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Aim of the study: Our hypothesis is that nirmatrelvir can penetrate the bloodâbrain barrier and reach effective concentrations in the brain. Furthermore, herbal formulations can help maintain nirmatrelvir levels in the body, suggesting potential interactions between these medications. Materials and methods: To investigate this hypothesis, an animal model combining multisite microdialysis, ultrahigh-performance liquid chromatography and tandem mass spectrometry (UHPLC-MS/MS) methods was developed to monitor nirmatrelvir levels in the blood and brain of rats. Results: The pharmacokinetic results showed that the area under the curve (AUC) of nirmatrelvir in the blood and brain was 798.3 ± 58.56 and 187.2 ± 23.46 min µg/mL, respectively, after the administration of nirmatrelvir alone (15 mg/kg, iv). When the Scutellaria baicalensis formulations were administered for five consecutive days prior to drug administration, the AUC of nirmatrelvir in the blood increased. Conclusions: These results provide constructive preclinical information that the concentrations of nirmatrelvir in the blood and brain were greater than the effective concentration (EC90) for more than 6 h, and the Scutellaria baicalensis formulations had synergistic pharmacokinetic effects by increasing the concentration of nirmatrelvir in the blood.
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Acetaminophen (APAP), or paracetamol, is one of the most widespread and commonly used non-prescription pain medication in the world, and is effective at managing wide range of pain, including headache, muscle ache, and minor arthritic pain. While the pharmacokinetics of APAP is generally understood, there is a lack of data for its transfer ratio especially into the knee. A novel multi-microdialysis model was developed to simultaneously sample from blood, forelimb extensor muscle, brain striatum, and the knee joint cavity in the same experimental subject to investigate the potential interaction between APAP and Achyranthes bidentata Blume (A. bidentata), another widely used traditional Chinese medicininal herb especially for pain in the lower extremity. Rats were pre-treated with A. bidentata extract (ABex), APAP was then administered (60â¯mg/kg, i.v.), dialysates then subsequently analyzed using HPLC-PDA. Our analysis demonstrated that APAP concentrations, achieved after its administration either alone or in combination with ABex (1 and 3â¯g/kg, q.d. gavage), could be modelled effectively with a one-compartment model. The distribution ratio (AUCorgan/AUCblood) of blood-to-muscle, blood-to-brain and blood-to-knee was 0.372 ± 0.053, 0.277 ± 0.095 and 0.191 ± 0.042, respectively after administration of APAP (60â¯mg/kg, i.v.). No significant difference was observed between the pharmacokinetics of APAP administered alone and in combination with ABex; and APAP concentration exceed the half maximal effective concentration (EC50) in all sampled organs for close to 3â¯hours with one single dose of drug administration, providing evidence for its broad-range analgesic effect.
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Acetaminofen , Articulação do Joelho , Ratos Sprague-Dawley , Animais , Acetaminofen/farmacocinética , Acetaminofen/sangue , Ratos , Masculino , Articulação do Joelho/metabolismo , Extratos Vegetais/farmacocinética , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Analgésicos não Narcóticos/farmacocinética , Analgésicos não Narcóticos/sangue , Analgésicos não Narcóticos/administração & dosagem , Músculo Esquelético/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Interações Ervas-Drogas , Distribuição Tecidual , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/administração & dosagemRESUMO
Ritonavir, an excellent inhibitor of CYP3A4, has recently been combined with nirmatrelvir to form Paxlovid for the treatment of severe acute respiratory syndrome coronavirus 2 infections. The root of Scutellaria baicalensis Georgi (S. baicalensis), a traditional Chinese medicinal (TCM) herb commonly used to treat heat/inflammation in the lung and digestive tracts, which are major organs targeted by viral infections, contains flavones that can influence the CYP3A metabolism pathway. To investigate the ability of ritonavir to cross the bloodbrain barrier (BBB) and its potential herb-drug interactions with an equivalent TCM clinical dose of S. baicalensis, multisite microdialysis coupled with an LCMS/MS system was developed using rat model. Pretreatment with S. baicalensis extract for 5 days, which contains less flavones than those used in previous studies, had a significant influence on ritonavir, resulting in a 2-fold increase in the total concentration of flavones in the blood and brain. Treatment also boosted the maximum blood concentration of flavones by 1.5-fold and the maximum brain concentration of flavones by 2-fold, all the while exerting no noticeable influence on the transfer ratio across the bloodbrain barrier. These experimental results demonstrated that the use of a typical traditional Chinese medicinal dose of S. baicalensis is sufficient to influence the metabolic pathway and synergistically increase the concentration of ritonavir in rats.
