia/genética , Versicanas/química , Versicanas/genética , Cicatrização , Animais , Sistemas CRISPR-Cas , Proliferação de Células , Células Cultivadas , Matriz Extracelular/metabolismo , Técnicas de Introdução de Genes , Masculino , Camundongos , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Versicanas/metabolismo
16.
Biomed Pharmacother ; 112: 108610, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30797145

RESUMO

Osteoarthritis (OA) is a common degenerative joint disease, which is closely related to cartilage degradation. Anthocyanins, a natural flavonoid pigments, exhibit strong antioxidant and anti-inflammatory properties. However, the effect of anthocyanin on inflammatory response in OA has not been investigated. Our results showed that cyanidin-3-O-glucoside (C3G) and peonidin-3-O-glucoside (P3G), the main anthocyanins found in three Thai purple rice cultivars, attenuated the inhibition of porcine cartilage degradation in an experimental model. The effects of three Thai purple rice extracts were related to their high concentration of anthocyanins. Moreover, protocatechuic acid (PA), the main metabolite of anthocyanin, has chondroprotective potential by reducing glycosaminoglycans and collagen breakdown in IL-1ß/OSM-induced porcine cartilage explants in long-term condition. The induction of matrix metalloproteinases (MMPs) caused by IL-1ß-stimulated human chondrocytes was also attenuated by C3G, P3G, and their metabolites. Furthermore, C3G, P3G, and their metabolites pretreatment significantly inhibited IκBα degradation, the level of p-p65, and ERK/MAPK pathway. Additionally, PA pretreatment enhanced the phosphorylation of JNK in IL-1ß-stimulated human chondrocytes. These findings indicated that anthocyanin in Thai purple rice exhibited anti-inflammatory effects in IL-1ß-stimulated human chondrocytes by inhibiting NF-κB and ERK/MAPK signaling pathway.


Assuntos
Antocianinas/farmacologia , Condrócitos/metabolismo , Interleucina-1beta/toxicidade , Sistema de Sinalização das MAP Quinases/fisiologia , Metaloproteinases da Matriz/biossíntese , NF-kappa B/metabolismo , Oryza , Animais , Antocianinas/isolamento & purificação , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Células Cultivadas , Condrócitos/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica , Humanos , Interleucina-1beta/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinases da Matriz/genética , Suínos
17.
Eur J Orthod ; 40(5): 496-503, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-29253140

RESUMO

Background/objectives: Maxillary tooth distal movement is a treatment option for Class II malocclusion. This prospective clinical study (split-mouth design) was aimed to compare chondroitin sulphate (CS) levels in gingival crevicular fluid (GCF), the rates of tooth movement, and patient pain and discomfort during segmental maxillary posterior tooth distal movement using either 120 or 180 g of retraction force. Materials and methods: Twenty patients (6 males and 14 females; aged 18.85 ± 4.38 years) with Class II malocclusion were recruited. The force magnitudes were controlled at 120 or 180 g, randomly assigned to either the right or left five-tooth segments. Gingival crevicular fluid samples were collected with Periopaper® strips. Competitive ELISA with monoclonal antibody was used to measure CS levels in GCF. The rates of segmental maxillary posterior tooth distal movement, and the amount of pain and discomfort were evaluated. Results: The median CS levels during the segmental distal movement period were significantly greater than those before the segmental distal movement period (P < 0.05). At each 1-week period during segmental distal movement, the differences between the median CS levels induced by the two different force magnitudes were not significantly different. The rates of segmental distal movement induced by the two different force magnitudes were not significantly different. The mean visual analog scale scores for pain and discomfort with 180 g of retraction force was significantly greater than that with 120 g (P < 0.05). Conclusions: One hundred and twenty grams of retraction force was sufficient to cause segmental distal movement, as indicated by biochemically assessed bone remodeling activity and a similar rate of tooth movement to that caused by 180 g of retraction force; it also produced less patient pain and discomfort. Trial Registration: The study has been registered as TCTR20170728001.


Assuntos
Má Oclusão Classe II de Angle/terapia , Técnicas de Movimentação Dentária/métodos , Adolescente , Adulto , Remodelação Óssea/fisiologia , Sulfatos de Condroitina/metabolismo , Dente Canino , Feminino , Líquido do Sulco Gengival/metabolismo , Humanos , Masculino , Má Oclusão Classe II de Angle/patologia , Má Oclusão Classe II de Angle/fisiopatologia , Maxila/patologia , Fenômenos Mecânicos , Dor/etiologia , Medição da Dor/métodos , Estudos Prospectivos , Técnicas de Movimentação Dentária/efeitos adversos , Adulto Jovem
18.
Cell Biochem Biophys ; 76(1-2): 279-292, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28831668

