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1.
Xenobiotica ; 50(5): 545-551, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31524030

RESUMO

Hydroxysafflor yellow A (HSYA) is the most pharmaceutically relevant compound in Xuebijing (XBJ) for traumatic brain injury (TBI) treatment. We aimed to investigate biofluids pharmacokinetics of HSYA from XBJ to ensure the drug safety and to guide the clinical use.A sensitive, rapid and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to investigate pharmacokinetics of HSYA in TBI patients after intravenous administration of XBJ. Non-compartmental methods using DAS 3.0 software were applied to analyse the pharmacokinetic parameters.A similar half-life (Plasmat1/2: 14.55 ± 3.51 h vs. CSFt1/2: 15.73 ± 3.63) was observed. HSYA reached the peak level rapidly, but exhibited a strongly slow absorption phase from blood to cerebrospinal fluid (CSF, PlasmaTmax: 0.69 ± 0.26 h vs. CSFTmax: 4.0 ± 2.62 h). HSYA exhibited much higher Cmax (PlasmaCmax: 9342.76 ± 2489.23 µg/L vs. CSFCmax: 98.08 ± 14.51 µg/L) and AUC0-t (PlasmaAUC0-t: 57490.5 ± 5560.3 µg h/L vs. CSFAUC0-t: 1851.6 ± 269.1 µg h/L), yet a shorter CL (PlasmaCL: 0.02 ± 0.002 L/h/kg vs. CSFCL: 0.55 ± 0.01 L/h/kg) in plasma than in CSF. The AUCCSF/AUCplasma of HSYA was almost 3.37%.In summary, the results demonstrate that part of HSYA come across blood-brain barrier after XBJ administration. This study provides evidence for better understanding the pharmacokinetics and potential for clinical guidance of XBJ for TBI treatment.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Chalcona/análogos & derivados , Medicamentos de Ervas Chinesas/metabolismo , Quinonas/metabolismo , Administração Intravenosa , Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/líquido cefalorraquidiano , Chalcona/sangue , Chalcona/líquido cefalorraquidiano , Chalcona/metabolismo , Humanos , Farmacocinética , Quinonas/sangue , Quinonas/líquido cefalorraquidiano
2.
Zhongguo Zhong Yao Za Zhi ; 44(17): 3792-3797, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31602955

RESUMO

This paper was aimed to establish screening methods of anaphylactoid reaction caused by safflower yellow for injection based on RBL-2 H3 cell degranulation model and mice model for acute anaphylactoid reaction,and evaluate the hypersensitivity caused by safflower yellow for injection from different batches. An in vitro cell model was used to keep the cells stimulated for an hour with different batches of safflower yellow for injection as the drug group,serum-free MEM medium as negative control group and 30 mg·L-1 C48/80 as positive control group respectively. The supernatant was then absorbed,and neutral red staining technique was used to detect the effect of safflower yellow injection on the degranulation of RBL-2 H3 cells with the positive cell rate of degranulation as the indicator.An in vivo model was established to validate the experimental results,and mice model for acute anaphylactoid reaction and ELISA method were adopted to detect the plasma histamine content,and screen the hypersensitivity caused by safflower yellow for injection at the animal level by using plasma histamine content as a test index. The results of the neutral red staining experiments showed that the positive control C48/80 could cause cell degranulation,and most of the cells were deeply stained. There was significant difference in positive cell rate between different batches of safflower yellow and positive control group. In the mice model for acute anaphylactoid reaction,it was found that the positive control C48/80 significantly increased the histamine content in the plasma of mice,while the safflower yellow in each batch did not cause a significant increase in plasma histamine( P<0. 000 1). The mechanism of anaphylactoid reaction is relatively complicated. This study was mainly based on the release of histamine and other active substances by degranulation of mast cells. No significant degranulation reaction of RBL-2 H3 cells induced by safflower yellow for injection was detected,nor was the plasma histamine level significantly increased in mice from the in vitro and in vivo aspects.


