Self Emulsifying Delivery System of Cissus quadrangularis: Evidence of Enhanced Efficacy and Promising Pharmacokinetic Profile in the Management of Osteoporosis.

Treatment therapies used to manage osteoporosis are associated with severe side effects. So worldwide herbs are widely studied to develop alternative safe & effective treatments. Cissus quadrangularis (CQ) has a significant role in bone health and fracture healing. It is documented that its extracts increase osteoblastic differentiation & mineralization. Currently, Cissus quadrangularis is available in the form of tablets in the market for oral delivery. But these conventional forms are associated with poor bioavailability. There is a need for a novel drug delivery system with improving oral bioavailability. Therefore, a Cissus quadrangularis-loaded self-emulsifying drug delivery system (CQ-SEDDS) was developed which disperses rapidly in the gastrointestinal fluids, yielding nano-emulsions containing a solubilized drug. This solubilized form of the drug can be easily absorbed through lymphatic pathways and bypass the hepatic first-pass effect. The emulsification efficiency, zeta potential, globule size, in-vitro dissolution, ex-vivo, in-vivo and bone marker studies were performed to assess the absorption and permeation potential of CQ incorporated in SEDDS. CQ-SEDDS with excipients Tween 80, Cremophor RH40, Transcutol HP & α-Tocopherol acetate had shown about 76% enhancement in the bioavailability of active constituents of CQ. This study provided the pre-clinical data of CQ-SEDDS using osteoporotic rat model studies.

St. John's wort extract with a high hyperforin content does not induce P-glycoprotein activity at the human blood-brain barrier.

St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P-gp activity at the human blood-brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)-targeted P-gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P-gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3-6%) for 12-19 days (1800 mg/day), the activity of P-gp at the BBB was assessed by means of PET imaging with the P-gp substrate [11C]metoclopramide and the activity of peripheral P-gp and CYPs was assessed by administering a low-dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P-gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P-gp-mediated efflux of [11C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P-gp induction at the human BBB despite its ability to induce peripheral P-gp and CYPs. Simultaneous intake of SJW with CNS-targeted P-gp substrate drugs is not expected to lead to P-gp-mediated drug interactions at the BBB.

Investigation of the drug-drug interaction and incompatibility mechanism between Aconitum carmichaelii Debx and Pinellia ternata (Thunb.) Breit.

ETHNOPHARMACOLOGICAL RELEVANCE: The combination of Aconitum carmichaelii Debx (Chuanwu, CW) and Pinellia ternata (Thunb.) Breit (Banxia, BX) forms an herbal pair within the eighteen incompatible medicaments (EIM), indicating that BX and CW are incompatible. However, the scientific understanding of this incompatibility mechanism, especially the corresponding drug-drug interaction (DDI), remains complex and unclear. AIM OF THE STUDY: This study aims to explain the DDI and potential incompatibility mechanism between CW and BX based on pharmacokinetics and cocktail approach. MATERIALS AND METHODS: Ultraperformance liquid chromatography-tandem mass spectrometry methods were established for pharmacokinetics and cocktail studies. To explore the DDI between BX and CW, in the pharmacokinetics study, 10 compounds were determined in rat plasma after administering CW and BX-CW herbal pair extracts. In the cocktail assay, the pharmacokinetic parameters of five probe substrates were utilized to assess the influence of BX on cytochrome P450 (CYP) isoenzyme (dapsone for CYP3A4, phenacetin for CYP1A2, dextromethorphan for CYP2D6, tolbutamide for CYP2C9, and omeprazole for CYP2C19). Finally, the DDI and incompatibility mechanism of CW and BX were integrated to explain the rationality of EIM theory. RESULTS: BX not only enhances the absorption of aconitine and benzoylaconine but also accelerates the metabolism of mesaconitine, benzoylmesaconine, songorine, and fuziline. Moreover, BX affects the activity of CYP enzymes, which regulate the metabolism of toxic compounds. CONCLUSIONS: BX altered the activity of CYP enzymes, consequently affecting the metabolism of toxic compounds from CW. This incompatibility mechanism may be related to the increased absorption of these toxic compounds in vivo.

