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1.
Biomol Ther (Seoul) ; 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34475273

RESUMO

Eupafolin, a constituent of the aerial parts of Phyla nodiflora, has neuroprotective property. Because reducing the synaptic release of glutamate is crucial to achieving pharmacotherapeutic effects of neuroprotectants, we investigated the effect of eupafolin on glutamate release in rat cerebrocortical synaptosomes and explored the possible mechanism. We discovered that eupafolin depressed 4-aminopyridine (4-AP)-induced glutamate release, and this phenomenon was prevented in the absence of extracellular calcium. Eupafolin inhibition of glutamate release from synaptic vesicles was confirmed through measurement of the release of the fluorescent dye FM 1-43. Eupafolin decreased 4-AP-induced [Ca2+]i elevation and had no effect on synaptosomal membrane potential. The inhibition of P/Q-type Ca2+ channels reduced the decrease in glutamate release that was caused by eupafolin, and docking data revealed that eupafolin interacted with P/Q-type Ca2+ channels. Additionally, the inhibition of calcium/calmodulindependent protein kinase II (CaMKII) prevented the effect of eupafolin on evoked glutamate release. Eupafolin also reduced the 4-AP-induced activation of CaMK II and the subsequent phosphorylation of synapsin I, which is the main presynaptic target of CaMKII. Therefore, eupafolin suppresses P/Q-type Ca2+ channels and thereby inhibits CaMKII/synapsin I pathways and the release of glutamate from rat cerebrocortical synaptosomes.

2.
Medicina (Kaunas) ; 57(8)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34440990

RESUMO

Background and Objectives: Iris-claw intraocular lens (ICIOL) could be implanted in the anterior chamber (AC) or retropupillary (RP) in eyes lacking capsular and/or zonular support. Several studies have focused on comparing the efficacy and complications of these two techniques and we designed this research to review the published literatures. Materials and Methods: Peer-reviewed studies were collected through network databases (PubMed, Scopus, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov) and analyzed. The primary outcome was the standardized mean differences (SMDs) of pre- and post-operative corrected distant visual acuity (CDVA). The secondary outcome was the SMDs of pre- and post-operative intraocular pressure (IOP), endothelial cell counts (ECC), and the odds ratios (ORs) of post-operative IOP elevation and cystoid macular edema (CME). Comprehensive Meta-Analysis software was utilized to conduct statistical analysis. Results: Six studies (one randomized controlled trial and five retrospective case series) were relevant and included a total of 516 eyes (255 and 261 eyes in the AC ICIOL and RP ICIOL groups, respectively). The quantitative analysis showed no significant differences in CDVA (SMD: 0.164, 95% confidence interval (CI): -0.171 to 0.500), ECC (SMD: -0.011, 95% CI: -0.195 to 0.173), and IOP elevation events (OR: 0.797, 95% CI: 0.459 to 1.383). Lesser IOP reduction (SMD: 0.257, 95%CI: 0.023 to 0.490) and a relative increase in the incidence of CME (OR:2.315, 95% CI: 0.950 to 5.637) were observed in the AC ICIOL group compared with RP ICIOL group. Conclusions: Our meta-analysis indicated that AC and RP ICIOL seem to have equivalent visual outcomes. RP ICIOL may perform slightly better with more IOP reduction and lesser CME. More randomized controlled trials, which have higher patient participation and more outcomes are needed to confirm our conclusions.


Assuntos
Afacia Pós-Catarata , Lentes Intraoculares , Câmara Anterior , Afacia Pós-Catarata/cirurgia , Humanos , Implante de Lente Intraocular/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Acuidade Visual
3.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361003

RESUMO

Atopic dermatitis (AD) is a chronic and persistent inflammatory skin disease characterized by eczematous lesions and itching, and it has become a serious health problem. However, the common clinical treatments provide limited relief and are accompanied by adverse effects. Therefore, there is a need to develop novel and effective therapies to treat AD. Neferine is a small molecule compound isolated from the green embryo of the mature seeds of lotus (Nelumbo nucifera). It has a bisbenzylisoquinoline alkaloid structure. Relevant studies have shown that neferine has many pharmacological and biological activities, including anti-inflammatory, anti-thrombotic, and anti-diabetic activities. However, there are very few studies on neferine in the skin, especially the related effects on inflammatory skin diseases. In this study, we proved that it has the potential to be used in the treatment of atopic dermatitis. Through in vitro studies, we found that neferine inhibited the expression of cytokines and chemokines in TNF-α/IFN-γ-stimulated human keratinocyte (HaCaT) cells, and it reduced the phosphorylation of MAPK and the NF-κB signaling pathway. Through in vivo experiments, we used 2,4-dinitrochlorobenzene (DNCB) to induce atopic dermatitis-like skin inflammation in a mouse model. Our results show that neferine significantly decreased the skin barrier damage, scratching responses, and epidermal hyperplasia induced by DNCB. It significantly decreased transepidermal water loss (TEWL), erythema, blood flow, and ear thickness and increased surface skin hydration. Moreover, it also inhibited the expression of cytokines and the activation of signaling pathways. These results indicate that neferine has good potential as an alternative medicine for the treatment of atopic dermatitis or other skin-related inflammatory diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Benzilisoquinolinas/farmacologia , Dermatite Atópica/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Benzilisoquinolinas/uso terapêutico , Dermatite Atópica/etiologia , Dermatite Atópica/metabolismo , Dinitroclorobenzeno/toxicidade , Células HaCaT/efeitos dos fármacos , Células HaCaT/metabolismo , Humanos , Interferon gama/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
4.
Biomolecules ; 11(7)2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34356663