Assuntos
Anafilaxia/induzido quimicamente , Degranulação Celular/efeitos dos fármacos , Chalcona/análogos & derivados , Mastócitos/efeitos dos fármacos , Animais , Células Cultivadas , Chalcona/efeitos adversos , Histamina/sangue , Camundongos
3.
Inorg Chem ; 58(19): 12954-12963, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31550148

RESUMO

The luminescent chalcone gold(I) conjugates [Au(PPh3)(AN3E)]PF6(1) and [Au(SIMes)(AN3E)]PF6 (2) (AN3E = (E)-3-(9-anthracenyl)-1-(4-pyridyl)propenone; SIMes = N,N'-dimesitylimidazolidin-2-ylidene; Mes = 2,4,6-trimethylphenyl)) were prepared and characterized; complex 1 was also characterized by X-ray crystallography. In MTT assays against a panel of three human colon, a melanoma and a breast cancer cell lines both complexes were antiproliferative with low micromolar IC50 values. It is noteworthy that HCT116p53-/- colon carcinoma cells lacking functional p53 (a vital tumor suppressor) were more susceptible to them than the wildtype parent cell line. In flow cytometry analyses, the gold conjugates induced a significant arrest in G2/M phase primarily. Complexes 1 and 2 quickly increased the production of reactive oxygen species (ROS) and induced mitochondrial membrane potential depolarization, higher ROS values being obtained after coadministration with enzymatic inhibitors. The free chalcone AN3E and its gold(I) complex conjugates located in the cell mitochondria according to confocal microscopy. In addition, complexes 1 and 2 showed in vivo antivascular effects on the chorioallantoic membrane (CAM) of fertilized specific-pathogen-free (SPF) chicken eggs.


Assuntos
Inibidores da Angiogênese/farmacologia , Antracenos/farmacologia , Antineoplásicos/farmacologia , Chalcona/farmacologia , Neoplasias do Colo/tratamento farmacológico , Compostos Organoáuricos/farmacologia , Inibidores da Angiogênese/química , Animais , Antracenos/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalcona/análogos & derivados , Galinhas , Cristalografia por Raios X , Células HCT116 , Humanos , Modelos Moleculares , Compostos Organoáuricos/química
4.
Molecules ; 24(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31510069

RESUMO

In this study, an in vitro tyrosinase inhibition assay in combination with ultra performance liquid chromatography-orbitrap mass spectrometry (UPLC-orbitrap-MS) was developed for the rapid screening and identification of tyrosinase modulators from roots of Angelica keiskei. Of the 15 candidates considered, nine chalcones, xanthoangelols (1), B (2), D (3), E (4), G (5), H (6), 4-hydroxyderricin (7), xanthokeismin B (8) and (2E)-1-[4-hydroxy-2-(2-hydroxy-2-propanyl)-2,3-dihydro-1-benzofuran-7-yl]-3-(4-hydroxyphenyl)-2-propen-1-one (9), five coumarins, umbelliferone (10), selinidin (11), isopimpinellin (12), phellopterin (13) and xanthyletin (14), and one other compound, ashitabaol A (15), were distinguished between the test samples and the controls with statistical significance, and the structure of each compound was determined by comparing with in-house standards and the literature. Among these, six compounds, xanthoangelol (1), xanthoangelol D (3), xanthoangelol H (6), 4-hydroxyderricin (7), laserpitin (16) and isolaserpitin (17), were isolated from roots of A. keiskei. Of the compounds isolated, compounds 1, 7 and 16 were subjected to tyrosinase inhibitory assay, and the IC50 values were 15.87 ± 1.21, 60.14 ± 2.29 and >100 µM, respectively. The present study indicated that the combination of in vitro tyrosinase inhibition assay coupled with UPLC-MS/MS could be widely applied to the rapid screening of active substances from various natural resources.


Assuntos
Angelica/química , Inibidores Enzimáticos/química , Monofenol Mono-Oxigenase/química , Raízes de Plantas/química , Chalcona/análogos & derivados , Chalcona/química , Chalconas/química , Cromatografia Líquida , Cumarínicos/química , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Espectrometria de Massas em Tandem , Umbeliferonas/química
6.
Biol Pharm Bull ; 42(11): 1942-1946, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31462605

RESUMO

Amyloid ß protein (Aß) causes neurotoxicity and cognitive impairment in Alzheimer's disease (AD). Oxidative stress is closely related to the pathogenesis of AD. We have previously reported that 2',3'-dihydroxy-4',6'-dimethoxychalcone (DDC), a component of green perilla, enhances cellular resistance to oxidative damage through the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway. Here, we investigated the effects of DDC on cortical neuronal death induced by Aß. When Aß and DDC had been preincubated for 3 h, the aggregation of Aß was significantly suppressed. In this condition, we found that DDC provided a neuroprotective action on Aß-induced cytotoxicity. Treatment with DDC for 24 h increased the expression of heme oxygenase-1 (HO-1), and this was controlled by the activation of the Nrf2-ARE pathway. However, DDC did not affect Aß-induced neuronal death under any of these conditions. These results suggest that DDC prevents the aggregation of Aß and inhibits neuronal death induced by Aß, and although it activates the Nrf2-ARE pathway, this mechanism is less involved its neuroprotective effect.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Chalcona/análogos & derivados , Chalcona/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/metabolismo , Heme Oxigenase-1/metabolismo , Síndromes Neurotóxicas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Perilla , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
7.
Food Funct ; 10(8): 4661-4673, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31292579

