N-tert-Butoxycarbonyl-N-(2-(tritylthio)ethoxy)glycine as a Building Block for Peptide Ubiquitination.

N-Boc-N-(2-(tritylthio)ethoxy)glycine has been developed as a building block for peptide ubiquitination, which is fully compatible with solid-phase Fmoc chemistry and common peptide modifications including phosphorylation, methylation, acetylation, biotinylation, and fluorescence labeling. The optimal conditions for peptide cleavage and auxiliary removal were obtained. The utility of this building block in peptide ubiquitination was demonstrated by the synthesis of seven ubiquitinated histone and Tau peptides bearing various modifications. Cys residues were well tolerated and did not require orthogonal protection. The structural integrity and folding of the synthesized ubiquitinated peptides were confirmed by enzymatic deubiquitination of a fluorescently labeled ubiquitin conjugate. The synthetic strategy using this building block provides a practical approach for the preparation of ubiquitinated peptides with diverse modifications.

Application of N-Terminal Site-Specific Biotin and Digoxigenin Conjugates to Clinical Anti-drug Antibody Assay Development.

Biotin- and digoxigenin (DIG)-conjugated therapeutic drugs are critical reagents used for the development of anti-drug antibody (ADA) assays for the assessment of immunogenicity. The current practice of generating biotin and DIG conjugates is to label a therapeutic antibody with biotin or DIG via primary amine groups on lysine or N-terminal residues. This approach modifies lysine residues nonselectively, which can impact the ability of an ADA assay to detect those ADAs that recognize epitopes located at or near the modified lysine residue(s). The impact of the lysine modification is considered greater for therapeutic antibodies that have a limited number of lysine residues, such as the variable heavy domain of heavy chain (VHH) antibodies. In this paper, for the first time, we report the application of site-specifically conjugated biotin- and DIG-VHH reagents to clinical ADA assay development using a model molecule, VHHA. The site-specific conjugation of biotin or DIG to VHHA was achieved by using an optimized reductive alkylation approach, which enabled the majority of VHHA molecules labeled with biotin or DIG at the desirable N-terminus, thereby minimizing modification of the protein after labeling and reducing the possibility of missing detection of ADAs. Head-to-head comparison of biophysical characterization data revealed that the site-specific biotin and DIG conjugates demonstrated overall superior quality to biotin- and DIG-VHHA prepared using the conventional amine coupling method, and the performance of the ADA assay developed using site-specific biotin and DIG conjugates met all acceptance criteria. The approach described here can be applied to the production of other therapeutic-protein- or antibody-based critical reagents that are used to support ligand binding assays.

Highly efficient near-infrared solid solution phosphors with excellent thermal stability and tunable spectra for pc-LED light sources toward NIR spectroscopy applications.

Near-infrared (NIR) luminescent materials have attracted wide research interest due to their unique photophysical properties for designing NIR light-emitting diodes (NIR LEDs). Here, a series of Cr3+-activated NIR-emitting solid solution phosphors, Gd1-xLux(Al1-xScx)3(BO3)4:0.01Cr3+ (GLASB:Cr3+) (x = 0 to 0.5), are successfully synthesized via a cosubstitution approach. The GLASB:Cr3+ phosphors reveal extraordinary optical performance with a desirable high IQE of 93.6%, considerable broadened FWHM (from 128 nm to 196 nm) and redshift of 119 nm (747 → 866 nm) as the amount of [Lu3+-Sc3+] ion doping increases. Moreover, their photoluminescent thermal stability is substantially improved, maintaining 105.7% of the initial integral intensity up to 150 °C, namely zero-thermal-quenching. The NIR pc-LED fabricated using the GLASB:Cr3+ phosphor generates an NIR output power of 46 mW and an electro-optical efficiency of 37% at a 120 mA input current. Finally, the characteristic NIR emission of this phosphor can not only be utilized in the fields of night-vision technology and biometric identification, but also exhibits a perfect match with the absorption of the bacteriochlorophyll (BChl) and light-harvesting protein (LHP) of photosynthetic bacteria (PSB), presenting a high application prospect for improving PSB photosynthesis.

Effect of Bifidobacterium animalis subsp. lactis SF on enhancing the tumor suppression of irinotecan by regulating the intestinal flora.

