Antidepressive Agents/therapeutic use* ; Serotonin ; Serotonin Plasma Membrane Transport Proteins

Multi-drug resistance(MDR)refers to the loss of sensitivity of tumor cells to traditional chemotherapeutics agents under the mediation of various mechanisms,resulting in the reduction of chemotherapy efficacy.Current studies suggest that a variety of factors,including cell membrane transporter-mediated efflux of anti-tumor drugs,special microenvironment in tumor tissue,DNA self-repair and anti-apoptotic process,and epithelial-mesenchymal cell transformation,may contribute to the formation of MDR.Cell membrane transporter-mediated drug efflux refers to an increase in the amount of anti-tumor drug pumped out of the cell through the up-regulation of the ATP-binding cassette transporter on tumor cell membrane,which reduces the concentration of the drug in the cell,thus forming MDR.An effective method to inhibit the efflux pump caused by overexpression of membrane transporters plays an important role in overcoming MDR.As a promising drug delivery system,multifunctional nanoparticles have demonstrated many advantages in antitumor therapy.Meanwhile,nanoparticles with tailored design are capable of overcoming MDR when combined with a variety of strategies.This paper described in detail the studies relevant to the use of multifunctional nano-sized drug delivery system combined with different strategies,such as co-delivery of agents,external responsiveness or target modification for intervention with efflux pump in order to reverse MDR.This paper provides reference for the development of nano-sized drug delivery system and the formulation of reversal strategy in the future.
Antineoplastic Agents/therapeutic use* ; Cell Membrane ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Humans ; Membrane Transport Proteins/therapeutic use* ; Multifunctional Nanoparticles ; Nanoparticles ; Neoplasms/drug therapy* ; Tumor Microenvironment

OBJECTIVETo observe the effect of Bushen Huoxue Granule (BHG) on dopamine (DA) neurotransmitter and dopamine transporter (DAT) in the brain of patients with Parkinson's disease (PD) as an adjunctive therapy.

METHODSNinety-four PD patients were randomly assigned to two groups, 47 in each group. Madopar was given to all as the basic treatment group. The placebo was given to those in the control group while BHG was given to those in the treatment. The therapeutic course for all was three months. Before and after treatment DA levels in the brain of patients were detected by encephalofluctuograph (EFG) technique. Changes of DAT in the striatum of patients in the treatment group were detected by positron emission tomography (PET) and region of interest (ROI) analysis.

RESULTS(1) Before treatment the DA level was lower in the two groups than the normal value, showing significant difference (P < 0.01), but with no significant difference between the two groups (P > 0.05). After treatment the DA level obviously increased in the two groups, showing significant difference from that before treatment (P < 0.01). No significant difference existed in the DA level in the two groups when compared with the normal value (P > 0.05), but with significant difference between the two groups (P < 0.05). Better results were obtained in the treatment group than in the control group. (2) The DAT radioactive accumulation inside the striatum increased obviously in the treatment group after treatment. ROI analysis showed the total ratio of striatum/cerebellum before and after treatment was 1.86 +/- 0.32 and 2.61 +/- 0.53 respectively, showing statistical difference (P < 0.05).

CONCLUSIONBHG could improve the DA level of PD patients, and increasing DAT contents in the striatum, thus playing a role in effectively treating PD.

Aged ; Brain ; metabolism ; Dopamine ; metabolism ; Dopamine Plasma Membrane Transport Proteins ; metabolism ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Parkinson Disease ; drug therapy ; metabolism ; Phytotherapy

OBJECTIVE: To explore the potential molecular mechanism of tetrahydropalmatine (THP) on acute myocardial ischemia (AMI). METHODS: First, the target genes of THP and AMI were collected from SymMap Database, Traditional Chinese Medicine Database and Analysis Platform, and Swiss Target Prediction, respectively. Then, the overlapping target genes between THP and AMI were evaluated for Grene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein-protein interaction network analysis. The binding affinity between the protein and THP was assessed by molecular docking. Finally, the protective effects of THP on AMI model and oxygen and glucose deprivation (OGD) model of H9C2 cardiomyocyte were explored and the expression levels of target genes were detected by RT-qPCR in vivo and in vitro. RESULTS: MMP9, PPARG, PTGS2, SLC6A4, ESR1, JAK2, GSK3B, NOS2 and AR were recognized as hub genes. The KEGG enrichment analysis results revealed that the potential target genes of THP were involved in the regulation of PPAR and hormone pathways. THP improved the cardiac function, as well as alleviated myocardial cell damage. Furthermore, THP significantly decreased the RNA expression levels of MMP9, PTGS2, SLC6A4, GSK3B and ESR1 (P<0.05, P<0.01) after AMI. In vitro, THP significantly increased H9C2 cardiomyocyte viability (P<0.05, P<0.01) and inhibited the RNA expression levels of PPARG, ESR1 and AR (P<0.05, P<0.01) in OGD model. CONCLUSIONS THP could improve cardiac function and alleviate myocardial injury in AMI. The underlying mechanism may be inhibition of inflammation, the improvement of energy metabolism and the regulation of hormones.
Humans ; Matrix Metalloproteinase 9 ; Network Pharmacology ; Cyclooxygenase 2 ; Molecular Docking Simulation ; PPAR gamma ; Myocardial Ischemia/genetics* ; Glucose ; RNA ; Drugs, Chinese Herbal/therapeutic use* ; Serotonin Plasma Membrane Transport Proteins

