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.

Natural compound library screening to identify berberine as a treatment for rheumatoid arthritis.

OBJECTIVE: Fibroblast-like synoviocytes (FLS) play a critical role on the exacerbation and deterioration of rheumatoid arthritis (RA). Aberrant activation of FLS pyroptosis signaling is responsible for the hyperplasia of synovium and destruction of cartilage of RA. This study investigated the screened traditional Chinese medicine berberine (BBR), an active alkaloid extracted from the Coptis chinensis plant, that regulates the pyroptosis of FLS and secretion of inflammatory factors in rheumatoid arthritis. METHODS: First, BBR was screened using a high-throughput drug screening strategy, and its inhibitory effect on RA-FLS was verified by in vivo and in vitro experiments. Second, BBR was intraperitoneally administrated into the collagen-induced arthritis rat model, and the clinical scores, arthritis index, and joint HE staining were evaluated. Third, synovial tissues of CIA mice were collected, and the expression of NLRP3, cleaved-caspase-1, GSDMD-N, Mst1, and YAP was detected by Western blot. RESULTS: The administration of BBR dramatically alleviated the severity of collagen-induced arthritis rat model with a decreased clinical score and inflammation reduction. In addition, BBR intervention significantly attenuates several pro-inflammatory cytokines (interleukin-1ß, interleukin-6, interleukin-17, and interleukin-18). Moreover, BBR can reduce the pyroptosis response (caspase-1, NLR family pyrin domain containing 3, and gasdermin D) of the RA-FLS in vitro, activating the Hippo signaling pathway (Mammalian sterile 20-like kinase 1, yes-associated protein, and transcriptional enhanced associate domains) so as to inhibit the pro-inflammatory effect of RA-FLS. CONCLUSION: These results support the role of BBR in RA and may have therapeutic implications by directly repressing the activation, migration of RA-FLS, which contributing to the attenuation of the progress of CIA. Therefore, targeting PU.1 might be a potential therapeutic approach for RA. Besides, BBR inhibited RA-FLS pyroptosis by downregulating of NLRP3 inflammasomes (NLRP3, caspase-1) and eased the pro-inflammatory activities via activating the Hippo signaling pathway, thereby improving the symptom of CIA.

Spatial Visual Imagery (SVI)-Based Electroencephalograph Discrimination for Natural CAD Manipulation.

With the increasing demand for natural interactions, people have realized that an intuitive Computer-Aided Design (CAD) interaction mode can reduce the complexity of CAD operation and improve the design experience. Although interaction modes like gaze and gesture are compatible with some complex CAD manipulations, they still require people to express their design intentions physically. The brain contains design intentions implicitly and controls the corresponding body parts that execute the task. Therefore, building an end-to-end channel between the brain and computer as an auxiliary mode for CAD manipulation will allow people to send design intentions mentally and make their interaction more intuitive. This work focuses on the 1-D translation scene and studies a spatial visual imagery (SVI) paradigm to provide theoretical support for building an electroencephalograph (EEG)-based brain-computer interface (BCI) for CAD manipulation. Based on the analysis of three spatial EEG features related to SVI (e.g., common spatial patterns, cross-correlation, and coherence), a multi-feature fusion-based discrimination model was built for SVI. The average accuracy of the intent discrimination of 10 subjects was 86%, and the highest accuracy was 93%. The method proposed was verified to be feasible for discriminating the intentions of CAD object translation with good classification performance. This work further proves the potential of BCI in natural CAD manipulation.

Nitrogenous compounds from Aesculus wilsonii seeds.

