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

OBJECTIVETo assess the anti-tumor immune response to percutaneous cryoablation in patients with local prostate cancer.

METHODSWe treated 10 patients with local prostate cancer by percutaneous cryoablation, collected the blood samples before and 2 weeks after the treatment and isolated peripheral blood mononuclear cells (PBMCs). Protein lysates were made by biopsy from autologous prostate cancer or non-cancer tissues. The levels of serum TNF-alpha, IFN-gamma, IL4 and IL-10 were determined by enzyme-linked immunosorbent assay (ELISA) and the Th1/Th2 ratio was calculated by the IFN-gamma/IL-4 ratio. The number of IFN-gamma + T cells under the stimulation of different protein lysates was counted by enzyme link immunol spot (ELISPOT). And the cytolytic activity of cytotoxic T lymphocytes (CTL) was detected by LDH assay.

RESULTSCompared with pre-treatment, the levels of TNF-alpha and IFN-gamma, the Th1/ Th2 ratio and the number of IFN-gamma + T cells induced by tumor protein lysates in PBMCs were increased significantly after cryosurgery (P < 0.01), while the levels of IL4 and IL-10 decreased slightly, and the non-tumor protein lysates induced no obvious changes in the number of IFN-gamma T cells. The cytolytic activity of cytotoxic T lymphocytes against human prostate cancer cells LNCaP was markedly increased, but not that against renal cancer cells GRC-1. One case of recurrence was found during the 3-6 months follow-up.

CONCLUSIONPercutaneous cryoablation for prostate cancer could induce a tumor-specific immune response.

Aged ; Cryosurgery ; Humans ; Interferon-gamma ; blood ; Interleukin-10 ; blood ; Interleukin-4 ; blood ; Male ; Middle Aged ; Prostatic Neoplasms ; immunology ; therapy ; T-Lymphocytes, Cytotoxic ; immunology ; Th1 Cells ; immunology ; Th2 Cells ; immunology ; Tumor Necrosis Factor-alpha ; blood

The metabolic transformation of the drugs containing carboxylic acid groups can lead to the formation of acyl glucuronide metabolites through catalysis by glucuronosyltransferase, and produce pro-acyl glucuronide intermediate metabolites with electronic activity. Then, protein or DNA adducts appeared after a series of non-enzyme or enzyme reactions. These adducts would change the protein activity and potentially lead to idiosyncratic and genotoxicity. In this paper, we discussed the chemical activity, drug-induced mechanisms, distribution and toxicity resulting from this metabolic activation for these drugs, and stated the status and prospects of research in this field.
Biological Transport, Active ; Biotransformation ; Carboxylic Acids ; metabolism ; toxicity ; DNA Damage ; drug effects ; Drug-Related Side Effects and Adverse Reactions ; Glucuronides ; metabolism ; toxicity ; Glucuronosyltransferase ; metabolism ; Hepatocytes ; metabolism ; Humans ; Pharmaceutical Preparations ; 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 investigate the effects of immunization with fusions of dendritic cells and H22 cells on tumor-bearing mice and their possible mechanisms.

METHODSFusion cells of DC and H22 cells were prepared with polyethylene glycol (PEG). Expression of MHC and costimulatory molecules by dendritomas were determined by FACs. To study the antitumor immune preventative and therapeutic effects, fusions were subcutaneously injected into tumor-bearing mice. The cytotoxic T lymphocyte (CTL) activity was determined by LDH method, the expression of TNF-a and IFN-g in tumors were assayed by RT-PCR.

RESULTSThe data showed that the hybridomas of DC and H22 cells acquired both DC and H22 cell phenotypes. Immunization of BALB/C mice with DC/H22 fusions induced potent CTL activity (mean CTL activity=0.624+/-0.024, compared with DC + H22, DC, H22 groups, F = 65.46) and a protective immunity against a high dose of H22 tumor challenge. After treatment with hybridomas, the survival time of tumor-bearing mice was greatly extended (x2=18.45). The expression levels of TNF-a and IFN-g mRNA were remarkably increased (TNF-a, F = 47.84; IFN-g, F = 37.23).

CONCLUSIONSThe hybridomas of DC and H22 cells could induce effective antitumor immune responses and may have a useful potential in prevention and management of the recurrences and metastases of HCC.

Animals ; Cancer Vaccines ; immunology ; Carcinoma, Hepatocellular ; genetics ; immunology ; Cell Fusion ; Dendritic Cells ; immunology ; Female ; Hybridomas ; Immunization ; Interferon-gamma ; biosynthesis ; genetics ; Liver Neoplasms, Experimental ; genetics ; immunology ; prevention & control ; Mice ; Mice, Inbred BALB C ; Polyethylene Glycols ; T-Lymphocytes, Cytotoxic ; immunology ; Tumor Necrosis Factor-alpha ; biosynthesis ; genetics ; Vaccination

OBJECTIVETo study the effect of aluminum chloride on motor and species-typical behaviors in mice.

METHODSMale ICR mice were administered with drinking double distilled water only containing AlCl(3) (10, 50, 300 mg x kg(-1) x d(-1)), and control group with drinking double distilled water only for 100 days. Spontaneous activity test, grip strength, beam traversal, tightrope task, food hoarding, and nest construction were used to study the effect of chloride aluminum on motor and species-typical behaviors in mice.

RESULTSThe frequencies of spontaneous activity in low dose group, medium dose group and high dose group [(81.53 +/- 8.97), (71.67 +/- 8.37), (66.73 +/- 6.96) times respectively] were lower than that in control [(106.46 +/- 8.21) times] (P < 0.01), and were negatively correlated with doses (r(s) = -0.42, P < 0.01). Grip strength scores in medium dose group (19.19 +/- 1.48) and high dose group (13.36 +/- 1.46) respectively were lower than that in control (24.31 +/- 1.43) (P < 0.05, P < 0.01). Food hoarding was greater in high dose group [96.10 (90.20-99.00) g] than that in control group [84.00 (78.00-90.00) g (P < 0.05)]. The rest of parameters were of no statistical significance.

CONCLUSIONSubchronic exposure to AlCl(3) in mice may diminish motor activity and grip strength, but motor coordination was not impaired; alteration in food hoarding suggests damage to hippocampus cell.

Aluminum Compounds ; toxicity ; Animals ; Behavior, Animal ; drug effects ; Chlorides ; toxicity ; Dose-Response Relationship, Drug ; Male ; Mice ; Mice, Inbred ICR ; Motor Activity ; drug effects