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1.
Phytomedicine ; 62: 152948, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31129431

RESUMO

BACKGROUND: Huangqi decoction (HQD), a classic traditional herbal medicine, has been used for liver fibrosis, but its effect on intrahepatic chronic cholestatic liver injury remains unknown. PURPOSE: In the present study, we investigated the hepatoprotective effect of HQD and the underlying molecular mechanisms in 3, 5-diethoxycarbonyl-1, 4-dihydroxychollidine (DDC)-induced chronic cholestatic mice. METHODS: The DDC-induced cholestatic mice were administrated HQD for 4 or 8 weeks. Serum biochemistry and morphology were investigated. The serum and liver bile acid (BA) levels were detected by ultra performance liquid chromatography-tandem mass spectrometry. The liver expression of BA metabolizing enzymes and transporters, and inflammatory and fibrotic markers was measured by real-time polymerase chain reaction, western blotting, and immunohistochemistry. RESULTS: HQD treatment for 4 or 8 weeks ameliorated DDC-induced liver injury by improving impaired hepatic function and tissue damage. HQD treatment for 8 weeks further decreased the liver expression of cytokeratin 19, tumor growth factor (TGF)-ß, collagen I, and α-smooth muscle actin, and ameliorated ductular reaction and liver fibrosis. HQD markedly decreased the accumulation of serum and liver BA. The expression of BA-metabolizing enzymes, cytochrome P450 2b10 and UDP glucuronosyltransferase 1 A1, and multidrug resistance-associated protein 2, Mrp3, and Mrp4 involved in BA homeostasis was increased by 4 weeks of HQD treatment. The expression of BA uptake transporter Na+-taurocholate cotransporting polypeptide was decreased and that of Mrp4 was increased after 8 weeks of HQD treatment. Nuclear factor-E2-related factor-2 (Nrf2) was remarkably induced by HQD treatment. Additionally, HQD treatment for 8 weeks decreased the liver expression of inflammatory factors, interleukin (IL)-6, IL-1ß, tumor necrosis factor-α, monocyte chemoattractant protein-1, and intracellular adhesion molecule-1. HQD suppressed the nuclear factor (NF)-κB pathway. CONCLUSION: HQD protected mice against chronic cholestatic liver injury and biliary fibrosis, which may be associated with the induction of the Nrf2 pathway and inhibition of the NF-κB pathway, ameliorating BA-stimulated inflammation.

2.
Biosci Rep ; 39(4)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30944202

RESUMO

Berberine is a natural alkaloid that has antineoplastic effects. However, in hepatoma cells like HepG2, the expressions of uptake transporters are minimal but efflux transporters are relatively high. Hence, how berberine enters and reaches a cytocidal concentration remains to be elucidated. In the present study, we revealed the accumulation mechanism of berberine in HepG2 cells. Cell organelles were isolated based on differential centrifugation; berberine concentration was measured using a liquid chromatography-tandem mass chromatography method or flow cytometry. Subcellular distribution of berberine was observed using a laser scanning confocal microscopy. The results showed that berberine was concentration-, temperature-, and time-dependently taken up and accumulated in HepG2 cells. Membrane drug transporters and cell membrane potential had limited effects in berberine uptake. However, qualitative and quantitative studies showed that berberine was enriched in the mitochondria; inhibition of mitochondrial membrane potential (MMP) by carbonyl cyanide 3-chlorophenylhydrazone (CCCP) significantly decreased the intracellular berberine by up to 70%. More importantly, MMP not only significantly enhanced berberine uptake driven by cell membrane potential (P<0.01) but also inhibited p-glycoprotein (P-gp)-mediated berberine efflux (P<0.01). In brief, our results for the first time showed that MMP played crucial roles in berberine accumulation in HepG2 cells.