Eight nitrogenous compounds including five undescribed ones, aeswilnitrousol A (1), aeswilnitrousosides BD (2-4), and 6-(2-hydroxy-3-methylbutylamino)-8-oxoadenine (5) were isolated from the seeds of Aesculus wilsonii. Their structures and absolute configurations were established based on spectroscopic determination, calculated electronic circular dichroism (ECD) analysis, as well as chemical reaction methods. Among the three known compounds, 7 and 8 were obtained from the Aesculus genus for the first time, and 6 was gained from this plant initially. The 13C NMR data of 7 and 8 were reported for the first time. Moreover, the inhibitory effect of all the isolates against LPS-induced nitric oxide production in RAW264.7 macrophages was evaluated. As a result, compounds 2 and 8 exhibited anti-inflammatory activity in a concentration-dependent manner at 10, 25, and 50 µM.

Electroacupuncture alleviates ciliary muscle cell apoptosis in lens-induced myopic guinea pigs through inhibiting the mitochondrial signaling pathway.

AIM: To investigate the effect of electroacupuncture (EA) on the mitochondria-dependent apoptotic signaling pathway in the ciliary muscle of guinea pigs with negative lens-induced myopia (LIM). METHODS: Guinea pigs were randomly divided into normal control (NC) group, LIM group, LIM+SHAM acupoint (LIM+SHAM) group, and LIM+EA group. Animals in the NC group received no intervention, while those in other three groups were covered with -6.0 diopter (D) lenses on right eyes. Meanwhile, animals in the LIM+EA group received EA at Hegu (LI4) combined with Taiyang (EX-HN5) acupoints, while those in the LIM+SHAM group were treated at sham points. After treatments for 1, 2, and 4wk, morphological changes in ciliary muscles were observed with hematoxylin and eosin (H&E) staining and nick end labeling (TUNEL), and the expression of the mitochondrial apoptotic signaling pathway-related molecules in ciliary muscles was measured by real-time quantitative polymerase chain reaction (qPCR) and Western blot. Additionally, the adenosine triphosphate (ATP) contents were also determined in ciliary muscles. RESULTS: Axial length increased significantly in the LIM and LIM+SHAM groups and decreased in the LIM+EA group. The ciliary muscle fibers were broken and destroyed in both LIM and LIM+SHAM groups, whereas those in the LIM+EA group improved significantly. TUNEL assay showed the number of apoptotic cells increased in the LIM and LIM+SHAM groups, whereas reduced in the LIM+EA group. ATP contents showed a significant decrease in the LIM and LIM+SHAM groups, whereas increased after EA treatment. Compared with the NC group, the dynamin-related protein 1 (DRP1), Caspase3, and apoptotic protease activator 1 (APAF1) levels were significantly increased in the LIM group and decreased in the LIM+EA group. CONCLUSION: The results provide evidence of EA inhibiting the development of myopia by regulating the mitochondrial apoptotic signaling pathway.

Efficacy of early biologic therapy versus late/conventional therapy in children and adolescents with Crohn's disease: A systematic review and meta-analysis.

Background: The objective of this study was to estimate the effectiveness of early biologics compared to conventional treatment in the management of Crohn's disease among pediatric and adolescent patients. Methods: A comprehensive literature search was conducted in four electronic databases to identify relevant studies published from inception to 2023. The inclusion criteria comprised randomized controlled trials (RCTs) and cohort studies that reported on the efficacy and clinical outcomes of early biologic therapy compared to late/conventional therapy in children with Crohn's disease. The quality of the studies was assessed using the Cochrane Risk of Bias tool and the Newcastle Ottawa scale. Results: A total of 13 studies (2 RCTs and 11 cohort studies), involving 861 patients, were included in the meta-analysis. The results demonstrated that early biologic therapy was associated with a significantly higher rate of clinical remission (risk ratio [RR] 1.30, 95% confidence interval [CI] 1.10-1.54), lower relapse rates (RR 0.33, 95% CI 0.21-0.53), and improved mucosal healing (RR 1.47, 95% CI 1.10-1.97) compared to late/conventional therapy. However, it should be noted that there was evidence of publication bias among studies reporting clinical remission. Conclusion: In conclusion, early biologic therapy is significantly more effective in achieving clinical remission (within two years of diagnosis), promoting mucosal healing, and reducing relapse rates in pediatric and adolescent patients with Crohn's disease, compared to late/conventional therapy. These findings emphasize the importance of initiating biological therapy early in the treatment of Crohn's disease in this patient population.

