ANA- 12 inhibits spinal inflammation and alleviates acute and chronic pain in rats by targeted blocking of BDNF/TrkB signaling / 南方医科大学学报

OBJECTIVE@#To investigate the inhibitory effect of ANA-12 that blocks brain-derived neurotrophic factor (BDNF)/ tropomyosin receptor kinase B (TrkB) signaling on inflammatory pain in rats and explore the underlying mechanism.@*METHODS@#Forty-two adult SD rats were randomized into BDNF-induced acute pain group (n=24) and CFA-induced chronic pain group. The former group were randomly divided into 4 subgroups, including a control group, ANA-12 treatment group, BDNF treatment group, and BDNF+ANA-12 treatment group; the latter group were subgrouped into control group, CFA treatment group (CFA) and CFA + ANA-12 treatment group. The effects of ANA-12 treatment on pain behaviors of the rats with BDNF-induced acute pain and CFA-induced chronic inflammatory pain were observed. Western blotting was used to examine TrkB signaling and expressions of microglia marker protein Iba1 and TNF-α in the spinal cord of the rats.@*RESULTS@#BDNF injection into the subarachnoid space significantly increased the number of spontaneous paw withdrawal of the rats (P < 0.05), which was obviously reduced by ANA-12 treatment (P < 0.05). The rats with intraplantar injection of CFA, showed significantly increased ipsilateral mechanical stimulation sensitivity (P < 0.05), and ANA-12 treatment obviously increased the ipsilateral foot withdrawal threshold (P < 0.05). Treatment with either BDNF or CFA significantly increased the phosphorylation level of TrkB (Y705) in the spinal cord of the rats (P < 0.05), which was significantly lowered by ANA-12 treatment (P < 0.05). Treatment with BDNF and CFA both significantly up-regulated the expressions of Iba1 and TNF-α in the spinal cord (P < 0.05), but ANA-12 significantly reduced their expression levels (P < 0.05).@*CONCLUSION@#ANA-12 can reduce spinal cord inflammation and relieve acute and chronic pain in rats by targeted blocking of BDNF/TrkB signaling.

Advances in the research of pharmacogenomics of tamoxifen / 药学学报

Tamoxifen (TAM) is the most common nonsteroidal antiestrogen agent, which has been widely used in the prevention of recurrence of estrogen or progesterone receptor-positive breast cancer in patients. It is metabolized by cytochrome P450 oxidases to its active metabolite (4-hydroxytamoxifen, 4-OH-TAM) and endoxifen (EDF), which played a critical role in the therapy. 4-OH-TAM and EDF have 30-to 100-fold more potency than TAM in the suppression of estrogen-dependent breast cancer cell proliferation. CYP3A4 and CYP2D6, as the key drug-metabolizing enzymes in those metabolic actions, are known to have several alleles. Genetic polymorphisms of CYP2D6 and CYP3A4 will influence the plasma concentrations of active TAM metabolites and clinical outcomes for breast cancer patients treated with TAM. The genetic polymorphisms of drug transporters, involved in the disposition of active TAM metabolites, also have the potential to influence the plasma concentrations of active TAM metabolites and clinical outcome for the treatment of breast cancer. In this review, we summarized the association of the genetic polymorphisms in the metabolic enzymes and transporters involved in the metabolism and disposition of TAM with the metabolite concentration, efficacy and adverse effects of TAM, which provides a fundamental reference for further pharmacogenomic study and clinical use of TAM.

Transplacental transport mechanisms of drugs for transplacental treatment of fetal tachyarrhythmia of MDCKII/MDCKII-BCRP cell line / 药学学报

To study the transport mechanisms of drugs for transplacental treatment of fetal tachyarrhythmia, MDCKII-BCRP and MDCKII cell models was used. MDCKII-BCRP and MDCKII cell monolayer model was used to investigate the bi-direction transport of sotalol, propranolol, propafenone, procainamide and flecainide. Drug concentrations were measured by HPLC-UV or chemiluminescence. The apparent permeability coefficient (P(app)), efflux rate (R(E)) and net efflux rate (R(net)) were calculated. Drugs with R(net) greater than 1.5 were further investigated using cellular accumulation experiments with or without a BCRP inhibitor. The R(net) of sotalol, propranolol, propafenone and procainamide were less than 1.5, while R(net) of flecainide with concentrations of 20 and 5 μmol x L(-1) were 1.6 and 1.9, respectively. The results showed that the transport of flecainide on MDCKII-BCRP cell monolayer could be mediated by BCRP; and the affinity increased when the concentration of flecainide decreased. Cellular accumulation experiments further suggested that accumulation of flecainide in MDCKII-BCRP cells was significantly lower than that in MDCKII cells in a concentration-dependent manner. BCRP inhibitor quercetin (50 μmol x L(-1)) significantly increased the accumulation of flecainide in MDCKII-BCRP cells (P < 0.05). Our preliminary data showed that flecainide but not sotalol, propranolol, propafenone or procainamide can be a substrate of BCRP. Thus the effect of flecainide may be affected by the BCRP in the maternal placental trophoblast membrane layer when treating fetal tachyarrhythmia.