AIMTo investigate the chronic cardioprotection of testosterone against ischemia/reperfusion injury and acute effect against H2O2-stress injury.

METHODSThe vas deferens were ligated bilaterally and the testes removed from male Sprague-Dawley rats, and testosterone propionate was supplemented every day. Eight weeks after gonadectomy, all the hearts were mounted on a Langendorff apparatus to assess the level of lactate dehydrogenase (LDH) in the coronary effluent and the infarct size. Isolated adult ventricular myocytes were obtained by enzymatic dissociation, in which H2O2-stress injury model was copied. The myocyte contraction was determined, and mitochondrial reactive oxygen species (ROS) production was measured by loading with fluorescent probe DCFH-DA.

RESULTSIn gonadectomy model, pretreatment with testosterone propionate significantly decreases the LDH release and the infarct size. In the isolated myocytes model, testosterone attenuated the decreases of +/- dL/dtmax and dL which produced by H2O2-stress, and prevented the production of ROS induced by H2O2-stress. Co-treatment with atractyloside or 5-HD attenuated the effect of testosterone.

CONCLUSIONThe findings show the chronic cardioprotection of testosterone against ischemia/reperfusion injury and acute effect against H2O2-stress injury via opening of mitoK(ATP) channel or/and the inhibiting mitochondrial permeability transition pore.

Animals ; Cardiotonic Agents ; pharmacology ; Hydrogen Peroxide ; KATP Channels ; metabolism ; Male ; Mitochondrial Membrane Transport Proteins ; drug effects ; Myocardial Reperfusion Injury ; metabolism ; physiopathology ; prevention & control ; Orchiectomy ; Oxidative Stress ; drug effects ; Rats ; Rats, Sprague-Dawley ; Testosterone ; pharmacology ; therapeutic use

INTRODUCTIONEfavirenz is an inducer of drug metabolism enzymes. We studied the effect of efavirenz and ritonavir-boosted darunavir on serum unconjugated and conjugated bilirubin, as probes for UGT1A1 and bile transporters.

MATERIALS AND METHODSHealthy volunteers were enrolled in a clinical trial. There were 3 periods: Period 1, 10 days of darunavir 900 mg with ritonavir 100 mg once daily; Period 2, 14 days of efavirenz 600 mg with darunavir/ritonavir once daily; and Period 3, 14 days of efavirenz 600 mg once daily. Serum bilirubin (conjugated and unconjugated) concentrations were obtained at baseline, at the end of each phase and at exit.

RESULTSWe recruited 7 males and 5 females. One subject developed grade 3 hepatitis on efavirenz and was excluded. Mean serum unconjugated bilirubin concentrations were 6.09 μmol/L (95% confidence interval [CI], 4.99 to 7.19) at baseline, 5.82 (95% CI, 4.88 to 6.76) after darunavir/ritonavir, 4.00 (95% CI, 2.92 to 5.08) after darunavir/ritonavir with efavirenz, 3.55 (95% CI, 2.58 to 4.51) after efavirenz alone and 5.27 (95% CI, 3.10 to 7.44) at exit (P <0.01 for the efavirenz phases). Mean serum conjugated bilirubin concentrations were 3.55 μmol/L (95% CI, 2.73 to 4.36) at baseline, 3.73 (95% CI, 2.77 to 4.68) after darunavir/ritonavir, 2.91 (95% CI, 2.04 to 3.78) after darunavir/ritonavir with efavirenz, 2.64 (95% CI, 1.95 to 3.33) after efavirenz alone and 3.55 (95% CI, 2.19 to 4.90) at exit (P <0.05 for the efavirenz phases).