3.
Biomed Pharmacother ; 112: 108701, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30818137

RESUMO

Natural bear bile has been used for liver disease in East Asia for thousands of years. However, its use has restrictions. In the current study, the therapeutic effects and potential mechanisms of cultured bear bile powder (CBBP) against hepatic fibrosis were evaluated in a dimethylnitrosamine (DMN)-induced rat model. CBBP treatment significantly improved DMN-induced hepatic necrosis and inflammatory infiltration. Additionally, CBBP remarkably alleviated the increased hepatic collagen content and expression of alpha-smooth muscle actin. Serum metabolomics revealed that 14 serum metabolites, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were decreased in DMN-treated rats, which was reversed by CBBP. Pathway analyses revealed that the main metabolic pathways affected by CBBP were related to fatty acid biosynthesis and metabolism, and biosynthesis of unsaturated fatty acids. EPA and DHA are ligands of peroxisome proliferator activated receptors (PPARs). CBBP treatment significantly stimulated liver mRNA and protein expression of PPARα and PPARγ. CBBP also markedly increased liver expression of PPARα target genes, which are involved in fatty acid ß-oxidation, and down-regulated IL-6, a downstream inflammatory gene of PPARγ. In conclusion, CBBP has the potential to attenuate liver fibrosis and its mechanism involves the promotion of the liver expression of PPARα and PPARγ. Our results may help in the development of a novel substitute for bear bile and therapeutic strategies for fibrotic liver diseases.


Assuntos
Bile/metabolismo , Citoproteção/efeitos dos fármacos , Dimetilnitrosamina/toxicidade , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Animais , Bile/química , Citoproteção/fisiologia , Relação Dose-Resposta a Droga , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Cirrose Hepática Experimental/prevenção & controle , Distribuição Aleatória , Ratos , Ratos Wistar , Ursidae
4.
Drug Metab Rev ; : 1-18, 2018 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-30270675

RESUMO

After administration, drug molecules usually enter target cells to access their intracellular targets. In eukaryotic cells, these targets are often located in organelles, including the nucleus, endoplasmic reticulum, mitochondria, lysosomes, Golgi apparatus, and peroxisomes. Each organelle type possesses unique biological features. For example, mitochondria possess a negative transmembrane potential, while lysosomes have an intraluminal delta pH. Other properties are common to several organelle types, such as the presence of ATP-binding cassette (ABC) or solute carrier-type (SLC) transporters that sequester or pump out xenobiotic drugs. Studies on subcellular drug distribution are critical to understand the efficacy and toxicity of drugs along with the body's resistance to them and to potentially offer hints for targeted subcellular drug delivery. This review summarizes the results of studies from 1990 to 2017 that examined the subcellular distribution of small molecular drugs. We hope this review will aid in the understanding of drug distribution within cells.

5.
Molecules ; 23(8)2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111723

RESUMO

Pharmacokinetic studies are crucial for elucidating the effective constituents and formula compatibility of traditional Chinese medicines (TCMs). However, studies have usually been limited to single dosages and detection of systemic blood concentrations. To obtain comprehensive pharmacokinetic information, here we propose a multi-dosage and multi-sampling (blood from portal vein or systemic circulation, and liver) strategy to comparatively study the pharmacokinetics of multi-form TCMs, i.e., pure constituents, TCMs, or TCM formula extracts. Based on this strategy, we studied the pharmacokinetics of pure berberine, berberine in CoptidisRhizoma (CRE), and berberine in CoptidisRhizoma-GlycyrrhizaeRadix etRhizoma extracts (CR-GRE). After simple calculation and comparison of the obtained area under the curve (AUC) values, the results revealed the drastically different pharmacokinetic properties of pure berberine compared to CRE and CR-GRE. The results contribute to explaining the pharmacological loss of berberine activity after purification and the compatibility of the CR-GR drug pair. The results also innovatively showed that it was intestinal absorption that differentiated the pharmacokinetics of CRE and pure berberine, and CRE and CR-GRE. In conclusion, we propose a composite strategy to comparatively study the pharmacokinetics of TCMs, which could provide sufficient information to obtain a comprehensive view, before follow-up mechanism-of-action studies.