Research progress on the molecular mechanism of electroacupuncture at "Zusanli" (ST36) for regulating gastrointestinal dysfunction. / 电针"足三里"è°ƒèŠ‚èƒƒè‚ åŠŸèƒ½å¼‚å¸¸çš„åˆ†å­æœºåˆ¶ç ”ç©¶è¿›å±•.

Gastrointestinal dysfunction is manifested as digestive symptoms. Clinically, Zusanli (ST36) is crucial in the acupoint prescriptions of acupuncture no matter which type of the disease is differentiated in traditional Chinese medicine, but the underlying mechanism remains to be explored. Aiming to summarize the current status of the researches in terms of ameliorating gastrointestinal mucosal damage and regulating gastrointestinal motility disorders, we systematically reviewed the basic researches on the intervention with electroacupuncture (EA) at "ST36" in treatment of the diseases related to gastrointestinal dysfunction in the past 5 years, after searching the articles from Chinese and English databases. The results suggest that EA at ST36 may regulate the local gastrointestinal inflammation, oxidative stress and immune microenvironment to relieve gastrointestinal mucosal damage and adjust gastrointestinal motility disorders by means of modulating the central and peripheral nerve signaling as well as the function of mast cells and Cajal interstitial cells.

Purification and identification of xanthine oxidase inhibitory peptides from enzymatic hydrolysate of α-lactalbumin and bovine colostrum casein.

The development of food-derived Xanthine Oxidase (XO) inhibitors is critical to the treatment of hyperuricemia and oxidative stress-related disease. Few studies report on milk protein hydrolysates' XO inhibitory activity, with the mechanism of their interaction remaining elusive. Here, different commercial enzymes were used to hydrolyze α-lactalbumin and bovine colostrum casein. The two proteins hydrolyzed by alkaline protease exhibited the most potent XO inhibitory activity (bovine casein: IC50 = 0.13 mg mL-1; α-lactalbumin: IC50 = 0.28 mg mL-1). Eight potential XO inhibitory peptides including VYPFPGPI, GPVRGPFPIIV, VYPFPGPIPN, VYPFPGPIHN, QLKRFSFRSFIWR, LVYPFPGPIHN, AVFPSIVGR, and GFININSLR (IC50 of 4.67-8.02 mM) were purified and identified from alkaline protease hydrolysates by using gel filtration, LC-MS/MS and PeptideRanker. The most important role of inhibiting activity of peptides is linked to hydrophobic interactions and hydrogen bonding based on the results of molecular docking and molecular dynamics simulation. The enzymatic hydrolysate of α-lactalbumin and bovine colostrum casein could be a competitive candidates for hyperuricemia-resisting functional food.

Apoptotic effects of phenols from the twigs and leaves of Garcinia nujiangensis.

In order to find potential agents for treating cancer disease in naturally occurring compounds, we conducted a systematic phytochemical investigation on the endemic species of Garcinia nujiangensis. Three new biphenyl derivatives (1-3) and one new polycyclic polyprenylated benzophenone (4), together with four known benzophenone analogues (5-8), have been isolated from the CH2Cl2 extract of the twigs and leaves of G. nujiangensis. Their structures were determined by detailed spectroscopic analyses and comparison with structurally related known analogues. Experimental and calculated ECD method was used to determine the absolute configuration of 1 and 4. Moreover, compounds 5-7 were isolated for the first time from this species. The cytotoxicities of the new compounds were evaluated using HL-60, HepG2, and A549 human cancer cell lines. Compound 4 showed more significant antiproliferative effects against HepG2 cells with an IC50 value of 11.38 ± 0.79 µM than that of three biphenyl derivatives. The morphological features of apoptosis were evaluated in 4-treated HepG2 cells. Compound 4 effectively prevented the cell cycle progression of HepG2 cells in G2 phase. Additionally, western blot analysis indicated that treatment of 4 on HepG2 cells led to decreased expression of anti-apoptotic Bcl-2 and pro-Caspase-3, and increased protein expression of both pro-apoptotic Bax and cleaved PARP with reference to ß-actin. Overall, our results suggested that the active polycyclic polyprenylated benzophenone derivatives in the twigs and leaves of G. nujiangensis can be used as a valuable source of bioactive compounds for the pharmaceutical industry.

