RESUMEN
Postmenopausal osteoporosis (PMOP) arises from the disruption in bone remodeling caused by estrogen deficiency, leading to a heightened susceptibility to osteoporotic fractures in aging women. Tetrahydroberberine (THB) is a chemical compound extracted from Corydalis yanhusuo, a member of the traditional Chinese medicine series "Zhejiang eight taste", possessing a variety of pharmacological functions such as lowering lipids and preventing muscle atrophy. However, the impact of THB on PMOP has not been systematically explored. In vitro experiments supported that THB suppresses osteoclast formation and resorption of bone concentration-dependently. Further experiments confirmed that these inhibitory effects of THB were related to inhibition on expressions of osteoclast-specific genes, the mitogen-activated protein kinase (MAPK) pathway, and the nuclear factor kappa-B (NF-κB) pathway and an increased apoptosis level in mature osteoclasts. Additionally, THB treatment mitigated the ovariectomy-induced bone loss and improved the skeletal microarchitecture in vivo. In conclusion, THB has such potential to improve the PMOP status.
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The promotion of excess low-density lipoprotein (LDL) clearance stands as an effective clinical approach for treating hyperlipidemia. Tetrahydroberberine, a metabolite of berberine, exhibits superior bioavailability compared to berberine and demonstrates a pronounced hypolipidemic effect. Despite these characteristics, the impact of tetrahydroberberine on improving excessive LDL clearance in hyperlipidemia has remained unexplored. Thus, this study investigates the potential effects of tetrahydroberberine on high-fat diet-induced hyperlipidemia in mice. The findings reveal that tetrahydroberberine exerts a more potent lipid-lowering effect than berberine, particularly concerning LDL-cholesterol in hyperlipidemic mice. Notably, tetrahydroberberine significantly reduces serum levels of upstream lipoproteins, including intermediate-density lipoprotein (IDL) and very low-density lipoprotein, by promoting their conversion to LDL. This reduction is further facilitated by the upregulation of hepatic LDL receptor expression induced by tetrahydroberberine. Intriguingly, tetrahydroberberine enhances the apolipoprotein E (ApoE)/apolipoprotein B100 (ApoB100) ratio, influencing lipoprotein assembly in the serum. This effect is achieved through the activation of the efflux of ApoE-containing cholesterol in the liver. The ApoE/ApoB100 ratio exhibits a robust negative correlation with serum levels of LDL and IDL, indicating its potential as a diagnostic indicator for hyperlipidemia. Moreover, tetrahydroberberine enhances hepatic lipid clearance without inducing lipid accumulation in the liver and alleviates existing liver lipid content. Importantly, no apparent hepatorenal toxicity is observed following tetrahydroberberine treatment for hyperlipidemia. In summary, tetrahydroberberine demonstrates a positive impact against hyperlipidemia by modulating lipoprotein assembly-induced clearance of LDL and IDL. The ApoE/ApoB100 ratio emerges as a promising diagnostic indicator for hyperlipidemia, showcasing the potential clinical significance of tetrahydroberberine in lipid management.
Asunto(s)
Berberina , Berberina/análogos & derivados , Hiperlipidemias , Ratones , Animales , Lipoproteínas IDL/metabolismo , Berberina/farmacología , Berberina/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Triglicéridos , Colesterol/metabolismo , Apolipoproteínas E/genética , LDL-Colesterol , Hígado/metabolismoRESUMEN
In an effort for fighting with dreadful drug resistance, iminotetraberberine was hybridized with metronidazole to construct a unique type of potential broad-spectrum antibacterial iminotetrahydroberberine-corbelled metronidazoles. Some prepared hybrids exerted promising inhibitory effects against the tested microorganisms in comparison to the natural berberine, clinical metronidazole and norfloxacin. Noticeably, phenyl oxime derivative 8e displayed a broad antibacterial spectrum with a quite low MIC value of 0.024 mM against P. aeruginosa, being 63-, 62- and 2-fold to berberine, metronidazole and norfloxacin, respectively. The active compound 8e with low cytotoxicity under effective bacteriostatic concentration could decrease biofilm viability and show much lower trend to induce the resistant development than norfloxacin in the tested period. Mechanism investigation showed that compound 8e could disturb the bacterial membrane to lead to the leakage of cellular contents, thus exerting potent antibacterial potency. It was also revealed that compound 8e could interact with penicillin binding protein via multi-site non-covalent binding in docking simulation. The above results manifested that iminotetrahydroberberine-corbelled metronidazoles might bring hope for the exploitation of new broad-spectrum antibacterial agents with a membrane-destruction mechanism.