Integrated pharmacokinetic-pharmacodynamic modeling and metabolomic research on polyphenol-rich fraction of Thymus quinquecostatus Celak. Alleviating cerebral ischemia-reperfusion injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Thymus quinquecostatus Celak., a member of thymus genus in Lamiaceae family, has been used as a folk medicine for relieving exterior syndrome and alleviating pain in China. The polyphenol-rich fraction (PRF) derived from Thymus quinquecostatus Celak. had been validated that it can protect cerebral ischemia-reperfusion injury (CIRI) by activating Keap1/Nrf2/HO-1 signaling pathway. AIM OF THIS STUDY: To explore effective components and their pharmacokinetic and pharmacodynamic characteristics as well as possible mechanisms of PRF in treating CIRI. MATERIALS AND METHODS: Normal treated group (NTG) and tMCAO model treated group (MTG) rats were administrated PRF intragastrically. The prototype components and metabolites of PRF in plasma and brain were analyzed by the UPLC-Q-Exactive Orbitrap MSn method. Subsequently, the pharmacokinetics properties of indicative components were performed based on HPLC-QQQ-MS/MS. SOD and LDH activities were determined to study the pharmacodynamic (PD) properties of PRF. The PK-PD relationship of PRF was constructed. In addition, the effect of PRF on endogenous metabolites in plasma and brain was investigated using metabolomic method. RESULTS: Salvianic acid A, caffeic acid, rosmarinic acid, scutellarin, and apigenin-7-O-glucuronide were selected as indicative components based on metabolic analysis. The non-compartmental parameters were calculated for indicative components in plasma and brain of NTG and MTG rats. Furthermore, single-component and multi-component PK-PD modeling involved Emax, Imax PD models for effect indexes were fitted as well as ANN models were established, which indicated that these components can work together to regulate SOD and LDH activities in plasma and SOD activity in brain tissue to improve CIRI. Additionally, PRF may ameliorate CIRI by regulating the disorder of endogenous metabolites in lipid metabolism, amino acid metabolism, and purine metabolism pathways in vivo, among which lipid metabolism and purine metabolism are closely related to oxidative stress. CONCLUSION: The PK-PD properties of effect substances and mechanisms of PRF anti-CIRI were further elaborated. The findings provide a convincing foundation for the application of T. quinquecostatus Celak. in the maintenance of human health disorders.

Dracocephalum moldavica L.: An updated comprehensive review of its botany, traditional uses, phytochemistry, pharmacology, and application aspects.

Dracocephalum moldavica, known as Xiang-qing-lan (in Chinese), is a traditional folk medicine, which was commonly used by Mongolian and Xinjiang Uyghurs area. Dracocephalum moldavica has the effects of purging liver fire, clearing stomach heat, hemostasis. It is used for treating insufficient heart and blood, weakened brain function, weak feeling and spirit disease etc. This review aimed to summarize the botany, traditional uses, phytochemistry, pharmacology and application of Dracocephalum moldavica, which expected to provide theoretical support for future utilization and highlight the further investigation of this vital plant. In addition to the essential oil, approximately 154 compounds have been isolated and identified from aerial parts of the Dracocephalum moldavica, including flavonoids, terpenoids, lignans, phenylpropanoids, phenols, glycosides, polysaccharide and other compounds. Extensive pharmacological activities of the extracts or compounds of Dracocephalum moldavica in vivo and in vitro were confirmed including cardiovascular protection, antioxidative, antimicrobial, antifungal, anti-complementary and chronic mountain sickness. Moreover, Dracocephalum moldavica is used in a wide range of applications in food, biological pesticides and cosmetics. In the future, Dracocephalum moldavica needs further study, such as paying more attention to quality control, toxicity, pharmacological mechanism and pharmacokinetics.