RESUMO

Melanoma represents less than 5% of skin cancers, but is the most lethal, mainly because of its high-metastatic potential and resistance to various therapies. Therefore, it is important to develop effective treatments, especially chemotherapeutic drugs with cytotoxicity, anti-metastaticity, and few side effects. One such natural product is hispidulin, a flavone distributed in plants of the Asteraceae. Previous studies have demonstrated that hispidulin has various pharmacological benefits, such as anti-tumor, anti-inflammation, and anti-allergic effects. This study aims to explore the effects of hispidulin against melanoma in vitro and in vivo. Results revealed that hispidulin selectively decreased the cell viability of A2058 cells in a dose- and time-dependent manner. Hispidulin induced cells accumulated in the sub-G1 phase via activating caspase 8 and 9, increased cleaved caspase 3, and cleaved PARP expression. Hispidulin was able to decrease AKT and ERK phosphorylation, which facilitated cell growth and survival. Moreover, hispidulin promoted reactive oxygen species generation in cells and suppressed cell migration through downregulated matrix metalloproteinase-2 expression. Hispidulin significantly inhibited tumor growth in a xenograft model. Based on these results, hispidulin produces its anti-melanoma effects by inducing cancer cell apoptosis and reducing its migration. Therefore, we suggest hispidulin as a potent therapeutic candidate for melanoma treatment.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Flavonas/farmacologia , Melanoma/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Melanoma/patologia , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Int Immunopharmacol ; 96: 107620, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33862555

RESUMO

Histamine is released from mast cells when tissues are inflamed or stimulated by allergens. Activation of histamine receptors and calcium influx via TRPV1 could be related to histamine-induced itch and skin inflammation. Quercetin is known to have anti-inflammatory and anti-itching effects. This study aims to understand whether quercetin can directly affect histamine-induced calcium influx in human keratinocyte. In it, we investigated quercetin, which acts on histamine-induced intracellular free calcium ([Ca2+]i) elevation in human keratinocyte. Changes in [Ca2+]i were measured using spectrofluorometry and confocal Imaging. We detected the expression of IL-8 after treatment of quercetin using qRT-PCR and evaluated its anti-itching effect in BALB/c mice. We also performed a docking study to estimate the binding affinity of quercetin to H4 receptors. We found that quercetin pretreatment decreased histamine-induced [Ca2+]i elevation in a concentration-dependent manner. The inhibitory effect of quercetin on histamine-induced [Ca2+]i elevation was blocked by JNJ7777120, a selective H4 antagonist, as well as by U73122, a PLC inhibitor, and by GF109203X, a PKC inhibitor. We also found that H4 agonist (4-methylhistamine)-induced [Ca2+]i elevation could be inhibited by quercetin. Moreover, the selective TRPV1 blocker capsazepine significantly suppressed the quercetin-mediated inhibition of histamine-induced [Ca2+]i elevation, whereas the TRPV4 blocker GSK2193874 had no effect. Last, quercetin decreased histamine and H4 agonist-induced IL-8 expression in keratinocyte and inhibited the scratching behavior-induced compound 48/80 in BALB/c mice. The molecular docking study also showed that quercetin exhibited high binding affinities with H4 receptors (autodock scores for H4 = -8.7 kcal/mol). These data suggest that quercetin could decrease histamine 4 receptor-induced calcium influx through the TRPV1 channel and could provide a molecular mechanism of quercetin in anti-itching, anti-inflammatory, and unpleasant sensations.

6.
Chem Res Toxicol ; 34(4): 1133-1139, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33755440

RESUMO

Ultraviolet rays are the main cause of skin aging. Isoflavone structures are good anti-ultraviolet natural compounds and have an especially strong anti-ultraviolet B (UVB) effect. However, the anti-ultraviolet A (UVA) effect of isoflavones is more controversial. Therefore, this study aims to discover which isoflavone analogue possesses a strong anti-ultraviolet A. We found the isoflavonoid intermediate deoxybenzoin-3A (DOB-3A) to be a similar isoflavone structural compound with strong anti-ultraviolet A effects. Ultraviolet rays with a wavelength of 350 nm are used to irradiate the fibroblasts of the human skin. Western blot, flow cytometry, and transmission electron microscope analyses were used to explore its anti-ultraviolet A mechanism. We established the results that DOB-3A (1) reduced the death of fibroblasts caused by ultraviolet A, (2) avoided the damage to the organelles and structures after UVA irradiation, (3) inhibited the generation of intracellular reactive oxygen species (ROS) and hydrogen peroxide-induced damage, and (4) decreased the phosphorylation of mitogen-activated protein kinases (MAPK) caused by UVA. Based on the above findings, DOB-3A is a very good anti-ultraviolet A isoflavone-related structure. Because it is simple to synthesize and has good effects, DOB-3A is a suitable anti-ultraviolet A product with an isoflavone structure. Moreover, DOB-3A's structure provides a reference for the synthesis of anti-UVA isoflavones.


