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1.
Int J Mol Sci ; 21(5)2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32120831

RESUMO

Methamphetamine (METH) is an addictive psychostimulant showing neurotoxicity through neuronal apoptosis and the neuro-inflammatory pathway. Lupenone, a lupane triterpenoid, is an isolated compound exhibiting anti-oxidative, anti-inflammation, and anti-diabetic activities. However, whether lupenone plays a protective role against apoptosis induced by METH in SH-SY5y neuroblastoma cells remains unknown. In the present study, we elucidated that lupenone had no toxicity to SH-SY5y cells at different concentrations. On the other hand, we found that the treatment of SH-SY5y cells with an optimal concentration of lupenone could lead to protection against cell death induced by METH. AnnexinV/PI apoptosis analysis revealed a dramatically reduced level of the apoptotic cell population in lupenon and METH treated SH-SY5y cells. Moreover, diminished expression of anti-apoptotic proteins, including Bcl-2, Caspase3, Caspase7, and Caspase8 in METH-exposed SH-SY5y cells, was significantly recovered by treatment with lupenone. This protection in the expression of anti-apoptotic proteins was due to an increased phosphorylation level of PI3K/Akt in METH-treated SH-SY5y cells pre-incubated with lupenone. These findings suggest that lupenone can protect SH-SY5y cells against METH-induced neuronal apoptosis through the PI3K/Akt pathway.

2.
Molecules ; 25(3)2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033079

RESUMO

Recently, many natural products with unique structure and promising pharmacological potential have been reported from marine-derived microorganisms. The macrolactin A (MA), 15-epi-dihydromacrolactin F (DMF) and macrolactin F (MF) were obtained from the culture broth extract of a marine sediment derived microorganism Bacillus sp. HC001. In this study, MA, DMF and MF inhibited the production and expression of proinflammatory mediators of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated RAW264.7 and BV2 cells. Also, MA, DMF and MF exert anti-inflammatory effects through the expression of heme oxygenase (HO) -1, a stress-inducing enzyme that converts heme to carbon monoxide (CO), iron and biliberdine. Toll-like receptor 4 (TLR4) expressed by lipopolysaccharide (LPS) was inhibited by increased expression of HO-1 transcription factor Nrf2 and down regulation of BTB Domain And CNC Homolog 1 (BACH1), inhibited phosphorylation of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7, TAK1) and nuclear factor kappaB (NF-κB). These results show that MA, DMF and MF effectively inhibited TLR4 by regulating BACH1 and HO-1/Nrf2 signals in LPS-stimulated RAW264.7 and BV2 cells, which suggests the possibility of use as an anti-inflammatory agent.

3.
J Ethnopharmacol ; 250: 112484, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-31843576

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: A promising approach to treat a variety of diseases are considered as complementary and alternative herbal medicines. Prunus serrulata var. spontanea L. (Rosaceae) is used as herbal medicine to treat allergic diseases according to the Donguibogam, a tradition medical book of the Joseon Dynasty in Korea. AIM OF THE STUDY: We prepared the aqueous extract of the bark of P. serrulata (AEBPS) and aimed to investigate the effects in mouse anaphylaxis models and various types of mast cells, including RBL-2H3, primary cultured peritoneal and bone marrow-derived mast cells. MATERIALS AND METHODS: We used ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) and immunoglobulin (Ig) E-mediated passive cutaneous anaphylaxis (PCA) models, in vivo. The control drug dexamethasone (10 mg/kg) was used to compare the effectiveness of AEBPS (1-100 mg/kg). In vitro, IgE-stimulated mast cells were used to confirm the role of AEBPS (1-100 µg/mL). For statistical analyses, p values less than 0.05 were considered to be significant. RESULTS: In ASA model, oral administration of AEBPS suppressed the hypothermia and increased level of serum histamine in a dose-dependent manner. AEBPS attenuated the serum IgE, OVA-specific IgE, and interleukin (IL)-4. Oral administration of AEBPS also blocked mast cell-dependent PCA. AEBPS suppressed degranulation of mast cells by reducing intracellular calcium level in mast cells. AEBPS inhibited tumor necrosis factor-α and IL-4 expression and secretion in a concentration-dependent manner through the reduction of nuclear factor-κB. CONCLUSIONS: On the basis of these findings, AEBPS could serve as a potential therapeutic target for the management of mast cell-mediated allergic inflammation and as a regulator of mast cell activation.

