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1.
J Environ Pathol Toxicol Oncol ; 39(2): 137-147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749123

RESUMO

Lung carcinogenesis is one of the main sources of cancer-related mortality globally and it is estimated that nearly 1 million people die from it every year. The 5-year survival rate of lung carcinogenesis is reported at just 15%. The aim of the current research was to investigate the immunomodulatory effect of eriocitrin against benzo(a)pyrene [B(a) P]-induced lung tumorigenesis in Swiss albino mice. The lung sarcoma was provoked through oral gavage of B(a)P (50 mg/kg body weight) two times/week for four weeks. CEA, lung weight, lipid peroxidation (LPO), body weight, immuno-globulin (IgG, IgA, and IgM), tumor incidence, serum marker enzymes (LDH, AHH, λ-GT, and 5'-NTs), hematological counts (leucocytes, lymphocytes, neutrophils, absolute numbers of lymphocytes and neutrophils), antioxidants (SOD and CAT), inflammatory modulators (IL-1ß, IL-6, and TNF-α), immune complexes (avidity index, phagocyte index, NBT reduction, and SIC) and histopathological changes were analyzed. Moreover, the status of apoptosis proteins (Bax, caspase-9, and caspase-3) and cell proliferative protein (cyclin D1 and cyclin A) expression was determined by Western blot and PCNA by immunohistochemical analysis. B(a)P-challenged cancer-bearing mice exhibited augmented levels of lipid peroxidation, tumor incidence, lung weight, CEA, serum marker enzymes, IgA, SIC, cell proliferative markers, and inflammatory cytokines with concurrent decrease in body weight, antioxidant levels, hematological counts, immunoglobulins, immune complexes, and apoptotic protein expression. The eriocitrin treatments caused significant reversion of all these marker to previous levels. Overall, the results propose the immunomodulatory prospective of eriocitrin against B(a) P-induced lung carcinogenesis on Swiss albino mice.


Assuntos
Flavanonas/farmacologia , Fatores Imunológicos/farmacologia , Neoplasias Pulmonares/prevenção & controle , Animais , Anticarcinógenos/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Benzo(a)pireno/toxicidade , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Imunoglobulinas/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Fagócitos/efeitos dos fármacos
2.
J Environ Pathol Toxicol Oncol ; 39(2): 191-199, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749127

RESUMO

We have proven that naringin, a phytonutrient, diminishes oxidative damage and inflammatory responses by modulating PPAR-γ expressions in ultraviolet-B radiation (UVB)-induced NIH-3T3 cells. However, the role of naringin against DNA damage, photoaging, and apoptosis in NIH-3T3 cells has yet to be studied, necessitating investigation. We show that Naringin pretreatment significantly reduces UVB-induced alkaline DNA damage and potentially modulates NER gene (XPC, TFIIH, XPE, ERCC1, and GAPDH) expression, thereby augmenting DNA repair. We determined experimentally that naringin pretreatment prevents UVB-induced nuclear fragmentation in NIH-3T3 cells, as well as altering UVB-induced apoptotic marker (Bax, BCl-2, Caspase-9, and Caspase-3) expression in them. In addition, naringin pretreatment inhibits UVB-stimulated matrix metalloproteinase (MMP-2, MMP-9 and MMP-13) expression in these 3T3 cells. Therefore, we report that naringin can effectively avert UVB-mediated DNA damage, photoaging, and apoptosis in NIH-3T3 cells.


Assuntos
Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Flavanonas/farmacologia , Raios Ultravioleta/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Apoptose/efeitos da radiação , Reparo do DNA/efeitos da radiação , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Camundongos , Células NIH 3T3 , Protetores contra Radiação/farmacologia , Envelhecimento da Pele/efeitos dos fármacos
3.
Life Sci ; 258: 118192, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32781062

RESUMO

The present study was conducted to identify possible health - promoting effects of wogonin (Wog) on testicular dysfunction in rats caused by cadmium. Pre-treatment of cadmium chloride (Cd: 5 mg/kg b.wt.) administered rats with wogonin (10 mg/kg b.wt) resulted in significant improvement in Cd-induced decrease in body and organ (testes and epididymides) weights. Wogonin treatment significantly improved Cd-induced reduction in sperm quality and quantity, steroidogenic gene (SFI, StAR, CYP11A1, 3ß-HSD, CYP17A1 and 17ß-HSD) and protein (SF1, StAR and CYP17A1) expressions and serum testosterone levels. Wogonin treatment provided significant protection to Cd-induced aggression in testicular oxidative (elevated levels of MDA) and anti-oxidative (diminished activities of SOD, CAT and GPx) status. Wog significantly up-regulated mRNA levels of Nrf2, NQO1 and HO-1 and down-regulation of Keap1 in cadmium treated testes. Wogonin administration significantly suppressed Cd-stimulated increase in inflammatory reactions (increase in NF-κB p65 DNA, p-IKKß, TNF-α levels and decrease in IL-10 levels). Wogonin prevented apoptotic damage by enhanced protein distribution of caspase-9, caspase-3, and Bax due to Cd exposure. Furthermore, Wogonin presented significant protection to histo-morphometric changes resulted after Cd administration. Taken together, the findings of this study provided clear evidence of the therapeutic potential of Cd-induced testicular toxicity at least partly due to its antioxidant, anti-inflammatory and anti-apoptotic properties.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cádmio/toxicidade , Flavanonas/farmacologia , Substâncias Protetoras/farmacologia , Transdução de Sinais , Testículo/patologia , Animais , Biomarcadores/metabolismo , Peso Corporal/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Epididimo/efeitos dos fármacos , Epididimo/patologia , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios/sangue , Inflamação/patologia , Masculino , Oxirredução , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Esteroides/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo
4.
Life Sci ; 259: 118183, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32781058

