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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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Acetaminofén , Articulación de la Rodilla , Ratas Sprague-Dawley , Animales , Acetaminofén/farmacocinética , Acetaminofén/sangre , Ratas , Masculino , Articulación de la Rodilla/metabolismo , Extractos Vegetales/farmacocinética , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Analgésicos no Narcóticos/farmacocinética , Analgésicos no Narcóticos/sangre , Analgésicos no Narcóticos/administración & dosificación , Músculo Esquelético/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Interacciones de Hierba-Droga , Distribución Tisular , Medicamentos Herbarios Chinos/farmacocinética , Medicamentos Herbarios Chinos/administración & dosificaciónRESUMEN
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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Antivirales , Barrera Hematoencefálica , Interacciones de Hierba-Droga , Microdiálisis , Extractos Vegetales , Ratas Sprague-Dawley , Ritonavir , Scutellaria baicalensis , Animales , Ritonavir/farmacocinética , Ritonavir/farmacología , Scutellaria baicalensis/química , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Ratas , Microdiálisis/métodos , Masculino , Antivirales/farmacocinética , Extractos Vegetales/farmacocinética , Extractos Vegetales/farmacología , Espectrometría de Masas en Tándem/métodos , Encéfalo/metabolismo , Medicamentos Herbarios Chinos/farmacocinética , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/administración & dosificaciónRESUMEN
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 , Hepatitis D , Neoplasias Hepáticas , Simportadores , Ratones , Animales , Humanos , Virus de la Hepatitis Delta/genética , Virus de la Hepatitis Delta/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Ratones Endogámicos C57BL , Hepatitis D/tratamiento farmacológico , Hepatitis D/patología , Virus de la Hepatitis B/fisiología , Hepatocitos , Ratones Transgénicos , Simportadores/metabolismoRESUMEN
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 , Lignanos , Piper , Ratones , Animales , Lipopolisacáridos/toxicidad , FN-kappa B/metabolismo , Kadsura/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Endotoxemia/inducido químicamente , Endotoxemia/tratamiento farmacológico , Antiinflamatorios/efectos adversos , Interleucina-6/genética , Interleucina-6/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Inflamación/metabolismo , Lignanos/uso terapéuticoRESUMEN
[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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Tratamiento Farmacológico de COVID-19 , Complicaciones Infecciosas del Embarazo , Adenosina/análogos & derivados , Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Líquido Amniótico , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , Biotransformación , Femenino , Feto/metabolismo , Furanos/metabolismo , Placenta/metabolismo , Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Pirroles/metabolismo , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem/métodosRESUMEN
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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Antiinflamatorios/farmacología , Diterpenos/farmacología , Quinasa I-kappa B/antagonistas & inhibidores , Magnoliopsida/química , FN-kappa B/antagonistas & inhibidores , Animales , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Diterpenos/química , Diterpenos/aislamiento & purificación , Quinasa I-kappa B/metabolismo , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , FN-kappa B/metabolismo , Células RAW 264.7RESUMEN
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 , Virus de la Hepatitis B/fisiología , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Simportadores/metabolismo , Internalización del Virus/efectos de los fármacos , ADN Circular/metabolismo , Ergosterol/farmacología , Células Hep G2 , Hepatitis B/patología , Hepatitis B/virología , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/genética , Humanos , Transportadores de Anión Orgánico Sodio-Dependiente/genética , Simportadores/genética , Replicación ViralRESUMEN
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 , Extractos Vegetales/metabolismo , Animales , Apigenina/química , Chrysanthemum/metabolismo , Flavonoides/química , Flavonoides/metabolismo , Flores/química , Hidrólisis , Luteolina/química , Estructura Molecular , Extractos Vegetales/química , Hojas de la Planta/química , Tallos de la Planta/química , Ratas , Ratas Sprague-DawleyRESUMEN
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 , Cuerpo Estriado/metabolismo , Medicamentos Herbarios Chinos/farmacocinética , Trastornos Parkinsonianos/tratamiento farmacológico , Polygala/química , Ambroxol/metabolismo , Ambroxol/uso terapéutico , Animales , Área Bajo la Curva , Análisis Químico de la Sangre , Barrera Hematoencefálica , Encéfalo/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Medicamentos Herbarios Chinos/metabolismo , Medicamentos Herbarios Chinos/uso terapéutico , Interacciones de Hierba-Droga , Masculino , Microdiálisis/métodos , Ratas Sprague-Dawley , Espectrometría de Masas en TándemRESUMEN