Assuntos
Derme/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Raios Ultravioleta , Derme/metabolismo , Fibroblastos/metabolismo , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
7.
Colloids Surf B Biointerfaces ; 202: 111658, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33677134

RESUMO

TiO2 acts as an inorganic sunscreen and photocatalyst to protect humans from environmental pollutants. We incorporated TiO2 into mesoporous silica (SBA-15) for skin application to prevent environmental stresses including UVA irradiation and pollutant invasion. Organic ultraviolet (UV)A filters such as avobenzone and oxybenzone were then loaded into mesoporous support for synergistic sunscreen efficiency. The as-prepared formulations with different TiO2 amounts (10 %-50 %) were fabricated. The pore size decreased from 4.72 to 4.00 nm following the increase in TiO2 percentage. TiO2/SBA-15 captured about 60 % fluoranthene and 80 % furfural within 3 h with no significant difference due to different TiO2 content. The in vitro photoprotection assessed by UVA/UVB ratio exhibited the increase in Boots star rating from 2 to 3 to 5 by entrapment of avobenzone into TiO2/SBA-15. Thirty-percent TiO2/SBA-15 in hydrogel decreased avobenzone and oxybenzone deposition by 70 % and 80 % compared to free form, respectively. Avobenzone and TiO2 supplementation to SBA-15 significantly alleviated skin cell death and neutrophil recruitment in the photoaged mouse skin compared to the SBA-15 application alone. Compared to the UVA-irradiated skin, 30 % TiO2/SBA-15 showed a 2.5- and 3.1-fold decline in IL-1ß and IL-6 levels, respectively. The TiO2/SBA-15 hybrid was considered non-irritant based on results of cytotoxicity assay, skin histology, and cutaneous barrier function. Our data indicate that the versatile mesoporous silica is an effective system for topical use in sunscreen and skin protection.


Assuntos
Poluentes Ambientais , Protetores Solares , Adsorção , Dióxido de Silício , Pele , Protetores Solares/farmacologia , Titânio , Raios Ultravioleta
8.
J Med Food ; 24(3): 209-217, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33739887

RESUMO

Decreasing synaptic release of glutamate may counteract glutamate excitotoxicity in many neurological diseases. In this study, we investigated the effect of albanin A, a constituent in the root bark of Morus alba L., on the release of glutamate in rat cerebral cortex nerve endings (synaptosomes). We found that albanin A at 5-30µM suppressed 4-aminopyridine (4-AP)-induced release of glutamate. This phenomenon was abolished by extracellular calcium removal or by vesicular transporter inhibition, and was associated with a decrease in intrasynaptosomal Ca2+ levels. However, albanin A had no effect on the synaptosomal membrane potential. The inhibition of N- and P/Q-type Ca2+ channels, calmodulin, adenylate cyclase (AC), and protein kinase A, abolished the effect of albanin A on the glutamate release evoked by 4-AP. Moreover, the albanin A-mediated inhibition of glutamate release was prevented by the Ca2+/calmodulin-stimulated AC1 inhibitor. Western blot showed that AC1, but not AC8, was presented in the synaptosomes, and albanin A reduced 4-AP-induced increases in synaptosomal cyclic adenosine monophosphate content. In addition, albanin A pretreatment substantially attenuated neuronal damage in a rat model of kainic acid-induced glutamate excitotoxicity. Our data reveal that albanin A suppresses glutamate release by decreasing Ca2+/calmodulin/AC1 activation in synaptosomes and exerts neuroprotective effect in vivo.