RESUMO

Cancer, being a multifactorial disease has diverse presentation in different subgroups which is mainly attributed to heterogenous presentation of tumor cells. This cancer cell heterogeneity is the major reason for variable response to standard chemotherapeutic regimes owing to which high relapse rate and multi-drug resistance has increasingly been reported over the past decade. Interestingly, the research on natural compounds in combination with standard therapies have reported with interesting and promising results from the pre-clinical trials and few of which have also been tested in other phases of clinical trials. This review focusses on baicalein, an emerging anti-cancerous natural compound, its chemistry and mechanism of action. In view of promising pre-clinical this review is mainly motivated by the results observed from baicalein treatment of different cancer cell population. With the advancing scientific evidence on the anti-malignant potential of baicalein with respect to its pharmacological activities encompassing from anti-inflammatory to anti-angiogenic/anti-metastatic effects, the focus is mainly directed to understanding the precise mechanism of action of baicalein. In the process of understanding the underlying signaling cascades, the role of mitogen activated protein kinase (MAPK), mammalian target of rapamycin (mTOR), AKT serine/threonine protein kinase B (AKT), poly(ADP-ribose) polymerase (PARP), matrix metalloproteinases-2 (MMP-2), matrix metalloproteinases-9 (MMP-9) and caspase-3/-8,-9 have been highlighted as the major players for baicalein anti-malignant potential. This is also supported by the interesting pre-clinical findings which cumulatively pave the way ahead for development of baicalein as an adjunct anti-cancer treatment with chemotherapeutic agents.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Apoptose/efeitos dos fármacos , Humanos , Metástase Neoplásica/prevenção & controle , Neoplasias/patologia
5.
J Pharmacol Sci ; 143(4): 300-306, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32534995

RESUMO

Drug and therapies currently used to treat human bone diseases have a lot of severe side effects. Liquiritigenin is a flavonoid extracted from Glycyrrhiza glabra roots which has been reported to have positive effects in vitro on osteoblasts activity and bone mineralization as well as inhibitory effect on osteoclasts differentiation and activity in vitro. The present study was aimed to evaluate the in vivo effects of liquiritigenin on bone structure and metabolism in physiological and pathological conditions using Danio rerio as experimental animal model. Treatments with liquiritigenin were performed on embryos to evaluate the osteogenesis during skeletal development. Other treatments were performed on adult fish affected by glucocorticoid-induced osteoporosis to assay the therapeutic potential of liquiritigenin in the reversion of bone-loss phenotype in scale model. Liquiritigenin treatment of zebrafish embryo significantly enhances the osteogenesis during development in a dose-dependent manner. In addition, liquiritigenin inhibits the formation of the osteoporotic phenotype in adult zebrafish model of glucocorticoid-induced osteoporosis preventing osteoclast activation in scales. Interestingly, liquiritigenin does not counteract the loss of osteoblastic activity in scales. The liquiritigenin exhibits in vivo anti-osteoporotic activity on adult fish scale model. It can be considered a good candidate to develop new drugs against osteoporosis.


Assuntos
Flavanonas/farmacologia , Flavanonas/uso terapêutico , Glucocorticoides/efeitos adversos , Osteoclastos/efeitos dos fármacos , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Animais , Modelos Animais de Doenças , Osteogênese/efeitos dos fármacos , Estimulação Química , Peixe-Zebra
6.
J Biol Regul Homeost Agents ; 34(2): 421-433, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32515177