CONCLUSIONEfavirenz decreased unconjugated bilirubin by 42%, suggesting UGT1A1 induction. Efavirenz also decreased conjugated bilirubin by 26%, suggesting induction of bile efflux transporters. Ritonavir-boosted darunavir had no effect on bilirubin concentrations. These results indicate that efavirenz may reduce concentrations of drugs or endogenous substances metabolized by UGT1A1 or excreted by bile efflux transporters.

Adult ; Aged ; Anti-HIV Agents ; therapeutic use ; Benzoxazines ; pharmacology ; Biological Transport ; Confidence Intervals ; Darunavir ; Dose-Response Relationship, Drug ; Drug Interactions ; Enzyme Induction ; drug effects ; Female ; Glucuronosyltransferase ; biosynthesis ; blood ; HIV Infections ; drug therapy ; HIV Protease Inhibitors ; Humans ; Incidental Findings ; Male ; Membrane Transport Proteins ; drug effects ; metabolism ; Middle Aged ; Ritonavir ; pharmacology ; Sulfonamides ; pharmacology ; Young Adult

BACKGROUNDOur previous studies have demonstrated that the levels of 5-hydroxytryptamine (5-HT) and 5-HT 2A receptor (5-HT2AR) in serum and platelet were associated with depression and myocardial infarction (MI), and pretreatment with ginseng fruit saponins (GFS) before MI and depression had an effect on the 5-HT system. In this study, the effects of GFS on the 5-HT system in the Sprague-Dawley (SD) rats with MI, depression, and MI + depression were evaluated.

METHODSA total of eighty SD rats were allocated to four groups: MI, depression, MI + depression, and control groups (n = 20 in each group). Each group included two subgroups (n = 10 in each subgroup): Saline treatment subgroup and GFS treatment subgroup. The levels of 5-HT, 5-HT2AR, and serotonin transporter (SERT) were quantified in serum, platelet lysate, and brain tissue through the enzyme-linked immunosorbent assay method, respectively.

RESULTSCompared with those in the saline treatment subgroups, the levels of 5-HT in serum and platelet lysate statistically significantly increased in the GFS treatment subgroups of MI, depression, and MI + depression groups (serum: all P = 0.000; platelet lysate: P = 0.002, 0.000, 0.000, respectively). However, the 5-HT levels in brain homogenate significantly decreased in the GFS treatment subgroups compared with those in the saline treatment subgroups in MI and depression groups (P = 0.025 and 0.044 respectively), and no significant difference was observed between saline and GFS treatment subgroups in MI + depression group (P = 0.663). Compared with that in GFS treatment subgroup of control group, the 5-HT2AR levels in the platelet lysate significantly decreased in GFS treatment subgroups of MI, depression, and MI + depression groups (all P = 0.000). Compared to those in the saline treatment subgroups, the serum SERT levels significantly decreased in the GFS treatment subgroups in MI, depression, and MI + depression groups (P = 0.009, 0.038, and P = 0.001, respectively), while the SERT levels of platelet lysate significantly decreased in GFS treatment subgroup of MI group (P = 0.000), significantly increased in GFS treatment subgroup of depression group (P = 0.019), and slightly changed in GFS treatment subgroup of MI + depression group (P = 0.219). No significant changes for SERT levels in brain homogenate could be found between the saline and GFS treatment subgroups in MI, depression, and MI + depression groups (P = 0.421, 0.076 and P = 0.642).

CONCLUSIONSThis study indicated that GFS might inhibit the reuptake of 5-HT from serum to platelet according to decreased 5-HT2AR in platelet and SERT in serum and platelet. The change of 5-HT in serum after GFS treatment was inconsistent with that in the brain. It seemed that GFS could not pass through the blood-brain barrier to affect the central serotonergic system.

Animals ; Blood-Brain Barrier ; drug effects ; metabolism ; Depression ; drug therapy ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Myocardial Infarction ; drug therapy ; Panax ; chemistry ; Rats ; Rats, Sprague-Dawley ; Receptor, Serotonin, 5-HT2B ; metabolism ; Saponins ; chemistry ; therapeutic use ; Serotonin ; metabolism ; Serotonin Plasma Membrane Transport Proteins ; metabolism

OBJECTIVETo investigate the associations between the drug responses to obsessive -pulsive disorder (OCD) and six functional genes related with serotonin and dopamine.