Assuntos
Ácido Glutâmico , Morus , Adenilil Ciclases , Animais , Cálcio/metabolismo , Calmodulina , Córtex Cerebral/metabolismo , Terminações Nervosas/metabolismo , Casca de Planta , Ratos , Ratos Sprague-Dawley , Sinaptossomos/metabolismo
9.
FASEB J ; 35(3): e21393, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33570794

RESUMO

UV irradiation can injure the epidermis, resulting in sunburn, inflammation, and cutaneous tissue disorders. Previous studies demonstrate that EGFR in keratinocytes can be activated by UVB and contributes to inflammation. Poly (ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme and plays an essential role in DNA repair under moderate stress. In this study, we set out to understand how PARP-1 regulates UVB irradiation-induced skin injury and interplays with EGFR to mediate the inflammation response. We found that PARP-1 deficiency exacerbated the UVB-induced inflammation, water loss, and back skin damage in mice. In human primary keratinocytes, UVB can activate PARP-1 and enhance DNA damage upon PARP-1 gene silencing. Moreover, PARP-1 silencing and PARP inhibitor olaparib can suppress UVB-induced COX-2 and MMP-1 expression, but enhance TNF-α and IL-8 expression. In addition, EGFR silencing or EGFR inhibition by gefitinib can decrease UVB-induced COX-2, TNF-α, and IL-8 expression, suggesting EGFR activation via paracrine action can mediate UVB-induced inflammation responses. Immunoblotting data revealed that PARP-1 inhibition decreases UVB-induced EGFR and p38 activation. Pharmacological inhibition of p38 also dramatically led to the attenuation of UVB-induced inflammatory gene expression. Of note, genetic ablation of PARP-1 or EGFR can attenuate UVB-induced ROS production, and antioxidant NAC can attenuate UVB-induced EGFR-p38 signaling axis and PARP-1 activation. These data suggest the regulatory loops among EGFR, PARP-1, and ROS upon UVB stress. PARP-1 not only serves DNA repair function but also orchestrates interactions to EGFR transactivation and ROS production, leading to p38 signaling for inflammatory gene expression in keratinocytes.


Assuntos
Receptores ErbB/fisiologia , Inflamação/etiologia , Queratinócitos/efeitos da radiação , Poli(ADP-Ribose) Polimerase-1/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Pele/efeitos da radiação , Ativação Transcricional , Raios Ultravioleta , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia , Animais , Células Cultivadas , Ciclo-Oxigenase 2/genética , Reparo do DNA , Receptores ErbB/genética , Humanos , Interleucina-8/genética , Camundongos , Transdução de Sinais/fisiologia
10.
Food Funct ; 11(11): 9858-9867, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33089839

RESUMO

3ß,7ß,25-Trihydroxycucurbita-5,23(E)-dien-19-al (TCD) is a triterpenoid isolated from wild bitter gourd that is a common tropical vegetable with neuroprotective effects. Because excessive glutamate release is a major cause of neuronal damage in various neurological disorders, the aims of this study were to examine the effect of TCD on glutamate release in vitro and to examine the effect of TCD in vivo. In rat cerebrocortical synaptosomes, TCD reduced 4-aminopyridine (4-AP)-stimulated glutamate release and Ca2+ concentration elevation, but had no effect on plasma membrane potential. TCD-mediated inhibition of 4-AP-induced glutamate release was dependent on the presence of extracellular calcium; persisted in the presence of the glutamate transporter inhibitor dl-TBOA, P/Q-type Ca2+ channel blocker ω-agatoxin IVA, and intracellular Ca2+-releasing inhibitors dantrolene and CGP37157; and was blocked by the vesicular transporter inhibitor bafilomycin A1 and the N-type Ca2+ channel blocker ω-conotoxin GVIA. Molecular docking studies have demonstrated that TCD binds to N-type Ca2+ channels. TCD-mediated inhibition of 4-AP-induced glutamate release was abolished by the Ca2+-dependent protein kinase C (PKC) inhibitor Go6976, but was unaffected by the Ca2+-independent PKC inhibitor rottlerin. Furthermore, TCD considerably reduced the phosphorylation of PKC, PKCα, and myristoylated alanine-rich C kinase substrate, a major presynaptic substrate for PKC. In a rat model of kainic acid (KA)-induced excitotoxicity, TCD pretreatment substantially attenuated KA-induced neuronal death in the CA3 hippocampal region. These results suggest that TCD inhibits synaptosomal glutamate release by suppressing N-type Ca2+ channels and PKC activity and exerts protective effects against KA-induced excitotoxicity in vivo.

11.
Eur J Pharmacol ; 889: 173589, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32961171

RESUMO

Neferine, a bisbenzylisoquinoline alkaloid present in Nelumbo nucifera, has been reported to exhibit neuroprotective effects. Because reduced glutamatergic transmission through inhibition of glutamate release has been proposed as a mechanism of neuroprotection, we investigated whether and how neferine inhibits glutamate release in the nerve terminals of the cerebral cortex of rats. The results demonstrated that neferine inhibits the glutamate release that is evoked by the potassium channel blocker 4-aminopyridine, doing so in a dose-dependent manner. This effect was prevented by removing extracellular calcium and blocking vesicular transporters or N- and P/Q-type calcium channels but not by blocking glutamate transporters. Neferine decreased the 4-aminopyridine-stimulated elevation in intrasynaptosomal calcium concentration; however, it had no effect on the synaptosomal membrane potential. The inhibition of glutamate release by neferine was also eliminated by the selective 5-hydroxytryptamine 1A (5HT1A) receptor antagonist WAY100635, Gi/o protein inhibitor pertussis toxin, adenylyl cyclase inhibitor MDL12330A, and protein kinase A inhibitor H89. Moreover, immunocytochemical analysis revealed the presence of 5-HT1A receptor proteins in the vesicular transporter of glutamate type 1 positive synaptosomes. The molecular docking study also demonstrated that neferine exhibited the highest binding affinity with 5-HT1A receptors (Autodock scores for 5-HA1A = -11.4 kcal/mol). Collectively, these results suggested that neferine activates 5-HT1A receptors in cortical synaptosomes, which decreases calcium influx and glutamate release through the activation of Gi/o protein and the inhibition of adenylyl cyclase/cAMP/protein kinase A cascade.


