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1.
Int J Mol Sci ; 22(19)2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34639219

RESUMO

A five-step transformation of a spiroketal side chain of tigogenin into an indolizidine system present in solanidane alkaloids such as demissidine and solanidine was elaborated. The key intermediate in the synthesis was spiroimine 3 readily obtained from tigogenin by its RuO4 oxidation to 5,6-dihydrokryptogenin followed by amination with aluminum amide generated in situ from DIBAlH and ammonium chloride. The mild reduction of spiroimine to a 26-hydroxy-dihydropyrrole derivative and subsequent mesylation resulted in the formation of 25-epidemissidinium salt or 23-sulfone depending on reaction conditions.


Assuntos
Diosgenina/química , Iminas/química , Alcaloides de Solanáceas/química , Alcaloides de Solanáceas/síntese química , Espirostanos/química
2.
Zhongguo Zhong Yao Za Zhi ; 46(14): 3672-3677, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34402291

RESUMO

To explore the effect of ophiopogonin D on main fatty acid metabolic enzymes in human cardiomyocyte AC-16,so as to provide reference for cardiovascular protection mechanism and safe clinical application of Ophiopogon japonicus.CCK-8 (cell counting kit-8) was used to detect the effect of different concentrations of ophiopogonin D on the viability of cardiomyocytes.Meanwhile,the effect of different concentrations of ophiopogonin D on the morphology and quantity of cardiomyocytes was observed under microscope.The effect of ophiopogonin D on the mRNA expression of CYP2J2,CYP4F3,CYP4A11,CYP4A22 and CYP4F2 in cardiomyocytes was detected by RT-PCR.Western blot was used to detect the protein expression of CYP4F3 in different concentrations of ophiopogonin D.Compared with the control group,low-concentration ophiopogonin D had no effect on the viability of cardiomyocytes.However,ophiopogonin D with a concentration of higher than 20µmol·L~(-1)could promote the viability.Under the microscope,ophiopogonin D with a concentration of below 100µmol·L~(-1)had no significant effect on the morphology and number of cardiomyocytes.RT-PCR results showed that compared with the control group,5µmol·L~(-1)ophiopogonin D could slightly up-regulate mRNA expressions of CYP2J2 and CYP4F3,while high-concentration ophiopogonin D (10 and 20µmol·L~(-1)) could significantly induce mRNA expressions of CYP2J2and CYP4F3 in a dose-dependent manner (P<0.05).The same concentration of ophiopogonin D had a little effect on the mRNA expressions of CYP4A11,CYP4A22 and CYP4F2.Western blot results showed that 20µmol·L~(-1)ophiopogonin D could significantly induce the protein expression of CYP4F3 in a dose-dependent manner (P<0.05).Based on the above results,ophiopogonin D (less than100µmol·L~(-1)) has no effect on the viability of AC-16 cardiomyocytes.Ophiopogonin D (less than 100µmol·L~(-1)) can selectively induce the expressions of CYP2J2 and CYP4F3,regulate the metabolic pathway of fatty acid signaling molecules,and thus protecting the cardiovascular system.


Assuntos
Saponinas , Espirostanos , Ácidos Graxos , Humanos , Miócitos Cardíacos , Saponinas/farmacologia , Espirostanos/farmacologia
3.
Phytomedicine ; 91: 153686, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34333330

RESUMO

BACKGROUND: A crosstalk exists between diabetes and Alzheimer's disease (AD), and diabetic encephalopathy displays AD-like disorders. Sarsasapogenin (Sar) has strong anti-inflammatory efficacy, showing neuroprotection and memory-enhancement effects. PURPOSE: This study aims to verify the ameliorative effects of Sar on diabetic encephalopathy in vivo and in vitro, and to clarify the mechanisms from attenuation of AD-like pathology. METHODS: Streptozotocin-induced type 1 diabetic rats and high glucose-cultured SH-SY5Y cells were used in this study. After Sar treatment (20 and 60 mg/kg) for consecutive 9 weeks, Morris water maze and novel object recognition tasks were performed. Hematoxylin-eosin staining was used for examining loss of neurons in CA1 area and ki67 expression for reflecting neurogenesis in DG area of hippocampus. Aß production pathway and tau phosphorylation kinase cascade were examined in these two models. RESULTS: Sar improved learning and memory ability, loss of neurons and reduction of neurogenesis in the hippocampus of diabetic rats. Moreover, Sar suppressed Aß overproduction due to up-regulation of BACE1 in protein and mRNA and tau hyperphosphorylation from inactivation of AKT/GSK-3ß cascade in the hippocampus and cerebral cortex of diabetic rats and high glucose-cultured SH-SY5Y cells, and PPARγ antagonism abolished the effects of Sar on key molecules in the two pathways. Additionally, it was found that high glucose-stimulated Aß overproduction was prior to tau hyperphosphorylation in neurons. CONCLUSION: Sar alleviated diabetic encephalopathy, which was obtained through inhibitions of Aß overproduction and tau hyperphosphorylation mediated by the activation of PPARγ signaling. Hence, Sar is a good candidate compound for AD-like disorders.