6.
Biomed Chromatogr ; 32(5): e4178, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29243282

RESUMO

A rapid, sensitive and accurate UPLC-MS/MS method was developed for the simultaneous quantification of components of Huangqi decoction (HQD), such as calycosin-7-O-ß-d-glucoside, calycosin-glucuronide, liquiritin, formononetin-glucuronide, isoliquiritin, liquiritigenin, ononin, calycosin, isoliquiritigenin, formononetin, glycyrrhizic acid, astragaloside IV, cycloastragenol, and glycyrrhetinic acid, in rat plasma. After plasma samples were extracted by protein precipitation, chromatographic separation was performed with a C18 column, using a gradient of methanol and 0.05% acetic acid containing 4mm ammonium acetate as the mobile phase. Multiple reaction monitoring scanning was performed to quantify the analytes, and the electrospray ion source polarity was switched between positive and negative modes in a single run of 10 min. Method validation showed that specificity, linearity, accuracy, precision, extraction recovery, matrix effect and stability for 14 components met the requirements for their quantitation in biological samples. The established method was successfully applied to the pharmacokinetic study of multiple components in rats after intragastric administration of HQD. The results clarified the pharmacokinetic characteristics of multiple components found in HQD. This research provides useful information for understanding the relation between the chemical components of HQD and their therapeutic effects.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Feminino , Flavonoides/sangue , Flavonoides/química , Flavonoides/farmacocinética , Glucosídeos/sangue , Glucosídeos/química , Glucosídeos/farmacocinética , Glicosídeos/sangue , Glicosídeos/química , Glicosídeos/farmacocinética , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Terpenos/sangue , Terpenos/química , Terpenos/farmacocinética
7.
Oncotarget ; 8(57): 97137-97152, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29228599

RESUMO

This study explored the effects of chicken bile powder (CBP), a 2000-year-old Chinese medicine, on α-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis in mice. CBP treatment for 14 days significantly ameliorated ANIT-induced changes in serum alanine aminotransferase, aspartate aminotransferase, bile acids, bilirubin, γ-glutamyl transpeptidase, alkaline phosphatase, and liver tissue morphology. Serum metabolomics showed changes in 24 metabolites in ANIT-exposed mice; 16 of these metabolites were reversed by CBP treatment via two main pathways (bile acid biosynthesis and arachidonic acid metabolism). Additionally, CBP administration markedly increased fecal and biliary bile acid excretion, and reduced total and hydrophobic bile acid levels in the livers of cholestatic mice. Moreover, CBP increased liver expression of bile acid efflux transporters and metabolic enzymes. It also attenuated ANIT-induced increases in hepatic nuclear factor-κB-mediated inflammatory signaling, and increased liver expression of the nuclear farnesoid X receptor (FXR) in cholestatic mice. CBP also activated FXR in vitro in HEK293T cells expressing mouse Na+-taurocholate cotransporting polypeptide. It did not ameliorate the ANIT-induced liver injuries in FXR-knockout mice. These results suggested that CBP provided protection from cholestatic liver injury by restoring bile acid homeostasis and reducing inflammation in a FXR-dependent manner.

8.
Front Pharmacol ; 8: 938, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29311939

RESUMO

Intrahepatic cholestasis is a serious symptom of liver disorders with limited therapies. In this study, we investigated the efficacy of Huangqi decoction (HQD), a two-herb classic traditional Chinese medicine (TCM), in the treatment of alpha-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis in mice. HQD treatment ameliorated impaired hepatic function and tissue damage. A metabolomics study revealed that the endogenous metabolites significantly affected by HQD were related to bile acid (BA) biosynthesis and glutathione metabolism pathways. HQD treatment decreased the intrahepatic accumulation of cytotoxic BAs, normalized serum BA levels, and increased biliary and urinary BA excretion. Additionally, HQD restored the hepatic glutathione content and suppressed reactive oxygen species (ROS) in cholestatic mice. Protein and gene analysis revealed that HQD increased the expression of the hepatic metabolizing enzymes cytochrome P450 (CYP) 2B10 and UDP glucuronosyltransferase family 1 member A1 (UGT1A1), as well as multidrug resistance-associated protein 2 (Mrp2), Mrp3, and Mrp4, which play crucial roles in BA homeostasis. Further, HQD increased the protein expression of glutamate-cysteine ligase, which is involved in the synthesis of glutathione. Importantly, HQD increased the nuclear expression of nuclear factor-E2-related factor-2 (Nrf2). In conclusion, HQD protects against intrahepatic cholestasis by reversing the disordered homeostasis of BAs and glutathione.