Assuntos
Benzilisoquinolinas/farmacologia , Córtex Cerebral/metabolismo , Ácido Glutâmico/metabolismo , Nelumbo , Terminações Nervosas/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Animais , Benzilisoquinolinas/química , Benzilisoquinolinas/isolamento & purificação , Córtex Cerebral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/isolamento & purificação , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Simulação de Acoplamento Molecular , Terminações Nervosas/efeitos dos fármacos , Estrutura Secundária de Proteína , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/química
12.
Neurochem Int ; 140: 104845, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32911011

RESUMO

Indole-3-carbinol (I3C), found in cruciferous vegetables, has been proposed to exhibit neuroprotective effects. This study aimed to investigate the effect of the I3C derivative [1(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (CIM), which has superior pharmacokinetic properties to I3C, on glutamate release in rat cerebrocortical nerve terminals (synaptosomes). We observed that CIM dose-dependently inhibited glutamate release evoked by the potassium channel blocker 4-aminopyridine (4-AP). CIM-mediated inhibition of glutamate release was attributed to reduced exocytosis, as it correlated with the removal of extracellular calcium and blocking of the vesicular glutamate transporter but not the glutamate transporter. In addition, CIM decreased 4-AP-evoked intrasynaptosomal Ca2+ elevation; however, it did not alter the synaptosomal membrane potential. The inhibition of P/Q-typeCa2+ channels abolished the effect of CIM on 4-AP-evoked glutamate release, and the effect was not prevented by intracellular Ca2+ release inhibitors. Moreover, the molecular docking study showed that CIM exhibited the highest binding affinity with the P/Q-type Ca2+channels. Finally, the CIM-mediated inhibition of glutamate release was sensitive to calmodulin, adenylate cyclase (AC), and protein kinase A (PKA) inhibitors. Based on these results, we propose that CIM, through the direct suppression of P/Q-type Ca2+ channels, decreases Ca2+ influx and the activation of Ca2+/calmodulin/AC/PKA signaling, thereby inhibiting glutamate release. This finding is crucial for understanding the role of CIM in the central nervous system and for exploiting its potential in therapeutic interventions.

13.
Int J Mol Sci ; 21(15)2020 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-32748894

RESUMO

BACKGROUND: Diabetes mellitus (DM) is a chronic inflammatory disease, which causes multiple complications. Diabetic retinopathy (DR) is among these complications and is a dominant cause of vision loss for diabetic patients. Numerous studies have shown that chrysin, a flavonoid, has many biological activities such as anti-oxidation and anti-inflammation. However, it is rarely used in ocular diseases. In this study, we examined the inhibitory effects of flavonoid on high glucose induced migration of chorioretinal endothelial cells (RF/6A cells) and its mechanism. MATERIALS AND METHODS: The viability of RF/6A cells treated with chrysin was examined with a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The migration of RF/6A cells was assessed by the transwell migration and scratch wound assays. The expression of AKT, ERK, vascular endothelial growth factor (VEGF), HIF-1α and MMP-2 were determined by western blotting. To observe the mRNA expression of VEGF receptor (VEGFR), qRT-PCR, was utilized. RESULTS: The results showed that chrysin can dose-dependently inhibit the RF/6A cell migration in vitro transwell and the scratch wound assays which are induced by high glucose. After pretreatment of RF/6A cells with different concentrations of chrysin, they did not produce any cytotoxicity in MTT assay. Moreover, chrysin down-regulated both phosphorylated AKT and ERK, as well as attenuated the expression levels of MMP-2. It also decreased the expression of the VEGF transcription factor and VEGF. Furthermore, it was shown that chrysin could suppress the protein and mRNA expression levels of VEGFR. CONCLUSION: The results indicate that chrysin could down-regulate the phosphorylation of AKT, ERK and MMP-2 and reduce the effects of VEGF and VEGFR in a high glucose environment. It further inhibits the high glucose-induced migration of RE/6A cells. Therefore, chrysin may have the potential for visual protection.