RESUMO

Hydroxysafflor yellow A (HSYA) is the main active ingredient of edible plant safflower. HSYA has demonstrated anti-inflammatory effects. The inflammatory response is the key mechanism responsible for asthma, and the pro-inflammatory platelet-activating factor (PAF) is known to play a role in the pathology of bronchial asthma. In this study, we stimulated human bronchial smooth muscle cells (HBSMCs) with PAF and examined the effects of HSYA on the resulting asthma-related process. PAF stimulation induced HBSMC activation, induced proliferation, increased expression of the pro-inflammatory cytokines interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α, and activated asthma-related signaling pathways. All these effects were significantly inhibited by treatment with HSYA (9, 27, 81 µmol L-1). The effects of HSYA were prevented by the addition of a PAF receptor (PAFR) antagonist or by PAFR gene silencing with small interfering RNA. These results suggest that HSYA may inhibit PAF-induced activation of HBSMCs by targeting the PAFR. Overall, these findings provide evidence that HSYA can be applied as a potential therapeutic agent in the treatment of bronchial asthma.


Assuntos
Brônquios/efeitos dos fármacos , Chalcona/análogos & derivados , Músculo Liso/metabolismo , Fator de Ativação de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Quinonas/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Brônquios/metabolismo , Chalcona/farmacologia , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Músculo Liso/efeitos dos fármacos , NF-kappa B/genética , NF-kappa B/metabolismo , Fator de Ativação de Plaquetas/genética , Glicoproteínas da Membrana de Plaquetas/genética , Receptores Acoplados a Proteínas-G/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
8.
Zhongguo Zhong Yao Za Zhi ; 44(12): 2566-2571, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31359725

RESUMO

This study was to investigate the mechanism of safflower yellow injection for regulating inflammatory response against myocardial ischemia-reperfusion injury( MIRI) in rats. Male Wistar rats were randomly divided into sham operation group,model group,Hebeishuang group,safflower yellow injection high,medium and low dose groups. MIRI model was established by ligating left anterior descending coronary artery. Myocardial histopathological changes were observed by HE staining; myocardial infarct size was detected by TTC staining; content and changes of tumor necrosis factor-α( TNF-α) and interleukin-6( IL-6),serum creatine kinase( CK),aspartate aminotransferase( AST),and lactate dehydrogenase( LDH) were detected by biochemical method or enzyme-linked immunosorbent assay( ELISA). Western blot assay was used to detect the protein expression of Toll-like receptor 4( TLR4) and nuclear factor-κB( NF-κB p65) in myocardial tissues. The results showed that as compared with the sham operation group,the myocardial arrangement of the model group was disordered,with severe edemain the interstitial,significantly increased area of myocardial infarction,increased activities of AST,CK and LDH in serum,and significantly increased contents of TNF-α and IL-6; the expression levels of TLR4 and NF-κB( p65) protein in myocardial tissues were also increased. As compared with the model group,the myocardial tissues were arranged neatlyin the Hebeishuang group and safflower yellow injection high,medium and low dose groups; the edema was significantly reduced; the myocardial infarct size was significantly reduced; the serum AST,CK,LDH activity and TNF-α,IL-6 levels were significantly decreased,and the expression levels of TLR4 and NF-κB( p65) protein in myocardial tissues were decreased. As compared with the Hebeishuang group,the myocardial infarct size was larger in the safflower yellow injection high,medium and low dose groups; the activities of AST,CK and LDH in serum and the contents of TNF-α and IL-6 in serum were higher,but there was no statistically significant difference in the expression levels of TLR4 and NF-κB( p65) protein in tissues. It is suggested that safflower yellow injection has a significant anti-MIRI effect,and its mechanism may be related to the regulation of TLR-NF-κB pathway to inhibit inflammatory response.