9.
Front Pharmacol ; 7: 345, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27733832

RESUMO

Background and purpose: Silymarin, a standardized extract of the milk thistle seeds, has been widely used to treat chronic hepatitis, cirrhosis, and other types of toxic liver damage. Despite increasing studies on the action of silymarin and its major active constituent, silybin in their therapeutic properties against insulin resistance, diabetes and hyperlipidaemia in vitro and in vivo, the mechanism underlying silymarin action remains unclear. Experimental approach: C57BL/6 mice were fed high-fat diet (HFD) for 3 months to induce obesity, insulin resistance, hyperlipidaemia, and fatty liver. These mice were then continuously treated with HFD alone or mixed with silymarin at 40 mg/100 g for additional 6 weeks. Biochemical analysis was used to test the serum lipid and bile acid profiles. Farnesyl X receptor (FXR) and nuclear factor kappa B (NF-κB) transactivities were analyzed in liver using a gene reporter assay based on quantitative RT-PCR. Key results: Silymarin treatment ameliorated insulin resistance, dyslipidaemia and inflammation, and reconstituted the bile acid pool in liver of diet-induced obesity. Associated with this, silybin and silymarin enhanced FXR transactivity. Consistently, in HepG2 cells, silybin inhibited NF-κB signaling, which was enhanced by FXR activation. Conclusion and implications: Our results suggest that silybin is an effective component of silymarin for treating metabolic syndrome by stimulating FXR signaling.

10.
Drug Metab Rev ; 48(1): 1-26, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26915920

RESUMO

Traditional Chinese medicine (TCM) has a long history of medical use in China and is still used worldwide. Unexpected herb-drug interactions (HDIs) may lead to adverse drug reactions or loss of therapeutic efficacy of the victim drug. Here, based on searches of Medline, EBSCO, Science Direct and Web of Science using various keywords, we summarize the TCM-derived pharmacokinetic HDIs that were reported from 1990 to 2015 and discuss the underlying mechanisms. In general, many pre-clinical and clinical pharmacokinetic HDIs have been reported. Our searches show that TCMs cause pharmacokinetic interactions with therapeutic drugs mainly by inhibiting or inducing drug-metabolizing enzymes and transporters. However, most of the interactions result from a small number of prescription medications and the actual potential for harm is low. Moreover, such HDIs can be avoided by discontinuing the TCMs. Despite the extensive number of reports on TCM-derived HDIs, the findings are frequently conflicting and can be confusing. The causes of the conflicts vary, but we classified them into three basic categories as follows: (1) complicated nature and poor quality control of TCMs, (2) different responses of various test systems to TCM exposure and (3) diverse study designs. Accordingly, we propose rational study designs for future HDI research. We also propose that a specific authoritative guide be established that provides recommendations for HDI studies. This review provides insights into the progress and challenges in TCM-derived pharmacokinetic HDI research.


Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Interações Ervas-Drogas , Animais , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Medicina Tradicional Chinesa/efeitos adversos , Medicina Tradicional Chinesa/métodos
11.
Sci Rep ; 6: 20110, 2016 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-26822920

RESUMO

Pharmacological activities of some natural products diminish and even disappear after purification. In this study, we explored the mechanisms underlying the decrease of acute oral toxicity of Coptidis Rhizoma extract after purification. The water solubility, in vitro absorption, and plasma exposure of berberine (the major active compound) in the Coptidis Rhizoma extract were much better than those of pure berberine. Scanning electron microscopy, laser scanning confocal microscopy (LSCM), and dynamic light scattering experiments confirmed that nanoparticles attached to very fine precipitates existed in the aqueous extract solution. The LSCM experiment showed that the precipitates were absorbed with the particles by the mouse intestine. High-speed centrifugation of the extract could not remove the nanoparticles and did not influence plasma exposure or acute oral toxicity. However, after extract dilution, the attached precipitates vanished, although the nanoparticles were preserved, and there were no differences in the acute oral toxicity and plasma exposure between the extract and pure berberine. The nanoparticles were then purified and identified as proteinaceous. Furthermore, they could absorb co-dissolved berberine. Our results indicate that naturally occurring proteinaceous nanoparticles in Coptidis Rhizoma extract act as concentration-dependent carriers that facilitate berberine absorption. These findings should inspire related studies in other natural products.