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Antibacterianos , Berberina , Antibacterianos/farmacología , Antibacterianos/química , Metronidazol/farmacología , Norfloxacino/farmacología , Pruebas de Sensibilidad Microbiana , Berberina/farmacología , Berberina/química , Proteínas de Unión a las Penicilinas , Pseudomonas aeruginosa , Oximas/farmacologíaRESUMEN
A chiral liquid chromatography-mass spectrometry (LC-MS/MS) approach was developed and verified for the first time in order to quantify the three alkaloids, namely tetrahydropalmatine (THP), tetrahydroberberine (THB) and tetrahydrocoptisine (THC) in Rhizoma Corydalis. Solid-phase extraction was used to prepare sample solution. Enantiomeric separation was obtained on a Chiralpak IC column using acetonitrile-water-ammonia (90:10: 0.1, v/v/v) as mobile phase. The detection was carried out in multiple reaction monitoring (MRM) mode with positive electrospray ionization source. Transitions of m/z 356.0â192.0, m/z 340.0â176.0 and m/z 324.1â176.0 were monitored for THP, THB and THC respectively. All calibration curves showed good linearity (r2 ≥0.9994) within the test ranges. The lower limit of quantification (LLOQ) was 1.0 ng mL-1 and 1.5 ng mL-1 for (+)- and (-)-THP, 1.0 ng mL-1 and 3.0 ng mL-1 for (+)- and (-)-THB, 1.5 ng mL-1and 1.8 ng mL-1 for (+)- and (-)-THC, respectively. The precision, repeatability, and stability tests all meet the requirements. The average recoveries of the analytes ranged from 98.9 % to 101.3 %. Ultimately, the established method was successfully applied to the quantitative analysis of these alkaloid enantiomers extracted from Rhizoma Corydalis of different habitats.
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Alcaloides , Corydalis , Acetonitrilos , Alcaloides/química , Amoníaco , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida/métodos , Corydalis/química , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodos , AguaRESUMEN
A series of berberine and tetrahydroberberine sulfonate derivatives were prepared and tested against the tyrosyl-DNA phosphodiesterase 1 (Tdp1) DNA-repair enzyme. The berberine derivatives inhibit the Tdp1 enzyme in the low micromolar range; this is the first reported berberine based Tdp1 inhibitor. A structure-activity relationship analysis revealed the importance of bromine substitution in the 12-position on the tetrahydroberberine scaffold. Furthermore, it was shown that the addition of a sulfonate group containing a polyfluoroaromatic moiety at position 9 leads to increased potency, while most of the derivatives containing an alkyl fragment at the same position were not active. According to the molecular modeling, the bromine atom in position 12 forms a hydrogen bond to histidine 493, a key catalytic residue. The cytotoxic effect of topotecan, a clinically important topoisomerase 1 inhibitor, was doubled in the cervical cancer HeLa cell line by derivatives 11g and 12g; both displayed low toxicity without topotecan. Derivatives 11g and 12g can therefore be used for further development to sensitize the action of clinically relevant Topo1 inhibitors.
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Antineoplásicos Fitogénicos/síntesis química , Berberina/análogos & derivados , Inhibidores de Fosfodiesterasa/síntesis química , Hidrolasas Diéster Fosfóricas/química , Inhibidores de Topoisomerasa I/farmacología , Topotecan/farmacología , Antineoplásicos Fitogénicos/metabolismo , Antineoplásicos Fitogénicos/farmacología , Berberina/química , Berberina/farmacología , Sitios de Unión , Reparación del ADN/efectos de los fármacos , Combinación de Medicamentos , Diseño de Fármacos , Sinergismo Farmacológico , Células HeLa , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Inhibidores de Fosfodiesterasa/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , Unión Proteica , Conformación Proteica , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/química , Topotecan/químicaRESUMEN
Dihydroberberine (DHBER), the partially reduced form of the alkaloid berberine (BER), is known to exhibit important biological activities. Despite this fact, there have been only few studies that concern the biological properties of functionalized DHBER. Attracted by the potentiality of this latter compound, we have realized the preparation of new arylhydrazono-functionalized DHBERs, starting from BER and some α-bromohydrazones. On the other hand, also the fully reduced form of BER, namely tetrahydroberberine (THBER), and its derivatives have proven to present different biological activities. Therefore, the obtained arylhydrazono-functionalized DHBERs were reduced to the corresponding arylhydrazono-THBERs. The antiproliferative activity of both arylhydrazono-DHBERs and -THBERs has been evaluated on NCI-H1975 lung cancer cells.