Assuntos
Doença de Alzheimer , Encefalopatias/tratamento farmacológico , Diabetes Mellitus Experimental , Espirostanos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases , Linhagem Celular , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , PPAR gama , Fosforilação , Ratos , Proteínas tau/metabolismo
4.
Clin Exp Hypertens ; 43(8): 723-729, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34396877

RESUMO

Background/objectives: Steroidal saponins are widely distributed in medicinal plants with potential applications in cardiovascular disorders. Gitogenin, a saponin, has not been explored as antihypertensive; this investigation was aimed to explore its blood pressure lowering potential and underlying mechanisms.Methodology: The effect of gitogenin was evaluated on blood pressure in vivo, using normotensive rat model and the underlying cardiovascular mechanism(s) in vitro, in isolated rat aorta and in atria preparations using PowerLab data acquisition system (ADInstrument, Australia).Results: Intravenous injection of gitogenin decreased mean arterial pressure (MAP) in anesthetized rats. Atropine (1 mg/kg) and L-NAME (100 mg/kg) pretreatment significantly (*p < .05) attenuated effect on MAP to gitogenin. In isolated intact aortic rings, gitogenin induced endothelium-dependent vasodilatation (maximum 65%), which was ablated (maximum 22%) with L-NAME (100 mg/kg) and atropine (1 µM) pretreatment or endothelium removal. Gitogenin was found more potent against angiotensin II precontractions without effect on high K+ and low K+ precontractions. In isolated rat right atria, gitogenin suppressed rate and force of contractions. Atropine (1 µM) pretreatment partially inhibited effect of gitogenin on force and eliminated its effect on rate. Combined atropine (10 µM) and atenolol (0.5 µM) pretreatment was without effect on force of contractions but eliminated effect of gitogenin on rate with 25% increase.Conclusion: These findings indicate that antihypertensive effect of gitogenin is the outcome of vascular and cardiac effects; agonistic effect on vascular M3 and cardiac M2 receptors; and being more selective for M2. Increase in the rate of atrial contraction might be of clinical importance.


Assuntos
Hipertensão , Saponinas , Animais , Aorta Torácica , Pressão Sanguínea , Endotélio Vascular , Hipertensão/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Saponinas/farmacologia , Espirostanos , Vasodilatação
5.
Am J Chin Med ; 49(6): 1449-1471, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34263719

RESUMO

Gut microbiota has been proven to play an important role in many metabolic diseases and cardiovascular disease, particularly atherosclerosis. Ophiopogonin D (OPD), one of the effective compounds in Ophiopogon japonicus, is considered beneficial to metabolic syndrome and cardiovascular diseases. In this study, we have illuminated the effect of OPD in ApoE knockout (ApoE[Formula: see text] mice on the development of atherosclerosis and gut microbiota. To investigate the potential ability of OPD to alleviate atherosclerosis, 24 eight-week-old male ApoE[Formula: see text] mice (C57BL/6 background) were fed a high-fat diet (HFD) for 12 weeks, and 8 male C57BL/6 mice were fed a normal diet, serving as the control group. ApoE[Formula: see text] mice were randomly divided into the model group, OPD group, and simvastatin group ([Formula: see text]= 8). After treatment for 12 consecutive weeks, the results showed that OPD treatment significantly decreased the plaque formation and levels of serum lipid compared with those in the model group. In addition, OPD improved oral glucose tolerance and insulin resistance as well as reducing hepatocyte steatosis. Further analysis revealed that OPD might attenuate atherosclerosis through inhibiting mTOR phosphorylation and the consequent lipid metabolism signaling pathways mediated by SREBP1 and SCD1 in vivo and in vitro. Furthermore, OPD treatment led to significant structural changes in gut microbiota and fecal metabolites in HFD-fed mice and reduced the relative abundance of Erysipelotrichaceae genera associated with cholesterol metabolism. Collectively, these findings illustrate that OPD could significantly protect against atherosclerosis, which might be associated with the moderation of lipid metabolism and alterations in gut microbiota composition and fecal metabolites.


Assuntos
Aterosclerose/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Saponinas/farmacologia , Espirostanos/farmacologia , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Saponinas/química , Espirostanos/química
6.
Biochem Pharmacol ; 192: 114675, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34252407

RESUMO

Podocyte injury following abnormal podocyte autophagy plays an indispensable role in diabetic nephropathy (DN), therefore, restoration of podocyte autophagy is considered as a feasible strategy for the treatment of DN. Here, we investigated the preventive effects of sarsasapogenin (Sar), the main active ingredient in Anemarrhena asphodeloides Bunge, on the podocyte injury in diabetic rats, and tried to illustrate the mechanisms underlying the effects in high glucose (HG, 40 mM)-treated podocytes (MPs). Diabetes model was established in rats with single streptozocin (60 mg· kg-1) intraperitoneal administration. The rats were then treated with Sar (20, 60 mg· kg-1· d-1, i.g.) or a positive control drug insulin (INS) (40 U· kg-1· d-1, i.h.) for 10 weeks. Our results showed that both Sar and insulin precluded the decreases of autophagy-related proteins (ATG5, Beclin1 and LC3B) and podocyte marker proteins (podocin, nephrin and synaptopodin) in the diabetic kidney. Furthermore, network pharmacology was utilized to assess GSK3ß as the potential target involved in the action of Sar on DN and were substantiated by significant changes of GSK3ß signaling in the diabetic kidney. The underlying protection mechanisms of Sar were explored in HG-treated MPs. Sar (20, 40 µM) or insulin (50 mU/L) significantly increased the expression of autophagy- related proteins and podocyte marker proteins in HG-treated MPs. Furthermore, Sar or insulin treatment efficiently regulatedphosphorylation at activation and inhibition sites of GSK3ß. To sum up, this study certifies that Sar meliorates experimental DN through targeting GSK3ß signaling pathway and restoring podocyte autophagy.