RESUMO

Naringenin is a flavonoid compound with antioxidant effects. It is used to treat oxidative stress-related diseases, but its mechanism is unclear. In this experiment, we explored whether naringenin can increase the expression of superoxide dismutase 1(SOD1), reduce the oxidative stress of PC12 cells induced by homocysteine (Hcy), and decrease the apoptosis of PC12 cells induced by Hcy by inhibiting the expression of mir-224-3p. Different concentrations of Hcy (1, 3, 5, 8, and 10 mmol/L) was used to analyze effect of homocysteine on PC12 cells. A total of 5 mmol/L Hcy was used to induce the excitatory and neurotoxicity model of PC12 cells in vitro. The cells were divided into normal control, Hcy induction, Hcy + Naringenin (25 µM), Hcy + Naringenin (50 µM), Hcy + Naringenin (75 µM), Hcy + Naringenin (100 µM), and Hcy + Naringenin (150 µM) groups. The relative survival rate and activities of the PC12 cells were determined by the MTT method, and the apoptosis rate of the PC12 cells was determined by using flow cytometry. The Western blot method was used to determine the expressions of SOD1, Bax, Caspase-3, Caspase-8, and Bcl-2 in the PC12 cells induced by Hcy. The expressions of SOD1 mRNA and miR-224-3p in the Hcy-induced PC12 cells were determined by RT-PCR. Results found that Hcy increased the expression of miR-224-3p in a dose-dependent manner but decreased that of SOD1 mRNA and protein. Hcy also increased oxidative stress in the PC12 cells and the proapoptotic proteins Bax, Caspase-3, and Caspase-9. Furthermore, it decreased the expression of anti-apoptotic protein Bcl-2 and the activity and survival rate of the HT22 cells, but it increased the apoptosis of the PC12 cells. The treatment of Hcy-induced PC12 cells with different concentrations of naringenin for 24 h decreased the expression of miR-224-3p in a dose-dependent manner and increased the expressions of SOD1 mRNA and protein. The treatment also decreased the oxidative stress in the PC12 cells and the expressions of pro-apoptotic proteins Bax, Caspase-3, and Caspase-9; increased the expression of anti-apoptotic protein Bcl- 2; decreased the apoptosis of the PC12 cells; and increased the PC12 cells.The results suggest that Naringenin can decrease the apoptosis and oxidative stress of PC12 cells induced by Hcy and increase the activities and survival rates of PC12 cells. The mechanism may be related to naringenin decreasing the expression of miR-224-3p in PC12 cells induced by Hcy and increasing the expressions of SOD1 mRNA and protein.


Assuntos
Flavanonas/farmacologia , MicroRNAs/genética , Neuroproteção , Superóxido Dismutase-1/genética , Animais , Apoptose , Caspase 3 , Caspase 9 , Homocisteína , Estresse Oxidativo , Células PC12 , Ratos , Regulação para Cima , Proteína X Associada a bcl-2
7.
Food Chem ; 331: 127337, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32585547

RESUMO

Naringenin (NG) is a flavonoid with many bioactive properties, however, its bitterness limits its use in foods. It is known that complex formation with proteins can mask this undesirable sensory property. Therefore, a trained panel evaluated the effect of bovine lactoferrin (LF) on NG bitterness using time-intensity analysis. LF reduced the maximum bitterness intensity and overall bitterness perception for NG by 27% and 33%, respectively. Isothermal titration nanocalorimetry (ITC), molecular docking (DC), and molecular dynamics (MD) were used to characterize NG-LF binding. These techniques provided similar values of ΔG° for binding ( [Formula: see text]  = -33.42 kJ mol-1; [Formula: see text]  = -32.22 kJ mol-1; [Formula: see text]  = -31.84 kJ mol-1). ITC showed that the complex formation is primarily entropy driven and DC suggested that NG binds at a hydrophobic site in LF. Here are presented strategic tools for promoting NG incorporation in food and health products.


Assuntos
Flavanonas/metabolismo , Flavanonas/farmacologia , Lactoferrina/química , Lactoferrina/metabolismo , Paladar , Adulto , Animais , Calorimetria/métodos , Bovinos , Entropia , Feminino , Flavanonas/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Termodinâmica
8.
PLoS One ; 15(6): e0234484, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32511271

RESUMO

Inflammation plays a crucial role in the defense response of the innate immune system against pathogen infection. In this study, we selected 4 compounds for their potential or proven anti-inflammatory and/or anti-microbial properties to test on our in vitro model of bacteria-infected THP-1-derived macrophages. We first compared the capacity of sulforaphane (SFN), wogonin (WG), oltipraz (OTZ), and dimethyl fumarate (DMF) to induce the nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of the antioxidant, anti-inflammatory response pathways. Next, we performed a comparative evaluation of the antioxidant and anti-inflammatory efficacies of the 4 selected compounds. THP-1-derived macrophages and LPS-stimulated macrophages were treated with each compound and expression levels of genes coding for inflammatory cytokines IL-1ß, IL-6, and TNF-α were quantified by RT-qPCR. Moreover, expression levels of genes coding for M1 (IL-23, CCR7, IL-1ß, IL-6, and TNF-α) and M2 (PPARγ, MRC1, CCL22, and IL-10) markers were determined in classically-activated M1 macrophages treated with each compound. Finally, the effects of each compound on the intracellular bacterial survival of gram-negative E. coli and gram-positive S. aureus in THP-1-derived macrophages and PBMC-derived macrophages were examined. Our data confirmed the anti-inflammatory and antioxidant effects of SFN, WG, and DMF on LPS-stimulated THP-1-derived macrophages. In addition, SFN or WG treatment of classically-activated THP-1-derived macrophages reduced expression levels of M1 marker genes, while SFN or DMF treatment upregulated the M2 marker gene MRC1. This decrease in expression of M1 marker genes may be correlated with the decrease in intracellular S. aureus load in SFN- or DMF-treated macrophages. Interestingly, an increase in intracellular survival of E. coli in SFN-treated THP-1-derived macrophages that was not observed in PBMC-derived macrophages. Conversely, OTZ exhibited pro-oxidant and proinflammatory properties, and affected intracellular survival of E. coli in THP-1-derived macrophages. Altogether, we provide new potential therapeutic alternatives in treating inflammation and bacterial infection.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Infecções por Escherichia coli/tratamento farmacológico , Inflamação/tratamento farmacológico , Ativação de Macrófagos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/imunologia , Estresse Oxidativo/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Fumarato de Dimetilo/farmacologia , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/imunologia , Flavanonas/farmacologia , Humanos , Inflamação/imunologia , Isotiocianatos/farmacologia , Leucócitos Mononucleares , Ativação de Macrófagos/imunologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Estresse Oxidativo/imunologia , Pirazinas/farmacologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/efeitos dos fármacos , Células THP-1
9.
PLoS One ; 15(5): e0233138, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32421738