Assuntos
Anti-Inflamatórios/farmacologia , Chalcona/análogos & derivados , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Animais , Aspartato Aminotransferases/sangue , Chalcona/farmacologia , Creatina Quinase/sangue , Interleucina-6/metabolismo , L-Lactato Desidrogenase/sangue , Masculino , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
9.
J Pharm Biomed Anal ; 174: 1-7, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31153133

RESUMO

A simple, precise and reliable LC-MS/MS method was developed and validated for simultaneous quantification of vitexin, notoginsenoside R1, hydroxysafflor yellow A, ginsenoside Rd, puerarin, daidzein and senkyunolide I as components of Naodesheng (NDS) in rat serum. The Linearity ranges in rat serum were 0.045-4.5 µg/mL for vitexin, 0.0476-4.76 µg/mL for notoginsenoside R1, 0.0422-4.22 µg/mL for hydroxysafflor yellow A, 0.0426-4.26 µg/mL for ginsenoside Rd, 0.0436-4.36 µg/mL for puerarin, 0.026-2.6 µg/mL for daidzein, and 0.05-5 µg/mL for senkyunolide I, with the correlation coefficients greater than 0.99. The established method was validated in terms of intra- and inter-day precision and accuracy, recovery, matrix effect and stability. Furthermore, the method was successfully applied for pharmacokinetic study of these seven components in rat serum after oral administration of NDS.


Assuntos
Cromatografia Líquida/métodos , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Benzofuranos/sangue , Calibragem , Chalcona/análogos & derivados , Chalcona/sangue , Ginsenosídeos/sangue , Isoflavonas/sangue , Limite de Detecção , Modelos Lineares , Quinonas/sangue , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Fatores de Tempo
10.
Int J Mol Med ; 44(2): 405-416, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173173

RESUMO

Hydroxysafflor Yellow A (HSYA) may reduce ischemia/reperfusion (I/R) injury. However, the underlying molecular mechanisms remain unclear. The present study explored the effect and the mechanisms of HSYA on myocardial injury in vivo and in vitro. Myocardial infarct size was assessed by Evans blue/2,3,5­triphenyltetrazoliumchloride staining. Levels of cardiac troponin I (cTnI), interleukin­6 (IL­6), lactate dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured using commercial kits. Alteration of mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) generation was determined by fluorescent signals. Apoptosis was detected by terminal deoxynucleotidyl­transferase­mediated dUTP nick­end labeling staining, flow cytometry assay and caspase­3 activity. Expression levels of the apoptosis­associated proteins were detected by reverse transcription quantitative polymerase chain reaction and western blot analysis. In vivo, animals treated with HSYA presented less severe myocardial injury and decreased janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) activity, improved antioxidant capacity and decreased apoptosis. In vitro, compared with the hypoxia (H)/reoxygenation (R) + HSYA group, AG490 and S1491 treatment decreased the releases of cTnI, IL­6 and LDH and enhanced the resistance to oxidative stress by maintaining MMP and decreasing ROS generation. In addition, AG490 and S1491 were also identified to alleviate the H/R­induced apoptosis by inhibiting caspase 3 activity and modulating the expression levels of cleaved caspase­3, tumor necrosis factor receptor superfamily member 6 (Fas), Fas ligand, B­cell lymphoma 2 (Bcl­2) and Bcl­2­associated X protein. These data suggested that inactivation of the JAK2/STAT1 pathway strengthened the HSYA­induced protective effect in H/R­induced myocardial injury. In conclusion, the treatment of HSYA was effective in decreasing IR­induced myocardial injury, and this may be largely dependent on the JAK2/STAT1 pathway. Therefore, the present study provided a potential strategy to prevent myocardial I/R injury.


Assuntos
Chalcona/análogos & derivados , Janus Quinase 2/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Quinonas/uso terapêutico , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/uso terapêutico , Chalcona/uso terapêutico , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos Sprague-Dawley
11.
J Pediatr Endocrinol Metab ; 32(7): 653-665, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31194681

RESUMO

Diabetic nephropathy (DN) is considered as one of the most popular microvascular complications of diabetes and the leading cause of death among diabetic patients. Currently, even though safflower yellow (SY) is widely adapted in the clinical treatment of DN, no meta-analysis can guarantee the safety of this treatment. This paper aims to evaluate the dominant method of SY on DN disease. The reliable source of information for randomized controlled trials (RCTs) and clinical research is listed as follows: the Chinese Biomedical Literature database, Chongqing VIP, Embase, the Cochrane Library and the China Academic Journals Full-text Database (CNKI). The CNKI search included Chinese journal articles, the full-text of important conferences and dissertations up to March 30, 2017. We picked out some particularly influential outcome variables including urinary albumin excretion rate (UAER), fasting blood sugar (FBG), blood urea nitrogen (BUN) and high-sensitivity C-reactive protein (hs-CRP) in each extracted study. In total, 1289 participants were included in this meta-analysis. The efficacy of SY alone or combined with Western medicine in the treatment of DN was better with statistically significant factors (odds ratio [OR] = 3.6, 95% confidence interval [CI] [2.37, 5.47], p < 0.00001). We found that SY lessened the UAER, heightened the proportion of blood sugar and beneficially improved other detective indicators related to DN. Therefore, SY used alone or in combination with Western medicine was significantly more efficacious with lower toxicity than Western medicine alone.