4.
Phytother Res ; 33(11): 2948-2959, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31478281

RESUMO

The balance between the osteoblasts and the osteoclasts is important for the maintenance of the skeleton of the human body. The osteoclasts absorb bone after differentiated into polymorphonuclear cells by the fusion of monocytes/macrophages. We have found that 6,7,4'-Trihydroxyflavone (THF), a compound from the heartwood of Dalbergia Odorifera inhibits receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation, actin ring formation, and bone resorption in RAW 264.7 cells and bone marrow macrophage. THF significantly inhibited the c-Jun-N-terminal kinase signaling pathway without affecting extracellular signal-regulated kinase, p38, and AKT signaling. Moreover, THF inhibited the expression of c-Fos, nuclear factor-activated T cells cytoplasm 1, cathepsin K, and c-src by RANKL. We used a lipopolysaccharide (LPS)-induced bone loss model in mice. Consequently, bone volume per tissue volume, trabecular number's reduction was recovered in THF-treated mice, and trabecular separation's augmentation was also attenuated by THF administration. In summary, THF inhibits RANKL-induced osteoclast differentiation by MAPK signaling pathway and inhibits bone resorption by destroying the actin ring in mature osteoclasts. THF also prevented LPS-induced bone loss in a mice model. Thus, THF may be useful in the treatment of bone diseases associated with excessive osteoclast differentiation and bone resorption.


Assuntos
Reabsorção Óssea/prevenção & controle , Diferenciação Celular/efeitos dos fármacos , Isoflavonas/farmacologia , Osteoclastos/efeitos dos fármacos , Animais , Células Cultivadas , Dalbergia/química , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Osteoclastos/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
5.
Int J Environ Health Res ; : 1-14, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31407590

RESUMO

Particulate matter 2.5 (PM2.5), aerodynamic diameter ≤ 2.5 µm, is the primary air pollutant that plays the key role for lung injury resulted from the loss of vascular barrier integrity. Cudratricusxanthone O (CTXO) is a novel xanthone compound isolated from the root of Cudrania tricuspidata Bureau. Here, we investigated the beneficial effects of CTXO against PM-induced lung endothelial cell (EC) barrier disruption and pulmonary inflammation. Permeability, leukocyte migration, activation of proinflammatory proteins, generation of reactive oxygen species (ROS), and histology were examined in PM2.5-treated ECs and mice. CTXO significantly scavenged PM2.5-induced ROS and inhibited the ROS-induced activation of p38 mitogen-activated protein kinase (MAPK). Concurrently, CTXO activated Akt, which helped maintain endothelial integrity. Furthermore, CTXO reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in the bronchoalveolar lavage fluid in PM-induced lung tissues. These results indicated that CTXO may exhibit protective effects against PM-induced inflammatory lung injury and vascular hyperpermeability.

6.
Front Pharmacol ; 10: 869, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31427975

RESUMO

Mast cells are effector cells that induce allergic inflammation by secreting inflammatory mediators. Gomisin M2 (G.M2) is a lignan isolated from Schisandra chinensis (Turcz). Baill. exhibiting anti-cancer activities. We aimed to investigate the anti-allergic effects and the underlying mechanism of G.M2 in mast cell-mediated allergic inflammation. For the in vitro study, we used mouse bone marrow-derived mast cells, RBL-2H3, and rat peritoneal mast cells. G.M2 inhibited mast cell degranulation upon immunoglobulin E (IgE) stimulation by suppressing the intracellular calcium. In addition, G.M2 inhibited the secretion of pro-inflammatory cytokines. These inhibitory effects were dependent on the suppression of FcεRI-mediated activation of signaling molecules. To confirm the anti-allergic effects of G.M2 in vivo, IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA) models were utilized. Oral administration of G.M2 suppressed the PCA reactions in a dose-dependent manner. In addition, G.M2 reduced the ASA reactions, including hypothermia, histamine, interleukin-4, and IgE production. In conclusion, G.M2 exhibits anti-allergic effects through suppression of the Lyn and Fyn pathways in mast cells. According to these findings, we suggest that G.M2 has potential as a therapeutic agent for the treatment of allergic inflammatory diseases via suppression of mast cell activation.