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Enantioselective analysis is critically important in the pharmaceutical and agricultural industries. However, most of the methods reported were developed for the analysis of pure racemates acquired from chemical synthesis or purification. Direct analysis of chiral enantiomers in complex matrices has rarely been reported. This work demonstrated capillary electrophoresis-mass spectrometry (CE-MS) for the enantioselective analysis of botanical drugs for the first time, using a widely used botanical drug, Corydalis Rhizoma, as an example. The method was used for the simultaneous enantioselective analysis of dl-tetrahydropalmatine and (RS)-tetrahydroberberine (canadine) in Corydalis Rhizoma extract. Using (2-hydroxypropyl)-ß-cyclodextrin as the chiral selector, a partial filling technique was used to avoid signal suppression and contamination of the MS detector. Post column organic modifier was used to assist with ionization in the flow through microvial CE-MS interface, therefore, organic solvents was not used in the background electrolyte. The completely aqueous background electrolyte contributed to better chiral separations. The CE-MS method established here can directly determine the analytes in their complex matrix without any pre-purification steps, while also offering high sensitivity and low operational costs (including sample, chiral selector and solvent). In the method validation process, good linearity (râ¯>â¯0.993), sensitivity and accuracy (recoveries within 89.1-110.0%) were demonstrated. The CE-MS technique was shown to be able to provide good selectivity for the simultaneous chiral separation of multiple pairs of enantiomers in complex matrices.
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Corydalis/química , Electroforesis Capilar/métodos , Espectrometría de Masas/métodos , Extractos Vegetales/análisis , Berberina/análogos & derivados , Berberina/análisis , Berberina/química , Alcaloides de Berberina/análisis , Alcaloides de Berberina/química , Límite de Detección , Modelos Lineales , Modelos Químicos , Extractos Vegetales/química , Reproducibilidad de los Resultados , EstereoisomerismoRESUMEN
Tetrahydroberberine (THB), otherwise known as canadine, is a natural alkaloid showing significant pharmacological properties and antioxidant protection against oxidative damage. Herein, we synthetized structurally complex THB analogues, namely pyrrolino-tetrahydroberberines (PTHBs) 4a-g, containing the pyrrolino[2,3-b]pyridine system, by means of the reactions of 1,2-diaza-1,3-dienes and 7,8-dihydroberberine. Aim of the study was to explore the in vitro antioxidant properties of PTHBs in comparison to THB thus to identify the most effective against free radical-induced oxidative injury, by using three different antioxidant tests: the ORAC method, the DNA nicking assay, and the DCFH-DA cellular assay. As a result, PTHB 4d emerged among the other THB analogues by exhibiting the best antioxidant properties. First, it was the only compound having an ORAC value completely comparable to that of THB, indicating the same ability to neutralize peroxyl radicals. Secondly, 4d showed an even better antioxidant capacity than THB in protecting DNA against ferrous ion-induced strand breaks. These observations were also confirmed in NCTC-2544 human keratinocytes exposed to hydrogen peroxide. Indeed, 4d protected cells against oxidation more efficiently than THB both in the short (1 and 3â¯h) and long (24â¯h) period of incubation, possibly suggesting increased cell membrane permeability and/or intracellular stability of 4d as compared to THB.
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Antioxidantes/farmacología , Berberina/análogos & derivados , Pirroles/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Berberina/síntesis química , Berberina/química , Berberina/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , ADN/efectos de los fármacos , Roturas del ADN , Relación Dosis-Respuesta a Droga , Compuestos Ferrosos/antagonistas & inhibidores , Compuestos Ferrosos/farmacología , Radicales Libres/antagonistas & inhibidores , Radicales Libres/farmacología , Humanos , Peróxido de Hidrógeno/farmacología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Estructura Molecular , Pirroles/síntesis química , Pirroles/química , Relación Estructura-ActividadRESUMEN
To discover more derivatives with better glucose-lowering efficacy compared with berberine, twenty-three novel compounds with 4,7,12,12a-tetrahydro-5H-thieno[3',2':3,4]pyrido[1,2-b]isoquinoline or 5,8,12,12a-tetrahydro-6H-thieno[2',3':4,5]pyrido[2,1-a]isoquinoline cores were designed, synthesized, and biologically evaluated in vitro in continuation of our previous work on indirect activators of adenosine 5'-monophosphate-activated protein kinase (AMPK). Nine compounds effectively stimulated glucose consumption (>2.3-fold at 10 µM) in L6 myotube cells, and two compounds (4d and 4s) exhibited superior inhibitory activity (<57.6% at 5 µM) compared with berberine on gluconeogenesis in rat primary hepatocytes. Additionally, these compounds significantly up-regulated the phosphorylation of AMPK and its substrate, acetyl-CoA carboxylase (ACC) and slightly decreased the mitochondrial membrane potential in L6 myotube cells.