Assuntos
Chalcona/análogos & derivados , Diabetes Mellitus/fisiopatologia , Nefropatias Diabéticas/prevenção & controle , Chalcona/uso terapêutico , Nefropatias Diabéticas/epidemiologia , Humanos , Incidência , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Recent Pat Anticancer Drug Discov ; 14(2): 187-197, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31096897

RESUMO

BACKGROUND: A recent patent has been issued for hydroxysafflor yellow A (HSYA) as a drug to prevent blood circulation disorders. Hydroxysafflor yellow B (HSYB), an isomer of HSYA with antioxidative effects, has been isolated from the florets of Carthamus tinctorius. The effects of HSYB on the proliferation of cancer cells and its mechanism of action have not been investigated. OBJECTIVE: The aims of this study were to investigate the anti-cancer effects and the molecular mechanism of HSYB for breast cancer MCF-7 cells. METHODS: MTT assays and colony formation assays were used to assess the survival and proliferation of MCF-7 cells, respectively. Hoechst 33258 and flow cytometry were used to measure cell apoptosis and flow cytometry to determine effects on the cell cycle. Western blots were used to measure protein levels. RESULTS: Treatment with HSYB reduced survival and proliferation of human breast cancer MCF-7 cells in a dose-dependent manner. Furthermore, HSYB arrested the MCF-7 cell cycle at the S phase and downregulated cyclin D1, cyclin E, and CDK2. Compared with a control group, HSYB suppressed the protein levels of p-PI3K, PI3K, AKT, and p-AKT in MCF-7 cells. In addition, HSYB decreased the levels of Bcl- 2, increased the levels of Bax, cleaved caspase-3 and caspase-9, and subsequently induced MCF-7 cell apoptosis. CONCLUSION: These data demonstrate that HSYB arrests the MCF-7 cell cycle at the S phase and induces cell apoptosis. Patent US20170246228 indicates that HSYB can be potentially used for the prevention and treatment of human breast cancer.


Assuntos
Adenocarcinoma/patologia , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Pigmentos Biológicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Chalcona/análogos & derivados , Chalcona/química , Chalcona/farmacologia , Feminino , Humanos , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pigmentos Biológicos/química , Quinonas/química , Quinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos
13.
Biomed Pharmacother ; 114: 108815, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30954890

RESUMO

This study aimed to explore mechanisms of the effects of hydroxysafflor yellow A (HSYA) on neural stem cells (NSCs) after heat stress (HS). Rat NSCs cells were cultured at 42 °C to impose heat stress. Cell counting kit-8 and Edu assay were used to analyze NSC proliferation. Annexin V/PI apoptosis kit was used to detect NSC apoptosis. Expression and phosphorylation of autophagy and apoptosis-associated proteins were determined by western blotting. We showed that HSYA significantly promoted proliferation and attenuated apoptosis of NSCs after heat stress. HSYA also increased Bcl-2 expression but decreased the expression of Bax and cleaved caspase-3 in NSCs induced by heat stress. In addition, HSYA decreased p38 and Hsp27-78 phosphorylation and MK-2 expression after heat stress, which was consistent with NSCs treated with SB203850 treatment or p38 knockdown. Furthermore, we demonstrated that heat stress increased LC3-II expression and mTOR phosphorylation, and decreased the expression of p62 in NSCs, while HSYA, SB203850 treatment or p38 knockdown reversed these alterations. In conclusion, HSYA significantly reversed the apoptosis and autophagy of NSCs induced by heat stress (P < 0.05), via downregulating MK2 expression and p38 and Hsp27-78 phosphorylation.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Chalcona/análogos & derivados , Resposta ao Choque Térmico/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Quinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Chalcona/farmacologia , Proteínas de Choque Térmico/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Ratos
14.
Hum Exp Toxicol ; 38(6): 685-693, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30873871