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Antivirais , Barreira Hematoencefálica , Interações Ervas-Drogas , Microdiálise , Extratos Vegetais , Ratos Sprague-Dawley , Ritonavir , Scutellaria baicalensis , Animais , Ritonavir/farmacocinética , Ritonavir/farmacologia , Scutellaria baicalensis/química , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Ratos , Microdiálise/métodos , Masculino , Antivirais/farmacocinética , Extratos Vegetais/farmacocinética , Extratos Vegetais/farmacologia , Espectrometria de Massas em Tandem/métodos , Encéfalo/metabolismo , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagemRESUMO
Hepatitis D virus (HDV), which co-infects or superinfects patients with hepatitis B virus, is estimated to affect 74 million people worldwide. Chronic hepatitis D is the most severe form of viral hepatitis and can result in liver cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Currently, there are no efficient HDV-specific drugs. Therefore, there is an urgent need for novel HDV therapies that can achieve a functional cure or even eliminate the viral infection. In the HDV life cycle, agents targeting the entry step of HDV infection preemptively reduce the intrahepatic viral RNA. Human sodium taurocholate co-transporting polypeptide (hNTCP), a transporter of bile acids on the plasma membrane of hepatocytes, is an essential entry receptor of HDV and is a promising molecular target against HDV infection. Here, we investigated the effect of ergosterol peroxide (EP) on HDV infection in vitro and in vivo. EP inhibited HDV infection of hNTCP-expressing dHuS-E/2 hepatocytes by interrupting the early fusion/endocytosis step of HDV entry. Furthermore, molecular modeling suggested that EP hinders LHBsAg binding to hNTCP by blocking access to S267 and V263. In addition, we generated hNTCP-expressing transgenic (Tg) C57BL/6 mice using the Cre/loxP system for in vivo study. EP reduced the liver HDV RNA level of HDV-challenged hNTCP-Cre Tg mice. Intriguingly, EP downregulated the mRNA level of liver IFN-γ. We demonstrate that EP is a bona fide HDV entry inhibitor that acts on hNTCP and has the potential for use in HDV therapies.
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Carcinoma Hepatocelular , Hepatite D , Neoplasias Hepáticas , Simportadores , Camundongos , Animais , Humanos , Vírus Delta da Hepatite/genética , Vírus Delta da Hepatite/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Camundongos Endogâmicos C57BL , Hepatite D/tratamento farmacológico , Hepatite D/patologia , Vírus da Hepatite B/fisiologia , Hepatócitos , Camundongos Transgênicos , Simportadores/metabolismoRESUMO
Sepsis results from uncontrolled inflammation, characterized by cytokine storm and immunoparalysis. To assess whether galgravin, a natural lignan isolated from Piper kadsura, can be used to treat sepsis, models of bacterial lipopolysaccharide (LPS)-activated macrophages and LPS-induced endotoxemia mice were used. Galgravin suppressed NF-κB activation in LPS-activated RAW 264.7 macrophages without causing significant cytotoxicity, in which proinflammatory molecules like TNF-α, IL-6, iNOS, and COX-2 were downregulated. In addition, the expression of TNF-α and IL-6 was also suppressed by galgravin in LPS-activated murine bone marrow-derived macrophages. Moreover, galgravin significantly downregulated the mRNA expression of TNF-α, IL-6, and iNOS in the lungs and decreased TNF-α and IL-6 in the serum and IL-6 in the bronchoalveolar lavage fluid of LPS-challenged mice. The COX-2 expression in tissues, including the lung, liver, and kidney, as well as the lung alveolar hemorrhage, was also reduced by galgravin. The present study reveals the anti-inflammatory effects of galgravin in mouse models and implies its potential application in inflammation diseases.