Extraction of structurally intact and well-stabilized rice bran oil bodies as natural pre-emulsified O/W emulsions and investigation of their rheological properties and components interaction.

The isolated plant oil bodies (OBs) have shown promising applications as natural pre-emulsified O/W emulsions. Rice bran OBs can be used as a new type plant-based resource with superior fatty acids composition and abundant γ-oryzanol. This paper investigated the method of extracting structurally intact and stable rice bran OBs. Due to the adequate steric hindrance and electrostatic repulsion effects, rice bran OBs extracted by NaHCO3 medium had smaller particle size, better physical stability, and natural structure. The protein profile of NaHCO3-extracted rice bran OBs showed oleosin-L and oleosin-H, while exogenous proteins in PBS and enzyme-assisted- extracted rice bran OBs could interact with interfacial proteins through hydrophobic forces to aggregate adjacent OBs, further remodeling the OBs interface. It was also found that the small-sized rice bran OBs could adsorb on the interface of the larger-sized rice bran OBs like Pickering stabilizers. Rice bran OBs exhibited pseudoplastic fluids characteristic, but underwent a transition from solid-like to liquid-like behavior depending on the extraction method. The disorder of NaHCO3-extracted rice bran OBs protein molecules increased their surface hydrophobicity. The random coil structure favored more proteins adsorption at the interface of rice bran OBs extracted by PBS. Enzyme-assisted extraction of rice bran OBs had the highest content of ß-sheet structure, which facilitated the stretching and aggregation of protein spatial structure. It was also confirmed the hydrogen bonding and hydrophobic interaction between the triacylglycerol or phospholipid and proteins molecules, and the membrane compositions of rice bran OBs differed between extraction methods.

Meat systems produced with Monascus pigment water-in-oil-in-water multiple emulsion as pork fat replacers.

Multiple emulsions have drawn great attentions from researchers in the production of low-fat foods. The Monascus pigment W/O/W multiple emulsions were prepared by a two-step emulsification procedure with Monascus pigment as inner water phase, flaxseed gum (FG) as internal water phase gel, soybean oil as oil phase, and pea protein isolate (PPI) as outer water phase. We aimed to investigate the quality of pork emulsion systems in which pork fat was replaced by W/O/W emulsions. The results revealed that addition of W/O/W emulsions reduced lipid contents from 11.22% to 5.09%, enhanced protein level from 15.77% to 17.02%, increased polyunsaturated fatty acid composition from 23.36% to 59.63%, improved water-holding capacity and oxidative stability compared to the control samples with pork fat. It was demonstrated that meat systems could achieve dual functions including decreasing the total fat content without affecting the hardness of the meat systems and color retention.

Potential Mechanisms of Action of Chinese Patent Medicines for COVID-19: A Review.

Coronavirus disease 2019 (COVID-19) is an emergent infectious pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is highly contagious and pathogenic. COVID-19 has rapidly swept across the world since it was first discovered in December 2019 and has drawn significant attention worldwide. During the early stages of the outbreak in China, traditional Chinese medicines (TCMs) were involved in the whole treatment process. As an indispensable part of TCM, Chinese patent medicines (CPMs) played an irreplaceable role in the prevention and treatment of this epidemic. Their use has achieved remarkable therapeutic efficacy during the period of medical observation and clinical treatment of mild, moderate, severe, and critical cases and during convalescence. In order to better propagate and make full use of the benefits of TCM in the treatment of COVID-19, this review will summarize the potential target of SARS-CoV-2 as well as the theoretical basis and clinical efficacy of recommended 22 CPMs by the National Health Commission and the Administration of TCM and local provinces or cities in the treatment of COVID-19. Additionally, the study will further analyze the drug composition, potential active ingredients, potential targets, regulated signaling pathways, and possible mechanisms for COVID-19 through anti-inflammatory and immunoregulation, antiviral, improve lung injury, antipyretic and organ protection to provide meaningful information about the clinical application of CPMs.