Assuntos
Movimento Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Flavonoides/farmacologia , Glucose/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Linhagem Celular , Movimento Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Expressão Gênica/efeitos dos fármacos , Macaca mulatta , Metaloproteinase 2 da Matriz/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/genética
14.
Toxins (Basel) ; 12(8)2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32722241

RESUMO

Osteogenesis in human arterial smooth muscle cell (HASMC) is a key feature of uremic vascular calcification (UVC). Concerning pro-oxidant properties of p-cresyl sulfate (PCS), the therapeutic effect of reactive oxygen species (ROS) scavenger on PCS triggered inflammatory signaling transduction in osteogenesis was investigated in this translational research. Based on severity level of chronic kidney disease (CKD), arterial specimens with immunohistochemistry stain were quantitatively analyzed for UVC, oxidative injury and osteogenesis along with PCS concentrations. To mimic human UVC, HASMC model was used to explore whether PCS-induced ROS could trigger mitogen-activated protein kinase (MAPK) pathways with nuclear factor-κB (NF-κB) translocation that drive context-specific gene/protein expression, including Runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP). In parallel with PCS accumulation, CKD arteries corresponded with UVC severity, oxidative DNA damage (8-hydroxy-2'-deoxyguanosine), Runx2 and ALP. PCS directly phosphorylated extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/P38 (pERK/pJNK/pP38) and modulated NF-κB translocation to promote expressions of Runx2 and ALP in HASMC. Notably, intracellular ROS scavenger attenuated pERK signaling cascade and downstream osteogenic differentiation. Collectively, our data demonstrate PCS induces osteogenesis through triggering intracellular ROS, pERK/pJNK/pP38 MAPK pathways and NF-κB translocation to drive Runx2 and ALP expressions, culminating in UVC. Beyond mineral dysregulation, osteocytic conversion in HASMC could be the stimulation of PCS. Thus PCS may act as a pro-osteogenic and pro-calcific toxin. From the perspective of translational medicine, PCS and intracellular ROS could serve as potential therapeutic targets for UVC in CKD patients.


Assuntos
Cresóis/metabolismo , Miócitos de Músculo Liso/metabolismo , Osteogênese , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/metabolismo , Ésteres do Ácido Sulfúrico/metabolismo , Uremia/metabolismo , Calcificação Vascular/metabolismo , Idoso , Idoso de 80 Anos ou mais , Artérias/citologia , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/cirurgia , Transdução de Sinais , Uremia/complicações , Calcificação Vascular/etiologia
15.
Toxins (Basel) ; 12(6)2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32498221

RESUMO

The nephrotoxicity of aristolochic acids (AAs), p-cresyl sulfate (PCS) and indoxyl sulfate (IS) were well-documented, culminating in tubulointerstitial fibrosis (TIF), advanced chronic kidney disease (CKD) and fatal urothelial cancer. Nonetheless, information regarding the attenuation of AAs-induced nephropathy (AAN) and uremic toxin retention is scarce. Propolis is a versatile natural product, exerting anti-oxidant, anti-cancer and anti-fibrotic properties. We aimed to evaluate nephroprotective effects of propolis extract (PE) in a murine model. AAN was developed to retain circulating PCS and IS using C57BL/6 mice, mimicking human CKD. The kidney sizes/masses, renal function indicators, plasma concentrations of PCS/IS, tissue expressions of TIF, α-SMA, collagen IaI, collagen IV and signaling pathways in transforming growth factor-ß (TGF-ß) family were analyzed among the control, PE, AAN, and AAN-PE groups. PE ameliorated AAN-induced renal atrophy, renal function deterioration, TIF, plasma retention of PCS and IS. PE also suppressed α-SMA expression and deposition of collagen IaI and IV in the fibrotic epithelial-mesenchymal transition. Notably, PE treatment in AAN model inhibited not only SMAD 2/3-dependent pathways but also SMAD-independent JNK/ERK activation in the signaling cascades of TGF-ß family. Through disrupting fibrotic epithelial-mesenchymal transition and TGF-ß signaling transduction pathways, PE improves TIF and thereby facilitates renal excretion of PCS and IS in AAN. In light of multi-faced toxicity of AAs, PE may be capable of developing a new potential drug to treat CKD patients exposed to AAs.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Túbulos Renais/efeitos dos fármacos , Própole/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Uremia/tratamento farmacológico , Animais , Ácidos Aristolóquicos , Cresóis/sangue , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose , Indicã/sangue , Túbulos Renais/enzimologia , Túbulos Renais/patologia , Camundongos Endogâmicos C57BL , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/enzimologia , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Ésteres do Ácido Sulfúrico/sangue , Fator de Crescimento Transformador beta/metabolismo , Uremia/induzido quimicamente , Uremia/metabolismo , Uremia/patologia
16.
J Ethnopharmacol ; 263: 113037, 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-32485302