RESUMO

Naringenin is flavonoid mainly found in citrus fruits which has shown several biological properties. In this work, we evaluated the therapeutic potential of the flavonoid Naringenin. Five-month-old B6.MRL-Faslpr/J lupus-prone mice were administered daily orally with Naringenin for seven months. We showed that Naringenin treatment at 50 or 100 mg/kg inhibited the splenomegaly and decreased the levels of anti-nuclear and anti-dsDNA autoantibodies. Furthermore, a reduction in serum concentration of TNF-α, IFN-γ and IL-6 was observed in the mice provided with Naringenin. Interestingly, serum levels of IL-10 increased. Naringenin decreased the frequency and absolute numbers of splenic effector memory T cells. Additionally, in order to be able to evaluate whether Naringenin prevented kidney damage, twelve-week-old MRL/MpJ-Faslpr/J mice, an accelerated lupus model, were orally administered with Naringenin at 100 mg/kg for six weeks. Surprisingly, Naringenin treatment prevented kidney damage and reduced the development of fibrosis similar to cyclophosphamide group. Moreover, Naringenin treatment increased the percentage of regulatory T cells in this aggressive model of lupus. Together, these results suggest a potential ability of Naringenin to reduce the autoimmunity in lupus-prone mice by modulation of T-cell subsets and cytokines profile that mitigate the development of important lupus clinical manifestations.


Assuntos
Citocinas/imunologia , Flavanonas/farmacologia , Memória Imunológica/efeitos dos fármacos , Nefrite Lúpica/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Animais , Modelos Animais de Doenças , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Masculino , Camundongos , Linfócitos T Reguladores/patologia
10.
Am J Chin Med ; 48(3): 679-702, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32329644

RESUMO

Autophagy is a process of active programmed cell death, where a dying cell induces autophagosomes and subsequently regulated by degradative machinery. The aim of this study was to investigate the mechanism behind induction of autophagic cell death by Naringin flavonoid in AGS cancer cells. Growth inhibition of AGS cells showed downregulation of PI3K/Akt/mTOR signaling by Naringin treatment. Transmission electron microscopy observation showed swollen mitochondria and lysosome near peri-nuclear zone fused with autophagic vacuoles. Rapamycin pre-treatment with Naringin showed significant decrease in mTOR phosphorylation and increase in LC3B activation in AGS cells. Decrease in mTOR phosphorylation is associated with lysosomal function activation was observed by time-dependent treatment of Naringin. Induction of lysosomal membrane permeabilization (LMP) was observed by LAMP1 activation leading lysosomal cell death by releasing Cathepsin D from lysosomal lumen to cytosol. Naringin treated AGS cells showed up-regulating BH3 domain Bad, down-regulating Bcl-xL, and Bad phosphorylation and significant mitochondrial fluorescence intensity expression. Significant localization of mitochondria and LC3B activation was examined by person coefficient correlation. Activation of ERK1/2-p38 MAPKs and production of intracellular ROS has been observed over Naringin treatment. It has also been elucidated that pre-treatment with NAC inhibited mitochondria-LC3B colocalization, where ROS acted as upstream of ERK1/2-p38 MAPKs activation. Lysosomal cell death involvement has been evaluated by BAF A1 pre-treatment, inhibiting LAMP1, Cathepsin D, ROS, and blocking autophagolysosome in AGS cell death. Taken together, these findings show that, Naringin induced autophagy cell death involves LMP mediated lysosomal damage and BH3 protein Bad activation in AGS cancer cells.