The gut microbiota plays a role in tumor therapy by participating in immune regulation. Here, we demonstrated through 8-day probiotic supplementation experiments and fecal microbiota transplantation experiments that Bifidobacterium animalis subsp. lactis SF enhanced the antitumor effect of irinotecan and prevented the occurrence of intestinal damage by modulating the gut microbiota and reducing the relative abundance of pro-inflammatory microbiota. Therefore, the intestinal inflammation was inhibited, the TGF-ß leakage was reduced, and the PI3K/AKT pathway activation was inhibited. Thus, the tumor apoptotic autophagy was finally promoted. Simultaneously, the reduction of TGF-ß relieved the immunosuppression caused by CPT-11, promoted the differentiation of CD4+ and CD8+ T cells in tumor tissue, and consequently inhibited tumor growth and invasion. This study disclosed the mechanism of B. lactis SF assisting CPT-11 in antitumor activity and suggested that B. lactis SF plays a new role in anticancer effects as a nutritional intervention.

Highly Stable Orange-Red Long-Persistent Luminescent CsCdCl3 :Mn2+ Perovskite Crystal.

Halide perovskite has been widely studied as a new generation of photoelectronic materials. However, their thermal and humidity-induced emission quenching have greatly limited their utility and reliability. Here, we report a hexagonal Mn2+ -doped CsCdCl3 perovskite crystal that possesses stable photoluminescence (PL) at both high temperature and humidity. The room temperature long-persistent luminescence (LPL) of the single crystals lasts up to 1480 s and can be adjusted by changing the concentration of Mn2+ ion doping. The characteristic emission of d-d transition of Mn2+ is realized, and the photoluminescence quantum yield (PLQY) is up to 91.4 %, it can maintain more than 90 % of the initial PL spectral integral area at 150 °C (423 K). High humid stability PL can be achieved more than 75 % of the initial PL intensity after 55 days of immersion in water. These excellent properties show the application prospect of the LPL material in lighting indication and anti-counterfeiting.

Whole genome and acid stress comparative transcriptome analysis of Lactiplantibacillus plantarum ZDY2013.

Previous study has reported that Lactiplantibacillus plantarum ZDY2013 which was screened from traditional Chinese fermented soybeans has a strong acid resistance. The purpose of this study was to uncover the genes potentially related to its genetic adaptation and probiotic profiles, based on comparative genomic and comparative transcriptome analysis. We got the basic information about L. plantarum ZDY2013 and identified genes which are related to genetic adaptation and probiotic profiles, including carbohydrate transport and metabolism, cell wall/membrane/envelope biogenesis, proteolytic enzyme systems and amino acid biosynthesis, CRISPR adaptive immunity, stress responses, ability to adhere to the host intestinal wall, exopolysaccharide (EPS) biosynthesis, and bacteriocin biosynthesis. Comparative transcriptome showed CK group (normal MRS culture L. plantarum ZDY2013) and SCL group (pH 3.0 MRS culture L. plantarum ZDY2013) had 652 significant differentially expressed genes including 310 up-regulated genes and 342 down-regulated genes. Besides that, these genes had been classified through KEGG and GO functional annotation. In addition, we also found top 20 KEGG pathways adjusted to acid stress. Then, some genes were selected to verify the transcriptome analysis and explore the mechanism of how L. plantarum ZDY2013 tolerate acid stress. We found that some genes of ABC transporter, phosphotransferase system, oxidation reduction process, membrane transporter and phosphorylation metabolism process had a significant change. These results suggested that comparative characterization of the L. plantarum ZDY2013 genome and transcriptome provided the genetic basis for further elucidating the functional mechanisms of it.

Enhancing Structural Rigidity via a Strategy Involving Protons for Creating Water-Resistant Mn4+-Doped Fluoride Phosphors.

The poor water resistance property of a commercial Mn4+-activated narrow-band red-emitting fluoride phosphor restricts its promising applications in high-performance white LEDs and wide-gamut displays. Herein, we develop a structural rigidity-enhancing strategy using a novel KHF2:Mn4+ precursor as a Mn source to construct a proton-containing water-resistant phosphor K2(H)TiF6:Mn4+ (KHTFM). The parasitic [HMnF6]- complexes in the interstitial site from the fall off the KHF2:Mn4+ are also transferred to the K2TiF6 host by ion exchange to form KHTFM with rigid bonding networks, improving the water resistance and thermostability of the sample. The KHTFM sample retains at least 92% of the original emission value after 180 min of water immersion, while the non-water-resistant K2TiF6:Mn4+(KTFM) phosphor maintains only 23%. Therefore, these findings not only illustrate the effect of protons on fluoride but also provide a novel insight into commercial water-resistant fluoride phosphors.