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Numerous epidemiological and clinical studies have demonstrated the protective role of dietary isoflavones against development of several chronic diseases. ISO-1, one fraction of isoflavone powders derived from soybean cake, is reported to attenuate inflammation and photodamage. AIM OF THE STUDY: Contact dermatitis is a common inflammatory skin disease, which accounts for most occupational skin disorders. Instead of oral administration, we aimed to explore the effects of topical ISO-1 application on contact dermatitis by using 2,4-dinitrochlorobenzene (DNCB)-stimulated HaCaT keratinocytes and DNCB-induced mouse dermatitis as models. MATERIALS AND METHODS: In the in vitro study, we first evaluated the biologic effects of DNCB on HaCaT keratinocytes. HaCaT keratinocytes were treated with 2,4-dinitrochlorobenzene (DNCB), and cell viability was measured by MTT assay. Then, we detect the prominent induction of IL-8 mRNA expression after DNCB and ISO-1 treatment by reverse transcription polymerase chain reaction (RT-PCR), and release of IL-8 from HaCaT keratinocytes was measured by ELISA assay. HaCaT keratinocytes were pretreated with ISO-1 and then treated with DNCB, phosphorylation of JNK, p38, ERK and IκBα was analyzed by western blot. In the in vivo study, the hairless mice were used for an induced contact dermatitis model. The surface changes in the dorsal skin after DNCB and ISO-1 treatment were recorded using photography, and TEWL, erythema were measured using an MPA-580 cutometer. Blood was also collected from mice for measurement of white blood cell counts. RESULTS: Results showed ISO-1 inhibited DNCB-induced IL-8 production and also suppressed DNCB-induced phosphorylation of JNK and p38, and IκBα in HaCaT. In the animal model of DNCB-induced contact dermatitis, topical ISO-1 treatment significantly decreased DNCB-induced erythema and transepidermal water loss (TEWL) in mouse skin. ISO-1 also reduced DNCB-induced skin thickening and increase of white blood cell count. CONCLUSIONS: ISO-1 is promising for improvement of DNCB-induced inflammation and skin barrier impairment, suggesting the potential application of topical ISO-1 for inflammatory dermatoses.


Assuntos
Dermatite de Contato/tratamento farmacológico , Dinitroclorobenzeno/toxicidade , Isoflavonas/uso terapêutico , Extratos Vegetais/uso terapêutico , Soja , Animais , Linhagem Celular Transformada , Dermatite de Contato/metabolismo , Relação Dose-Resposta a Droga , Humanos , Irritantes/toxicidade , Isoflavonas/isolamento & purificação , Isoflavonas/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Distribuição Aleatória
17.
J Dermatol Sci ; 98(2): 119-127, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32312639

RESUMO

BACKGROUND: Galectin-3 is widely expressed in many immunocytes and epithelial cells including skin keratinocytes. Galectin-3 can regulate immunological or inflammatory processes and plays a proinflammatory role in some disease models. Galectin-3 has a role in disorders related to ultraviolet (UV) photodamage such as apoptosis, skin squamous cell carcinoma and basal cell carcinoma. However, the evidence of galectin-3 in UVB-induced skin inflammation is still limited and the underlying molecular mechanism remains elusive. OBJECTIVE: We aimed to investigate the effects of galectin-3 in human epidermal keratinocytes and in mice after UVB irradiation. METHODS: Primary human epidermal keratinocytes with galectin-3 knockdown were used as the in vitro model. ELISA, QPCR, and western blotting were applied to evaluate the released cytokine, mRNA and protein expression. Histologic analysis, measurement of erythema and transepidermal water loss (TEWL) were applied to evaluate UVB-induced skin damage in galectin-3 knockout mice. RESULTS: In UVB-irradiated human keratinocytes, galectin-3 knockdown downregulated the UVB-induced ASC crosslinking, cleavage of caspase-1, and formation of active IL-1ß. Galectin-3 knockdown also decreased UVB-induced production of reactive oxygen species, p38 phosphorylation, and COX2 expression in human keratinocytes. After four days of UVB irradiation, galectin-3 knockout mice showed reduced gross erythema, histologic features of tissue inflammation, quantified levels of erythema and TEWL compared to wild type mice. The skin tissue lysate also showed less expression of active IL-1ß and COX2 in galectin-3 knockout mice. CONCLUSION: Galectin-3 may play a positive regulatory role in UVB-induced skin inflammation.


Assuntos
Proteínas Sanguíneas/metabolismo , Galectina 3/metabolismo , Galectinas/metabolismo , Transtornos de Fotossensibilidade/imunologia , Pele/patologia , Raios Ultravioleta/efeitos adversos , Animais , Caspase 1/metabolismo , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Galectina 3/genética , Humanos , Interleucina-1beta/metabolismo , Queratinócitos , Masculino , Camundongos Knockout , Transtornos de Fotossensibilidade/patologia , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Pele/citologia , Pele/imunologia , Pele/efeitos da radiação , Perda Insensível de Água/efeitos da radiação
18.
Sci Rep ; 10(1): 2932, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076123