7.
Food Chem Toxicol ; 132: 110651, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31254592

RESUMO

Aloin is the major anthraquinone glycoside obtained from the Aloe species and exhibits anti-inflammatory and anti-oxidative activities. However, the renal protective effects of aloin and underlying molecular mechanism remain unclear. This study was initiated to determine whether aloin could modulate renal functional damage in a mouse model of sepsis and to elucidate the underlying mechanisms. The potential of aloin treatment to reduce renal damage induced by cecal ligation and puncture (CLP) surgery in mice was measured by assessment of serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, total glutathione, glutathione peroxidase activity, catalase activity, and superoxide dismutase activity. Post-treatment with aloin resulted in a significant reduction in the deleterious renal functions by CLP, such as elevated BUN, creatinine, and urine protein. Moreover, aloin inhibited nuclear factor-κB activation and reduced the induction of nitric oxide synthase and excessive production of nitric acid. Aloin treatment also reduced the plasma levels of interleukin-6 and tumor necrosis factor-α, reduced lethality due to CLP-induced sepsis, increased lipid peroxidation, and markedly enhanced the antioxidant defense system by restoring the levels of superoxide dismutase, glutathione peroxidase, and catalase in kidney tissues. Our study suggested that aloin protects mice against sepsis-triggered renal injury.


Assuntos
Emodina/análogos & derivados , Nefropatias/prevenção & controle , Substâncias Protetoras/farmacologia , Sepse/prevenção & controle , Animais , Linhagem Celular , Emodina/farmacologia , Proteínas I-kappa B/metabolismo , Interleucina-6/metabolismo , Rim/lesões , Rim/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
Biochem Pharmacol ; 161: 73-88, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30633869

RESUMO

Leptin, a hormone primarily derived from adipose tissue, is known to induce tumor growth, but its underlying mechanisms of action are not clearly understood. Inflammasomes, acting as signaling platforms for controlling inflammatory responses, modulate tumor growth in a complicated manner. In this study, we investigated the role of inflammasomes in leptin-induced growth of breast cancer cells. Herein, we showed that leptin activated NLRP3 inflammasomes in MCF-7 breast cancer cells, as determined by activation of caspase-1, maturation of interleukin-1ß, and increased expression of the inflammasome components, including NLRP3 and ASC. Interestingly, inhibition of the inflammasome by treatment with a pharmacological inhibitor of caspase-1 or gene silencing of NLRP3 prevented leptin-induced increase in cell viability. Moreover, suppression of apoptosis and cell cycle promotion by leptin were also significantly abolished by gene silencing of NLRP3, clearly indicating a crucial role of NLRP3 inflammasomes in leptin-induced breast cancer growth. In addition, inhibition of estrogen receptor signaling or ROS production markedly blocked leptin-induced activation of NLRP3 inflammasomes, suggesting that estrogen receptor signaling and ROS production mediate inflammasomes activation by leptin. The stimulatory effect of leptin on inflammasomes activation was also observed in MCF-7 tumor xenograft model. Furthermore, the critical roles of inflammasomes activation in leptin-induced tumor growth, suppression of apoptotic gene expression, and induction of the genes stimulating cell cycle were confirmed in a tumor xenograft model. Taken together, these results demonstrate that inflammasomes activation plays a pivotal role in leptin-induced growth of breast cancer cells via modulation of both apoptosis and cell cycle.


Assuntos
Neoplasias da Mama/metabolismo , Leptina/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Estrogênicos/fisiologia , Animais , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Feminino , Humanos , Leptina/farmacologia , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
9.
Biomol Ther (Seoul) ; 27(2): 145-151, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30514054

RESUMO

Methamphetamine (METH) acts strongly on the nervous system and damages neurons and is known to cause neurodegenerative diseases such as Alzheimer's and Parkinson's. Flavonoids, polyphenolic compounds present in green tea, red wine and several fruits exhibit antioxidant properties that protect neurons from oxidative damage and promote neuronal survival. Especially, epicatechin (EC) is a powerful flavonoid with antibacterial, antiviral, antitumor and antimutagenic effects as well as antioxidant effects. We therefore investigated whether EC could prevent METH-induced neurotoxicity using HT22 hippocampal neuronal cells. EC reduced METH-induced cell death of HT22 cells. In addition, we observed that EC abrogated the activation of ERK, p38 and inhibited the expression of CHOP and DR4. EC also reduced METH-induced ROS accumulation and MMP. These results suggest that EC may protect HT22 hippocampal neurons against METH-induced cell death by reducing ER stress and mitochondrial damage.