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Endotoxemia , Kadsura , Lignanas , Piper , Camundongos , Animais , Lipopolissacarídeos/toxicidade , NF-kappa B/metabolismo , Kadsura/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Endotoxemia/induzido quimicamente , Endotoxemia/tratamento farmacológico , Anti-Inflamatórios/efeitos adversos , Interleucina-6/genética , Interleucina-6/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Inflamação/metabolismo , Lignanas/uso terapêuticoRESUMO
[This corrects the article DOI: 10.3389/fphar.2022.744439.].
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BACKGROUND: Remdesivir was the first prodrug approved to treat coronavirus disease 2019 (COVID-19) and has the potential to be used during pregnancy. However, it is not known whether remdesivir and its main metabolite, GS-441524 have the potential to cross the blood-placental barrier. We hypothesize that remdesivir and predominant metabolite GS-441524may cross the blood-placental barrier to reach the embryo tissues. METHODS: To test this hypothesis, ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) coupled with multisite microdialysis was used to monitor the levels of remdesivir and the nucleoside analogue GS-441524 in the maternal blood, fetus, placenta, and amniotic fluid of pregnant Sprague-Dawley rats. The transplacental transfer was evaluated using the pharmacokinetic parameters of AUC and mother-to-fetus transfer ratio (AUCfetus/AUCmother). FINDINGS: Our in-vivo results show that remdesivir is rapidly biotransformed into GS-441524 in the maternal blood, which then readily crossed the placenta with a mother-to-fetus transfer ratio of 0.51 ± 0.18. The Cmax and AUClast values of GS-441524 followed the order: maternal blood > amniotic fluid > fetus > placenta in rats. INTERPRETATION: While remdesivir does not directly cross into the fetus, however, its main metabolite, GS-441524 readily crosses the placenta and can reside there for at least 4 hours as shown in the pregnant Sprague-Dawley rat model. These findings suggest that careful consideration should be taken for the use of remdesivir in the treatment of COVID-19 in pregnancy. FUNDING: Ministry of Science and Technology of Taiwan.
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Tratamento Farmacológico da COVID-19 , Complicações Infecciosas na Gravidez , Adenosina/análogos & derivados , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Líquido Amniótico , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Biotransformação , Feminino , Feto/metabolismo , Furanos/metabolismo , Placenta/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Pirróis/metabolismo , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodosRESUMO
COVID-19 is a global epidemic. Developing adjuvant therapies which could prevent the virus from binding to cells may impair viral infection. This study produces a traditional Chinese medicine formula, Jing Guan Fang (JGF), based on ancient medical texts, and examines the efficacy and the mechanism by which JGF prevents viral infections. JGF reduces COVID-19 like symptoms. Functional studies show that JGF inhibits the formation of syncytium and reduces the formation of viral plaque. JGF is not toxic in vitro and in vivo. Mechanistically, JGF induces lysosomal-dependent ACE2 degradation and suppresses mRNA and the protein levels of TMPRSS2 in human lung WI-38 and MRC-5 cells. Mice that inhale JGF exhibit reduced ACE2 and TMPRSS2 protein levels in lung tissues. Together, these findings suggest that JGF may improve the COVID-19 like symptoms and inhibit viral infection. Moreover, JGF may be applicable as an adjuvant preventive strategy against SARS-CoV-2 infection in addition to the use of vaccines.