Comparative Pharmacokinetic Study of Rhubarb Anthraquinones in Normal and Nonalcoholic Fatty Liver Disease Rats.

BACKGROUND AND OBJECTIVES: Rhubarb anthraquinones contain five main components, that is, rhein, emodin, aloe-emodin, chrysophanol, and physcion, which demonstrate good therapeutic effects on nonalcoholic fatty liver disease (NAFLD). However, research on its pharmacokinetics in NAFLD remains lacking. This study aimed to investigate the pharmacokinetic differences of rhubarb anthraquinones in normal and NAFLD rats. METHODS: This study developed an NAFLD rat model by high-fat diet feeding for 6 weeks. Normal and NAFLD groups were orally administered different rhubarb anthraquinones doses (37.5, 75, and 150 mg/kg). The concentration of the rhein, emodin, aloe-emodin, chrysophanol, and physcion in plasma was determined by high-performance liquid chromatography-ultraviolet. RESULTS: The results revealed significant differences in pharmacokinetic behavior between normal and NAFLD rats. Compared with normal rats, NAFLD rats demonstrated significantly increased maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0 → ∞) of rhubarb anthraquinones (P < 0.05), as well as significantly prolonged time to reach maximum plasma concentration (Tmax), terminal elimination half-life (t1/2), and mean residence time (MRT) of rhubarb anthraquinones (P < 0.05). CONCLUSIONS: This study indicates significant differences in the pharmacokinetics of rhubarb anthraquinones between the physiological and NAFLD states of rats. Rhubarb anthraquinone demonstrated a longer retention time and slower absorption rate in NAFLD rats and exhibited higher bioavailability and peak concentration. This finding provides important information for guiding the clinical use of rhubarb anthraquinones under pathological conditions.

In Vitro Bioaccessibility Assessment of Phenolic Compounds from Encapsulated Grape Pomace Extract by Ionic Gelation.

Grape pomace is a by-product of winemaking characterized by a rich chemical composition from which phenolics stand out. Phenolics are health-promoting agents, and their beneficial effects depend on their bioaccessibility, which is influenced by gastrointestinal digestion. The effect of encapsulating phenol-rich grape pomace extract (PRE) with sodium alginate (SA), a mixture of SA with gelatin (SA-GEL), and SA with chitosan (SA-CHIT) on the bioaccessibility index (BI) of phenolics during simulated digestion in vitro was studied. A total of 27 individual phenolic compounds (IPCs) were quantified by UHPLC. The addition of a second coating to SA improved the encapsulation efficiency (EE), and the highest EE was obtained for SA-CHIT microbeads (56.25%). Encapsulation affected the physicochemical properties (size, shape and texture, morphology, crystallinity) of the produced microbeads, which influenced the delivery of phenolics to the intestine and their BI. Thus, SA-GEL microbeads had the largest size parameters, as confirmed by scanning electron microscopy (SEM), and the highest BI for total phenolic compounds and IPCs (gallic acid, 3,4-dihydroxybenzoic acid and o-coumaric acid, epicatechin, and gallocatechin gallate) ranged from 96.20 to 1011.3%. The results suggest that encapsulated PRE has great potential to be used as a functional ingredient in products for oral administration.

Evaluation of Cytochrome P450-Mediated Cannabinoid-Drug Interactions in Healthy Adult Participants.