10.
J Cell Physiol ; 233(7): 5441-5446, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29226969

RESUMO

Cudratricusxanthone A (CTXA), a natural bioactive compound extracted from the roots of Cudraniatricuspidata Bureau, is known to possess antithrombotic, antiproliferative, and antiinflammatory activities. It remains unclear that CTXA can improve hepatoprotective activity in vivo. The objective of this study was to investigate the effect of CTXA on lipopolysaccharide (LPS)-induced liver failure in mice, and to elucidate its underlying molecular mechanisms. Liver failure was induced by LPS (15 mg/kg, i.p.) in mice, and 12 hr later, they were treated intravenously with CTXA. Administration of LPS significantly increased mortality, serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and serum inflammatory cytokines. CTXA treatment effectively countered these effects of LPS. Further, LPS treatment markedly increased the expression of myeloperoxidase, phosphorylation of p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), and expressions of nuclear proteins, such as nuclear factor (NF)-κB and phosphorylated c-Jun. Additionally, LPS increased the serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6. All these effects of LPS were attenuated by CTXA. Moreover, CTXA increased the expression of sirtuin-1 (SIRT1) and reduced the expression of acetylated forkhead box O1 box O1 (Ac-FoxO1), acetylated Ac-p53, and acetylated nuclear factor-kappa beta (Ac-NF-κB). In conclusion, CTXA alleviates LPS-induced liver injury by reducing inflammatory responses and the potential mechanism is associated with SIRT1 signaling activation and finally could be used to treat liver diseases.


Assuntos
Fígado/efeitos dos fármacos , Moraceae/química , Sepse/tratamento farmacológico , Xantonas/administração & dosagem , Acetilação , Animais , Citocinas/genética , Proteína Forkhead Box O1/genética , Humanos , Lipopolissacarídeos/toxicidade , Fígado/lesões , Fígado/patologia , Falência Hepática/induzido quimicamente , Camundongos , NF-kappa B/genética , Sepse/complicações , Sepse/patologia , Proteína Supressora de Tumor p53/genética , Xantonas/química
11.
Mol Neurobiol ; 55(1): 554-566, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-27975170

RESUMO

Neurotrophic factors are essential for neuronal survival, plasticity, and development and have been implicated in the action mechanism of antidepressants. In this study, we assessed the neurotrophic factor-inducing and neuroprotective properties of antidepressants. In the first part of the study, we found that fluoxetine, imipramine, and milnacipran (i.p., 20 mg/kg/day for 1 week or 3 weeks) upregulated brain-derived neurotrophic factor in the striatum and substantia nigra both at 1 week and 3 weeks. In contrast, an increase in the glial-derived neurotrophic factor was more obvious at 3 weeks after the antidepressants treatment. Specifically, it was found that fluoxetine and imipramine are more potent in raising the levels of neurotrophic factors than milnacipran. Furthermore, antidepressants elevated the phosphorylation of extracellular signal-regulated-protein kinase (ERK1/2) and the serine/threonine kinase Akt. In the second part of the study, we compared the neuroprotective effects of fluoxetine, imipramine, and milnacipran in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Pretreament with fluoxetine, imipramine or milnacipran for 3 weeks reduced MPTP-induced dopaminergic neurodegeneration and microglial activation in the nigrostriatal pathway. Neurochemical analysis by HPLC exhibited that antidepressants attenuated the depletion of striatal dopamine. In consistent, beam test showed that behavioral impairment was ameliorated by antidepressants. Neuroprotective effects were more prominent in the fluoxetine or imipramine treatment group than in milnacipran treatment group. Finally, we found that neuroprotection of the antidepressants against 1-methyl-4-phenylpyridinium neurotoxicity in SH-SY5Y cells was attenuated by ERK or Akt inhibitor. These results indicate that neuroprotection by antidepressants might be associated with the induction of neurotrophic factors, and antidepressant could be a potential therapeutic intervention for treatment of Parkinson's disease.


Assuntos
Antidepressivos/uso terapêutico , Fatores de Crescimento Neural/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Regulação para Cima , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Antidepressivos/farmacologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/enzimologia , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Substância Negra/fisiopatologia , Regulação para Cima/efeitos dos fármacos
12.
Neuropharmacology ; 125: 396-407, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28807678