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Chloranthus oldhamii Solms (CO) is a folk medicine for treating infection and arthritis pain but its pharmacological activity and bioactive compounds remain mostly uncharacterized. In this study, the anti-inflammatory compounds of C. oldhamii were identified using an LPS-stimulated, NF-κB-responsive RAW 264.7 macrophage reporter line. Three diterpenoid compounds, 3α-hydroxy-ent-abieta-8,11,13-triene (CO-9), 3α, 7ß-dihydroxy-ent-abieta-8,11,13-triene (CO-10), and decandrin B (CO-15) were found to inhibit NF-κB activity at nontoxic concentrations. Moreover, CO-9 and CO-10 suppressed the expression of IL-6 and TNF-α in LPS-stimulated RAW 264.7 cells. The inhibitory effect of CO-9 on TNF-α and IL-6 expression was further demonstrated using LPS-treated bone marrow-derived macrophages. Furthermore, CO-9, CO-10, and CO-15 suppressed LPS-triggered COX-2 expression and downstream PGE2 production in RAW 264.7 cells. CO-9 and CO-10 also reduced LPS-triggered iNOS expression and nitrogen oxide production in RAW 264.7 cells. The anti-inflammatory mechanism of the most effective compound, CO-9, was further investigated. CO-9 attenuated LPS-induced NF-κB activation by reducing the phosphorylation of IKKα/ß (Ser176/180), IκBα (Ser32), and p65 (Ser534). Conversely, CO-9 did not affect the LPS-induced activation of MAPK signaling pathways. In summary, this study revealed new anti-inflammatory diterpenoid compounds from C. oldhamii and demonstrated that the IKK-mediated NK-κB pathway is the major target of these compounds.
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Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Magnoliopsida/química , NF-kappa B/antagonistas & inibidores , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Diterpenos/química , Diterpenos/isolamento & purificação , Quinase I-kappa B/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , NF-kappa B/metabolismo , Células RAW 264.7RESUMO
Hepatitis B virus (HBV) infection leads to severe liver diseases, including cirrhosis and hepatocellular carcinoma (HCC). More than 257 million individuals are chronically infected, particularly in the Western Pacific region and Africa. Although nucleotide and nucleoside analogues (NUCs) and interferons (IFNs) are the standard therapeutics for HBV infection, none eradicates HBV covalently closed circular DNA (cccDNA) from the infected hepatocytes. In addition, long-term treatment with NUCs increases the risk of developing drug resistance and IFNs may cause severe side effects in patients. Thus, a novel HBV therapy that can achieve a functional cure, or even complete elimination of the virus, is highly desirable. Regarding the HBV life cycle, agents targeting the entry step of HBV infection reduce the intrahepatic cccDNA pool preemptively. The initial entry step in HBV infection involves interaction between the pre-S1 domain of the large hepatitis B surface protein (LHBsAg) and the sodium taurocholate cotransporting polypeptide (NTCP), which is a receptor for HBV. In this study, ergosterol peroxide (EP) was identified as a new inhibitor of HBV entry. EP inhibits an early step of HBV entry into DMSO-differentiated immortalized primary human hepatocytes HuS-E/2 cells, which were overexpressed NTCP. Also, EP interfered directly with the NTCP-LHBsAg interaction by acting on the NTCP. In addition, EP had no effect on HBV genome replication, virion integrity or virion secretion. Finally, the activity of EP against infection with HBV genotypes A-D highlights the therapeutic potential of EP for fighting HBV infection.