Assuntos
Autofagia/efeitos dos fármacos , Flavanonas/farmacologia , Lisossomos/patologia , Neoplasias Gástricas/patologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Lisossomos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas
11.
PLoS One ; 15(4): e0231815, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348327

RESUMO

Reducing carbohydrates digestion by having a low glycaemic index (GI) foods has been linked to weight loss. Inhibiting related enzymes is an alternative way to decrease carbohydrate digestion. RCM-107 (Slimming Plus), an eight-herb formula that is modified from RCM-104, indicated significant weight-loss action in clinical trials. However, no published research has studied its mechanism of action on reducing carbohydrate absorption via suppressing the activities of porcine pancreatic alpha-amylase (PPA). In this paper, we used fluorescence PPA inhibition assay to investigate the inhibitory effects of RCM-107 and the individual herbs present in this herbal mixture on amylase activity. Subsequently, molecular docking predicted the key active compounds that may be responsible for the enzyme inhibition. According to our results, both the RCM-107 formula and several individual herbs displayed α-amylase inhibitory effects. Also, marginal synergistic effects of RCM-107 were detected. In addition, alisol B, (-)-epigallocatechin-3-gallate (EGCG) and plantagoside have been predicted as the key active compounds that may be responsible for the α-amylase inhibition effect of RCM-107 according to inter-residue contact analysis. Finally, Glu233, Gln63, His305, Asp300 and Tyr151 are predicted to be markers of important areas with which potential amylase inhibitors would interact. Therefore, our data has provided new knowledge on the mechanisms of action of the RCM-107 formula and its individual herbal ingredients for weight loss, in terms of decreasing carbohydrate digestion via the inhibition of pancreatic alpha-amylase.


Assuntos
Fármacos Antiobesidade/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Obesidade/tratamento farmacológico , alfa-Amilases Pancreáticas/antagonistas & inibidores , Perda de Peso/efeitos dos fármacos , Animais , Fármacos Antiobesidade/química , Metabolismo dos Carboidratos/efeitos dos fármacos , Catequina/análogos & derivados , Catequina/química , Catequina/farmacologia , Colestenonas/química , Colestenonas/farmacologia , Medicamentos de Ervas Chinesas/química , Ensaios Enzimáticos , Flavanonas/química , Flavanonas/farmacologia , Glucosídeos/química , Glucosídeos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Obesidade/metabolismo , alfa-Amilases Pancreáticas/química , alfa-Amilases Pancreáticas/metabolismo , Suínos
12.
BMC Complement Med Ther ; 20(1): 97, 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32293397

RESUMO

BACKGROUND: The hand, foot and mouth disease (HFMD) is a febrile and exanthematous childhood disease mainly caused by Enterovirus 71 (EV-A71). In severe HFMD, virulent EV-A71 strains can cause acute flaccid paralysis and cardiopulmonary edema leading to death. Currently, no FDA approved antiviral treatment or vaccine is available for EV-A71. Flavonoids such as silymarin and baicalein are known to possess in vitro antiviral properties against viruses. In this study, the cytotoxicity and antiviral activity of silymarin, baicalein and baicalin were investigated. METHODS: The cytotoxic effects of three flavonoids towards rhabdomyosarcoma (RD) cells were first examined using cell proliferation MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay. Compounds found to be non-cytotoxic in RD cells were evaluated for their in vitro antiviral properties against the EV-A71 subgenotype B4 strain 41 (5865/SIN/000009) using antiviral assays. Viral infectivity was determined by reduction of the formation of plaques in RD cells. For the measurement of RNA copy number, the real time quantitative reverse transcription PCR (qRT-PCR) was used. The most potent compound was further evaluated to determine the mode of action of inhibition by time course, virus attachment and entry assays in Vero cells. RESULTS: Silymarin was shown to exert direct extracellular virucidal effects against EV-A71 at 50% inhibitory concentration (IC50) of 15.2 ± 3.53 µg/mL with SI of 10.53. Similarly, baicalein exhibited direct extracellular virucidal effects against EV-A71 at a higher IC50 value of 30.88 ± 5.50 µg/mL with SI of 13.64. Besides virucidal activity, silymarin was shown to block both viral attachment and entry of EV-A71 to inhibit infection in Vero cells. CONCLUSIONS: Silymarin has a stronger inhibition activity against EV-A71 in comparison to baicalein. It could serve as a promising antiviral drug to treat EV-A71 infections.


Assuntos
Enterovirus Humano A/efeitos dos fármacos , Flavanonas/farmacologia , Flavonoides/farmacologia , Silimarina/farmacologia , Animais , Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Chlorocebus aethiops , Humanos , Células Vero
13.
Life Sci ; 249: 117535, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32151688