RESUMO

In spite of the massive research for the identification of neurorestorative or neuroprotective intervention for curing Parkinson's disease (PD), there is still lack of clinically proven neuroprotective agents. Metformin, a common anti-hyperglycemic drug has been known to possess neuroprotective properties. However, specific mechanisms by which metformin protects neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity remain to be elucidated. In this study, we assessed the neuroprotective effects of metformin in the subchronic MPTP model of PD, and explored its feasible mechanisms for neuroprotection. Animals received saline or MPTP injection (30 mg/kg/day) for the first 7 days, and then saline or metformin (200 mg/kg/day) for the next 7 days. Immunohistochemical stainings showed that metformin rescued the tyrosine hydroxylase-positive neurons and attenuated astroglial activation in the nigrostriatal pathway. In parallel, metformin restored dopamine depletion and behavioral impairments exerted by MPTP. Western blot analysis revealed that metformin ameliorated MPTP-induced α-synuclein phosphorylation which was accompanied by increased methylation of protein phosphatase 2A (PP2A), a phosphatase related to α-synuclein dephosphorylation. Moreover, the metformin regimen significantly increased the level of brain derived neurotrophic factor in the substantia nigra, and activated signaling pathways related to cell survival. Proof of concept study revealed that inhibition of PP2A or tropomyosin receptor kinase B reversed neuroprotective property of metformin in SH-SY5Y cells. Our results indicate that metformin provides neuroprotection against MPTP neurotoxicity, which might be mediated by inhibition of α-synuclein phosphorylation and induction of neurotrophic factors.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/metabolismo , Metformina/farmacologia , Fármacos Neuroprotetores/farmacologia , alfa-Sinucleína/metabolismo , Animais , Antiparkinsonianos/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Humanos , Intoxicação por MPTP/patologia , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Estudo de Prova de Conceito , Proteína Fosfatase 2/antagonistas & inibidores , Proteína Fosfatase 2/metabolismo , Receptor trkB/antagonistas & inibidores , Receptor trkB/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismo
13.
J Agric Food Chem ; 65(30): 6152-6157, 2017 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-28689410

RESUMO

Successive chromatography of EtOAc-soluble extracts of the fruiting body of Sparassis crispa (Wulf.) resulted in isolation of four new aromatic compounds, sparoside A (1) and sparalides A-C (3-5), two new naturally occurring compounds, 2 and 6, and eight known compounds, 7-14. The chemical structures were determined by interpretation of nuclear magnetic resonance and mass spectrometry spectroscopic data. Extract, solvent-soluble fractions of the extract, and all of the pure compounds isolated from the fractions were subjected to the mRNA expression assay for proprotein convertase subtilisin/kexin type 9 (PCSK9). Among them, sparoside A (1), hanabiratakelide A (8), adenosine (11), and 5α,6α-epoxy-(22E,24R)-ergosta-8(14),22-diene-3ß,7ß-diol (14) exhibited potent inhibitory activities on PCSK9 mRNA expression, with IC50 values of 20.07, 7.18, 18.46, and 8.23 µM, respectively (berberine, positive control, IC50 = 8.04 µM), suggesting that compounds 1, 8, 11, and 14 are suitable for use in supplements to the statins for hyperlipidemia treatments.


Assuntos
Inibidores Enzimáticos/química , Carpóforos/química , Extratos Vegetais/química , Polyporales/química , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores Enzimáticos/isolamento & purificação , Humanos , Cinética , Estrutura Molecular , Extratos Vegetais/isolamento & purificação , Polyporales/crescimento & desenvolvimento , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
15.
Food Chem Toxicol ; 106(Pt A): 404-410, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28595959

RESUMO

As a natural compound extracted from the roots of Cudrania tricuspidata Bureau, Cudratricusxanthone A (CTXA) is known to possess hepatoprotective, anti-inflammatory, and anti-proliferative activities. This study was aimed to clarify the role of CTXA in modulating renal functional damage in a mouse model of sepsis and to elucidate its underlying mechanisms. We examined the renal protective effects of CTXA on cecal ligation and puncture (CLP)-induced renal damage by assessment of serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, total glutathione, glutathione peroxidase activity, catalase activity, and superoxide dismutase activity. Post-treatment with CTXA resulted in a significant reduction in the deleterious renal functions by CLP, such as elevated BUN, creatinine, and urine protein. Induction of nitric oxide synthase and excessive production of nitric acid by CLP surgery were significantly reduced by post-treatment with CTXA via inhibiting nuclear factor-κB activation. Furthermore, the plasma levels of interleukin-6 and tumor necrosis factor-α were suppressed by CTXA post-treatment. Concurrently, CTXA treatment potently suppressed the CLP-induced septic lethality, rise of lipid peroxidation and markedly enhanced the antioxidant defense system by restoring the levels of superoxide dismutase, glutathione peroxidase, and catalase in kidney. The present results suggested that CTXA could protect against sepsis-triggered renal injury in mice.