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Ergosterol/análogos & derivados , Vírus da Hepatite B/fisiologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Internalização do Vírus/efeitos dos fármacos , DNA Circular/metabolismo , Ergosterol/farmacologia , Células Hep G2 , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Humanos , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Simportadores/genética , Replicação ViralRESUMO
BACKGROUND: The flower of Dendranthema morifolium Ramat Tzvel has been widely used as a nutritional health supplement worldwide. However, most of the studies have focused on the flower and the rest of the plant was neglected. Our hypothesis is that similar flavonoids may be present at different parts of D. morifolium, and the flavonoids may undergo a similar biotransformation pathway within the body. To investigate this hypothesis, an in vivo pharmacokinetic experimental model was developed to explore the comparative biotransformation of luteolin and apigenin after administration of D. morifolium extracts (10 g kg-1 , p.o.) in freely moving rats. Because luteolin and apigenin mainly underwent phase II metabolism, the metabolic enzymes of ß-glucuronidase/sulfatase or ß-glucuronidase were used to hydrolyze the plasma sample, depending on the biotransformation pathway involved. RESULTS: The results revealed that luteolin and apigenin mainly went through glucuronide and sulfate conjugations, respectively, in both the extract of flowers and the stem-and-leaf group. In addition, the area under the concentration curve (AUClast ) of luteolin glucuronides and sulfates in the group administered the stem-and-leaf extract was approximately 4.6 times higher than that of the flower extract group. The dominant products of biotransformation for apigenin were sulfates. CONCLUSION: These findings support our hypothesis that not only the flower parts of D. morifolium, but also the stem-and-leaf parts contain rich flavones, including glycosides and aglycone, and they undergo similar biotransformation pathways. © 2021 Society of Chemical Industry.
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Apigenina/metabolismo , Chrysanthemum/química , Luteolina/metabolismo , Extratos Vegetais/metabolismo , Animais , Apigenina/química , Chrysanthemum/metabolismo , Flavonoides/química , Flavonoides/metabolismo , Flores/química , Hidrólise , Luteolina/química , Estrutura Molecular , Extratos Vegetais/química , Folhas de Planta/química , Caules de Planta/química , Ratos , Ratos Sprague-DawleyRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ambroxol elevates glucocerebrosidase (GCase) activity and reduces nigrostriatal alpha-synuclein burden to better ameliorate motor function in Parkinson's disease (PD). Polygala tenuifolia is a potential alternative botanical medicine for the treatment of many nonmotor symptoms of PD commonly used in Taiwanese patients. Co-administration of these two medicines pose potential herb-drug interaction. AIM OF THE STUDY: Our hypothesis is that ambroxol and P. tenuifolia may potentially possess herbal drug synergetic effects in the blood and brain. MATERIALS AND METHODS: To investigate this hypothesis, a multiple microdialysis system coupled with validated ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for rat blood and brain samples. Experimental rats were divided into three groups: low-dose and high-dose ambroxol alone (10 mg/kg, i.v. and 30 mg/kg, i.v., respectively) and ambroxol (10 mg/kg, i.v.) pretreated with P. tenuifolia extract (1 g/kg, p.o. for 5 consecutive days). RESULTS: Ambroxol easily penetrated into the brain and reached a maximum concentration in the striatum at approximately 60 min after low- and high-dose treatment. The area under the concentration curve (AUC) ratio increased proportionally at the doses of 10 and 30 mg/kg, which suggested a linear pharmacokinetic manner of ambroxol. The brain penetration of ambroxol was approximately 30-34%, which was defined as the ambroxol AUC blood-to-brain distribution ratio (AUCbrain/AUCblood). The P. tenuifolia extract did not significantly alter the pharmacokinetics of ambroxol in the blood and brain of rats. CONCLUSION: The present study suggests that it is safety without pharmacokinetic interactions for this dosing regimen to use P. tenuifolia extract and ambroxol together.