RESUMO

AIM: Schizophrenia is a chronic, disabling and one of the major neurological illnesses affecting nearly 1% of the global population. Currently available antipsychotic medications possess limited effects. The current research aimed at investigating potential therapeutic add-on benefit to enhance the effects of clozapine anti-schizophrenic. MAIN METHODS: To induce schizophrenia, ketamine was administered at a dose of 25 mg/kg i.p. for 14 consecutive days. Naringin was administered to Wistar rats at a dose of 100 mg/kg orally, alone or in combination with clozapine 5 mg/kg i.p from day 8 to day 14. Furthermore, behavioral tests were conducted to evaluate positive, negative and cognitive symptoms of schizophrenia. In addition, neurotransmitters' levels were detected using HPLC. Moreover, oxidative stress markers were assessed using spectrophotometry. Furthermore, apoptotic and wnt/ß-catenin pathway markers were determined using western blotting (Akt, GSK-3ß and ß-catenin), colorimetric methods (Caspase-3) and immunohistochemistry (Bax, Bcl2 and cytochrome c). KEY FINDINGS: Ketamine induced positive, negative and cognitive schizophrenia symptoms together with neurotransmitters' imbalance. In addition, ketamine treatment caused significant glutathione depletion, lipid peroxidation and reduction in catalase activity. Naringin and/or clozapine treatment significantly attenuated ketamine-induced schizophrenic symptoms and oxidative injury. Additionally, ketamine provoked apoptosis via increasing Bax/Bcl2 expression, caspase-3 activity, and Cytochrome C and Akt protein expression while naringin/clozapine treatment significantly inhibited this apoptotic effect. Moreover, naringin activated the neurodevelopmental wnt/ß-catenin signaling pathway evidenced by increasing pGSK-3ß and reducing pß-catenin protein expression. SIGNIFICANCE: These findings may suggest that naringin possesses a potential therapeutic add-on effect against ketamine-induced schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Flavanonas/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Ketamina/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esquizofrenia/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Clozapina/administração & dosagem , Clozapina/farmacologia , Clozapina/uso terapêutico , Modelos Animais de Doenças , Flavanonas/administração & dosagem , Flavanonas/uso terapêutico , Masculino , Ratos , Ratos Wistar , Esquizofrenia/induzido quimicamente
14.
Life Sci ; 248: 117471, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32112868

RESUMO

AIMS: This study aimed to explore the protective effects and possible mechanisms of baicalein on Aß25-35-induced toxicity. MAIN METHODS: Thioflavin-T (Th-T) dye was used to determine the effects of baicalein on Aß25-35 aggregation in vitro. PC12 cells were stimulated with Aß25-35, then the effects of baicalein on apoptosis, mitochondrial membrane potential (MMP), adenosine triphosphate (ATP), mitochondrial respiratory complex I, reactive oxygen species (ROS) and nitric oxide (NO) levels were determined. Moreover, LC-MS metabolomics approach was used to detect metabolic changes induced by baicalein in Aß25-35-injured PC12 cells. KEY FINDINGS: The results showed that baicalein could inhibit the aggregation of Aß25-35 in vitro. Furthermore, pretreatment with baicalein significantly prevented Aß25-35-induced cell apoptosis, as manifested by increasing the levels of MMP, ATP and mitochondrial respiratory complex I, decreasing the contents of ROS and NO. LC-MS metabolomics revealed that baicalein can regulate 5 metabolites, mainly involving two metabolic pathways, arginine and proline metabolism, nicotinate and nicotinamide metabolism. SIGNIFICANCE: Our study revealed that baicalein has a protective effect on Aß25-35-induced neurotoxicity in PC12 cells, which may be related to inhibition of apoptosis and metabolic disorders.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Flavanonas/farmacologia , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Trifosfato de Adenosina/biossíntese , Peptídeos beta-Amiloides/toxicidade , Animais , Arginina/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Niacina/metabolismo , Niacinamida/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Fragmentos de Peptídeos/toxicidade , Prolina/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
15.
Horm Cancer ; 11(2): 97-110, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32146686

RESUMO

While flavonoids have been studied extensively for estrogen receptor activity, they have not been well studied for their ability to modify progesterone receptor (PR) and glucocorticoid receptor (GR) signaling. Three flavonoid compounds, tangeretin, wogonin, and baicalein, were selected for testing for PR and GR activity based on their structural similarity to known phytoprogesterone-like compounds. Each compound was docked in the binding pocket of PR and GR. Of these compounds, baicalein was predicted to be most likely to bind to both receptors. A fluorescence polarization competitive binding assay for PR and GR confirmed that baicalein binds to both the PR and GR with IC50 values of 15.30 µM and 19.26 µM, respectively. In Ishikawa PR-B and T47D cells, baicalein acted as a PR antagonist in a hormone response element (HRE) luciferase (Luc) assay. In OVCAR5 cells, which only express GR, baicalein was a GR agonist via an HRE/Luc assay and induced GR target genes, FKBP5 and GILZ. RU486, a PR and GR antagonist, abrogated baicalein's activity in OVCAR5 cells, confirming baicalein's activity is mediated through the GR. In vivo, baicalein administered intraperitoneally to female mice twice a week for 4 weeks at a dose of 25 mg/kg induced the GR target gene GILZ in the reproductive tract, which was blocked by RU486. In summary, baicalein has PR antagonist and GR agonist activity in vitro and demonstrates GR agonist activity in the uterus in vivo.