Maternal selenium deficiency during gestation is positively associated with the risks for LBW and SGA newborns in a Chinese population.

BACKGROUND: Maternal selenium (Se) deficiency is associated with some adverse pregnant outcomes. However, it remains controversial whether maternal Se deficiency during gestation enhances the risks for low-birth-weight (LBW) and small-for-gestational-age (SGA) newborns. METHODS: For our cohort study, total 3133 mother-and-infant pairs were selected. Maternal serum Se concentration was detected by graphite furnace atomic absorption spectrometry. According to international references for maternal serum Se concentration, subjects were divided into Se deficiency (<45.0 µg/L), Se insufficiency (45.0-94.9 µg/L) and Se sufficiency (≥95.0 µg/L). RESULTS: There was a positive relation of maternal serum Se concentration in gestation and neonatal birth weight. Further analysis showed that the risks for LBW and SGA in SD group were significantly higher than that in SI and SS group, the adjusted ORs for LBW and SGA newborns were 1.87 (95%CI: 1.02, 3.45; P = 0.04) and 1.47 (95%CI: 1.07, 2.02; P = 0.02) in SI group, and 3.92 (95%CI: 2.03, 7.57; P < 0.001) and 2.77 (95%CI: 1.92, 4.02; P < 0.001) in SD group compared to SS group. In different gender subgroup, positive relations were observed between maternal Se deficiency and the risk for LBW girls, as well as the risks for both SGA girls and boys. CONCLUSION: Maternal Se deficiency in gestation was positively associated with the risk for LBW girls, as well as the risks for both SGA girls and boys.

Discovery of natural adenosine monophosphate­activated protein kinase activators through virtual screening and activity verification studies.

The adenosine monophosphate­activated protein kinase (AMPK) is a promising target in drug development for various metabolic diseases. In the present study, the aim was to discover natural direct AMPK activators from natural sources, thus a virtual screening for direct AMPK activators was conducted by combining ligand­based and structure­based screening. A common­feature pharmacophore model (HipHop1) was generated with two hydrogen bond acceptor lipid features and one hydrophobic region feature. A total of 1,235 natural products were screened using the HipHop1 hypothesis and CDOCKER protocol successively. According to the docking score, seven hit compounds were selected for AMPK activation assays. Ultimately, (­)­catechin (compound 522) and licochalcone A (compound 1148) exhibited the highest AMPK activation activity. These findings may contribute to the development of AMPK activators from medicinal plants.

Corrigendum to "Monitoring unbound warfarin in drug combination therapy by pharmacokinetics and fluorospectrometry" [Chinese Herbal Medicines 11 (2019) 92-97].

[This corrects the article DOI: 10.1016/j.chmed.2018.10.002.].

An inhibitory effect of Berberine from herbal Coptis chinensis Franch on rat detrusor contraction in benign prostatic hyperplasia associated with lower urinary tract symptoms.