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Ambroxol/farmacocinética , Encéfalo/metabolismo , Corpo Estriado/metabolismo , Medicamentos de Ervas Chinesas/farmacocinética , Transtornos Parkinsonianos/tratamento farmacológico , Polygala/química , Ambroxol/metabolismo , Ambroxol/uso terapêutico , Animais , Área Sob a Curva , Análise Química do Sangue , Barreira Hematoencefálica , Encéfalo/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Interações Ervas-Drogas , Masculino , Microdiálise/métodos , Ratos Sprague-Dawley , Espectrometria de Massas em TandemRESUMO
Cutibacterium acnes (formerly Propionibacterium acnes) is a key pathogen involved in the development and progression of acne inflammation. The numerous bioactive properties of wild bitter melon (WBM) leaf extract and their medicinal applications have been recognized for many years. In this study, we examined the suppressive effect of a methanolic extract (ME) of WBM leaf and fractionated components thereof on live C. acnes-induced in vitro and in vivo inflammation. Following methanol extraction of WBM leaves, we confirmed anti-inflammatory properties of ME in C. acnes-treated human THP-1 monocyte and mouse ear edema models. Using a bioassay-monitored isolation approach and a combination of liquid-liquid extraction and column chromatography, the ME was then separated into n-hexane, ethyl acetate, n-butanol and water-soluble fractions. The hexane fraction exerted the most potent anti-inflammatory effect, suppressing C. acnes-induced interleukin-8 (IL-8) production by 36%. The ethanol-soluble fraction (ESF), which was separated from the n-hexane fraction, significantly inhibited C. acnes-induced activation of mitogen-activated protein kinase (MAPK)-mediated cellular IL-8 production. Similarly, the ESF protected against C. acnes-stimulated mouse ear swelling, as measured by ear thickness (20%) and biopsy weight (23%). Twenty-four compounds in the ESF were identified using gas chromatograph-mass spectrum (GC/MS) analysis. Using co-cultures of C. acnes and THP-1 cells, ß-ionone, a compound of the ESF, reduced the production of IL-1ß and IL-8 up to 40% and 18%, respectively. ß-ionone also reduced epidermal microabscess, neutrophilic infiltration and IL-1ß expression in mouse ear. We also found evidence of the presence of anti-inflammatory substances in an unfractionated phenolic extract of WBM leaf, and demonstrated that the ESF is a potential anti-inflammatory agent for modulating in vitro and in vivo C. acnes-induced inflammatory responses.
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Anti-Inflamatórios/química , Momordica charantia/química , Extratos Vegetais/química , Propionibacteriaceae/patogenicidade , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Linhagem Celular , Modelos Animais de Doenças , Edema/tratamento farmacológico , Edema/microbiologia , Edema/patologia , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Masculino , Camundongos Endogâmicos ICR , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Momordica charantia/metabolismo , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Monócitos/microbiologia , Extratos Vegetais/análise , Folhas de Planta/química , Folhas de Planta/metabolismoRESUMO
BACKGROUND: Dietary fat has been suggested to be the cause of various health issues. Obesity, hypertension, cardiovascular disease, diabetes, dyslipidemia, and kidney disease are known to be associated with a high-fat diet (HFD). Obesity and associated conditions, such as type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD), are currently a worldwide health problem. Few prospective pharmaceutical therapies that directly target NAFLD are available at present. A Traditional Chinese Medicine, ginseng-plus-Bai-Hu-Tang (GBHT), is widely used by diabetic patients to control glucose level or thirst. However, whether it has therapeutic effects on fat-induced hepatic steatosis and metabolic syndrome remains unclear. METHODS: This study was conducted to examine the therapeutic effect of GBHT on fat-induced obesity, hepatic steatosis, and insulin resistance in mice. RESULTS: GBHT protected mice against HFD-induced body weight gain, hyperlipidemia, and hyperglycemia compared with mice that were not treated. GBHT inhibited the expansion of adipose tissue and adipocyte hypertrophy. No ectopic fat deposition was found in the livers of HFD mice treated with GBHT. In addition, glucose intolerance and insulin sensitivity in HFD mice was also improved by GBHT. CONCLUSION: GBHT prevents changes in lipid and carbohydrate metabolism in a HFD mouse model. Our findings provide evidence for the traditional use of GBHT as therapy for the management of metabolic syndrome.