Novel Cyan-Green-Emitting Bi3+-Doped BaScO2F, R+ (R = Na, K, Rb) Perovskite Used for Achieving Full-Visible-Spectrum LED Lighting.

Cyan-emitting phosphors are important for near-ultraviolet (NUV) light-emitting diodes (LEDs) to gain high-quality white lighting. In the present work, a Bi3+-doped BaScO2F, R+ (R = Na, K, Rb) perovskite, which emits 506 nm cyan-green light under 360 or 415 nm excitation, is obtained via a high-temperature solid-state method for the first time. The obtained perovskite shows improved photoluminescence and thermal stability due to the charge compensation of Na+, K+, and Rb+ co-doping. Its spectral broadening is attributed to two centers Bi (1) and Bi (2), which are caused by the zone-boundary octahedral tilting due to the substitution of Bi3+ for the larger Ba2+. Employing the blend phosphors of Ba0.998ScO2F:0.001Bi3+,0.001K+ and the commercial BAM:Eu2+, YAG:Ce3+, and CaAlSiN3:Eu2+, a full-spectrum white LED device with Ra = 96 and CCT = 4434 K was fabricated with a 360 nm NUV chip. Interestingly, a novel strategy is proposed: the cyan-green Ba0.998ScO2F:0.001Bi3+,0.001K+ and orange Sr3SiO5:Eu2+ phosphors were packaged with a 415 nm NUV chip to produce the white LED with Ra = 85 and CCT = 4811 K.

Phase Transformation of a K2GeF6 Polymorph for Phosphors Driven by a Simple Precipitation-Dissolution Equilibrium and Ion Exchange.

Tuning crystal phase transformations is very important for obtaining polymorphs for phosphors with the ideal optical properties and stability. Mn4+-doped K2GeF6 (KGF) is a typical polymorphic phosphor, but the thermodynamic and kinetic mechanism of its phase transformation is still unclear. Herein, the phase transformation of polymorphs varying from P63mc KGF and trigonal KGF to P63mc Si4+-doped KGF is realized by introducing the synergistic action of an HF solution and Si4+ ions. The full structural refinements of KGF polymorphs at room temperature and the electronic band structure calculations were performed. The results show that the Si4+-doped hexagonal KGF polymorph with good photoluminescence properties is the most stable phase according to the calculated total energy landscape and relative formation energy. The morphologic changes were monitored in situ to clearly understand the rapid phase transformation mechanism, which proves that the phase transformation is driven by a simple precipitation-dissolution equilibrium and ionic exchange.

Effect of icariin on early ß-defensin-2 and T cell subsets in rats after tracheotomy. / ·ARTICLES··è®º 著·.

OBJECTIVES: To investigate the effect of icariin (ICA) on early ß-defensin-2 and T cell subsets in rats after tracheotomy. METHODS: A total of 54 SPF male Sprague-Dawley rats were randomly divided into a normal control group (group A), a model group (group B), and a model+ICA treatment group (group C), with 18 rats in each group. A tracheotomy intubation model of the B and C group was prepared. After 6 h of surgery, ICA intervention was given to group C. Groups A and B were given the same amount of normal saline. Lung tissue, alveolar lavage fluid and peripheral blood were taken at 24 h, 72 h and 168 h, respectively. The expression of rat ß-defensin-2 mRNA in lung tissue was detected by RT-PCR. The content of ß-defensin-2 in alveolar lavage fluid and peripheral blood serum was detected by ELISA. The content of peripheral blood T cell subsets (CD3+, CD4+, CD8+) was detected by flow cytometry, and the ratio of CD4+/CD8+ was calculated. RESULTS: After tracheotomy, the levels of ß-defensin-2 mRNA and ß-defensin-2 in lung tissue from the group B were increased significantly at 24 h, then they were decreased gradually, and decreased most significantly at 168 h (P<0.05). The content of ß-defensin-2 in peripheral blood of group B decreased gradually, and the content of ß-defensin-2 in 168 h was significantly lower than that in 24 h (P<0.05), but there was no significant difference between group B and group A (P>0.05). The level of CD3+ T cells in peripheral blood was significantly lower than that in the group A (P<0.05), but their was no significant difference in CD4+ and CD8+ T cells compared with group A (P>0.05). After ICA intervention in group C: lung tissue, alveolar lavage fluid, peripheral blood serum ß-defensin-2 content, and peripheral blood CD3+ and CD4+ T cell levels were gradually increased, significantly higher than those in the group B (P<0.05). CD8+ T cell level was significantly lower than that in the group A at 24 h (P<0.05), the CD4+/CD8+ ratio was significantly higher at 168 h than those in the group A or B (both P<0.01). CONCLUSIONS: ICA can improve the early lung immune function in rats with tracheotomy, which might be related to up-regulation of ß-defensin-2 in lung tissue and alveolar lavage fluid, concomitant with increases in CD3+ and CD4+ T cells and CD4+/CD8+ ratio in peripheral blood while reduction in CD8+ cells.

