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 investigate the prognostic factors for non-small cell lung cancer(NSCLC)in patients under 40 years of age.

METHODSThe clinicopathological data of 148 young patients with NSCLC were retrospectively analyzed. Kaplan-Meier and Cox regression analyses were used to analyze the relationship between prognostic factors and survival time.

RESULTSThe patients were followed-up for 6 - 148 months, and the follow-up rate was 100%. In the whole group, 122 patients died and 26 cases were surviving. The 1-, 3- and 5-year survival rates were 54.7%, 10.4% and 5.6%, respectively. The median survival time (MST) was 14.7 months. Kaplan-Meier analysis showed that Karnofsky performance status (KPS), clinical stage, treatment modality and serum CEA were related with prognosis (P < 0.05). Multivariate analysis indicated that KPS, clinical stage, treatment modality and serum CEA were independent prognostic factors (P < 0.05).

CONCLUSIONSKPS, CEA, clinical stage and treatment modalities are independent prognostic factors in young NSCLC patients.

Adolescent ; Adult ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Carcinoembryonic Antigen ; blood ; Carcinoma, Non-Small-Cell Lung ; blood ; drug therapy ; pathology ; radiotherapy ; surgery ; Combined Modality Therapy ; Female ; Follow-Up Studies ; Humans ; Karnofsky Performance Status ; Lung Neoplasms ; blood ; drug therapy ; pathology ; radiotherapy ; surgery ; Male ; Neoplasm Staging ; Pneumonectomy ; methods ; Proportional Hazards Models ; Retrospective Studies ; Survival Rate ; Young Adult

OBJECTIVETo screen a group of traditional Chinese medicines with effect on pregnane X receptor (PXR)-mediated transcription regulation of P450 3A4 (CYP3A4); and to study whether they can induce the expression of CYP3A4 with a dose, time-dependent manner.

METHODTransient cotransfection reporter gene assays were performed with pCI-hPXR-neo, pGL3-CYP3A4-Luc and beta-galactosidase expression plasmid in HepG2 cells.

RESULTRhizoma Curcumae, Atractylodes lancea, A. macrocaphala and Poria cocos could induce transcriptional expression of CYP3A4. In the dose-effect study, 24 h after induction, 500 mg x L(-1) Rhizoma Curcumae, A. lancea, A. macrocaphala and Poria cocos, respectively, could induce the CYP3A4 gene expression with (6.82 +/- 0.09), (6.76 +/- 0.20), (5.49 +/- 0.13) and (4.97 +/- 0.07) folds, as compared with 0.1% DMSO treated cells. In the time-effect study, 500 mg x L(-1) Rhizoma curcumae, A. lancea, A. macrocaphala and Poria cocos for 48 h could induce the CYP3A4 gene expression with (7.74 +/- 0.54), (7.34 +/- 0.10), (5.54 +/- 0.11) and (5.32 +/- 0.18) folds, compared with 0.1% DMSO treated cells.

CONCLUSIONRhizoma Curcumae, A. lancea, A. macrocaphala and Poria cocos could induce the expression of CYP3A4 gene transcription through activating PXR.

Cell Line, Tumor ; Cytochrome P-450 CYP3A ; genetics ; Drugs, Chinese Herbal ; pharmacology ; Humans ; Receptors, Steroid ; metabolism ; Transcription, Genetic ; drug effects

OBJECTIVETo explore the effect of Compound Tongtu Granule (CTG) on intestinal permeability in elderly sepsis patients.

METHODSEighty elderly sepsis patients were randomly assigned to the experimental group and the control group by randomized double blinded method, 40 in each group. On the basis of conventional antiseptic treatment program, patients in the experimental group took CTG, while those in the control group took placebos. The dosage for CTG or placebos was 14.3 g each package, one package each time, twice daily for 14 successive days. Patients' abdominal symptoms and signs, levels of serum inflammatory factors (high-sensitivity C-reactive protein and procalcitonin), levels of plasma endotoxin, and the intestinal permeability (IP, represented by urinary lactulose/mannitol excretion rate) were compared between the two groups before and after treatment.

RESULTSAfter 14-day treatment, patients in the experimental group had improved abdominal symptoms, increased frequency of defecation, significantly decreased levels of plasma endotoxin and IP, when compared with the control group (P < 0.05).

CONCLUSIONCTG could improve the intestinal barrier function in elderly sepsis patients.

Aged ; C-Reactive Protein ; metabolism ; Calcitonin ; metabolism ; Calcitonin Gene-Related Peptide ; Defecation ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Endotoxins ; metabolism ; Humans ; Intestines ; metabolism ; Permeability ; Protein Precursors ; metabolism ; Sepsis ; drug therapy ; physiopathology

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

OBJECTIVETo study if there is any association between frequency of HLA-DRB1 and DQB1 genes and susceptibility or resistance to Helicobacter pylori (Hp) infection among children of Yi ethnic group in Kunming for understanding the immunogenetic features of the digestive diseases associated with Hp infection.

METHODSPeripherial blood samples were collected from 156 children of Yi ethnic group in a primary school in Kunming city by cluster sampling and the blood Hp-IgG tests (ELISA) were performed. The samples were divided into two groups (Hp-IgG-positive group and Hp-IgG-negative group) according to the blood Hp-IgG test results. There were 61 children in Hp-IgG-positive group and 95 children in Hp-IgG-negative group. Forty children who were chosen from each group by simple random sampling underwent (13)carbon-urea breath test ((13)C-UBT). Thirty-three children who were Hp-IgG-positive and (13)C-UBT-positive were defined as currently Hp- infected group; 39 children who were Hp-IgG-negative and (13)C-UBT-negative were defined as Hp-non-infected group. DNA specimens were extracted from the lymphocytes of their peripheral blood samples. HLA-DRB1 and DQB1 DNA typing was performed by using polymerase chain reaction with sequence specific primers (PCR-SSP). HLA-DRB1, DQB1 allelic frequency distribution among currently Hp infected and non-infected children was compared.

RESULTSHLA-DRB1 * 12 gene frequency among children in Hp non-infected group was higher than that in the currently Hp-infected group (42.31% vs. 14.52%, P < 0.001, Pc < 0.012); however, HLA-DRB1 * 11 gene frequency in the Hp-non-infected group was lower than that in the currently Hp-infected group (3.85% vs. 12.9%, P < 0.05, Pc > 0.05). HLA-DQB1 * 0301 gene frequency in the Hp non-infected group was higher than that in the currently Hp-infected group (55.13% vs. 32.26%, P < 0.007, Pc < 0.05); however, HLA-DQB1 * 04 gene frequency in the Hp non-infected group was lower than that in currently Hp infected group (2.56% vs. 11.29%, P < 0.05, Pc > 0.05).

CONCLUSIONSHLA-DRB1 * 12 and HLA-DQB1 * 0301 gene may be associated with protection against Hp infection in Kunming Yi ethnic group children. Further studies with larger sample size are needed to clarify if HLA-DRB1 * 11 and HLA-DQB1 * 04 are associated with susceptible gene to Hp infection.

Adolescent ; Child ; China ; ethnology ; Gene Frequency ; Genetic Predisposition to Disease ; HLA-DQ Antigens ; genetics ; HLA-DQ beta-Chains ; HLA-DR Antigens ; genetics ; HLA-DRB1 Chains ; Helicobacter Infections ; ethnology ; genetics ; Helicobacter pylori ; Humans