Assuntos
Autofagia/efeitos dos fármacos , Nefropatias Diabéticas/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Glicogênio Sintase Quinase 3 beta/metabolismo , Podócitos/efeitos dos fármacos , Espirostanos/administração & dosagem , Animais , Autofagia/fisiologia , Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Masculino , Podócitos/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
7.
Molecules ; 26(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070073

RESUMO

Two new spirostanol sapogenins (5ß-spirost-25(27)-en-1ß,2ß,3ß,5ß-tetrol 3 and its 25,27-dihydro derivative, (25S)-spirostan-1ß,2ß,3ß,5ß-tetrol 4) and four new saponins were isolated from the roots and rhizomes of Convallaria majalis L. together with known sapogenins (isolated from Liliaceae): 5ß-spirost-25(27)-en-1ß,3ß-diol 1, (25S)-spirostan-1ß,3ß-diol 2, 5ß-spirost-25(27)-en-1ß,3ß,4ß,5ß-tetrol 5, (25S)-spirostan-1ß,3ß,4ß,5ß-tetrol 6, 5ß-spirost-25(27)-en-1ß,2ß,3ß,4ß,5ß-pentol 7 and (25S)-spirostan-1ß,2ß,3ß,4ß,5ß-pentol 8. New steroidal saponins were found to be pentahydroxy 5-O-glycosides; 5ß-spirost-25(27)-en-1ß,2ß,3ß,4ß,5ß-pentol 5-O-ß-galactopyranoside 9, 5ß-spirost-25(27)-en-1ß,2ß,3ß,4ß,5ß-pentol 5-O-ß-arabinonoside 11, 5ß-(25S)-spirostan-1ß,2ß,3ß,4ß,5ß-pentol 5-O-galactoside 10 and 5ß-(25S)-spirostan-1ß,2ß,3ß,4ß,5ß-pentol 5-O-arabinoside 12 were isolated for the first time. The structures of those compounds were determined by NMR spectroscopy, including 2D COSY, HMBC, HSQC, NOESY, ROESY experiments, theoretical calculations of shielding constants by GIAO DFT, and mass spectrometry (FAB/LSI HR MS). An attempt was made to test biological activity, particularly as potential chemotherapeutic agents, using in silico methods. A set of 12 compounds was docked to the PDB structures of HER2 receptor and tubulin. The results indicated that diols have a higher affinity to the analyzed targets than tetrols and pentols. Two compounds (25S)-spirosten-1ß,3ß-diol 1 and 5ß-spirost-25(27)-en-1ß,2ß,3ß,4ß,5ß-pentol 5-O-galactoside 9 were selected for further evaluation of biological activity.


Assuntos
Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Convallaria/química , Teoria da Densidade Funcional , Modelos Moleculares , Espectroscopia de Prótons por Ressonância Magnética , Sapogeninas/análise , Saponinas/análise , Espirostanos/análise , Simulação de Acoplamento Molecular , Sapogeninas/química , Sapogeninas/isolamento & purificação , Saponinas/química , Saponinas/isolamento & purificação , Espirostanos/química , Espirostanos/isolamento & purificação
8.
Am J Physiol Heart Circ Physiol ; 321(1): H185-H196, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34114892