ETHNOPHARMACOLOGICAL RELEVANCE: Coptis chinensis Franch (CCF), also known as Huang Lian in China, is a traditional Chinese medicine that commonly used for more than 2000 years. Clinically, CCF often used as anti-inflammatory, immune regulation and other effects. It has been reported that the decoction containing CCF can be used for the treatment of benign prostatic hyperplasia (BPH) or lower urinary tract symptoms (LUTS). AIM OF THE STUDY: This research aims to investigate the effect of CCF on inhibition of BPH development in vivo and in vitro, and further identify the active compound (s) and the possible mechanism involved in BPH-related bladder dysfunction. MATERIALS AND METHODS: Oestrodial/testosterone-induced BPH rat model was established as the in vivo model. The prostate index (PI) was calculated, the pathogenesis was analyzed and the micturition parameters were determined in the shamed-operated, BPH model and BPH + CCF groups after 4-week administration. The tension in detrusor strips was then assessed upon KCl or ACh stimulation with or without incubation of CCF or active compounds. To further investigate the signaling involved, rat detrusor cells were cultured as the in vitro models, the instantaneous calcium influx was measured and the ROCK-1 expression was detected. RESULTS: Increased PI value and the aggravated prostatic pathology were observed with voiding dysfunction in BPH rats, which were significantly blocked by oral CCF taken. ACh or KCl-induced contractile responses in detrusor strips were significantly inhibited and the micturition parameters were improved when incubation with CCF or its active compounds such as berberine. Both CCF and berberine suppressed the cellular calcium influx and ROCK-1 expression upon ACh stimulation, demonstrating that berberine was one of the active compounds that contributed to CCF-improved micturition symptoms and function. CONCLUSIONS: Taken together, our findings give evidence that CCF and its active compound berberine inhibited BPH and bladder dysfunction via Ca2+ and ROCK signaling, supporting their clinical use for BPH and BPH-related LUTS treatment.

Docking Studies on Potential Mechanisms for Decreasing Insulin Resistance by the Tangzhiqing Herbal Formula.

Insulin resistance (IR) is considered as one of the principal pathways of type 2 diabetes mellitus pathogenesis and is associated with a series of abnormal signaling pathways. Tangzhiqing (TZQ) herbal formula is a well-known antidiabetic traditional Chinese medicine and has been used to treat type 2 diabetes mellitus and prediabetes for many years in China. We selected 13 natural products as representative compounds of the main active components in TZQ to investigate the interaction of these natural products with key signal proteins associated with IR using two different docking calculations. Salvianolic acids A and C (phenolic acids from Salvia miltiorrhiza), rutin (a flavonoid from Morus alba), paeoniflorin (a saponin from Paeonia lactiflora), and quercitrin (a flavonoid from Crataegus pinnatifida) showed great docking abilities towards multiple target proteins. These results have contributed to a clearer understanding regarding the regulation mechanism of TZQ on IR and have provided direction for further pharmacological studies.

In Vitro Hepatic Uptake in Human and Monkey Hepatocytes in the Presence and Absence of Serum Protein and Its In Vitro to In Vivo Extrapolation.

It is well documented that human hepatic clearance based on in vitro metabolism or transporter assays systematically resulted in underprediction; therefore, large empirical scalars are often needed in either static or physiologically based pharmacokinetic (PBPK) models to accurately predict human pharmacokinetics (PK). In our current investigation, we assessed hepatic uptake in hepatocyte suspension in Krebs-Henseleit buffer in the presence and absence of serum. The results showed that the unbound intrinsic active clearance (CLu,int,active) values obtained by normalizing the unbound fraction in the buffer containing 10% serum were generally higher than the CLu,int,active obtained directly from protein free buffer, suggesting "protein-facilitated" uptake. The differences of CLu,int,active in the buffer with and without protein ranged from 1- to 925-fold and negatively correlated to the unbound serum binding of organic anion transporting polypeptide substrates. When using the uptake values obtained from buffer containing serum versus serum-free buffer, the median of scaling factors (SFs) for CLu,int,active reduced from 24.2-4.6 to 22.7-7.1 for human and monkey, respectively, demonstrating the improvement of in vitro to in vivo extrapolation in a PBPK model. Furthermore, values of CLu,int,active were significantly higher in monkey hepatocytes than that in human, and the species differences appeared to be compound dependent. Scaling up in vitro uptake values derived in assays containing species-specific serum can compensate for the species-specific variabilities when using cynomolgus monkey as a probe animal model. Incorporating SFs calibrated in monkey and together with scaled in vitro data can be a reliable approach for the prospective human PK prediction in early drug discovery. SIGNIFICANCE STATEMENT: We investigated the protein effect on hepatic uptake in human and monkey hepatocytes and improved the in vitro to in vivo extrapolation using parameters obtained from the incubation in the present of serum protein. In addition, significantly higher active uptake clearances were observed in monkey hepatocytes than in human, and the species differences appeared to be compound dependent. The physiologically based pharmacokinetic model that incorporates scaling factors calibrated in monkey and together with scaled in vitro human data can be a reliable approach for the prospective human pharmacokinetics prediction.