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Proteínas Quinasas Activadas por AMP/metabolismo , Diseño de Fármacos , Isoquinolinas/química , Proteínas Quinasas Activadas por AMP/química , Animales , Células Cultivadas , Glucosa/metabolismo , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Fibras Musculares Esqueléticas/citología , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Coptis japonica is widely distributed in Japan, and its dried rhizome is a source of the domestic herbal medicine Coptidis Rhizoma ( Oren). There are three varieties of C. japonica, two of which, namely, C. japonica var. anemonifolia and C. japonica var. major, are important as sources of traditional medicines. Coptis japonica var. anemonifolia and C. japonica var. major are distinguishable on the basis of their ternate or biternate compound leaves, respectively. In the Hokuriku area, where both C. japonica var. anemonifolia and C. japonica var. major grow naturally, some individual plants cannot be identified unambiguously on the basis of leaf morphology because changes in leaf morphology may occur due to intra-variety variation or crossbreeding between the two varieties. In addition, genetic differences between the two varieties have remained unclear. In this study, we employed new genetic and morphological classification approaches to discriminate between the two varieties. Based on the single nucleotide polymorphisms of the tetrahydroberberine oxidase gene, we found four conserved SNPs between the two varieties and were able to classify C. japonica into two varieties and crossbreeds. Furthermore, we introduced a new leaf type index based on the overall degree of leaflet dissection calculated by surface area of a leaflet and length of leaflet margin and petiolule. Using our new index we were able to discriminate between the two varieties and their crossbreeds more accurately than is possible with the conventional discrimination method. Our genetic and morphological classification methods may be used as novel benchmarks to discriminate between the two varieties and their crossbreeds.
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Coptis/química , Fitoterapia/métodos , Extractos Vegetales/química , Plantas Medicinales/química , Rizoma/química , JapónRESUMEN
A series of novel berberine derivatives, 4,7,12,12a-tetrahydro-5H-thieno[3',2':3,4]pyrido[1,2-b]isoquinolines was designed, synthesized, and biologically evaluated for their anti-diabetic activity. Following the evaluation in two types of cells, compounds 4aa, 4bq, and 4bv stimulated glucose consumption (1.8- to 2.3-fold), reduced gluconeogenesis (60-85%), inhibited mitochondria respiratory chain complex I and activated AMPK indirectly. In a db/db mice model, compounds 4bq and 4bv lowered fasting blood glucose at a dose of 120 mg/kg/day. In addition, compounds 4bq and 4bv were found to possess improved pharmacokinetic profiles (bioavailability 45 and 106%, respectively) compared to berberine. Compounds 4bq and 4bv exhibited no obvious hERG inhibition (IC50 > 10 µM).
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Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Activadores de Enzimas/metabolismo , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Isoquinolinas/química , Isoquinolinas/farmacología , Animales , Espectroscopía de Resonancia Magnética con Carbono-13 , Línea Celular , Activadores de Enzimas/farmacocinética , Hipoglucemiantes/síntesis química , Isoquinolinas/farmacocinética , Ratones , Espectroscopía de Protones por Resonancia Magnética , Ratas , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
The aim of this study was to investigate the effects of tetrahydroberberine (THB) and tetrahydropalmatine (THP) on the expression of mouse liver cytochrome P450s, and evaluate their liver toxicity in mice. Real-time polymerase chain reaction (PCR) and western blot analyses were used to analyze the expression of major P450 isoforms. Liver toxicity was evaluated by measuring serum biochemical parameters and performing histopathological analysis. The real-time PCR results showed that THB induced Cyp1a2 (1.66 ± 0.34 fold, P < 0.05), Cyp3a11 (1.57 ± 0.24 fold, P < 0.05), and Cyp2e1 (1.75 ± 0.97 fold, P < 0.05) mRNA expression, while THP inhibited Cyp1a2 (0.66 ± 0.12 fold, P < 0.05) mRNA expression. The western blot results confirmed that the expression of CYP1A2, CYP3A, and CYP2E1 proteins in the mouse liver was induced by THB, whereas that of CYP1A2 was inhibited by THP. Toxicological studies showed that THB (40 mg/kg, oral gavage) increased mouse serum aspartate transaminase and total bilirubin, and liver malondialdehyde levels, and induced liver edema. No obvious changes in serum and liver tissue biochemical parameters were found and no significant pathological changes were detected in liver tissues after THP administration. Our results provide more information on the toxicity of THB and THP, and their related drug-drug interactions.