RESUMO

High glucose (HG) induces vascular injury in diabetes. Hydroxysafflor yellow A (HSYA) has been used to ameliorate ischemic cardiovascular diseases in China for many years. In the present study, we assessed whether HSYA has a potential protective role in HG-induced human umbilical vein endothelial cell (HUVEC) injury. Cell viability was determined with an 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Cell apoptosis was detected by fluorescein isothiocyanate/propidium iodide staining assay. The endothelial cell permeability was measured with a permeability assay. Cell adhesion molecule (CAM) expression, vascular endothelial growth factor, and basic fibroblast growth factor levels were detected with an enzyme-linked immunosorbent assay. Reactive oxygen species (ROS) formation was measured with a DCF-DA assay. Protein expression of NADPH oxidase 4 (NOX4) was measured by Western blotting. Our data indicated that HG increases HUVEC apoptosis, vascular permeability, monocyte adhesion, the level of CAMs, the formation of ROS, and NOX4 expression. Our data revealed that HG increases vascular injury, which is attenuated by HSYA. Because vascular inflammation has a key role in the development of diabetes mellitus, our results implied that HSYA is considered as a potential agent for diabetic vascular injury treatment.


Assuntos
Chalcona/análogos & derivados , Glucose/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Pigmentos Biológicos/farmacologia , Quinonas/farmacologia , Adesão Celular/efeitos dos fármacos , Chalcona/farmacologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , NADPH Oxidase 4/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células THP-1 , Molécula 1 de Adesão de Célula Vascular/metabolismo
15.
Life Sci ; 223: 128-136, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30876941

RESUMO

AIMS: Liquorice is a widely used herbal medicine for treating various diseases native to southern Europe and parts of Asia. Isoliquiritin (ISL), a licorice root-derived flavonoid, has been reported to exhibit antioxidant, anti-inflammatory, anti-genotoxic activity and anti-depression activities. This study was aimed to explore the pro-angiogenic activity of ISL and explicate the underlying mechanism. MAIN METHODS: In vitro, ISL-treated human umbilical vein endothelial cells (HUVECs) were analyzed for cell viability, cell migration and tube formation. In vivo, pro-angiogenic effects were evaluated for the intersegmental vessels (ISVs) formation in transgenic zebrafish embryos [Tg(fli-1: EGFP)]. Furthermore, a blocking assay with eight pathways-specific kinase inhibitors were also used to determine the potential pro-angiogenic mechanism of ISL. KEY FINDINGS: ISL counteracted tyrosine kinase inhibitor II (VRI)-induced endothelial cell apoptosis and promoted cell migration and tube formation in HUVECs. ISL markedly rescued ISVs loss induced by VRI in zebrafish embryos, probably by activating vascular endothelial growth factor receptor-2 (VEGFR-2), phosphoinositide 3-kinase (PI3K), Raf and mitogen-activated protein kinase (MEK)-dependent signaling pathways. SIGNIFICANCE: Our study first discovered and confirmed the pro-angiogenic activity of ISL both in HUVECs and zebrafish. Thus, ISL could be developed as a potential therapeutic agent by the role of pro-angiogenic activity for the treatment of cardiovascular diseases, cerebrovascular diseases and other vascular diseases.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Chalcona/análogos & derivados , Desenvolvimento Embrionário/efeitos dos fármacos , Glucosídeos/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Peixe-Zebra/embriologia , Quinases raf/metabolismo , Animais , Animais Geneticamente Modificados , Vasos Sanguíneos/embriologia , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Chalcona/farmacologia , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/enzimologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais , Peixe-Zebra/genética
16.
Cell Biochem Funct ; 37(3): 128-138, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30883849

RESUMO

Xanthoangelol (XAG), a prenylated chalcone isolated from the Japanese herb Angelica keiskei Koidzumi, has been reported to exhibit antineoplastic properties. However, the specific anti-tumor activity of XAG in human hepatocellular carcinoma (HCC), and the relevant mechanisms are not known. Herein, we evaluated the effect of XAG against HCC in vitro and in vivo. Although XAG treatment did not significantly reduce the viability of the Hep3B and Huh7 cell lines, it suppressed cell migration, invasion, and EMT. This anti-metastatic effect of XAG was due to induction of autophagy, because treatment with the autophagy inhibitor 3-methyadenine (3-MA) or knockdown of the pro-autophagy Beclin-1 effectively abrogated the XAG-induced suppression of metastasis. Mechanistically, XAG induced autophagy via activation of the AMPK/mTOR signaling pathway, and XAG treatment dramatically increased the expression of p-AMPK while decreasing p-mTOR expression. In addition, blocking AMPK/mTOR axis with compound C abrogated the autophagy-mediated inhibition of metastasis. The murine model of HCC metastasis also showed that XAG effectively reduced the number of metastatic pulmonary nodules. Taken together, our results revealed that autophagy via the activation of AMPK/mTOR pathway is essential for the anti-metastatic effect of XAG against HCC. These findings not only contribute to our understanding of the anti-tumor activity of XAG but also provide a basis for its clinical application in HCC. Before this study, evidence of XAG on HCC was purely anecdotal; present study provides the first comprehensive assessments of XAG on HCC metastasis and investigates its underlying mechanism. Results suggest that XAG exerts anti-metastatic properties against HCC through inducing autophagy which is mediated by the activation of AMPK/mTOR signaling pathway. This research extends our knowledge about the antineoplastic properties of XAG and suggests that induction autophagy may represent future treatment strategies for metastatic HCC.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Chalcona/análogos & derivados , Neoplasias Hepáticas/patologia , Metástase Neoplásica/prevenção & controle , Angelica/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalcona/química , Chalcona/isolamento & purificação , Chalcona/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
17.
Int Immunopharmacol ; 71: 100-108, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30884345