Assuntos
Moraceae/química , Extratos Vegetais/administração & dosagem , Sepse/tratamento farmacológico , Xantonas/administração & dosagem , Animais , Antioxidantes/metabolismo , Modelos Animais de Doenças , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Rim/efeitos dos fármacos , Rim/enzimologia , Rim/lesões , Masculino , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Sepse/enzimologia , Sepse/genética , Sepse/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
16.
Fitoterapia ; 120: 194-198, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28602940

RESUMO

Bakuchicin is a furanocoumarin isolated from the seeds of Psoralea corylifolia, which is used in oriental medicine. However, limited information on the pharmacokinetics of bakuchicin is available and in addition, no determined method has been devised to quantify bakuchicin levels in the plasma. In the present study, we developed and validated a quantification method using liquid chromatography (LC) coupled with tandem mass spectrometry (LC-MS/MS), which was applied to a pharmacokinetic investigation in mouse plasma. LC was performed using an ACE 5 C18 column, and a mixture of acetonitrile and water containing 0.1% formic acid was used as the mobile phase at a flow rate of 220µL/min. Bakuchicin transition ions in multiple reaction-monitoring modes using positive ionization were observed at m/z 187.0 to m/z 131.0. Bakuchicin and the internal standard (reserpine) had retention times of 4.5 and 4.3min, respectively. Acceptable linearity (r2=0.996) was observed over the concentration range of 20-1000ng/mL, with a lower quantification limit of 20ng/mL in mouse plasma. This method was successfully applied to determine the pharmacokinetic parameters of bakuchicin in mouse plasma and showed that the bioavailability of bakuchicin was 58.3% at 5mg/kg oral administration.


Assuntos
Compostos Heterocíclicos com 3 Anéis/farmacocinética , Plasma/química , Psoralea/química , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Cromatografia Líquida , Masculino , Camundongos , Camundongos Endogâmicos ICR , Sementes/química , Espectrometria de Massas em Tandem
18.
Biochim Biophys Acta Gen Subj ; 1861(1 Pt A): 3180-3188, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27531709

RESUMO

BACKGROUND: Inhibition of fatty acid synthase (FAS) is regarded as a sensible therapeutic strategy for the development of optimal anti-cancer agents. Flavonoids exhibit potent anti-neoplastic properties. METHODS: The MeOH extract of Sophora flavescens was subjected to chromatographic analyses such as VLC and HPLC for the purification of active flavonoids. The DP4 chemical-shift analysis protocol was employed to investigate the elusive chirality of the lavandulyl moiety of the purified polyphenols. Induced Fit docking protocols and per-residue analyses were utilized to scrutinize structural prerequisites for hampering FAS activity. The FAS-inhibitory activity of the purified flavonoids was assessed via the incorporation of [3H] acetyl-CoA into palmitate. RESULTS: Six flavonoids, including lavandulyl flavanones, were purified and evaluated for FAS inhibition. The lavandulyl flavanone sophoraflavanone G (2) exhibited the highest potency (IC50 of 6.7±0.2µM), which was more potent than the positive controls. Extensive molecular docking studies revealed the structural requirements for blocking FAS. Per-residue interaction analysis demonstrated that the lavandulyl functional group in the active flavonoids (1-3 and 5) significantly contributed to increasing their binding affinity towards the target enzyme. CONCLUSION: This research suggests a basis for the in silico design of a lavandulyl flavonoid-based architecture showing anti-cancer effects via enhancement of the binding potential to FAS. GENERAL SIGNIFICANCE: FAS inhibition by flavonoids and their derivatives may offer significant potential as an approach to lower the risk of various cancer diseases and related fatalities. In silico technologies with available FAS crystal structures may be of significant use in optimizing preliminary leads.


Assuntos
Simulação por Computador , Inibidores Enzimáticos/farmacologia , Ácido Graxo Sintases/antagonistas & inibidores , Flavonoides/farmacologia , Células A549 , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Domínio Catalítico , Morte Celular/efeitos dos fármacos , Galinhas , Inibidores Enzimáticos/química , Ácido Graxo Sintases/metabolismo , Flavonoides/química , Humanos , Concentração Inibidora 50 , Células MCF-7 , Simulação de Acoplamento Molecular , Domínios Proteicos , Espectroscopia de Prótons por Ressonância Magnética , Sophora/química , Termodinâmica
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