Assuntos
Berberina , Medicamentos de Ervas Chinesas , Nanopartículas , Proteínas de Plantas , Animais , Berberina/farmacocinética , Berberina/toxicidade , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/toxicidade , Camundongos , Nanopartículas/química , Nanopartículas/toxicidade , Proteínas de Plantas/química , Proteínas de Plantas/toxicidade
12.
Yao Xue Xue Bao ; 51(9): 1429-35, 2016 09.
Artigo em Chinês | MEDLINE | ID: mdl-29924533

RESUMO

Entecavir (ETV), a guanosine nucleotide antiviral agent with activity against hepatitis B virus (HBV) and Huangqi decoction (HQD) that exerts significant therapeutic effects in liver cirrhosis are used as an effective drug combination in the treatment of liver cirrhosis with HBV. Therefore, this study was designed to assess the effect of HQD on ETV pharmacokinetics in rat plasma. Spraque-Dawley (SD) rats were randomized into single- and 7-day-dose experimental groups. The ETV and ETV-HQD groups were administered ETV and a simultaneous combination of ETV and HQD, respectively while the ETV-HQD-2h group received HQD 2 h after ETV treatment, all administered via intragastric (i.g.) gavage. A rapid, sensitive, and efficient ultra-high- performance liquid chromatography-linear trap quadrupole (UHPLC-LTQ)-Orbitrap method was developed and validated to determine ETV in rat plasma from blood samples collected at different time points following treatment. The linearity, accuracy, precision, recovery, matrix effects and stability of ETV were all satisfactory. The ETV-HQD group exhibited a decrease in the maximum plasma concentration (Cmax), and a delay in time to achieve Cmax (tmax) following single- and multi-dose administrations, and decreased area under the concentration- time curve (AUC0­t) following single dosing. ETV pharmacokinetics did not change significantly between the ETV and ETV-HQD-2h groups. In vitro everted intestinal sac models experiments indicated that HQD decreased the absorption of ETV. HQD prevented ETV from accessing the intestinal mucosa epithelial surface, thereby decreasing its absorption in rats.


Assuntos
Antivirais/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Guanina/análogos & derivados , Adulto , Animais , Antivirais/sangue , Cromatografia Líquida de Alta Pressão , Guanina/sangue , Guanina/farmacocinética , Humanos , Plasma , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
13.
PLoS One ; 10(3): e0122661, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25803610

RESUMO

Xiexin decoction, a herbal therapeutic agent commonly used in traditional Chinese medicine, is recognized for its beneficial effects on diabetic nephropathy exerted through the combined action of multiple components, including Rhizoma Coptidis alkaloids (A), Radix et Rhizoma Rhei polysaccharides (P), and Radix Scutellaria flavones (F). Our previous studies have shown that a combination of A, P, and F (APF) exhibits renoprotective effects against diabetic nephropathy. This study was aimed at determining the effects of APF on renal fibrosis in diabetic nephropathy and elucidating the underlying molecular mechanisms. To evaluate the effects of APF, in vivo, db/db diabetic mice were orally administered a low or high dose of APF (300 or 600 mg/kg, respectively) once a day for 8 weeks. We evaluated the blood and urine indices of metabolic and renal function, renal tissue histopathology, renal inflammation, and fibrosis. APF treatment significantly ameliorated glucose and lipid metabolism dysfunction, decreased urinary albumin excretion, normalized creatinine clearance, and reduced the morphological changes in renal tissue. Additionally, APF administration in db/db diabetic mice reduced the elevated levels of renal inflammation mediators such as intercellular adhesion molecule-1, monocyte chemotactic protein-1, tumor necrosis factor-α, interleukin-1ß, and active nuclear factor κB (NF-κB). APF treatment also reduced type I and IV collagen, transforming growth factor-ß1 (TGF-ß1), and TGF-ß1 type II receptor expression levels, and decreased the phosphorylation of Smad2/3 in the kidneys of db/db diabetic mice. These results suggest that APF reduces renal fibrosis in diabetic nephropathy through the NF-κB and TGF-ß1/Smad signaling pathways. In vitro, APF treatment reduced cell proliferation and protein expression of α-smooth muscle actin, collagen I, TGF-ß1 and NF-κB in mesangial cells cultured with high glucose concentrations. Our findings indicate that treatment with multi-component herbal therapeutic formulations may be a useful approach for the treatment of diabetic nephropathy.