Silenced CHOP protects pancreatic B-cell function by targeting peroxisome proliferator-activated receptor-γ coactivator-1α through nuclear factor-κB signaling pathway in diabetes mellitus.

AIMS: Diabetes mellitus (DM) is one of the most common metabolic diseases worldwide characterized by insulin resistance and pancreatic ß-cell dysfunction. In the previous study, endoplasmic reticulum (ER) stress could increase the C/EBP homologous protein (CHOP) expression through inhibiting C/EBß transcriptional activity. However, the role of CHOP and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in pancreatic ß-cell dysfunction remains unknown. The aim of the study was to investigate the effect of CHOP and PGC-1α in pancreatic ß-cell dysfunction and the potential mechanisms underlying its actions. METHODS: We established the pancreatic ß-cell dysfunction model to identify the biological features and functions of CHOP. Apoptosis was detected using Western blot analysis and real-time polymerase chain reaction (RT-PCR). RESULTS: Our results showed that high glucose (HG) increases CHOP and inhibits PGC-1α expression and ameliorates apoptosis in pancreatic ß cells. Silenced CHOP elevates the PGC-1α expression and ameliorates HG-induced apoptosis in pancreatic ß cells. Furthermore, upregulation of the PGC-1α alleviates HG-induced apoptosis in pancreatic ß cells. We also expounded that HG-activated phosphorylation of nuclear factor-κB through increasing PGC-1α expression. CONCLUSION: We verified the function and mechanism of CHOP and provide evidence that CHOP and PGC-1α may serve as potential candidates for the clinical treatment of DM.

[A four-generation pedigree affected with X-linked adrenal hypoplasia congenita due to a novel missense DAX1 mutation].

OBJECTIVE: To report on the clinical pictures of 7 patients from a pedigree affected with X-linked adrenal hypoplasia congenita (XL-AHC) and hypogonadotropic hypogonadism (HH) and the underlying mutations. METHODS: Seven patients were identified from a four-generation pedigree affected with XL-AHC and HH. Their clinical features, endocrinological changes, treatment and drug response were recorded. The patients were subjected to next-generation sequencing, and the result was verified by Sanger sequencing. PolyPhen-2 was used for predicting the influence of the mutation on protein production. RESULTS: Three deceased patients had manifested adrenal insufficiency (AI) within one year after birth. Two died at 6 and one died at 12. The four survivors presented with salient clinical and endocrinological features of AHC and HH, adrenal and testicular atrophy, and renin-angiotensin compensation. Two adult patients had testicular micro-stone detected by ultrasound.One of them also had remarkable seminiferous tubule degeneration by biopsy. The patients were followed up for 0.5 to 10 years. All required hyper-physiological dose of hydrocortisone to stabilize their clinical condition. In three patients, gonadotropic or androgen replacement induced cardinal masculine development but with unsatisfactory testis growth and sperm production.Genetic analysis revealed a novel missense c.827A>C (p.Q276P) mutation in a hotspot region within a highly conserved domain. PolyPhen-2 predicted the mutation to be highly hazardous. CONCLUSION: The novel p.Q276P mutation of the DAX1 gene probably underlies the XL-AHC and HH in this pedigree with variable clinical presentations in the patients.

S100A8 inhibits PDGF-induced proliferation of airway smooth muscle cells dependent on the receptor for advanced glycation end-products.