RESUMO

We assessed the efficacy of oral supplementation with the flavanoid apigenin on arterial function during aging and identified critical mechanisms of action. Young (6 mo) and old (27 mo) C57BL/6N mice (model of arterial aging) consumed drinking water containing vehicle (0.2% carboxymethylcellulose; 10 young and 7 old) or apigenin (0.5 mg/mL in vehicle; 10 young and 9 old) for 6 wk. In vehicle-treated animals, isolated carotid artery endothelium-dependent dilation (EDD), bioassay of endothelial function, was impaired in old versus young (70% ± 9% vs. 92% ± 1%, P < 0.0001) due to reduced nitric oxide (NO) bioavailability. Old mice had greater arterial reactive oxygen species (ROS) production and oxidative stress (higher nitrotyrosine) associated with greater nicotinamide adenine dinucleotide phosphate oxidase (oxidant enzyme) and lower superoxide dismutase 1 and 2 (antioxidant enzymes); ex vivo administration of Tempol (antioxidant) restored EDD to young levels, indicating ROS-mediated suppression of EDD. Old animals also had greater aortic stiffness as indicated by higher aortic pulse wave velocity (PWV, 434 ± 9 vs. 346 ± 5 cm/s, P < 0.0001) due to greater intrinsic aortic wall stiffness associated with lower elastin levels and higher collagen, advanced glycation end products (AGEs), and proinflammatory cytokine abundance. In old mice, apigenin restored EDD (96% ± 2%) by increasing NO bioavailability, normalized arterial ROS, oxidative stress, and antioxidant expression, and abolished ROS inhibition of EDD. Moreover, apigenin prevented foam cell formation in vitro (initiating step in atherosclerosis) and mitigated age-associated aortic stiffening (PWV 373 ± 5 cm/s) by normalizing aortic intrinsic wall stiffness, collagen, elastin, AGEs, and inflammation. Thus, apigenin is a promising therapeutic for arterial aging.NEW & NOTEWORTHY Our study provides novel evidence that oral apigenin supplementation can reverse two clinically important indicators of arterial dysfunction with age, namely, vascular endothelial dysfunction and large elastic artery stiffening, and prevents foam cell formation in an established cell culture model of early atherosclerosis. Importantly, our results provide extensive insight into the biological mechanisms of apigenin action, including increased nitric oxide bioavailability, normalization of age-related increases in arterial ROS production and oxidative stress, reversal of age-associated aortic intrinsic mechanical wall stiffening and adverse remodeling of the extracellular matrix, and suppression of vascular inflammation. Given that apigenin is commercially available as a dietary supplement in humans, these preclinical findings provide the experimental basis for future translational studies assessing the potential of apigenin to treat arterial dysfunction and reduce cardiovascular disease risk with aging.


Assuntos
Envelhecimento/metabolismo , Endotélio Vascular/efeitos dos fármacos , Inflamação/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espirostanos/farmacologia , Rigidez Vascular/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/metabolismo , Endotélio Vascular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo
9.
Mol Med Rep ; 24(1)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34080657

RESUMO

Nasopharyngeal carcinoma (NPC) is a common malignant tumor in South China and is characterized by a high death rate. Ophiopogonin B (OP­B) is a bioactive component of Radix Ophiopogon japonicus, which is frequently used in traditional Chinese medicine to treat cancer. The present study aimed to examine the anti­cancer properties of OP­B on NPC cells. Cell viability and cell proliferation were measured using MTT and EdU assays. Flow cytometry was used to measure cell apoptosis, reactive oxygen species and mitochondrial membrane potential. Western blotting was used to investigate the expression of apoptosis and Hippo signaling pathway proteins. OP­B inhibited the proliferation of NPC cells by inducing apoptosis and disturbing the mitochondrial integrity. OP­B enhanced ROS accumulation. In addition, OP­B promoted the expression of mammalian STE20­like kinase 1, large tumor suppressor 1 and phosphorylated yes­associated protein (YAP) and suppressed the expression of YAP and transcriptional enhanced associate domain in NPC cells. OP­B increased the expression of forkhead box transcription factor O1 in the nuclear fraction. In conclusion, OP­B has therapeutic potential and feasibility in the development of novel YAP inhibitors for NPC.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Saponinas/farmacologia , Espirostanos/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias Nasofaríngeas/patologia , Transdução de Sinais/efeitos dos fármacos
10.
Phytother Res ; 35(6): 3167-3180, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33885189

RESUMO

Sarsasapogenin (Sar), a natural steroidal compound, shows neuroprotection, cognition-enhancement, antiinflammation, antithrombosis effects, and so on. However, whether Sar has ameliorative effects on diabetes-associated cognitive impairment remains unknown. In this study, we found that Sar ameliorated diabetes-associated memory impairment in streptozotocin-induced diabetic rats, evidenced by increased numbers of crossing platform and percentage of time spent in the target quadrant in Morris water maze tests, and suppressed the nucleotide-binding domain and leucine-rich repeat containing protein 1 (NLRP1) inflammasome in hippocampus and cerebral cortex. Furthermore, Sar inhibited advanced glycation end-products and its receptor (AGEs/RAGE) axis and suppressed up-regulation of thrombin receptor protease-activated receptor 1 (PAR-1) in cerebral cortex. On the other hand, Sar mitigated high glucose-induced neuronal damages, NLRP1 inflammasome activation, and PAR-1 up-regulation in high glucose-cultured SH-SY5Y cells, but did not affect thrombin activity. Moreover, the effects of Sar were similar to those of a selective PAR-1 antagonist vorapaxar. Further studies indicated that activation of the NLRP1 inflammasome and NF-κB mediated the effect of PAR-1 up-regulation in high glucose condition by using PAR-1 knockdown assay. In summary, this study demonstrated that Sar prevented memory impairment caused by diabetes, which was achieved through suppressing neuroinflammation from activated NLRP1 inflammasome and NF-κB regulated by cerebral PAR-1. HIGHLIGHTS: Sarsasapogenin ameliorated memory impairment caused by diabetes in rats. Sarsasapogenin mitigated neuronal damages and neuroinflammation by down-regulating cerebral PAR-1. The NLRP1 inflammasome and NF-κB signaling mediated the pro-inflammatory effects of PAR-1. Sarsasapogenin was a pleiotropic neuroprotective agent and memory enhancer in diabetic rodents.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Espirostanos/farmacologia , Animais , Linhagem Celular , Regulação para Baixo , Hipocampo/efeitos dos fármacos , Humanos , Inflamassomos/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor PAR-1/genética , Receptor PAR-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estreptozocina
11.
Molecules ; 26(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916300