Understanding cannabis-drug interactions is critical given regulatory changes that have increased access to and use of cannabis. Cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (Δ9-THC), the most abundant phytocannabinoids, are in vitro reversible and time-dependent (CBD only) inhibitors of several cytochrome P450 (CYP) enzymes. Cannabis extracts were used to evaluate quantitatively potential pharmacokinetic cannabinoid-drug interactions in 18 healthy adults. Participant received, in a randomized cross-over manner (separated by ≥ 1 week), a brownie containing (i) no cannabis extract (ethanol/placebo), (ii) CBD-dominant cannabis extract (640 mg CBD + 20 mg Δ9-THC), or (iii) Δ9-THC-dominant cannabis extract (20 mg Δ9-THC and no CBD). After 30 minutes, participants consumed a cytochrome P450 (CYP) drug cocktail consisting of caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A). Plasma and urine samples were collected (0-24 hours). The CBD + Δ9-THC brownie inhibited CYP2C19 > CYP2C9 > CYP3A > CYP1A2 (but not CYP2D6) activity, as evidenced by an increase in the geometric mean ratio of probe drug area under the plasma concentration-time curve (AUC) relative to placebo (AUCGMR ) of omeprazole, losartan, midazolam, and caffeine by 207%, 77%, 56%, and 39%, respectively. In contrast, the Δ9-THC brownie did not inhibit any of the CYPs. The CBD + Δ9-THC brownie increased Δ9-THC AUCGMR by 161%, consistent with CBD inhibiting CYP2C9-mediated oral Δ9-THC clearance. Except for caffeine, these interactions were well-predicted by our physiologically-based pharmacokinetic model (within 26% of observed interactions). Results can be used to help guide dose adjustment of drugs co-consumed with cannabis products and the dose of CBD in cannabis products to reduce interaction risk with Δ9-THC.

Simultaneous pharmacokinetic assessment of phytopharmaceuticals in fenugreek extract using LC-MS/MS in Sprague-Dawley rats.

Fenugreek seeds are used in numerous marketed herbal formulations with therapeutic benefits. Some of its bioactive components such as 4-hydroxyisoleucine, trigonelline, raffinose, and pinitol are reported to possess potential therapeutic activities, such as antibacterial, antidiabetic, stomach stimulant, and anti-invasive, against hyperandrogenism and other allied diseases, including polycystic ovary syndrome. A fully validated, selective, and sensitive bioanalytical method for the simultaneous rapid quantification of the aforementioned bioactive components has been developed using hyphenated liquid chromatography electrospray tandem mass spectrometry. The analytes were separated within 5 min using gradient elution in a C18 column at a flow rate of 0.5 ml/min. Plasma protein precipitation technique was employed to isolate the analytes from the samples. Oral pharmacokinetic profile of the four bioactive components in Sprague-Dawley rats was further evaluated using noncompartmental analysis using Phoenix WinNonlin software.

Advances for pharmacological activities of Polygonum cuspidatum - A review.

CONTEXT: Polygonum cuspidatum Sieb. et Zucc (Polygonaceae), the root of which is included in the Chinese Pharmcopoeia under the name 'Huzhang', has a long history as a medicinal plant and vegetable. Polygonum cuspidatum has been used in traditional Chinese medicine for the treatment of inflammation, hyperlipemia, etc. OBJECTIVE: This article reviews the pharmacological action and the clinical applications of Polygonum cuspidatum and its extracts, whether in vivo or in vitro. We also summarized the main phytochemical constituents and pharmacokinetics of Polygonum cuspidatum and its extracts. METHODS: The data were retrieved from major medical databases, such as CNKI, PubMed, and SinoMed, from 2014 to 2022. Polygonum cuspidatum, pharmacology, toxicity, clinical application, and pharmacokinetics were used as keywords. RESULTS: The rhizomes, leaves, and flowers of Polygonum cuspidatum have different phytochemical constituents. The plant contains flavonoids, anthraquinones, and stilbenes. Polygonum cuspidatum and the extracts have anti-inflammatory, antioxidation, anticancer, heart protection, and other pharmacological effects. It is used in the clinics to treat dizziness, headaches, traumatic injuries, and water and fire burns. CONCLUSIONS: Polygonum cuspidatum has the potential to treat many diseases, such as arthritis, ulcerative colitis, asthma, and cardiac hypertrophy. It has a broad range of medicinal applications, but mainly focused on root medication; its aerial parts should receive more attention. Pharmacokinetics also need to be further investigated.