BACKGROUND: Airway remodeling is a key feature of asthma, characterized by increased proliferation of airway smooth muscle cells (ASMCs). S100A8 is a calcium-binding protein with a potential to regulate cell proliferation. Here, the effect of exogenous S100A8 protein on the proliferation of ASMCs induced by platelet-derived growth factor (PDGF) and the underlying molecular mechanism was investigated. METHODS: Rat ASMCs were cultured with or without a neutralizing antibody to the receptor for advanced glycation end-products (RAGE), a potential receptor for S100A8 protein. Purified recombinant rat S100A8 protein was then added into the cultured cells, and the proliferation of ASMCs induced by PDGF was detected by colorimetric-based WST-8 assay and ampedance-based xCELLigence proliferation assay. The expression levels of RAGE in ASMCs were analyzed using western blotting assay. RESULTS: Results showed that exogenous S100A8 inhibited the PDGF-induced proliferation of rat ASMCs in a dose-dependent manner with the maximal effect at 1 µg/ml in vitro. Furthermore, when ASMCs was pre-treated with anti-RAGE neutralizing antibody, the inhibitory effect of S100A8 on PDGF-induced proliferation was significantly suppressed. In addition, neither the treatment with S100A8 or PDGF alone nor the pre-treatment with rS100A8 followed by PDGF stimulation affected the expression levels of RAGE. CONCLUSIONS: Our study demonstrated that S100A8 inhibits PDGF-induced ASMCs proliferation in a manner dependent on membrane receptor RAGE.

Effect of N-methyl deuteration on pharmacokinetics and pharmacodynamics of enzalutamide.

Enzalutamide, a second-generation antiandrogen, has been developed for the treatment of castration-resistance prostate cancer. We synthesized the deuterated analogues 6 and found that it showed higher drug exposure and thus stronger antitumor potency in preclinical settings. Compound 6 is being developed clinically for the potential to be differentiated from enzalutamide through reduced dosages and a higher safety margin.

Associations of MDR1, TBXA2R, PLA2G7, and PEAR1 genetic polymorphisms with the platelet activity in Chinese ischemic stroke patients receiving aspirin therapy.

AIM: Aspirin resistance has an incidence of 5%-65% in patients with ischemic stroke, who receive the standard dose of aspirin, but the platelet function is inadequately inhibited, thereby leading to thrombotic events. Numerous evidence shows that thromboxane A2 receptor (TXA2 receptor, encoded by TBXA2R), lipoprotein-associated phospholipase A2 (Lp-PLA2, encoded by PLA2G7) and platelet endothelial aggregation receptor-1 (PEAR1, encoded by PEAR1) are crucial in regulating platelet activation, and P-glycoprotein (P-gp, encoded by MDR1) influences the absorption of aspirin in the intestine. In this study we examined the correlation between MDR1, TBXA2R, PLA2G7, PEAR1 genetic polymorphisms and platelet activity in Chinese ischemic stroke patients receiving aspirin therapy. METHODS: A total of 283 ischemic stroke patients receiving 100 mg aspirin for 7 d were genotyped for polymorphisms in MDR1 C3435T, TBXA2R (rs1131882), PLA2G7 (rs1051931, rs7756935), and PEAR1 (rs12566888, rs12041331). The platelet aggregation response was measured using an automatic platelet aggregation analyzer and a commercially available TXB2 ELISA kit. RESULTS: Thirty-three patients (11.66%) were insensitive to aspirin treatment. MDR1 3435TT genotype carriers, whose arachidonic acid (AA) or adenosine diphosphate (ADP)-induced platelet aggregation was lower than that of CC+CT genotype carriers, were less likely to suffer from aspirin resistance (odds ratio=0.421, 95% CI: 0.233-0.759). The TBXA2R rs1131882 CC genotype, which was found more frequently in the aspirin-insensitive group (81.8% vs 62.4%) than in the sensitive group, was identified as a risk factor for aspirin resistance (odds ratio=2.712, 95% CI: 1.080-6.810) with a higher level of AA-induced platelet aggregation. Due to the combined effects of PLA2G7 rs1051931 and rs7756935, carriers of the AA-CC haplotype had a higher level of ADP-induced platelet aggregation, and were at considerably higher risk of aspirin resistance than noncarriers (odds ratio=8.233, 95% CI: 1.590-42.638). CONCLUSION: A considerable portion (11.66%) of Chinese ischemic stroke patients are insensitive to aspirin treatment, which may be correlated with the MDR1 C3435T, TBXA2R (rs1131882), and PLA2G7 (rs1051931-rs7756935) polymorphisms.

A survey of detergents for the purification of stable, active human cystic fibrosis transmembrane conductance regulator (CFTR).