RESUMO

Cholinesterase (ChE) inhibition is an important treatment strategy for Alzheimer's disease (AD) as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are involved in the pathology of AD. In the current work, ChE inhibitory potential of twenty-four natural products from different chemical classes (i.e., diosgenin, hecogenin, rockogenin, smilagenin, tigogenin, astrasieversianins II and X, astragalosides I, IV, and VI, cyclocanthosides E and G, macrophyllosaponins A-D, kokusaginin, lamiide, forsythoside B, verbascoside, alyssonoside, ipolamide, methyl rosmarinate, and luteolin-7-O-glucuronide) was examined using ELISA microtiter assay. Among them, only smilagenin and kokusaginine displayed inhibitory action against AChE (IC50 = 43.29 ± 1.38 and 70.24 ± 2.87 µg/mL, respectively). BChE was inhibited by only methyl rosmarinate and kokusaginine (IC50 = 41.46 ± 2.83 and 61.40 ± 3.67 µg/mL, respectively). IC50 values for galantamine as the reference drug were 1.33 ± 0.11 µg/mL for AChE and 52.31 ± 3.04 µg/mL for BChE. Molecular docking experiments showed that the orientation of smilagenin and kokusaginine was mainly driven by the interactions with the peripheral anionic site (PAS) comprising residues of hAChE, while kokusaginine and methyl rosmarinate were able to access deeper into the active gorge in hBChE. Our data indicate that similagenin, kokusaginine, and methyl rosmarinate could be hit compounds for designing novel anti-Alzheimer agents.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Sítios de Ligação , Produtos Biológicos/isolamento & purificação , Inibidores da Colinesterase/isolamento & purificação , Furanos/química , Furanos/farmacologia , Concentração Inibidora 50 , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Quinolinas/química , Quinolinas/farmacologia , Espirostanos/química , Espirostanos/farmacologia , Relação Estrutura-Atividade
12.
Int J Biol Macromol ; 179: 475-484, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33675837

RESUMO

Many Chinese herbs are well known for their neuroprotective and anti-oxidant properties. Extracts of Salvia miltiorrhiza and Anemarrhenae asphodeloides, tanshinone IIA (tanIIA), salvianolic acid B (Sal B) and sarsasapogenin (ML-1), were selected to study their dissociation potential towards Aß42 peptide fibrils and neuroprotective effect on cells. Moreover, derivatives of sarsasapogenin (ML-2, ML-3 and ML-4) have been prepared by the addition of modified carbamate moiety. TanIIA and Sal B have shown to possess a strong ability to dissociate Aß42 fibrils. The dissociation potential of ML-1 increased upon the introduction of carbamate moiety with N-heterocycles. In silico data revealed that derivatives ML-4 and Sal B interact with Aß42 regions responsible for fibril stabilization through hydrogen bonds. Contrary, tanIIA binds close to a central hydrophobic region, which may lead to destabilization of fibrils. Sarsasapogenin derivative ML-2 decreased nitride oxide production, and derivative ML-4 enhanced the growth of neurites. The reported data highlight the possibility of using active compounds to design novel treatment agents for Alzheimer's disease.


Assuntos
Abietanos/farmacologia , Peptídeos beta-Amiloides/metabolismo , Benzofuranos/farmacologia , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/metabolismo , Espirostanos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Anemarrhena/química , Linhagem Celular , China , Humanos , Extratos Vegetais , Salvia miltiorrhiza/química
13.
J Ethnopharmacol ; 271: 113914, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33571617

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Shengmai San (SMS) has been commonly used as a traditional Chinese medicine for the treatment of cardiovascular disorders, of which drug interactions need to be assessed for the safety concern. There is little evidence for the alterations of hepatic and intestinal drug-metabolizing enzymes after repeated SMS treatments to assess drug interactions. AIM OF THE STUDY: The studies aim to illustrate the effects of repeated treatments with SMS on cytochrome P450s (CYPs), reduced nicotinamide adenine dinucleotide (phosphate)-quinone oxidoreductase (NQO), uridine diphosphate-glucuronosyltransferase (UGT), and glutathione S-transferase (GST) using in vivo rat model. MATERIALS AND METHODS: The SMS was prepared using Schisandrae Fructus, Ginseng Radix, and Ophiopogonis Radix (OR) (1:2:2). Chromatographic analyses of decoctions were performed using ultra-performance liquid chromatography (UPLC) and LC-mass spectrometry. Sprague-Dawley rats were orally treated with the SMS and its component herbal decoctions for 2 or 3 weeks. Hepatic and intestinal enzyme activities were determined. CYP3A expression and the kinetics of intestinal nifedipine oxidation (NFO, a CYP3A marker reaction) were determined. RESULTS: Schisandrol A, schisandrin B, ginsenoside Rb1 and ophiopogonin D were identified in SMS. SMS selectively suppressed intestinal, but not hepatic, NFO activity in a dose- and time-dependent manner. Hepatic and intestinal UGT, NQO and GST activities were not affected. A 3-week SMS treatment decreased the maximal velocity of intestinal NFO by 50%, while the CYP3A protein level remained unchanged. Among SMS component herbs, the decoction of OR decreased intestinal NFO activity. CONCLUSIONS: These findings demonstrate that 3-week treatment with SMS and OR suppress intestinal, but not hepatic CYP3A function. It suggested that the potential interactions of SMS with CYP 3A drug substrates should be noticed, especially the drugs whose bioavailability depends heavily on intestinal CYP3A.


Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Intestinos/enzimologia , Fígado/enzimologia , Animais , Biomarcadores/sangue , Ciclo-Octanos/análise , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/análise , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Combinação de Medicamentos , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/uso terapêutico , Ginsenosídeos/análise , Glucuronosiltransferase/metabolismo , Glutationa Transferase/metabolismo , Interações Ervas-Drogas , Intestinos/efeitos dos fármacos , Lignanas/análise , Fígado/efeitos dos fármacos , Masculino , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Nifedipino/metabolismo , Oxirredução/efeitos dos fármacos , Compostos Policíclicos/análise , Ratos Sprague-Dawley , Saponinas/química , Espirostanos/química
14.
Drug Des Devel Ther ; 15: 233-243, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33505158

RESUMO

Background: Reineckia carnea is commonly used to treat cough, pneumonia and other diseases in China. In our previous study, it was found that the ethanol extracts of Reineckia carnea have a strong inhibitory effect on the proliferation of human lung cancer A549 cells. Here, we isolated gracillin from ethanol extracts for the first time. Purpose: Clarify the antiproliferation effect of gracillin on A549 cells and further explore its mechanisms via the mitochondrial pathway. Methods: Gracillin was isolated and purified by silica gel, D-101 macroporous resin and preparative RP-HPLC, then identified by NMR and HR-MS. The inhibitory effects of gracillin on the proliferation of A549 cells were detected by the MTS method. Its mechanisms were further explored by flow cytometry and Western blot. Results: A steroid saponin, gracillin, was isolated and identified from Reineckia carnea for the first time. In a concentration-dependent and time-dependent manner, gracillin significantly inhibited the proliferation of A549 cells with an IC50 value at 2.54 µmol/L and induced morphological changes. The results of flow cytometry analysis showed that the apoptosis rate of A549 cells was significantly increased (p < 0.05), and the cells proportion was obviously arrested in S phase. The concentration of intracellular calcium was raised (p < 0.01), and the mitochondrial membrane potential was greatly decreased (p < 0.01). In addition, the expression levels of Bax, caspase-3, cleaved caspase-3, and cytochrome C were dramatically up-regulated while Bcl-2 was down-regulated (p < 0.05) in A549 cells. Conclusion: This study confirmed that gracillin has a significant antiproliferative effect on A549 cells. Gracillin could induce the apoptosis of A549 cells through the mitochondrial pathway, which might be associated with regulation of the concentration of intracellular calcium, the mitochondrial membrane potential and the expression levels of Bax, Bcl-2, caspase-3, cleaved caspase-3, and cytochrome C.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Liliaceae/química , Mitocôndrias/efeitos dos fármacos , Espirostanos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Humanos , Mitocôndrias/metabolismo , Espirostanos/química , Espirostanos/isolamento & purificação
15.
J Ethnopharmacol ; 271: 113853, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33485986

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ophiopogonin D (OP-D) is a steroidal saponin extracted from Ophiopogon japonicus (Thunb.) Ker Gawl. (Liliaceae), that has been traditionally used to treat cough, sputum, and thirst in some Asian countries. Recently, various pharmacological roles of OP-D have been identified, including anti-inflammatory, cardioprotective, and anti-cancer effects. However, whether OP-D can prevent diabetic myocardial injury remains unknown. AIM OF THE STUDY: In this study, we aimed to observe the effects of OP-D on the diabetic myocardium. MATERIALS AND METHODS: Leptin receptor-deficient db/db mice were used as an animal model for type 2 diabetes. The effects of OP-D on blood glucose, blood lipids, myocardial ultrastructure, and mitochondrial function in mice were observed after four weeks of intragastric administration. Palmitic acid was used to stimulate cardiomyocytes to establish a myocardial lipotoxicity model. Cell apoptosis, mitochondrial morphology, and function were observed. RESULTS: Blood glucose and blood lipid levels were significantly increased in db/db mice, accompanied by myocardial mitochondrial injury and dysfunction. OP-D treatment reduced blood lipid levels in db/db mice and relieved mitochondrial injury and dysfunction. OP-D inhibited palmitic acid induced-mitochondrial fission and dysfunction, reduced endogenous apoptosis, and improved cell survival rate in H9C2 cardiomyocytes. Both in vivo and in vitro models showed increased phosphorylation of DRP1 at Ser-616, reduced phosphorylation of DRP1 at Ser-637, and reduced expression of fusion proteins MFN1/2 and OPA1. Meanwhile, immunofluorescence co-localization analysis revealed that palmitic acid stimulated the translocation of DRP1 protein from the cytoplasm to the mitochondria in H9C2 cardiomyocytes. The imbalance of mitochondrial dynamics, protein expression, and translocation of DRP1 were effectively reversed by OP-D treatment. In isolated mice ventricular myocytes, palmitic acid enhanced cytoplasmic Ca2+ levels and suppressed contractility in ventricular myocytes, accompanied by activation of calcineurin, a key regulator of DRP1 dephosphorylation at Ser-637. OP-D reversed the changes caused by palmitic acid. CONCLUSIONS: Our findings indicate that OP-D intervention could alleviate lipid accumulation and mitochondrial injury in diabetic mouse hearts and palmitic acid-stimulated cardiomyocytes. The cardioprotective effect of OP-D may be mediated by the regulation of mitochondrial dynamics.