Cannabidiol in urine is not a proof of CBD consumption-lesson learned from urine sample analysis in routine caseworks.

PURPOSE: Cannabidiol (CBD) has been gaining popularity in recent years. Knowing that CBD products can contain more tetrahydrocannabinol (THC) than expected, interpretation of cannabinoids concentration in urine can be tricky, especially when low amounts of THC and CBD are found. Moreover, interpretation can also be difficult due to interindividual variation in pharmacokinetics. The objective of this work was to take a critical look at the data from our daily practice as a toxicology laboratory. METHODS: We have collected results obtained in a first batch of 1074 urine samples submitted to cannabinoids analysis, and results of cannabinoids content of a second batch of 719 seized materials. RESULTS: CBD was detected in 163 urine specimens (15%). Its concentration was higher than the limit of quantification of 5 ng/mL in 108 samples only (10% of the sampling population). Most of CBD-positive samples were associated with a high THC-COOH concentration (> 500 ng/mL in 63.8% of CBD-positive samples) suggesting only a few CBD consumers in our population. Cannabinoids composition of seized plant materials (drug type at first glance) revealed CBD in 110 of them (15% of the sampling population), with a concentration mostly below 1%. All of the resin samples were CBD positive, and contained more THC compared to flowers. CONCLUSIONS: We can conclude that urine samples from drug-type cannabis users contained a low amount of CBD, what was not described previously. These findings are useful for the interpretation of cannabinoids results in daily practice.

Identification of Protosappanoside D from Caesalpinia decapetala and Evaluation of Its Pharmacokinetic, Metabolism and Pharmacological Activity.

Protosappanoside D (PTD) is a new component isolated from the extract of Caesalpinia decapetala for the first time. Its structure was identified as protosappanin B-3-O-ß-D-glucoside by 1H-NMR, 13C-NMR, 2D-NMR and MS techniques. To date, the pharmacological activities, metabolism or pharmacokinetics of PTD has not been reported. Therefore, this research to study the anti-inflammatory activity of PTD was investigated via the LPS-induced RAW264.7 cells model. At the same time, we also used the UHPLC/Q Exactive Plus MS and UPLC-MS/MS methods to study the metabolites and pharmacokinetics of PTD, to calculate its bioavailability for the first time. The results showed that PTD could downregulate secretion of the pro-inflammatory cytokines. In the metabolic study, four metabolites were identified, and the primary degradative pathways in vivo involved the desaturation, oxidation, methylation, alkylation, dehydration, degradation and desugarization. In the pharmacokinetic study, PTD and its main metabolite protosappanin B (PTB) were measured after oral and intravenous administration. After oral administration of PTD, its Tmax was 0.49 h, t1/2z and MRT(0-t) were 3.47 ± 0.78 h and 3.06 ± 0.63 h, respectively. It shows that PTD was quickly absorbed into plasma and it may be eliminated quickly in the body, and its bioavailability is about 0.65%.

Angelica gigas: Signature Compounds, In Vivo Anticancer, Analgesic, Neuroprotective and Other Activities, and the Clinical Translation Challenges.