RESUMO

Osteoarthritis is a degenerative joint disease in which interleukin-1ß plays a major role in the inflammatory process. Administration of collagen hydrolysate was an optional treatment of osteoarthritis. Fish has become an interesting source of collagen hydrolysate because of religious reason and there is no risk from mad cow disease. However, the effects of different sizes of fish collagen hydrolysate on cartilage and chondrocyte metabolism have not been well studied yet. This study examined the effect of different sizes of fish collagen hydrolysate on cartilage metabolism. Three different sizes of fish collagen hydrolysate were prepared by size exclusion using centrifugation, which composed of small fraction (<3 kDa), medium fraction (3-10 kDa) and large fraction (>10 kDa). Using porcine cartilage explant, in physiological condition, all the three fractions had no effect on cartilage metabolism, but they could induce pro-MMP3 and pro-MMP13 secretions through activation of p-ERK and p-p38. In pathological condition induced by interleukin-1ß and oncostatin-M, small and medium fractions showed additive effect with interleukin-1ß and oncostatin-M on cartilage degradation, whereas large size had no effect. In addition, the effect of small size occurred through further activation of p-p65, which resulted in further induction of active-MMP13, while medium size had a different mechanism. In conclusion, all three fractions fish collagen hydrolysate had no effect on cartilage metabolism in physiological condition, but small and medium fractions had adverse effect on cartilage in pathological condition. Taken together, various sizes of fish collagen hydrolysate showed different effects on cartilage metabolism. Therefore, different sizes of fish collagen hydrolysates play different roles on cartilage metabolism, especially in the pathological condition.


Assuntos
Cartilagem Articular/efeitos dos fármacos , Colágeno/farmacologia , Proteínas de Peixes/farmacologia , Peixes/metabolismo , Animais , Cartilagem Articular/metabolismo , Células Cultivadas , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Colágeno/química , Colágeno/isolamento & purificação , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas de Peixes/química , Proteínas de Peixes/isolamento & purificação , Humanos , Técnicas In Vitro , Interleucina-1beta/metabolismo , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Oncostatina M/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais/efeitos dos fármacos , Suínos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Connect Tissue Res ; 59(4): 316-331, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-28956662

RESUMO

Osteoarthritis (OA) is the most common form of arthritis. Obesity has been believed to be an important risk factor for OA development and the progression of not only load-bearing joints, but low-load-bearing joints as well. Increased leptin has been the focus of a link between obesity and OA. In this study, the effects of pathological (100ng/ml) or supra-pathological (10µg/ml) concentrations of leptin alone or in combination with IL1ß on cartilage metabolisms were studied in porcine cartilage explant. The involved mechanisms were examined in human articular chondrocytes (HACs). Moreover, the protective effect of omega-3 polyunsaturated acids, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) was also investigated. Leptin (10µg/ml) alone or in combination with IL1ß could induce cartilage destruction, although lower concentrations had no effect. Leptin activated NFκB, ERK, JNK and p38 in HACs, which led to the induction of MMP3, MMP13 and ADAMTS4 secretions. The combined effect could further induce those enzymes through the additive effect on activation of NFκB and JNK. Interestingly, both EPA and DHA could inhibit cartilage damage induced by leptin plus IL1ß by reducing the activation of NFκB and JNK, which led to the decrease of ADAMTS4 secretion. Altogether, only a supra-pathological concentration of leptin alone or in combination with IL1ß could induce cartilage destruction, whereas a pathological one could not. This effect could be inhibited by EPA and DHA. To gain greater understanding of the link between leptin and OA, the effect of different levels of leptin on several states of OA cartilage requires further investigation.


Assuntos
Cartilagem Articular/patologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Interleucina-1beta/efeitos adversos , Leptina/efeitos adversos , Proteína ADAMTS4/metabolismo , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Ativação Enzimática/efeitos dos fármacos , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Suínos
20.
BMC Complement Altern Med ; 17(1): 532, 2017 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-29237438

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic synovitis, cartilage degradation and bone deformities. Synovitis is the term for inflammation of the synovial membrane, an early stage of RA. The pathogenesis of the disease occurs through cytokine induction. The major cytokine that increases the severity of RA is TNF-α. Thus, inhibition of the TNF-α cascade is an effective way to diminish the progression of the disease. We are interested in investigating the difference between primary human synovial fibroblast (hSF) cells and SW982 as synovitis models induced by TNF-α and in monitoring their responses to sesamin as an anti-inflammatory phytochemical. METHOD: The designed experiments were performed in hSF cells or the SW982 cell line treated with 10 ng/ml TNF-α with or without 0.25, 0.5 or 1 µM sesamin. Subsequently, pro-inflammatory cytokine genes and proteins were measured in parallel with a study of associated signalling transduction involved in inflammatory processes, including NF-κB and MAPK pathways. RESULTS: The results demonstrated that although hSF and SW982 cells responded to TNF-α induction in the same fashion, they reacted at different levels. TNF-α could induce IL-6, IL-8 and IL-1ß in both cell types, but the levels in SW982 cells were much higher than in hSF cells. This characteristic was due to the different induction of MAPKs in each cell type. Both cell types reacted to sesamin in almost the same fashion. However, hSF cells were more sensitive to sesamin than SW982 cells in terms of the anti-RA effect. CONCLUSIONS: The responses of TNF-α-induced hSF and SW982 were different at the signal transduction level. However, the two cell types showed almost the same reaction to sesamin treatment in terms of the end point of the response.


Assuntos
Dioxóis/farmacologia , Fibroblastos/efeitos dos fármacos , Lignanas/farmacologia , Membrana Sinovial/citologia , Sinovite/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Artrite Reumatoide , Linhagem Celular , Citocinas/metabolismo , Humanos , Modelos Biológicos , Transdução de Sinais/efeitos dos fármacos
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