RESUMO

Psoriasis is a common non-contagious chronic inflammatory skin lesion, with frequent recurrence. It mainly occurs due to aberrant regulation of the immune system leading to abnormal proliferation of skin cells. However, the pathogenic mechanisms of psoriasis are not fully understood. Although most of the current therapies are mostly efficient, the side effects can result in therapy stop, which makes the effectiveness of treatment strategies limited. Therefore, it is urgent and necessary to develop novel therapeutics. Here, we investigated the efficacy of chrysin, a plant flavonoid, which we previously reported to possess strong antioxidant and anti-inflammatory effects, against psoriasis-like inflammation. Our results revealed that chrysin significantly attenuated imiquimod-induced psoriasis-like skin lesions in mice, and improved imiquimod-induced disruption of skin barrier. Moreover, the TNF-α, IL-17A, and IL-22-induced phosphorylation of MAPK and JAK-STAT pathways, and activation of the NF-κB pathway were also attenuated by chrysin pretreatment of epidermal keratinocytes. Most importantly, chrysin reduced TNF-α-, IL-17A-, and IL-22-induced CCL20 and antimicrobial peptide release from epidermal keratinocytes. Thus, our findings indicate that chrysin may have therapeutic potential against inflammatory skin diseases. Our study provides a basis for further investigating chrysin as a novel pharmacologic agent and contributes to the academic advancement in the field of Chinese herbal medicine.


Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Quimiocina CCL20/metabolismo , Flavonoides/uso terapêutico , Imiquimode/efeitos adversos , Inflamação/tratamento farmacológico , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Pele/patologia , Animais , Quimiocina CCL20/genética , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Epiderme/patologia , Flavonoides/química , Flavonoides/farmacologia , Humanos , Hiperplasia , Interleucina-17/metabolismo , Interleucinas/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Psoríase/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Pele/efeitos dos fármacos , Pele/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismo
19.
Neurochem Int ; 133: 104629, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31816340

RESUMO

Excitotoxicity induced by excessive glutamate has been implicated in many brain disorders. Xanthohumol is a natural product derived from hops (Humulus lupulus L.), which is reported to have glutamate release-inhibiting activity. However, it is unknown whether xanthohumol has protective effects against glutamate-induced excitotoxicity. This study investigated the potential action of xanthohumol in a rat model of excitotoxicity induced by intraperitoneal injection of kainic acid (KA). Xanthohumol (10 or 50 mg/kg) administrated intraperitoneally 30 min prior to KA (15 mg/kg) considerably ameliorated KA-induced seizures, glutamate concentration elevation, and CA3 neuron death. The decrease of mitochondrial fusion protein Mfn-2 and antiapoptotic protein Bcl-2 expression in hippocampal tissues following KA injection were reversed by xanthohumol. Moreover, apoptotic protease activating factor 1 (Apaf-1) expression and caspase-3 activation in the hippocampus were inhibited by xanthohumol. These results suggest that xanthohumol up-regulates Mfn-2 and Bcl-2 to preserve mitochondrial function and suppress Apaf-1 and caspase-3 activation, thereby increasing neuron survival in rats after KA treatment. Therefore, xanthohumol has great potential for development into a therapeutic agent for improving glutamate-related nervous system diseases.


Assuntos
Flavonoides/farmacologia , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Mitocôndrias/efeitos dos fármacos , Propiofenonas/farmacologia , Animais , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos Sprague-Dawley
20.
Sleep Med ; 66: 15-20, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31785565

RESUMO

BACKGROUND: Epidemiological studies on the obstructive sleep apnea (OSA) and cancer relationship in humans are inconsistent. Furthermore, there are limited prospective studies on the association between OSA and the risk of colorectal cancer (CRC). This retrospective cohort study examined the longitudinal relationship between OSA and CRC in a nationwide population-based cohort. METHODS: We identified 4180 individuals newly diagnosed with OSA (the exposed cohort) and randomly selected 16,720 age- and sex-matched subjects without OSA (the nonexposed cohort) between 2000 and 2008 from Taiwan's National Health Insurance Research Database (NHIRD). The Kaplan-Meier method was used for calculating the cumulative incidence of CRC in each cohort. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and the accompanying 95% confidence intervals (CIs) for the association between OSA and CRC. RESULTS: After adjusting for potential confounders, patients with OSA were associated with a significantly higher risk of CRC than those without OSA (adjusted HR, 1.80; 95% CI, 1.28-2.52). The cumulative incidence of CRC was significantly higher in the OSA cohort than in the comparison cohort (log-rank test, p < 0.001). Furthermore, the association between OSA and CRC appeared to be enhanced with increasing frequency of OSA medical visits (adjusted HR [95% CI] was 1.61 [0.97-2.66] and 1.86 [1.26-2.75] for one visit and two or more visits, respectively). CONCLUSION: This population-based cohort study demonstrated that OSA was associated with an increased risk of CRC. Further large-scale prospective studies are needed to confirm our results.


Assuntos
Neoplasias Colorretais/epidemiologia , Vigilância da População , Apneia Obstrutiva do Sono/complicações , Adulto , Idoso , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taiwan
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