Angelica gigas Nakai (AGN) root is a medicinal herbal widely used in traditional medicine in Korea. AGN root ethanolic extract dietary supplements are marketed in the United States for memory health and pain management. We comprehensively reviewed the anticancer, analgesic, pro-memory and other bio-activities of AGN extract and its signature phytochemicals decursin, decursinol angelate, and decursinol a decade ago in 2012 and updated their anticancer activities in 2015. In the last decade, significant progress has been made for understanding the pharmacokinetics (PK) and metabolism of these compounds in animal models and single dose human PK studies have been published by us and others. In addition to increased knowledge of the known bioactivities, new bioactivities with potential novel health benefits have been reported in animal models of cerebral ischemia/stroke, anxiety, sleep disorder, epilepsy, inflammatory bowel disease, sepsis, metabolic disorders, osteoporosis, osteoarthritis, and even male infertility. Herein, we will update PK and metabolism of pyranocoumarins, review in vivo bioactivities from animal models and human studies, and critically appraise the relevant active compounds, the cellular and molecular pharmacodynamic targets, and pertinent mechanisms of action. Knowledge gaps include whether human pyranocoumarin PK metrics are AGN dose dependent and subjected to metabolic ceiling, or metabolic adaptation after repeated use. Critical clinical translation challenges include sourcing of AGN extracts, product consistency and quality control, and AGN dose optimization for different health conditions and disease indications. Future research directions are articulated to fill knowledge gaps and address these challenges.

Comparative pharmacokinetic studies of five C-glycosylflavones in normal and urolithiasis model rats following administration of total flavonoids from Desmodium styracifolium by liquid chromatography-tandem mass spectrometry.

The total flavonoids of Desmodium styracifolium are the flavonoid extracts purified from Desmodii Styracifolii Herba, which has conventionally been used for treating urolithiasis in China. In this study, a sensitive and simple liquid chromatography-tandem mass spectrometry method was developed to simultaneously determine five active components of the extracts in rat plasma. Chromatographic separation of the analytes (schaftoside, vicenin-1, vicenin-2, vicenin-3, and isovitexin) was performed on an ACQUITY UPLC HSS T3 Column under gradient elution conditions. The calibration curves were linear over ranges from 0.5 to 100 ng/ml for schaftoside, vicenin-1, vicenin-2, and vicenin-3, and 0.2-20 ng/ml for isovitexin. The relative standard deviation of intra- and inter-day precisions were ≤6.8% and ≤8.3%, respectively, and the accuracies (relative error) were within ±7.6%. The recoveries of the analytes ranged between 97.3% and 100.3%, and the matrix effects ranged from 98.6% to 113.8%. The method was successfully applied to the pharmacokinetic studies of the five active ingredients of Desmodium styracifolium, for the first time, in both normal and urolithiasis model rats. Results revealed that the plasma levels of these components were significantly increased under the pathological state. This study provided valuable information facilitating the clinical investigation of this medicine.

Anatomical and Phytochemical Characteristics of Different Parts of Hypericum scabrum L. Extracts, Essential Oils, and Their Antimicrobial Potential.

Hypericum (Hypericaceae) is a genus that comprises a high number of species around the world. In this study, the roots, aerial parts, flowers, fruits, and aerial parts with flowers from Hypericum scabrum were macerated separately by methanol and water and then fractionated by different solvents of, such as ethyl acetate, n-hexane, butanol, dichloromethane, aqueous residue sub-extracts, and ethnobotanical use. All the extracts, sub-extracts and essential oils of H. scabrum were investigated for the first time in detail for their antimicrobial, total phenolics, and antioxidant activities. Anatomical structures of the root, stem, leaf, upper and lower leaf surface, stamen, sepal, and petal of H. scabrum were examined. The biochemical layout of essential oils was determined by GC and GC/MS. The antioxidant activity was determined by free radical scavenging activity (by DPPH). Antimicrobial activity was applied against Candida albicans ATCC 10231, Escherichia coli ATCC 8739, Staphylococcus aureus ATCC 6538, Bacillus subtilis ATCC 19659, and C. tropicalis ATCC 750 using microdilution methods. The essentials of the aerial parts, flower, and fruit are characterized by the presence of monoterpene hydrocarbons, whereas roots oil include alkanes. The GC-FID and GC-MS analysis showed that major components of roots, aerial parts, flowers, and fruits oils were undecane (66.1%); α-pinene (17.5%), γ-terpinene (17.4%), and α-thujene (16.9%); α-pinene (55.6%), α-thujene (10.9%), and γ-terpinene (7.7%); α-pinene (85.2%), respectively. The aerial part sub-extracts indicated a greater level of total phenolics and antioxidant potential. The n-hexane sub-extracts (from aerial part, flower, and aerial part with flower) showed the best activity against B. subtilis, with 39.06 µg/mL MIC value. The presented research work indicates that H. scabrum can be a novel promising resource of natural antioxidant and antimicrobial compounds.