RESUMO

BACKGROUND: Chalcone, a natural product, has a wide range of biological activities. L2H17, a chalcone derivative, was synthesized and screened in our previous study and exhibited excellent anti-inflammatory property in vitro. This study investigated the therapeutic potential of L2H17 on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the role of heme oxygenase-1 (HO-1). MATERIALS AND METHODS: An ALI animal model was induced by LPS (10 mg/kg) intratracheal instillation. The effect of L2H17 on LPS-induced structural damage was determined using hematoxylin and eosin (HE) staining, and tissue edema extent was examined. Bronchoalveolar lavage fluid (BALF) was harvested to assess the levels of related cytokines by enzyme-linked immunosorbent assay (ELISA), and superoxide dismutase (SOD) activity was also assessed. HO-1 expression was determined using immunohistochemistry and western blotting. The effects of L2H17 on LPS stimulation in RAW 264.7 and the involvement of the HO-1 pathway were investigated. RESULTS: L2H17 alleviated the histopathological manifestations and tissue edema. Moreover, L2H17 decreased the production of pro-inflammatory factors in BALF and increased SOD activity. In vitro, L2H17 significantly reduced pro-inflammatory cytokine production. Additionally, L2H17 improved the expression of HO-1 in LPS-treated lung tissue and RAW 264.7. We also found that the inhibitory effect of L2H17 on the inflammatory responses was attenuated by an inhibitor of HO-1 activity, Tin protoporphyrin IX (SnPP). CONCLUSION: Our data confirmed that L2H17 can exert protective effect on ALI in vitro and in vivo by inhibiting inflammatory responses and modulating the HO-1 pathway.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Chalconas/uso terapêutico , Heme Oxigenase-1/metabolismo , Inflamação/tratamento farmacológico , Pulmão/patologia , Macrófagos/imunologia , Proteínas de Membrana/metabolismo , Animais , Anti-Inflamatórios/química , Chalcona/análogos & derivados , Chalconas/química , Modelos Animais de Doenças , Regulação da Expressão Gênica , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/genética , Humanos , Lipopolissacarídeos/imunologia , Pulmão/efeitos dos fármacos , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Metaloporfirinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Protoporfirinas/farmacologia , Células RAW 264.7
18.
Molecules ; 24(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897725

RESUMO

Targeted cancer therapy has become a high potential cancer treatment. Epidermal growth factor receptor (EGFR), which plays an important role in cell signaling, enhanced cell survival and proliferation, has been suggested as molecular target for the development of novel cancer therapeutics. In this study, a series of chalcone derivatives was screened by in vitro cytotoxicity against the wild type (A431 and A549) and mutant EGFR (H1975 and H1650) cancer cell lines, and, subsequently, tested for EGFR-tyrosine kinase (TK) inhibition. From the experimental screening, all chalcones seemed to be more active against the A431 than the A549 cell line, with chalcones 1c, 2a, 3e, 4e, and 4t showing a more than 50% inhibitory activity against the EGFR-TK activity and a high cytotoxicity with IC50 values of < 10 µM against A431 cells. Moreover, these five chalcones showed more potent on H1975 (T790M/L858R mutation) than H1650 (exon 19 deletion E746-A750) cell lines. Only three chalcones (1c, 2a and 3e) had an inhibitory activity against EGFR-TK with a relative inhibition percentage that was close to the approved drug, erlotinib. Molecular dynamics studies on their complexes with EGFR-TK domain in aqueous solution affirmed that they were well-occupied within the ATP binding site and strongly interacted with seven hydrophobic residues, including the important hinge region residue M793. From the above information, as well as ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, all three chalcones could serve as lead compounds for the development of EGFR-TK inhibitors.