Assuntos
Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Nefropatias/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Análise de Variância , Animais , Western Blotting , Primers do DNA/genética , Fibrose , Imuno-Histoquímica , Camundongos , Camundongos Mutantes , Microscopia Eletrônica , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Smad/antagonistas & inibidores , Fator de Crescimento Transformador beta1/antagonistas & inibidores
14.
J Ethnopharmacol ; 157: 126-33, 2014 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-25278183

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Xiexin decoction (XXD) has been used as a treatment for diabetes mellitus for more than 1300 years. XXD constituents with protective effects against diabetic nephropathy (DN) include Rhizoma Coptidis alkaloids (RA), Radix et Rhizoma Rhei polysaccharides (RP), and Radix Scutellaria flavones (RF). The aim of the study is to investigate the effects of combinations of RA, RP, and RF on DN and their mechanisms of action. MATERIALS AND METHODS: In vitro, high glucose-induced rat mesangial cells were treated with RA, RP, RF, and combinations thereof. Cell proliferation and levels of inflammatory factors were measured. In vivo, high-fat diet and streptozotocin-induced diabetic rats were treated with different combinations of RA, RP, and RF once per day for 12 weeks. Blood and urine biochemical parameters, renal tissue morphology, and inflammation were investigated. RESULTS: In vitro, the combination of the three groups of components inhibited mesangial cell proliferation and reduced the levels of monocyte chemotactic protein-1 (MCP-1) and collagen IV. The effects of the three constituent groups in combination were stronger than those of each group alone or combinations of two groups. In diabetic rats, combinations of the three groups of herb components ameliorated blood glucose, urinary albumin excretion and decreased renal mesangial matrix expansion and basement membrane thickening. In addition, the combinations reduced renal tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) protein levels, down-regulated the expression of nuclear factor κB (NF-κB) and transforming growth factor beta 1 (TGF-ß1), and up-regulated the expression of inhibitor of nuclear factor κB (IκB) protein. Among the three groups of herb components, RA produced the strongest effects, followed by RP, and then by RF. CONCLUSIONS: The combination of the three groups of herb components produced anti-DN effects through inhibition of inflammation mediated by NF-κB. Among the three groups of herb components, RA produced the strongest effect while RP and RF produced weaker effects.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Inflamação/tratamento farmacológico , Animais , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/patologia , Dieta Hiperlipídica , Medicamentos de Ervas Chinesas/química , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina
15.
Yao Xue Xue Bao ; 49(8): 1105-10, 2014 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-25322550

RESUMO

Mammal multidrug and toxin extrusion proteins (MATEs) play an important role in the transport of organic cations in the body. MATEs mediate the final excretion step for multiple organic cation drug used clinically and important endogenous substances. This article reviews the discovery, type, gene coding and polymorphism, body distribution, classification of substrates and inhibitors and their research method of MATEs. The article also discusses the major research significance of MATEs with examples.


Assuntos
Proteínas de Transporte de Cátions Orgânicos/metabolismo , Animais , Transporte Biológico , Cátions , Polimorfismo Genético
16.
Yao Xue Xue Bao ; 49(1): 16-22, 2014 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-24783500

RESUMO

Physiologically based pharmacokinetic model (PBPK), a mechanistic mathematic model, which can simulate the absorption, distribution, metabolism and excretion of drugs, is being more widely used in pharmaceutical research and development areas. This article reviews primarily the recent advances in the procedure of establishing a PBPK model, including specifying of the PBPK model structure, specification of the tissue model, writing of equations, set of model parameters, simulation and evaluation. Application significance, major challenges and future developments of PBPK model in pharmaceutical areas are also discussed.