Increase water solubility of Centella asiatica extract by indigenous bioenhancers could improve oral bioavailability and disposition kinetics of triterpenoid glycosides in beagle dogs.

A newly standardised extract of Centella asiatica (Centell-S) with better water solubility than the previous standardised extract of C. asiatica (ECa 233) was developed, and pharmacokinetic profiles of bioactive triterpenoids were investigated in beagle dogs. The test substances were administered via intravenous or oral administration with single and multiple doses for 7 days. The concentrations of major bioactive triterpenoids, including madecassoside, asiaticoside, madecassic acid, and asiatic acid, in biological samples were measured by liquid chromatography-tandem mass spectrometry. The dogs in this study showed good tolerability to all test substances, based on the physical appearance and blood chemistry 24 h after dosing. The major bioactive triterpenoids found in systemic blood circulation were madecassoside, asiaticoside, and asiatic acid; the concentration of these components ranged from 1 to 10,000 µg/L after intravenous administration of 1.0 mg/kg Centell-S. Oral administration of 10 and 20 mg/kg Centell-S generated approximately twofold higher plasma levels of both madecassoside and asiaticoside compared with equivalent doses of ECa 233. In addition, there was an accumulation of triterpenoid glycosides after multiple oral administrations of Centell-S for 7 days, while triterpenic acids showed little tendency for accumulation. Beagles had good tolerability to both standardised extracts of C. asiatica, and showed a similar pattern of bioactive triterpenoids to humans. Centell-S increased oral bioavailability of major triterpenoid glycosides and can be further developed into a phytopharmaceutical product.

Inhibitory effects of phenolic glycosides from Trollius chinensis Bunge on α-glucosidase: inhibition kinetics and mechanisms.

Two undescribed phenolic glycosides, trochinenols B and C (1 and2), together with four known analogues (3-6), were isolated from the functional tea Trollius chinensis Bunge and their α-glucosidase inhibitory kinetics and mechanisms were investigated. It was found that 1 inhibited α-glucosidase in a noncompetitive manner with an IC50 value of 25.96 µM, while 3 showed a notable inhibitory effect against α-glucosidase in an uncompetitive manner with an IC50 value of 3.14 µM. Analysis of synchronous fluorescence and circular dichroism spectroscopy indicated that the binding of 1 to α-glucosidase led to the rearrangement and conformational alteration of the α-glucosidase enzyme. Furthermore, molecular docking indicated that 1 had a high affinity close to the active site pocket of α-glucosidase and indirectly inhibited the catalytic activity of the enzyme. However, 3 was bound to the entrance part of the active center of α-glucosidase and could hinder the release of the substrate as well as the catalytic reaction product, eventually suppressing the catalytic activity of α-glucosidase.

The Therapeutic Effect of Acanthopanax senticosus Components on Radiation-Induced Brain Injury Based on the Pharmacokinetics and Neurotransmitters.

Acanthopanax senticosus (AS) is a medicinal and food homologous plant with many biological activities. In this research, we generated a brain injury model by 60Co -γ ray radiation at 4 Gy, and gavaged adult mice with the extract with AS, Acanthopanax senticocus polysaccharides (ASPS), flavones, syringin and eleutheroside E (EE) to explore the therapeutic effect and metabolic characteristics of AS on the brain injury. Behavioral tests and pathological experiments showed that the AS prevented the irradiated mice from learning and memory ability impairment and protected the neurons of irradiated mice. Meanwhile, the functional components of AS increased the antioxidant activity of irradiated mice. Furthermore, we found the changes of neurotransmitters, especially in the EE and syringin groups. Finally, distribution and pharmacokinetic analysis of AS showed that the functional components, especially EE, could exert their therapeutic effects in brain of irradiated mice. This lays a theoretical foundation for the further research on the treatment of radiation-induced brain injury by AS.