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Three new labdane-type diterpenoids, 6α-O-isovalerylnidorellol (1), (12S)-blumdane (2), and (12R)-epiblumdane (3), and three new bisnorditerpenoids, 6α-O-(3-methyl-2-butenoyl)sterebin A (5), 6α-O-angeloylsterebin A (6), and 6α-O-isovalerylsterebin A (7), plus 17 known compounds were isolated from Blumea aromatica. Their structures of the new compounds were proposed by detailed spectroscopic analysis. The absolute configuration at C-12 of blumdane (2) was determined by the modified Mosher's method. The anti-inflammatory and anti-immunosuppressive effects of these isolated compounds were assessed. Compounds 9, 16, and 23 (at 40 µM) showed a slight suppression of TNF-α production, but no or little effect on the expression of PD-L1 in granulocytic myeloid-derived suppressor cells was observed for all test compounds.
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Asteraceae/química , Diterpenos/química , Diterpenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Imunossupressores/química , Imunossupressores/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Folhas de Planta/química , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Células RAW 264.7 , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossínteseRESUMO
BACKGROUND: Boschniakia rossica is a well-known traditional Chinese medicine for tonifying kidney and improving impotence. Boschnaloside is the major iridoid glycoside in this herb but therapeutic benefits for diabetes remained to be evaluated. HYPOTHESIS/PURPOSE: The current investigation aims to study the antidiabetic effect and the underlying pharmacological mechanisms. STUDY DESIGN AND METHODS: Receptor binding, cAMP production, Ins secretion, glucagon-like peptide 1 (GLP-1) secretion, and dipeptidyl peptidase-4 activity assays were performed. Therapeutic benefits of orally administrated boschnaloside (150 and 300â¯mg/kg/day) were evaluated using severely 12-week old female diabetic db/db mice (Hemoglobin A1c >10%). RESULTS: Oral treatment of boschnaloside for 4 weeks improved diabetic symptoms including fasting blood sugar, hemoglobin A1c, glucose intolerance, and Homeostatic Model Assessment of Ins Resistance, accompanied by circulating GLP-1active and adiponectin levels. In addition, bochnaloside treatment improved islet/ß cell function associated with an alteration of the pancreatic and duodenal homeobox 1 level. It was shown that boschnaloside interacted with the extracellular domain of GLP-1 receptor and enhanced glucose stimulated Ins secretion. Boschnaloside also augmented the insulinotropic effect of GLP-1. Finally, the presence of boschnaloside caused a reduction of dipeptidyl peptidase-4 activity while enhanced GLP-1 secretion from STC-1 cells. CONCLUSION: It appears that bochnaloside at oral dosage greater than 150â¯mg/kg/day exerts antidiabetic effects in vivo through modulating the action of GLP-1.
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Medicamentos de Ervas Chinesas/farmacologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Iridoides/farmacologia , Administração Oral , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Transtornos do Metabolismo de Glucose/tratamento farmacológico , Transtornos do Metabolismo de Glucose/metabolismo , Hemoglobinas Glicadas/metabolismo , Hipoglicemiantes/administração & dosagem , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Iridoides/administração & dosagem , Camundongos , Orobanchaceae/química , Plantas Medicinais/química , RatosRESUMO
The hypothesis of this study is that fisetin and phase II conjugated forms of fisetin may partly undergo biliary excretion. To investigate this hypothesis, male Sprague-Dawley rats were used for the experiment, and their bile ducts were cannulated with polyethylene tubes for bile sampling. The pharmacokinetic results demonstrated that the average area-under-the-curve (AUC) ratios ( k (%) = AUCconjugate/AUCfree-form) of fisetin, its glucuronides, and its sulfates were 1:6:21 in plasma and 1:4:75 in bile, respectively. Particularly, the sulfated metabolites were the main forms that underwent biliary excretion. The biliary excretion rate ( kBE (%) = AUCbile/AUCplasma) indicates the amount of fisetin eliminated by biliary excretion. The biliary excretion rates of fisetin, its glucuronide conjugates, and its sulfate conjugates were approximately 144, 109, and 823%, respectively, after fisetin administration (30 mg/kg, iv). Furthermore, biliary excretion of fisetin is mediated by P-glycoprotein.