Assuntos
Antioxidantes/farmacologia , Flavanonas/farmacologia , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/metabolismo , Animais , Feminino , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Distribuição Aleatória , Receptores de Glucocorticoides/agonistas , Receptores de Progesterona/antagonistas & inibidores , Transdução de Sinais , Transfecção
16.
Int J Nanomedicine ; 15: 1101-1115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110010

RESUMO

Background: The clinical use of doxorubicin (DOX) is severely limited due to its cardiotoxicity. Thus, there is a need for prophylactic and treatment strategies against DOX-induced cardiotoxicity. Purpose: The purpose of this study was to develop a liquiritigenin-loaded submicron emulsion (Lq-SE) with enhanced oral bioavailability and to explore its efficacy against DOX-induced cardiotoxicity. Methods: Lq-SE was prepared using high-pressure homogenization and characterized using several analytical techniques. The formulation was optimized by central composite design response surface methodology (CCD-RSM). In vivo pharmacokinetic studies, biochemical analyses, reactive oxygen species (ROS) assays, histopathologic assays, and Western blot analyses were performed. Results: Each Lq-SE droplet had a mean particle size of 221.7 ± 5.80 nm, a polydispersity index (PDI) of 0.106 ± 0.068 and a zeta potential of -28.23 ± 0.42 mV. The area under the curve (AUC) of Lq-SE was 595% higher than that of liquiritigenin (Lq). Lq-SE decreased the release of serum cardiac enzymes and ameliorated histopathological changes in the hearts of DOX-challenged mice. Lq-SE significantly reduced oxidative stress by adjusting the levels of ROS, increasing the activity of antioxidative enzymes and inhibiting the protein expression of NOX4 and NOX2. Furthermore, Lq-SE significantly improved the inflammatory response through the mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) signalling pathway and induced cardiomyocyte apoptosis. Conclusion: Lq-SE could be used as an effective cardioprotective agent against DOX in chemotherapy to enable better treatment outcomes.


Assuntos
Cardiotoxicidade/prevenção & controle , Doxorrubicina/efeitos adversos , Emulsões/química , Flavanonas/farmacologia , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Cardiotônicos/farmacologia , Cardiotoxicidade/metabolismo , Emulsões/administração & dosagem , Feminino , Flavanonas/administração & dosagem , Flavanonas/farmacocinética , Coração/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
17.
Phytomedicine ; 68: 153179, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32062328

RESUMO

BACKGROUND: Intestinal epithelial barrier dysfunction, which involves myosin light chain kinase (MLCK) activation, contributes to the occurrence and progression of inflammation in inflammatory bowel disease (IBD). Wogonoside helps maintain intestinal homeostasis in mice with dextran sulfate sodium (DSS)-induced colitis, but it is unclear whether it modulates intestinal barrier function. PURPOSE: Here, we demonstrate that wogonoside protects against intestinal barrier dysfunction in colitis via the MLCK/pMLC2 pathway both in vivo and in vitro. METHODS: Caco-2 cell monolayers treated with the proinflammatory cytokine TNF-α showed barrier dysfunction and were assessed in the absence and presence of wogonoside for various physiological, morphological, and biochemical parameters. Colitis was induced by 3% DSS in mice, which were used as an animal model to explore the pharmacodynamics of wogonoside. We detected MLCK/pMLC2 pathway proteins via western blot analysis, assessed the cytokines IL-13 and IFN-γ via ELISA, tested bacterial translocation via fluorescence in situ hybridization (FISH) and a proper sampling of secondary lymphoid organs for bacterial culture. In addition, the docking affinity of wogonoside and MLCK was observed with DS2.5 software. RESULTS: Wogonoside alleviated the disruption of transepithelial electrical resistance (TER) in TNF-α exposured Caco-2 cell; FITC-dextran hyperpermeability; loss of the tight junction (TJ) proteins occludin, ZO-1 and claudin-1 in Caco-2 cell monolayers; and bacterial translocation in colitic mice. Moreover, wogonoside reduced the levels of the proinflammatory cytokines IL-13 and IFN-γ to maintain intestinal immune homeostasis. Transmission electron microscopy (TEM) confirmed that wogonoside ameliorated the destruction of intestinal epithelial TJs. Wogonoside not only inhibited the cytoskeletal F-actin rearrangement induced by TNF-α, stabilized the cytoskeletal structure, suppressed MLCK protein expression, and reduced MLC2 phosphorylation. In addition, the results of molecular docking analysis showed that wogonoside had a high affinity for MLCK and formed hydrogen bonds with the amino acid residue LYS261 and π bonds with LYS229. CONCLUSION: Collectively, our study indicates that wogonoside alleviates colitis by protecting against intestinal barrier dysfunction, and the potential mechanism may involve regulation of TJs via the MLCK/pMLC2 signaling pathway. Meanwhile, our study also explains the success of S. baicalensis in the treatment of ulcerative colitis (UC).