Mesembryanthemum tortuosum L. alkaloids modify anxiety-like behaviour in a zebrafish model.

ETHNOPHARMACOLOGICAL RELEVANCE: Mesembryanthemum tortuosum L. (previously known as Sceletium tortuosum (L.) N.E. Br.) is indigenous to South Africa and traditionally used to alleviate anxiety, stress and depression. Mesembrine and its alkaloid analogues such as mesembrenone, mesembrenol and mesembranol have been identified as the key compounds responsible for the reported effects on the central nervous system. AIM OF THE STUDY: To investigate M. tortuosum alkaloids for possible anxiolytic-like effects in the 5-dpf in vivo zebrafish model by assessing thigmotaxis and locomotor activity. MATERIALS AND METHODS: Locomotor activity and reverse-thigmotaxis, recognised anxiety-related behaviours in 5-days post fertilization zebrafish larvae, were analysed under simulated stressful conditions of alternating light-dark challenges. Cheminformatics screening and molecular docking were also performed to rationalize the inhibitory activity of the alkaloids on the serotonin reuptake transporter, the accepted primary mechanism of action of selective serotonin reuptake inhibitors. Mesembrine has been reported to have inhibitory effects on serotonin reuptake, with consequential anti-depressant and anxiolytic effects. RESULTS: All four alkaloids assessed decreased the anxiety-related behaviour of zebrafish larvae exposed to the light-dark challenge. Significant increases in the percentage of time spent in the central arena during the dark phase were also observed when larvae were exposed to the pure alkaloids (mesembrenone, mesembrenol, mesembrine and mesembrenol) compared to the control. However, mesembrenone and mesembranol demonstrated a greater anxiolytic-like effect than the other alkaloids. In addition to favourable pharmacokinetic and physicochemical properties revealed via in silico predictions, high-affinity interactions characterized the binding of the alkaloids with the serotonin transporter. CONCLUSIONS: M. tortuosum alkaloids demonstrated an anxiolytic-like effect in zebrafish larvae providing evidence for its traditional and modern day use as an anxiolytic.

Qualitative and Quantitative Analysis of Secondary Metabolites in Morphological Parts of Paulownia Clon In Vitro 112® and Their Anticoagulant Properties in Whole Human Blood.

It is not easy to find data in the scientific literature on the quantitative content of individual phytochemicals. It is possible to find groups of compounds and even individual compounds rather easily, but it is not known what their concentration is in cultivated or wild plants. Therefore, the subject of this study was to determine the content of individual compounds in the new Paulownia species, Oxytree, developed in a biotechnology laboratory in 2008 at La Mancha University in Spain. Six secondary metabolites were isolated, and their chemical structure was confirmed by spectral methods. An analytical method was developed, which was then used to determine the content of individual compounds in leaves, twigs, flowers and fruits of Paulownia Clon in Vitro 112®. No flavonoids were found in twigs and fruits of Oxytree, while the highest phenylethanoid glycosides were found in twigs. In this study, we also focused on biological properties (anticoagulant or procoagulant) of extract and four fractions (A-D) of different chemical composition from Paulownia Clon in Vitro 112 leaves using whole human blood. These properties were determined based on the thrombus-formation analysis system (T-TAS), which imitates in vivo conditions to assess whole blood thrombogenecity. We observed that three fractions (A, C and D) from leaves decrease AUC10 measured by T-TAS. In addition, fraction D rich in triterpenoids showed the strongest anticoagulant activity. However, in order to clarify the exact mechanism of action of the active substances present in this plant, studies closer to physiological conditions, i.e., in vivo studies, should be performed, which will also allow to determine the effects of their long-term effects.