Natural medicines (NMs) are indispensable sources for the development of modern drugs. However, the targets for most natural compounds are unknown and the current pharmacokinetic evaluation systems developed for target- defined drugs may not be directly applicable to NM- based drug discovery, which is a major bottleneck in bringing natural compounds to the clinic. We propose the concept of ″ reverse pharmacokinetics″ and discuss how a ″ reverse pharmacokinetics″ perspective could help clarify key questions in modern drug discovery from NMs with validated clinical benefits, thereby strengthening the translational potential. Reverse pharmacokinetics can provide physiologically relevant clues to the target identification and mechanistic study of NMs, which may also innovate drug discovery for complex diseases. We anticipate that an evolving deep understanding of the novel mode of action of natural compounds with a reverse pharmacokinetic insight may improve discovery of both single ingredient and multiple-component modern drugs from NMs.

Wnt/β-catenin signaling pathway plays an important role in the proliferation, growth, invasion, and metastasis of human cancers. Moreover, β-catenin/T-cell factor 4 (TCF4) interaction regulates the transcription of the key oncogenes in Wnt/β-catenin signaling pathway. Therefore, β-catenin/TCF4 interaction would be a promising therapeutic target for the development of highly selective anticancer agents. At present, most ongoing small-molecule inhibitors targeting β-catenin/TCF4 interaction, including PKF222-815, iCRT3/5/14, LF3, and sanguinarine, have been developed in preclinical studies for human cancer therapeutics. In this review, we summarized the research advances of up-to date inhibitors targeting β-catenin/TCF4 interaction, including the molecular structure and cellular functions of β-catenin in canonical Wnt signaling pathway. This review holds a hopeful avenue for the development of novel and highly selective Wnt inhibitors targeting β-catenin/TCF4 interaction for future anticancer strategy.

The pharmacokinetic research of traditional Chinese medicines (TMC) is an inalienable part of the chain of TCM modernization and plays an important role in the TCM novel drug development. However, the researching method and system that is consistent with the specific characteristics of TCM, i.e., multiple-components and targets, is still lacking. Furthermore, the current understanding of the critical scientific questions of TCM pharmacokinetics remains still unclear. This review makes a brief summary of our recent developments on the pharmacokinetic exploration of TCMs, mainly including integral pharmacokinetic study of multiple components, herbalome analysis both in vitro and in vivo, mechanism based compatibility study for herbal components interactions, and the representative pharmacokinetic study for single herbal compound. Furthermore, the critical scientific questions of TCM pharmacokinetics are discussed based on understanding the requirements of novel drug developments from TCM.
Animals ; Drug Combinations ; Drug Interactions ; Drug Synergism ; Drugs, Chinese Herbal ; isolation & purification ; pharmacokinetics ; Humans ; Medicine, Chinese Traditional ; Plants, Medicinal ; chemistry ; Principal Component Analysis ; Quantitative Structure-Activity Relationship

Objective To further investigated the effect of minocycline on the inhibition of microglial activation and subsequent protection of nigral DA neuron.Methods 20 rats injected with LPS in the substantia nigra (SN) were randomly divided into two groups (LPS group and LPS+Minocycline group).The behavior was observed on the 7~(th) d and 14~(th) d.The immunohistoehemistry,in situ hybridization and Western-blot were used to detect the levels of positive neuron,mRNA,protein of TH and OX-42. Results The slightly rotational behavior was observed in LPS+Minoeyeline group.The majority of mieroglias were activated in the two groups.Some microglia in the SNpc remained ramified in LPS+ Minocycline group.The numbers of hypertophie microglia in LPS+Minoeyeline group were less than that in LPS group.Western-blot showed that the protein of OX-42 in two LPS groups was higher than in normal group(P