Assuntos
Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Cardiomiopatias Diabéticas/prevenção & controle , Dinâmica Mitocondrial/efeitos dos fármacos , Saponinas/farmacologia , Saponinas/uso terapêutico , Espirostanos/farmacologia , Espirostanos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Calcineurina/metabolismo , Cálcio/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Modelos Animais de Doenças , Dinaminas/antagonistas & inibidores , Lipídeos/sangue , Fígado/efeitos dos fármacos , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Miócitos Cardíacos/efeitos dos fármacos , Ácido Palmítico/toxicidade , Ratos
16.
Xenobiotica ; 51(3): 262-267, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33115303

RESUMO

Ophiopogonin D is a commonly used herb in cardiology and pediatrics for its variuos pharmacological effects. It is necessary to investigate the effect of ophiopogonin D on the activity of cytochrome P450 enzymes (CYP450s) to provide more guidance for the clinical application of ophiopogonin D. Eight isoforms of CYP450s, including CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 were incubated with 100 µM ophiopogonin D in pooled human liver microsomes. The inhibition model and corresponding parameters were also investigated. Ophiopogonin D exerted a significant inhibitory effect on the activity of CYP3A4, 2C9, and 2E1 in a dose-dependent manner with the IC50 values of 8.08, 12.92, and 22.72 µM, respectively (p < 0.05). The inhibition of CYP3A4 by ophiopogonin D was performed non-competitively and time-dependently with the Ki value of 4.08 µM and the KI/Kinact value of 5.02/0.050 min-1·µM-1. Whereas, ophiopogonin D acts as a competitive inhibitor of CYP2E1 and 2C9 with the Ki value of 6.69 and 11.07 µM, respectively. The inhibitory effect of ophiopogonin D on the activity of CYP3A4, 2C9, and 2E1 indicated the potential drug-drug interaction between ophiopogonin D and drugs metabolized by these CYP450s, which needs further in vivo investigation and validation.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Saponinas/farmacologia , Espirostanos/farmacologia , Sistema Enzimático do Citocromo P-450 , Humanos , Microssomos Hepáticos/enzimologia
17.
Acta Pharmacol Sin ; 42(2): 272-281, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32699264

RESUMO

Insulin resistance is a major cause of type 2 diabetes and metabolic syndrome. Macrophage infiltration into obese adipose tissue promotes inflammatory responses that contribute to the pathogenesis of insulin resistance. Suppression of adipose tissue inflammatory responses is postulated to increase insulin sensitivity in obese patients and animals. Sarsasapogenin (ZGY) is one of the metabolites of timosaponin AIII in the gut, which has been shown to exert anti-inflammatory action. In this study, we investigated the effects of ZGY treatment on obesity-induced insulin resistance in mice. We showed that pretreatment with ZGY (80 mg·kg-1·d-1, ig, for 18 days) significantly inhibited acute adipose tissue inflammatory responses in LPS-treated mice. In high-fat diet (HFD)-fed obese mice, oral administration of ZGY (80 mg·kg-1·d-1, for 6 weeks) ameliorated insulin resistance and alleviated inflammation in adipose tissues by reducing the infiltration of macrophages. Furthermore, we demonstrated that ZGY not only directly inhibited inflammatory responses in macrophages and adipocytes, but also interrupts the crosstalk between macrophages and adipocytes in vitro, improving adipocyte insulin resistance. The insulin-sensitizing and anti-inflammatory effects of ZGY may result from inactivation of the IKK /NF-κB and JNK inflammatory signaling pathways in adipocytes. Collectively, our findings suggest that ZGY ameliorates insulin resistance and alleviates the adipose inflammatory state in HFD mice, suggesting that ZGY may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.