Assuntos
Chalcona/análogos & derivados , Chalcona/farmacologia , Fator de Crescimento Epidérmico/antagonistas & inibidores , Fator de Crescimento Epidérmico/genética , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Células A549 , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Simulação de Dinâmica Molecular , Mutação/genética
19.
Biomed Chromatogr ; 33(7): e4521, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30818413

RESUMO

Lizhong decoction (LZD), a classic formula, has been used to treat ulcerative colitis (UC) for thousands of years in clinical practice. However, the pharmacokinetic characteristics of its major bioactive components in rats under different physiological and pathological states are not clear. Thus, in this study, a rapid and sensitive analytical method, ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS/MS) method, was developed and applied to simultaneously determine glycyrrhizic acid, liquiritin, isoliquiritin, glycyrrhizin, isoliquiritigenin, 6-gingerol, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Re in normal and UC rats after oral administration of LZD extract. A Waters BEH C18 UPLC column was used for chromatographic separation, while acetonitrile and 0.1% formic acid were selected as mobile phase. The linearity of nine analytes was >0.9920. Inter- and intra-day accuracy was ≤ 11.4% and precision was from 1.1 to 12.7%. Additionally, stable and suitable extraction recoveries were also obtained. The established method was validated and found to be specific, accurate and precise for nine analytes. Furthermore, it was successfully applied to the pharmacokinetic investigation of nine major components after oral administration of LZD extracts to normal and model rats, respectively. The results showed that the pharmacokinetic parameters (Cmax , Tmax , AUC0-t , AUC0-∞ ) in the plasma of UC rats were significantly different from those of normal rats, which could provide a reference for the clinical application of LZD.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Colite Ulcerativa/metabolismo , Medicamentos de Ervas Chinesas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Chalcona/análogos & derivados , Chalcona/sangue , Chalcona/química , Chalcona/farmacocinética , Medicamentos de Ervas Chinesas/administração & dosagem , Ginsenosídeos/sangue , Ginsenosídeos/química , Ginsenosídeos/farmacocinética , Glucosídeos/sangue , Glucosídeos/química , Glucosídeos/farmacocinética , Ácido Glicirrízico/sangue , Ácido Glicirrízico/química , Ácido Glicirrízico/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
20.
Mol Med Rep ; 19(4): 3009-3020, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816517

RESUMO

Stroke is the second most frequent cause of mortality, resulting in a huge societal burden worldwide. Timely reperfusion is the most effective therapy; however, it is difficult to prevent ischemia/reperfusion (I/R) injury. In traditional Chinese medicine, hydroxysafflor yellow A (HSYA) has been widely used for the treatment of cerebrovascular disease and as a protective therapy against I/R injury. Evidence has demonstrated that HSYA could reduce the levels of reactive oxygen species and suppress cellular apoptosis; however, whether HSYA alters the metabolic profile as its underlying mechanism for neuroprotection remains unknown. In the present study, using a metabolomic screening, phenylalanine was identified to significantly increase in an experimental model of mouse cerebral I/R injury. Notably, western blotting and qPCR analysis were conducted to test the expression level of apoptosis­associated factors, and HSYA was identified to be able to protect neuronal cells by reducing phenylalanine level associated with I/R injury. Additionally, these findings were confirmed in primary mouse neurons and PC12 cells exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) stress. Of note, HSYA was observed to regulate the mRNA expression of key metabolic enzymes, phenylalanine hydroxylase, tyrosine aminotransferase and aspartate aminotransferase, which are responsible for phenylalanine metabolism. Furthermore, by performing mitochondrial labeling and JC­1 fluorescence assay, HSYA was identified to promote mitochondrial function and biogenesis suppressed by OGD/R. The findings of the present study demonstrated that I/R injury could increase the levels of phenylalanine, and HSYA may inhibit phenylalanine synthesis to enhance mitochondrial function and biogenesis for neuroprotection. The present study proposed a novel metabolite biomarker for cerebral I/R injury and the evaluated the efficacy of HSYA as a potential therapeutic treatment I/R injury.


Assuntos
Isquemia Encefálica/metabolismo , Chalcona/análogos & derivados , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/farmacologia , Fenilalanina/biossíntese , Quinonas/farmacologia , Traumatismo por Reperfusão/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Chalcona/farmacologia , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Biogênese de Organelas , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Resultado do Tratamento
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