AIM: This study was designed to explore the effects of short-term and long-term pretreatment of diammonium glycyrrhizinate (GLN) on the pharmacokinetics of entecavir (ETV) in rats. METHODS: Male SD rats were randomized into short-term and long-term experimental groups, respectively. In the short-term experiment, the control group received saline, the low dose group received GLN 13.5 mg·kg(-1) and the high dose group received GLN 40.5 mg·kg(-1). ETV (0.09 mg·kg(-1)) was given i.g. 0.5 h after saline/GLN administration. For the long-term experiment, rats were allocated into two experimental designs. The control group received saline/ETV (0.09 mg·kg(-1)), the low dose group received GLN 13.5 mg·kg(-1)/ETV 0.09 mg·kg(-1) + GLN 13.5 mg·kg(-1), while the high dose group received GLN 40.5 mg·kg(-1)/ETV 0.09 mg·kg(-1) + GLN 40.5 mg·kg(-1); all administration was continued for 15 days. On the 16(th) day, 0.09 mg·kg(-1) ETV was administrated to all groups. Blood samples were obtained at different time points after ETV administration to determine plasma ETV concentrations. RESULTS: Pretreatment with glycyrrhizin resulted in no significant alterations in the main pharmacokinetic parameters of ETV in the short-term and long-term administration experiments. CONCLUSION Diammonium glycyrrhizinate has no effect on ETV pharmacokinetics in rats.
Animals ; Drug Interactions ; Glycyrrhizic Acid ; pharmacology ; Guanine ; analogs & derivatives ; blood ; pharmacokinetics ; Male ; Rats ; Rats, Sprague-Dawley

To investigate the influence of Anxin granules combined with tirofiban on acute myocardial infarction (AMI) Patients after elective percutaneous coronary intervention (PCI). One hundred and twenty AMI patients were randomly divided into treatment group and control group. The patients in the two groups were all given Tirofiban 30mins before PCI . The treatment group was added Anxin granules 30 mins before and after PCI. Tissue factor (TF) and von willebrand factor (vWF) were tested at 6 hours after operation. Syndromatology alteration of traditional Chinese medicine (TCM) and bleeding complications were observed at 4 weeks after operation. Both TF and vWF at 6 hours after operation of the treatment group was lower than the control group significantly (P < 0.01), while the condition of myocardial ischemia at 90 mins after operation of the treatment group was better than control group with significance. The syndromatology alteration of TCM especially spontaneous perspiration and hypodynamia of the treatment group were improved significantly compared to control group 4 weeks after operation. All patients in both groups had no bleeding complications and thrombopenia. The study suggests that Anxin granules combined with tirofiba can improve the clinical efficacy and the endothelial function of AMI patients after PCI with no increase in bleeding events.
Aged ; Angioplasty, Balloon, Coronary ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Humans ; Middle Aged ; Myocardial Infarction ; complications ; metabolism ; surgery ; Postoperative Hemorrhage ; drug therapy ; etiology ; metabolism ; prevention & control ; Thromboplastin ; metabolism ; von Willebrand Factor ; metabolism

OBJECTIVETo investigate the value of application of mandibular outer cortex as bone graft by comparing its bone absorption with cranial outer cortex.

METHODS8 minitype grown-up pigs at the age of 8 - 12 months underwent surgery of taking out the same size (2.5 cm x 1.0 cm) of outer cortex from mandible and craninium. The volume of the outer cortex was measured by volume-displacement method. Then the outer cortex of mandible and cranium were onlay grafted to the each side of the pig snout, respectively. 12 weeks later, 2 pigs were randomly selected for histological examination. The other 6 pigs were killed 24 weeks after surgery for measurement of the bone graft volume and histologic examination.

RESULTSThe bone graft absorption rate was (41 +/- 5)% for mandibular outer cortex and (46 +/- 12)% for cranial outer cortex, showing no significant difference between them (P = 0.51). The histologic examination results also had no marked difference in the bony healing and reforming between the two graft.

CONCLUSIONSMandibular outer cortex is a good donor site for onlay bone graft in craniofacial region.

Animals ; Bone Plates ; Bone Regeneration ; Bone Transplantation ; methods ; Female ; Male ; Mandible ; transplantation ; Skull ; transplantation ; Swine ; Swine, Miniature

OBJECTIVETo determine the mutation responsible for the congenital fibrosis of the extraocular muscles type I(CFEOM1) in a Chinese family.

METHODSDirect sequencing of exons 20 and 21 in the KIF21A gene was performed for the proband. The mutation c.2860C to T in exon 21 was examined by allele specific-PCR (AS-PCR) analysis in other family members. Haplotype analysis was performed using four STR markers (D12S1668, D12S2194, D12S331 and D12S1048).

RESULTSA heterozygous mutation c.2860C to T in the KIF21A gene was identified in all three affected members with CFEOM1. Haplotype analysis suggested that the mutation might derive from maternal germline mosaicism.