Advances in rapid cooling treatment for heat stroke / 解放军医学杂志

Heat stroke is a life-threatening disease characterized clinically by central nervous system dysfunction and severe hyperthermia (core temperature rises to higher than 40 °C). The unchecked rise of body core temperature overwhelms intrinsic or extrinsic heat generation mechanism, thus overwhelms homoeostatic thermoregulation. Hyperthermia causes cellular and organ dysfunction with progressive exacerbation resulting in multi-organ failure and death. Rapid cooling to reduce core temperature as quickly as possible is the primary and most effective treatment, as it has been shown that the major determinant of outcome in heatstroke is the degree and duration of hyperthermia. If suppression of body temperature is delayed, the fatality rate will be elevated. Several cooling methods are available, including physical cooling by conduction, convection and evaporation with ice/cold water immersion, internal cooling by invasive methods such as hemofiltration, intravascular cooling, cold water gastric and rectal lavage, and cooling with drugs. It is crucial to formulate a scientific and reasonable strategy for the subsequent treatment in accordance with the patient's physical condition, the condition of cooling equipment, and the manipulator's proficiency in cooling methods and equipment usage. This article reviews the domestic and international advances in study of rapid and efficient cooling measures for heat stroke.

Forward genetic screening for zebrafish mutants defective in erythropoiesis / 南方医科大学学报

<p><b>OBJECTIVE</b>To screen and identify zebrafish mutants with erythropoiesis defects by N-ethyl-N-nitrosourea (ENU) mutagenesis and large-scale forward genetic screening using beta e 1 as the marker.</p><p><b>METHODS</b>The chemical mutagen ENU was used to treat healthy wild-type male fish (AB strain, F0). The surviving ENU-treated fish were mated with wild-type female fish to generate F1, and further F2 family was generated by F1 family intercross. The adult F2 fish were intercrossed within each F2 family and the resulting F3 embryos from each crossing were subjected to whole mount in situ hybridization (WISH) with the beta e 1 probe. Mutagenesis was performed by treating the male zebrafish with ENU to induce mutations in pre-meiotic germ cells to generate the founders, which were outcrossed to obtained the F1 fish. The F1 fish from different founders were mated to generate the F2 families. F3 embryos from the sibling cross in the F2 family were examined by whole mount in situ hybridization using beta e 1-globin probe. The putative mutants were then characterized with different hematopoiesis markers.</p><p><b>RESULTS AND CONCLUSION</b>We identified 4 beta e 1-deficient mutants with erythropoiesis defects, including two with specific erythiod lineage defects and two with concurrent lymphopoiesis defects.</p>

Progesterone promotes the proliferation and migration of cultured breast cancer cells / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the effects of progesterone on the growth and migration of breast cancer cells.</p><p><b>METHODS</b>MCF-7 and T-47D cells were cultured in DMEM and stimulated with 100 nmol/L progesterone for 48 h, and the cell proliferation was evaluated by MTT assay, cell migration by wound-healing assay and E-catherin expression by Western blotting.</p><p><b>RESULTS</b>Progesterone stimulated the cell proliferation and migration and down-regulated the expression of E-catherin in both MCF-7 and T-47D cells.</p><p><b>CONCLUSIONS</b>Progesterone stimulates the cell proliferation and migration of cultured breast cancer cells, suggesting the clinical significance of anti-progesterone therapy in breast cancer.</p>

Effect of Magnetic Fe_3O_4 Particles on Enzymatic Hydrolysis of Sunflower Seed Hull / 微生物学通报

The effect of magnetic Fe3O4 particles on cellulase in the enzymatic hydrolysis of sunflower seed hull was studied in different adding ways and additive amount. In the process of enzymatic hydrolysis of sunflower seed hull, the variations of cellulase activity, reducing sugar concentration and cellulose conversion were evaluated. After the reaction, the analysis of pH and surface tension of hydrolysate were also used to determine the mechanisms of cellulase by the magnetic effect. The results indicated that after adding magnetic Fe3O4, the cellulase activity, reducing sugar concentration and conversion of cellulose had an increased between the 0.5 g/L and 2.0 g/L cases after 48 h. When the additive amount of magnetic Fe3O4 was 2 g/L, the cellulase activity at 60 h was improved significantly by 25.9%. It was found that the concentration of reducing sugar was increased from 6.950 mg/mL to 8.775 mg/mL with magnetic Fe3O4 1.5 g/L. Simultaneously, compared with the blank, which the conversion of cellulose was 47.932%, the maximum celluloseconversion of samples with adding magnetic Fe3O4 was 60.531%. Besides, the stability of cellulase activity adding in times was better than in one time. After the reaction, the final surface tension of hydrolysate with 1.5 g/L magnetic Fe3O4 was the lowest in comparison with the blank. However, no significant differences were observed in the final pH of the hydrolysate.