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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Antiinflamatorios/química , Momordica charantia/química , Extractos Vegetales/química , Propionibacteriaceae/patogenicidad , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Línea Celular , Modelos Animales de Enfermedad , Edema/tratamiento farmacológico , Edema/microbiología , Edema/patología , Cromatografía de Gases y Espectrometría de Masas , Humanos , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Masculino , Ratones Endogámicos ICR , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Momordica charantia/metabolismo , Monocitos/citología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Monocitos/microbiología , Extractos Vegetales/análisis , Hojas de la Planta/química , Hojas de la Planta/metabolismoRESUMEN
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/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Femenino , Humanos , Inmunosupresores/química , Inmunosupresores/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , Hojas de la Planta/química , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Células RAW 264.7 , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
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 Herbarios Chinos/farmacología , Péptido 1 Similar al Glucagón/metabolismo , Hipoglucemiantes/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Iridoides/farmacología , Administración Oral , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Femenino , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Trastornos del Metabolismo de la Glucosa/tratamiento farmacológico , Trastornos del Metabolismo de la Glucosa/metabolismo , Hemoglobina Glucada/metabolismo , Hipoglucemiantes/administración & dosificación , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Iridoides/administración & dosificación , Ratones , Orobanchaceae/química , Plantas Medicinales/química , RatasRESUMEN
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.
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Flavonoides/farmacocinética , Animales , Bilis/metabolismo , Flavonoides/sangre , Flavonoles , Glucurónidos/sangre , Glucurónidos/farmacocinética , Eliminación Hepatobiliar , Cinética , Masculino , Ratas , Ratas Sprague-Dawley , Sulfatos/sangre , Sulfatos/farmacocinéticaRESUMEN
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.
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Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Bencenosulfonatos/farmacología , Descubrimiento de Drogas , Oxazoles/farmacología , Polimixina B/farmacología , Proteínas Bacterianas/metabolismo , ADN/metabolismo , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Farmacorresistencia Microbiana/efectos de los fármacos , Klebsiella pneumoniae/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Unión ProteicaRESUMEN
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.
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Amiloide/metabolismo , Disfunción Cognitiva/prevención & control , Medicamentos Herbarios Chinos/farmacología , Hígado Graso/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Glucemia/efectos de los fármacos , Homeostasis , Insulina/sangre , Resistencia a la Insulina , Leptina/sangre , Masculino , Ratones , Ratones Transgénicos , Estrés Fisiológico , Triglicéridos/metabolismoRESUMEN
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.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Flavonas/farmacocinética , Espectrometría de Masas en Tándem/métodos , Animales , Flavonas/sangre , Flavonas/química , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Sarcandra glabra (Thunb.) Nakai (Chloranthaceae) is a medicinal plant used as herbal tea or food supplement to promote human health. We isolated 14 phenolic compounds from the n-butanol fraction of S. glabra and investigated their anti-inflammatory potential using lipopolysaccharide (LPS)-activated RAW264.7 macrophages. We demonstrated that methyl isorinate, a previously uncharacterized compound in S. glabra, is able to suppress NF-κB activation and reduce the expression of iNOS and COX-2 as well as the phosphorylation of IκB in LPS-treated RAW264.7 cells. In addition, the production of two inflammatory cytokines (IL-6 and TNF-α), as well as release of reactive oxygen species, in the LPS-stimulated macrophages was also inhibited by this compound. Furthermore, the structure-activity relationships of all of the isolated phenolic compounds present were analyzed. Overall, this study revealed several anti-inflammatory compounds that were present in S. glabra, and the results suggest that these diverse phenolic compounds are associated with the anti-inflammatory effects of S. glabra.