Structural knowledge of the cystic fibrosis transmembrane conductance regulator (CFTR) requires developing methods to purify and stabilize this aggregation-prone membrane protein above 1mg/ml. Starting with green fluorescent protein- and epitope-tagged human CFTR produced in mammalian cells known to properly fold and process CFTR, we devised a rapid tandem affinity purification scheme to minimize CFTR exposure to detergent in order to preserve its ATPase function. We compared a panel of detergents, including widely used detergents (maltosides, neopentyl glycols (MNG), C12E8, lysolipids, Chaps) and innovative detergents (branched alkylmaltosides, facial amphiphiles) for CFTR purification, function, monodispersity and stability. ATPase activity after reconstitution into proteoliposomes was 2-3 times higher when CFTR was purified using facial amphiphiles. ATPase activity was also demonstrated in purified CFTR samples without detergent removal using a novel lipid supplementation assay. By electron microscopy, negatively stained CFTR samples were monodisperse at low concentration, and size exclusion chromatography showed a predominance of monomer even after CFTR concentration above 1mg/ml. Rates of CFTR aggregation quantified in an electrophoretic mobility shift assay showed that detergents which best preserved reconstituted ATPase activity also supported the greatest stability, with CFTR monomer half-lives of 6-9days in MNG or Chaps, and 12-17days in facial amphiphile. Cryoelectron microscopy of concentrated CFTR in MNG or facial amphiphile confirmed mostly monomeric protein, producing low resolution reconstructions in conformity with similar proteins. These protocols can be used to generate samples of pure, functional, stable CFTR at concentrations amenable to biophysical characterization.

Cholate-based synthesis of size-tunable cage compounds.

We describe cholate-based cage amphiphiles with a unique architecture that combines elements of structural rigidity and flexibility. The cage compounds are built by extending and bridging three polar chains underneath the concave steroid rings of cholate and capping with another rigid, symmetrically trifunctionalized cyanuric acid moiety. The connecting chains are varied to include, for instance, oligo(ethylene glycol) or chains containing 1,2,3-triazole units to present flexibility in the chemical and structural space and potentially deliver functional molecules for molecular recognition applications.

Design, synthesis and biological evaluation of deuterated Tivozanib for improving pharmacokinetic properties.

Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-1(VEGFR1), -2(VEGFR2), and -3(VEGFR3). Analog of Tivozanib with deuterium-for-hydrogen replacement in metabolically active site was prepared and evaluated in vitro. Compared to its prototype, deuterated Tivozanib compound HC-1144 retained in vitro activity against VEGFR tyrosine kinases. In vivo pharmacokinetic studies indicated HC-1144 clearly altered the blood circulation behavior, which was proved by significantly prolonged blood circulation half life time (t1/2) and increased AUC0-∞. Therefore, HC-1144 has the potential to be a novel inhibitor against VEGFR tyrosine kinases with long-acting plasma exposure.

Effect of scutellarin on the metabolism and pharmacokinetics of clopidogrel in rats.

Erigeron breviscapus (Vant.) Hand-Mazz, a traditional Chinese medicine, is often co-prescribed with clopidogrel for the treatment of ischemic vascular diseases. Scutellarin is the representative bioactive flavonoid isolated from this herb. The aim of this study was to explore the effect of scutellarin on the metabolism and pharmacokinetics of clopidogrel. The in vitro studies using rat liver microsomes showed that scutellarin significantly inhibited the metabolism of clopidogrel. The IC50 value was 2.1 µM. Ten male rats were employed to investigate the effect of scutellarin on the pharmacokinetics of clopidogrel in vivo. After pretreatment with scutellarin, there were significant increases in the AUC0-∞ (from 0.9 ± 0.4 to 1.7 ± 0.6 ng/ml h; p <0.05) and Cmax (from 0.4 ± 0.1 to 0.9 ± 0.1 ng/ml; p <0.05) of clopidogrel. The pharmacokinetic data for clopidogrel active metabolite showed significant decreases in AUC0-∞ (18.2 ± 5.6 to 11.4 ± 3.7 ng/ml h; p <0.05) and Cmax (from 8.2 ± 1.2 to 4.3 ± 0.3 ng/ml; p <0.05) after pretreatment with scutellarin. Collectively, the metabolism and pharmacokinetics of clopidogrel were significantly affected by scutellarin. This study indicated that potential herb-drug interaction between scutellarin and clopidogrel should be taken into consideration in clinical use.

Design, synthesis and biological evaluation of deuterated nintedanib for improving pharmacokinetic properties.

Nintedanib is a novel triple angiokinase inhibitor that inhibits three growth factors simultaneously. Deuterated derivatives of nintedanib at certain metabolically active sites were prepared and evaluated in vitro and in vivo. In particular, deuterated compound SKLB-C2202 had significantly improved pharmacokinetic properties compared with nintedanib. These efforts lay the foundation for further investigating the druggability of SKLB-C2202.