Biosurfactant trehalose lipid-enhanced ultrasound-assisted micellar extraction and determination of the main antioxidant compounds from functional plant tea.

Hydrosoluble trehalose lipid (a biosurfactant) was employed for the first time as a green extraction solution to extract the main antioxidant compounds (geniposidic acid, chlorogenic acid, caffeic acid, and rutin) from functional plant tea (Eucommia ulmoides leaves). Single-factor tests and response surface methodology were employed to optimize the extraction conditions for ultrasound-assisted micellar extraction combined with ultra-high-performance liquid chromatography in succession. A Box-Behnken design (three-level, three-factorial) was used to determine the effects of extraction solvent concentration (1-5 mg/mL), extraction solvent volume (5-15 mL), and extraction time (20-40 min) at a uniform ultrasonic power and temperature. In consequence, the best analyte extraction yields could be attained when the trehalose lipid solution concentration was prepared at 3 mg/mL, the trehalose lipid solution volume was 10 mL and the extraction time was set to 35 min. In addition, the recoveries of the antioxidants from Eucommia ulmoides leaves analyzed by this analytical method ranged from 98.2 to 102%. These results indicated that biosurfactant-enhanced ultrasound-assisted micellar extraction coupled with a simple ultra-high-performance liquid chromatography method could be effectively applied in the extraction and analysis of antioxidants from Eucommia ulmoides leaf samples.

Effect of Naoxintong Capsules on the Activities of CYP450 and Metabolism of Metoprolol Tartrate in Rats Evaluated by Probe Cocktail and Pharmacokinetic Methods.

Naoxintong capsule (NXT), a prescribed Chinese medicine, has been used clinically for more than 20 years and is widely received by patients. We determined five probe drugs, namely, omeprazole (CYP2C19), midazolam (CYP3A4), phenacetin (CYP1A2), tolbutamide (CYP2C9), and dextromethorphan (CYP2D6) to study the potential influences of NXT on the activities of CYP enzymes and assessed the pharmacokinetics effect of NXT on metoprolol tartrate in rat plasma. The study showed that AUC(0-24) and AUC(0-∞) of midazolam (CYP3A4) in NXT coadministration group (283.7 ± 65.2 h·ng·mL-1 and 292.0 ± 75.1 h·ng·mL-1 in group B; 295.7 ± 62.7 h·ng·mL-1 and 299.5 ± 60.0 h·ng·mL-1 in group C) were significantly decreased as compared to another group (416.8 ± 82.3 h·ng·mL-1 and 424.9 ± 77.9 h·ng·mL-1 in group A), while that of dextromethorphan (CYP2D6) showed an opposite tendency (540.7 ± 119.7 h·ng·mL-1 and 595.3 ± 122.2 h·ng·mL-1 in group A, 760.6 ± 184.9 h·ng·mL-1 and 788.7 ± 211.0 h·ng·mL-1 in group B, and 734.3 ± 118.5 h·ng·mL-1 and 757.2 ± 105.4 h·ng·mL-1 in group C). Moreover, NXT preadministration can enhance the metabolism of metoprolol tartrate and reduce the metabolism of O-demethylmetoprolol. The results indicated that NXT had potential effects in inducing CYP3A4 and inhibiting CYP2D6 in the metabolism of metoprolol tartrate. It suggests that patients who coadministered NXT and metoprolol tartrate should be advised of potential herb-drug interactions (HDIs) to reduce therapeutic failure or accelerated toxicity of conventional drug treatment.