CONCLUSIONThis Chinese family with CFEOM1 may be caused by a c.2860C to T mutation in the KIF21A gene.

Alleles ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; Child ; China ; Exons ; Female ; Fibrosis ; Haplotypes ; Humans ; Kinesin ; genetics ; Mutation ; genetics ; Oculomotor Muscles ; metabolism ; pathology ; Pedigree ; Phenotype ; Syndrome

OBJECTIVEVitamin D deficiency rickets often causes growth retardation, impaired bone formation and hypocalcemia in children. It is well known that rickets is mainly caused by vitamin D deficiency, but whether there is hereditary susceptibility of children to develop vitamin D deficiency rickets is unknown. Vitamin D receptor (VDR) gene has been used as one of genetic markers in studying the metabolic diseases of bone. The present study aimed to explore the hereditary susceptibility of children to develop rickets through studying the association between VDR gene start codon polymorphism and vitamin D deficiency rickets,

METHODSThe subjects were selected from Kunming city, every subject was of Han ethnic group. The subjects were composed of two groups, the patient group consisted of 48 children with active vitamin D deficiency rickets which was diagnosed clinically and confirmed radiologically; the control group was composed of 92 normal children. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), DNA sequence analysis and genetic analysis methods were used. A restriction fragment length polymorphism in the start codon of VDR gene (FokI) was tested in both groups.

RESULTSVDR gene start codon polymorphism was tested successfully for every subject. Frequencies of FF, Ff and ff genotypes were 46%, 33% and 21% in the rickets group, and 22%, 52% and 26% in the control group, respectively. A significant difference was found in the frequency distribution of VDR genotype between two groups (chi(2) = 8.912, P = 0.012). In the patient group, Ff and ff genotypes were less common than control group, but the FF genotype was more common than control group (OR = 3.046), indicating that FF genotype may be significantly associated with vitamin D deficiency rickets. Moreover, VDR allele frequencies of FokI polymorphism also showed significant difference between the two groups (chi(2) = 5.451, P = 0.020), F alleles were more common in patient group than in control group. DNA sequence analysis identified that the start codon of F allele was mutated from ATG to ACG.

CONCLUSIONThere is an association between VDR gene start codon polymorphism and vitamin D deficiency rickets. This study suggested the possibility that VDR gene polymorphism might be important in determining an individual's susceptibility to development of vitamin D deficiency rickets.

Base Sequence ; Child, Preschool ; Codon, Initiator ; genetics ; DNA Mutational Analysis ; Female ; Gene Frequency ; Genotype ; Humans ; Infant ; Male ; Point Mutation ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Polymorphism, Restriction Fragment Length ; Receptors, Calcitriol ; genetics ; Rickets ; genetics ; Vitamin D Deficiency ; genetics

Hydrophilic low molecular drugs, peptides and proteins, which are always poor in bioavailability, are mainly absorbed through the paracellular way in which the tight junction is the elementary framework. The tight junctions are a multiple unit structure composed of multiprotein complex that affiliates with the underlying apical actomyosin ring. Tight junction proteins are identified including transmembrane proteins (occludin, claudin and JAM) , cytoplasmic plaque proteins (ZO-1, ZO-2, ZO-3 and cingulin) and cytoskeleton. Traditional absorption enhancers can usually impair mucous membranes which constraint the utilization of these enhancers. Recently, with the increasing knowledge of the structure and function of tight junctions, many new absorption enhancers have been developed such as NO donor, CPE, Zot, and so on. In vivo and in vitro studies have shown that these enhancers could be effectively used to increase the absorption of paracellular markers and low bioavailable drug across intestinal epithelium with lower side effect. In short, the transient opening of the tight junctions by these enhancers provides new ideas that could help in novel drug delivery of therapeutic agents.
Animals ; Biological Availability ; Cell Adhesion Molecules ; metabolism ; Cholera Toxin ; pharmacology ; Claudin-1 ; Cytoskeleton ; metabolism ; Decanoic Acids ; pharmacology ; Drug Delivery Systems ; Enterotoxins ; pharmacology ; Humans ; Intestinal Absorption ; drug effects ; Membrane Proteins ; metabolism ; Nitric Oxide Donors ; pharmacology ; Occludin ; Phosphoproteins ; metabolism ; Receptors, Cell Surface ; metabolism ; Tight Junctions ; metabolism ; physiology ; Zonula Occludens-1 Protein