Assuntos
Miosinas Cardíacas/metabolismo , Colite/tratamento farmacológico , Flavanonas/farmacologia , Glucosídeos/farmacologia , Cadeias Leves de Miosina/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Animais , Células CACO-2 , Colite/induzido quimicamente , Colite/metabolismo , Sulfato de Dextrana/toxicidade , Flavanonas/química , Glucosídeos/química , Humanos , Mucosa Intestinal/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Fosforilação , Proteínas de Junções Íntimas/metabolismo
18.
Phytother Res ; 34(8): 1734-1744, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32067280

RESUMO

The liver is a vital metabolic organ for drug and xenobiotic metabolism which is influenced by chemical and natural toxins. Liver injury is associated with systemic oxidative stress, which leads to cellular necrosis, fibrosis, tissue lipid peroxidation, and depletion in glutathione levels. Considering the lack of reliable hepato-protective drugs in modern medicine, plant-derived phytoconstituents seem to be a noteworthy option. Naringin is an abundant flavonoid found in citrus fruits with various pharmacological benefits such as antioxidant, anti-inflammatory, and antiapoptotic, activities. In this review, we summarize available data from recent studies about the hepatoprotective effects of naringin against chemical toxicants and discuss the possible mechanisms of actions.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Citrus/química , Flavanonas/uso terapêutico , Fígado/efeitos dos fármacos , Animais , Feminino , Flavanonas/farmacologia , Humanos , Masculino , Ratos
19.
J Photochem Photobiol B ; 204: 111775, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31935591

RESUMO

Wogonin (5,7-dihydroxy-8-methoxy flavone), an active component isolated from the root of Scutellaria baicalensis Georgi. Neurotoxic effects of γ irradiation have been established in humans and animals. The current study was designed to evaluate whether wogonin could restrain γ irradiation-induced neurotoxicity in rats and to explore the underlying mechanisms. Rats were divided into five groups, 10 rats each. Group 1 was orally administered distilled water and served as control. Group 2 received an oral daily dose of wogonin (30 mg/kg). Rats in group 3 were exposed to a whole-body single dose of γ-irradiation. Animals in group 4 received an oral daily dose of wogonin (30 mg/kg) for 15 days then exposed to a whole-body single dose of γ-irradiation. In group 5, rats were exposed to a whole-body single dose of γ-irradiation then were orally administered a daily dose of wogonin (30 mg/kg) for 15 days. There were significant increases in malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and Interleukin 6 (IL-6) levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) mRNA and protein expression. Whereas significant decreases in reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) level as well as nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) mRNA and protein expression in the irradiated group when compared with the relevant control. The cerebral cortex of irradiated rats showed vacuolization and nuclear pyknosis in the neuronal cells and focal gliosis. Wogonin administration pre- or post-irradiation significantly ameliorated all these previous effects. Wogonin had antioxidant and anti-inflammatory effects and ameliorated the histopathological changes in the brain.


Assuntos
Encéfalo/efeitos dos fármacos , Flavanonas/farmacologia , Raios gama , Fármacos Neuroprotetores/farmacologia , Administração Oral , Animais , Encéfalo/metabolismo , Encéfalo/efeitos da radiação , Medicamentos de Ervas Chinesas/farmacologia , Glutationa/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Malondialdeído/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
20.
PLoS One ; 15(1): e0227631, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31945778

RESUMO

Currently prescribed medications for the treatment of Alzheimer's disease (AD) that are based on acetylcholinesterase inhibition only offer symptomatic relief but do not provide protection against neurodegeneration. There appear to be an intense need for the development of therapeutic strategies that not only improve brain functions but also prevent neurodegeneration. The oxidative stress is one of the main causative factors of AD. Various antioxidants are being investigated to prevent neurodegeneration in AD. The objective of this study was to investigate the neuroprotective effects of naringenin (NAR) against AlCl3+D-gal induced AD-like symptoms in an animal model. Rats were orally pre-treated with NAR (50 mg/kg) for two weeks and then exposed to AlCl3+D-gal (150 mg/kg + 300 mg/kg) intraperitoneally for one week to develop AD-like symptoms. The standard drug, donepezil (DPZ) was used as a stimulator of cholinergic activity. Our results showed that NAR pre-treatment significantly protected AD-like behavioral disturbances in rats. In DPZ group, rats showed improved cognitive and cholinergic functions but the neuropsychiatric functions were not completely improved and showed marked histopathological alterations. However, NAR not only prevented AlCl3+D-gal induced AD-like symptoms but also significantly prevented neuropsychiatric dysfunctions in rats. Results of present study suggest that NAR may play a role in enhancing neuroprotective and cognition functions and it can potentially be considered as a neuroprotective compound for therapeutic management of AD in the future.


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Flavanonas/farmacologia , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Acetilcolinesterase/genética , Cloreto de Alumínio/toxicidade , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Função Executiva/efeitos dos fármacos , Galactose/toxicidade , Masculino , Síndromes Neurotóxicas/etiologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar
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