Assuntos
Simulação por Computador , Modelos Biológicos , Farmacocinética , Animais , Transporte Biológico , Humanos , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Software , Distribuição Tecidual
17.
J Ethnopharmacol ; 153(3): 714-24, 2014 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-24704592

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Yinchenzhufu decoction (YCZFD) is a classical Chinese herbal formula and has been used to treat severe jaundice in chronic liver injuries since the Qing Dynasty (18th century CE). To identify the components absorbed into the blood in YCZFD and explore their pharmacokinetic profile for understanding the effective ingredients of YCZFD. MATERIALS AND METHODS: After rats were given YCZFD by intragastric administration, the plasma was processed by precipitation of protein. The compounds in YCZFD extract and the plasma were identified by using high-resolution mass spectrometry with a database-directed strategy. The pharmacokinetics of multiple compounds from YCZFD in rat plasma was studied by using the established UPLC-MS/MS method. RESULTS: Forty compounds in YCZFD extract and 21 prototype compounds with 11 metabolites in rat plasma were detected after oral administration. The pharmacokinetic parameters of glycyrrhizic acid, glycyrrhetic acid, cinnamic acid, ononin, atractylenolide III, and liquiritin from YCZFD were obtained in rats. CONCLUSIONS: The identified constituents and the pharmacokinetic features of YCZFD are helpful for understanding the material bases of its therapeutic effects.


Assuntos
Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/análise , Feminino , Masculino , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacocinética , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
18.
Int J Neuropsychopharmacol ; 17(6): 871-81, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24513083

RESUMO

Phosphodiesterase-5 (PDE5) inhibitors are predominantly used in the treatment of erectile dysfunction, and have been recently shown to have a potential therapeutic effect for the treatment of Alzheimer's disease (AD) through stimulation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signalling by elevating cGMP, which is a secondary messenger involved in processes of neuroplasticity. In the present study, the effects of a PDE5 inhibitor, icarrin (ICA), on learning and memory as well as the pathological features in APP/PS1 transgenic AD mice were investigated. Ten-month-old APP/PS1 transgenic mice overexpressing human amyloid precursor protein (APP695swe) and presenilin 1 (PS1-dE9) were given ICA (30 and 60 mg/kg) or sildenafil (SIL) (2 mg/kg), age-matched wild-type (WT) mice were given ICA (60 mg/kg), and APP/PS1 and WT control groups were given an isovolumic vehicle orally twice a day for four months. Results demonstrated that ICA treatments significantly improved learning and memory of APP/PS1 transgenic mice in Y-maze tasks. The amyloid precursor protein (APP), amyloid-beta (Aß1-40/42) and PDE5 mRNA and/or protein levels were increased in the hippocampus and cortex of APP/PS1 mice, and ICA treatments decreased these physiopathological changes. Furthermore, ICA-treated mice showed an increased expression of three nitric oxide synthase (NOS) isoforms at both mRNA and protein levels, together with increased NO and cGMP levels in the hippocampus and cortex of mice. These findings demonstrate that ICA improves learning and memory functions in APP/PS1 transgenic mice possibly through the stimulation of NO/cGMP signalling and co-ordinated induction of NOS isoforms.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , GMP Cíclico/metabolismo , Flavonoides/farmacologia , Óxido Nítrico/metabolismo , Nootrópicos/farmacologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos Transgênicos , Óxido Nítrico Sintase/metabolismo , Fragmentos de Peptídeos/metabolismo , Inibidores da Fosfodiesterase 5/farmacologia , Presenilina-1/genética , Presenilina-1/metabolismo , Distribuição Aleatória
19.
J Pharm Biomed Anal ; 92: 35-46, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24469098