Assuntos
Flavonoides/farmacocinética , Animais , Bile/metabolismo , Flavonoides/sangue , Flavonóis , Glucuronídeos/sangue , Glucuronídeos/farmacocinética , Eliminação Hepatobiliar , Cinética , Masculino , Ratos , Ratos Sprague-Dawley , Sulfatos/sangue , Sulfatos/farmacocinéticaRESUMO
A new antibacterial drug is urgently needed. We employed a protein-DNA complex-guided pharmacophore modeling approach to screen inhibitors against the response regulator PmrA of polymyxin B-resistant Klebsiella pneumoniae (KP). The identified lead, E1 (IC50 = 10.2 µM), targeted the DNA-binding domain of PmrA (KD = 1.7 µM), whose conserved residues R171, R198, K203, and Y214 have been shown to be hotspots for antimicrobial development. Treatment of E1 restored the susceptibility of KP to polymyxin B.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Benzenossulfonatos/farmacologia , Descoberta de Drogas , Oxazóis/farmacologia , Polimixina B/farmacologia , Proteínas de Bactérias/metabolismo , DNA/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Ligação ProteicaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Metabolic syndrome and vascular dysfunction was suggested to be the risk factors for Alzheimer's disease (AD). Xuefu Zhuyu decoction (XZD) is a traditional Chinese medicine used to treat metabolic syndrome and cardiac-cerebral vascular disease. The effects of XZD on ameliorating metabolic syndrome, amyloid-related pathologies and cognitive impairment in an animal model of AD with metabolic stress was investigated. MATERIALS AND METHOD: The animal model of AD with metabolic stress was created by administrating high-fat diet and a low-dose injection of streptozotocin prior to the appearance of senile plaques in APP/PS1 transgenic mice. The diabesity-associated metabolic changes and AD-related pathological alterations were examined. RESULTS: We found that XZD reduced body weight, insulin and leptin level, HOMA-IR, hepatic triglyceride, serum Aß42 in the metabolic stressed AD animal. XZD also ameliorated oral glucose tolerant, Aß deposition, astrocyte and microglia activation in the vicinity of plaques, and nesting behavior in the metabolic stressed AD animal. CONCLUSION: The results of this study suggest that XZD is able to reduce the peripheral metabolic stress-mediated vascular hypoperfusion, neuroinflammation and AD-related pathology in APP/PS1 mice.
Assuntos
Amiloide/metabolismo , Disfunção Cognitiva/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Fígado Gorduroso/tratamento farmacológico , Inflamação/tratamento farmacológico , Obesidade/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Glicemia/efeitos dos fármacos , Homeostase , Insulina/sangue , Resistência à Insulina , Leptina/sangue , Masculino , Camundongos , Camundongos Transgênicos , Estresse Fisiológico , Triglicerídeos/metabolismoRESUMO
The purpose of this study was to investigate the pharmacokinetics of the polymethoxylated flavonoids kumatakenin, pachypodol, and retusin, which contain two, three, or four methoxy substitutions, using a validated ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method in rats. The pharmacokinetic results demonstrated that the elimination half-lives for kumatakenin, pachypodol, and retusin were 30 ± 11.6, 39.4 ± 19.5, and 106.9 ± 26 min, respectively, for the low dose group and 54.5 ± 16.5, 33.8 ± 10, and 134.6 ± 34.7 min for the high dose group. The results suggested that the area under the curve values (AUC) for the analytes did not correlate with the number of methoxy groups. Pachypodol had the lowest AUC, which may have been correlated with lipophilicity, for both the low and high dose groups. In conclusion, the polymethoxylated flavonoid pachypodol is more hydrophilic than kumatakenin or retusin, which were correlated with the pharmacokinetic results.