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Alcaloides de Berberina/toxicidad , Berberina/análogos & derivados , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Animales , Aspartato Aminotransferasas/sangre , Berberina/toxicidad , Bilirrubina/sangre , Citocromo P-450 CYP3A , Glutatión/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Malondialdehído/metabolismo , Ratones Endogámicos C57BL , ARN Mensajero/metabolismoRESUMEN
Tetrahydroberberine (THB) belongs to the alkaloid of tetrahydroisoquinoline, which is derived from the roots of Corydalis yanhusuo and can also be hydrogenated from berberine. THB has a variety of significant biological activities compared to berberine. It is reported that THB has the effects of anti-hypertension, anti-arrhythmia, anti-fibrillation and against acute myocardial infarction, and also can treat and protect the injury of ischemic and reperfusion. Moreover, other research has found its effects upon anti-oxidant and regulating the functions of gastrointestinal tract. By searching literature of domestic and foreign from Pubmed, CNKI and other databases, pharmacological activities of THB were summarized in this paper, in order to provide reference for the further study of THB.
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Objective: To establish HPLC method for the simultaneous determination of protopine, palmatine hydrochloride, berberine hydrochloride, dehydrocorydaline, tetrahydropalmatine, tetrahydroberberine, and corydaline in Cuyanhusuo Granule. Methods: The analysis was performed on Ultimate AQ-C18 column (250 mm×4.6 mm, 5 μm) by gradient elution of acetonitrile-0.1% phosphoric acid (adjust to pH 6.0 with triethylamine) (10:90). The UV detection wavelength was set at 280 nm and the flow rate was 1.0 mL/min. Results: The linear ranges of protopine, palmatine hydrochloride, berberine hydrochloride, dehydrocorydaline, tetrahydropalmatine, tetrahydroberberine, and corydaline were 6.8-119.0 (r=0.9999), 24.38-426.65 (r=0.9999), 8.88-155.40 (r=0.9999), 77.66-1359.05 (r=0.9999), 41.4-724.5 (r=0.9999), 6.70-117.25 (r=0.9999), and 25.50-446.25 ng (r=0.9999). The average recoveries (n=6) were 98.2% (RSD=2.0%), 99.6% (RSD=2.8%), 100.2% (RSD=1.3%), 99.0% (RSD=2.2%), 100.8% (RSD=2.6%), 98.7% (RSD=2.5%), and 97.7% (RSD=2.2%), respectively. Conclusion: This method is simple and rapid, and can be used for the quality control of Cuyanhusuo Granule with satisfactory separation and repeatability.
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Tetrahydroberberine (systematic name: 9,10-dimethoxy-5,8,13,13a-tetrahydro-6H-benzo[g][1,3]benzodioxolo[5,6-a]quinolizine), C20H21NO4, a widely distributed naturally occurring alkaloid, has been crystallized as a racemic mixture about an inversion center. A bent conformation of the molecule is observed, with an angle of 24.72â (5)° between the arene rings at the two ends of the reduced quinolizinium core. The intermolecular hydrogen bonds that play an apparent role in crystal packing are 1,3-benzodioxole -CH2···OCH3 and -OCH3···OCH3 interactions between neighboring molecules.
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Alcaloides/química , Alcaloides/farmacología , Alcaloides de Berberina/química , Alcaloides de Berberina/farmacología , Cristalografía por Rayos X , Conformación Molecular , Estructura MolecularRESUMEN
The action of Tetrahydroberberine ( THB ) on arrhythmias of the animal models were studied. The arrhythmias induced by CaCl2 and BaCl2 were significantly counteracted by THB ( 30mg/kg ip ) without markedly changing the hemodynamic parameters of rats, but those evoked by aconitine or ouabain were not inhibited in rats or guinea pigs. THB ( 40mg/kg ip) was used to be prevented the arrhythmias induced by ischaemia-reperfusion of left anterior des-cending coronary artery in rats. It could decrease the incidence of vetricular fibrillation, short restored time of the sinus rhythm and diminish the mortality. THB ( 10mg/kg iv ) effectively reduced the incidence of the ventricular arrhythmia induced by hypothalamic electric stimulation in rabbits. The results indicate that THB possess significant antiarrhythmic effect. It may be concerned the action of THB to blok calcium entry