RESUMO

Fuzi Xiexin Tang (FXT) is a classic traditional Chinese medicine formula which has been employed in clinical for more than 1800 years. The distinctive preparation method (maceration) recorded in ancient time is different from one in modern clinical practice (decoction). Aim of this study is to investigate the pharmacokinetic difference of alkaloids, flavones and anthraquinones in rats after oral administration of decoction of FXT (DFXT, 30gkg(-1)), maceration of FXT (MFXT, 30gkg(-1)) and decoction of Aconiti Lateralis Radix Preparata (DAR, 6gkg(-1)) by a validated UPLC-MS/MS method. Plasma concentrations and pharmacokinetic parameters of 16 active constituents (aconitine, hypaconitine, mesaconitine, benzoylaconine, benzoylhypaconine, benzoylmesaconine, berberine, palmatine, jatrorrhizine, coptisine, baicalin, wogonin, wogonoside, emodin, aloe-emodin, rhein) in rat were quantified and compared. Different preparative methods resulted in significant difference on exposure and pharmacokinetic characteristics of alkaloids, flavones and anthraquinones from FXT, especially protoberberine alkaloids. Concentrations of monoester-diterpenoid alkaloids were below the LOD in rat plasma after administration of DFXT and MFXT because of the existence of other three herbs from FXT. Maceration could decrease the absorption of flavones while increased the absorption of anthraquinones. Cmax of emodin and rhein were 3.1 and 10.3 times increased, while eliminations of these two constituents were 8.0 and 19.0 times slower after administration of MFXT. Bioavailability of both flavones and anthraquinones increased after administration of MFXT, especially emodin and rhein increasing as much as 13.5 and 20.7 times. Herb-herb interaction between DAR and other three herbs from FXT significantly influenced the exposure of aconitum alkaloids.


Assuntos
Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Absorção , Administração Oral , Alcaloides/química , Alcaloides/farmacocinética , Animais , Antraquinonas/química , Antraquinonas/farmacocinética , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão/métodos , Flavonas/química , Flavonas/farmacocinética , Medicina Tradicional Chinesa/métodos , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos
20.
Yao Xue Xue Bao ; 48(9): 1464-70, 2013 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-24358782

RESUMO

In this paper, absorption and pharmacokinetic study of Radix Rehmanniae was studied by liquid chromatography coupled with mass spectrometry method after oral administration to rats. By comparing the chromatograms of ultraviolet, full scan, extracted ion and selective reaction monitoring (SRM) of standard solution, Radix Rehmanniae, blank plasma and rat plasma post drug administration, catalpol and ajugol were found to be the main compounds absorbed from Radix Rehmanniae. Plasma concentrations of aucubin, dihydrocatalpol, rehmannioside A (or rehmannioside B/ melittoside) and rehmannioside D were very low. Quantitative method for catalpol and aucubin and semi-quantitative method for other compounds in rat plasma were established. The pharmacokinetic study of those absorbed components was conducted after oral administration of 6 g x kg(-1) Radix Rehmanniae water extract to rats. Cmax, t(1/2) and AUC(0-infinity) of catalpol and ajugol were (2349.05 +/- 1438.34) and (104.25 +/- 82.05) ng x mL(-1), (0.86 +/- 0.32) and (0.96 +/- 0.37) h, (4407.58 +/- 2734.89) and (226.66 +/- 188.38) ng x h x mL(-1), respectively. tmax was at 1.00 h for catalpol and ajugol. Both catalpol and ajugol were absorbed and excreted rapidly.


Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Glucosídeos Iridoides/farmacocinética , Glicosídeos Iridoides/farmacocinética , Piranos/farmacocinética , Rehmannia/química , Administração Oral , Animais , Área Sob a Curva , Medicamentos de Ervas Chinesas/química , Feminino , Glucosídeos Iridoides/sangue , Glucosídeos Iridoides/química , Glicosídeos Iridoides/sangue , Glicosídeos Iridoides/química , Masculino , Estrutura Molecular , Raízes de Plantas/química , Plantas Medicinais/química , Piranos/sangue , Piranos/química , Ratos , Ratos Sprague-Dawley
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