Assuntos
Inflamação/tratamento farmacológico , Resistência à Insulina , Obesidade/tratamento farmacológico , Espirostanos/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Tecido Adiposo/efeitos dos fármacos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/complicações , Células RAW 264.7 , Espirostanos/administração & dosagem
18.
Acta Pharmacol Sin ; 42(5): 726-734, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32855531

RESUMO

The inhalation of particulate matter (PM) is closely related to respiratory damage, including acute lung injury (ALI), characterized by inflammatory fluid edema and disturbed alveolar-capillary permeability. Ruscogenin (RUS), the main active ingredient in the traditional Chinese medicine Ophiopogonis japonicus, has been found to exhibit anti-inflammatory activity and rescue LPS-induced ALI. In this study, we investigated whether and how RUS exerted therapeutic effects on PM-induced ALI. RUS (0.1, 0.3, 1 mg·kg-1·d-1) was orally administered to mice prior to or after intratracheal instillation of PM suspension (50 mg/kg). We showed that RUS administration either prior to or after PM challenge significantly attenuated PM-induced pathological injury, lung edema, vascular leakage and VE-cadherin expression in lung tissue. RUS administration significantly decreased the levels of cytokines IL-6 and IL-1ß, as well as the levels of NO and MPO in both bronchoalveolar lavage fluid (BALF) and serum. RUS administration dose-dependently suppressed the phosphorylation of NF-κB p65 and the expression of TLR4 and MyD88 in lung tissue. Furthermore, TLR4 knockout partly diminished PM-induced lung injury, and abolished the protective effects of RUS in PM-instilled mice. In conclusion, RUS effectively alleviates PM-induced ALI probably by inhibition of vascular leakage and TLR4/MyD88 signaling. TLR4 might be crucial for PM to initiate pulmonary lesion and for RUS to exert efficacy against PM-induced lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Endotélio/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Espirostanos/uso terapêutico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/patologia , Animais , Técnicas de Inativação de Genes , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/patologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos ICR , Fator 88 de Diferenciação Mieloide/metabolismo , Material Particulado , Substâncias Protetoras/uso terapêutico , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
19.
J Cell Mol Med ; 25(2): 801-812, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33259114

RESUMO

Colorectal cancer (CRC) accounts for about 10% of all annually diagnosed cancers and cancer-related deaths worldwide. STAT3 plays a vital role in the occurrence and development of tumours. Gracillin has shown a significant antitumour activity in tumours, but its mechanism remains unknown. The human CRC cell lines HCT116, RKO, and SW480 and immunodeficient mice were used as models to study the effects of gracillin on cell proliferation, migration and apoptosis. These were evaluated by cell viability, colony formation, wound-healing migration and cell apoptosis assays. Luciferase reporter assay, and immunostaining and western blot analyses were used to explore the specific mechanism through which gracillin exerts its effects. Gracillin significantly reduces viability and migration and stimulates apoptosis in human CRC cells. It also significantly inhibits tumour growth with no apparent physiological toxicity in animal model experiments. Moreover, gracillin is found to inhibit STAT3 phosphorylation and STAT3 target gene products. In addition, gracillin inhibits IL6-induced nuclear translocation of P-STAT3. Gracillin shows potent efficacy against CRC by inhibiting the STAT3 pathway. It should be further explored as a unique STAT3 inhibitor for the treatment of CRC.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Espirostanos/farmacologia , Espirostanos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Ethnopharmacol ; 264: 113381, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32946961

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Recently, a new drug combination GRS comprising ginsenoside Rb1 (G-Rb1), ruscogenin (R-Rus) and schisandrin (S-SA) was screened based on ShengMai preparations, which exhibited a prominent cardioprotective effects against myocardial ischemia/reperfusion (MI/R) injury. AIM OF THE STUDY: To investigate their systemic and individual mechanism of each compound in combination GRS. MATERIALS AND METHODS: The mice model of MI/R and hypoxia/reoxygenation (H/R)-induced cardiomyocytes injury were performed to explore the respective characteristics of each compound in GRS against myocardial injury. RESULTS: Each component in the combination GRS attenuated MI/R injury as evidenced by decreased myocardial infarct size, ameliorated histological features, and improved biochemical indicators. Meanwhile, ingredient G, R and S in combination also individually performed a significant decrease of apoptotic index in MI/R mice and H/R-induced cardiomyocytes injury. Mechanistically, component G in GRS could markedly increase the ATP content in cardiomyocytes through activation of AMPKα phosphorylation. Interestingly, the anti-apoptotic actions of G were profoundly attenuated by knockdown of AMPKα, while no alteration was observed on composition R and S. Moreover, component R in GRS significantly reduced the IL-6 and TNF-α mRNA expression, as well as the content of IL-6 via the modulation of NF-κB signaling pathway. Further, component S exhibited the most powerful anti-oxidative capacity in GRS and remarkably decreased the production of MDA and ROS, and potential mechanisms might at least in part through activating the Akt-14-3-3 signaling pathway and inhibiting the phosphorylation of Bad and ERK1/2. CONCLUSIONS: Our results indicated that the respective mechanism of each compound in combination GRS against MI/R injury might closely associated with energy metabolism modulation, suppression of inflammation and oxidative stress.


Assuntos
Ciclo-Octanos/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Ginsenosídeos/administração & dosagem , Lignanas/administração & dosagem , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Compostos Policíclicos/administração & dosagem , Espirostanos/administração & dosagem , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Ciclo-Octanos/isolamento & purificação , Combinação de Medicamentos , Medicamentos de Ervas Chinesas/isolamento & purificação , Ginsenosídeos/isolamento & purificação , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Lignanas/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos ICR , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Compostos Policíclicos/isolamento & purificação , Ratos , Espirostanos/isolamento & purificação , Resultado do Tratamento
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