METHODSOne hundred and thirteen OCD nuclear families were collected. The OCD patients were treated with serotonin reuptake inhibitors (SRIs) for 8 weeks and the drug responses were assessed using the Yale-Brown obsessive-compulsive scale (Y-BOCS). The patients were divided into drug responders group and non-responders group according to the reducing rate of Y-BOCS score. The genotypes of six genes were determined with the Amp-FLP and Amp-RFLP techniques and analyzed by transmission disequilibrium test (TDT). The six genes are serotonin 2A receptor (5-HT2A), serotonin transporter (5-HTT), dopamine D2 receptor ( DRD2), dopamine D4 receptor (DRD4), catechol-O- methyltransferase (COMT) and monoamine oxidase A (MAOA).

RESULTSNo association was found between the six genes and different drug responses groups. However, there was significant difference between the drug responders and non-responders in homozygosity at the 5-HT2A -1438G/A locus (chi(2)=4.69, P=0.03).

CONCLUSIONThe results suggested that the 5-HT2A may play some roles in the effects of drug treatment on OCD.

Adolescent ; Adult ; Catechol O-Methyltransferase ; genetics ; Female ; Humans ; Male ; Monoamine Oxidase ; genetics ; Obsessive-Compulsive Disorder ; drug therapy ; genetics ; Pharmacogenetics ; methods ; Receptor, Serotonin, 5-HT2A ; genetics ; Receptors, Dopamine D2 ; genetics ; Receptors, Dopamine D4 ; genetics ; Serotonin Plasma Membrane Transport Proteins ; genetics ; Serotonin Uptake Inhibitors ; therapeutic use ; Treatment Outcome ; Young Adult

To investigate the effect of Rehmanniae Radix on depression-like behavior and monoamine neurotransmitters of chronic unpredictable mild stress(CUMS) model rats. CUMS combined with isolated feeding was used to induce the depression model of rats. The depression-like behavior of rats was evaluated by sucrose preference test, open field test, and forced swim test. Hematoxylin-Eosin(HE) staining was used to investigate the pathological changes of neurons in the CA1 and CA3 area of hippocampus. Ultra performance liquid chromatography-tandem mass spectrometry(UPLC-MS) was used to detect the contents of 5-hydroxytryptamine(5-HT), 5-hydroxyindoleacetic acid(5-HIAA), dopamine(DA), 3,4-dihydroxyphenylacetic acid(DOPAC), homovanillic acid(HVA), norepinephrine(NE), and 3-methoxy-4-hydroxyphenyl glycol(MHPG) in rats. Western blot was used to detect the protein expressions of tryptophan hydroxylase 2(TPH2), serotonin transporter(SERT), and monoamine oxidase A(MAO-A) in the hippocampus of rats. Compared with the normal group, depressive-like behavior of rats was obvious in the model group. The arrangements of neurons in the CA1 and CA3 area of hippocampus were loose and disorderly. The levels of 5-HT, 5-HIAA, and 5-HT/5-HIAA in the hippocampal area were decreased(P<0.01). The protein expression of TPH2 was decreased(P<0.01), but those of SERT and MAO-A were increased(P<0.01). In the Rehmanniae Radix groups with 1.8 g·kg~(-1) and 7.2 g·kg~(-1), the depression-like behavior of CUMS rats and pathological changes of neurons in CA1, CA3 area of hippocampus were improved. The protein expression of TPH2(P<0.05, P<0.01) was increased, and those of SERT and MAO-A were down-regulated(P<0.05, P<0.01). The levels of 5-HT, 5-HIAA, and 5-HT/5-HIAA in hippocampus were increased(P<0.05, P<0.01). The changes in DA, DOPAC, HVA, DA/(DOPAC +HVA), NE, DHPG, and NE/DHPG were not statistically significant. The results suggested that Rehmanniae Radix improved depression-like behavior of CUMS rats, and the mechanism might be related to the regulation of synthesis, transportation, and metabolism of 5-HT neurotransmitter in the hippocampus.
3,4-Dihydroxyphenylacetic Acid/pharmacology* ; Animals ; Antidepressive Agents/therapeutic use* ; Chromatography, Liquid ; Depression/drug therapy* ; Disease Models, Animal ; Dopamine ; Eosine Yellowish-(YS)/pharmacology* ; Hematoxylin/pharmacology* ; Hippocampus/metabolism* ; Homovanillic Acid/pharmacology* ; Hydroxyindoleacetic Acid/metabolism* ; Methoxyhydroxyphenylglycol/pharmacology* ; Monoamine Oxidase/metabolism* ; Neurotransmitter Agents/metabolism* ; Norepinephrine/pharmacology* ; Plant Extracts ; Rats ; Rehmannia/chemistry* ; Serotonin/metabolism* ; Serotonin Plasma Membrane Transport Proteins/pharmacology* ; Stress, Psychological/metabolism* ; Tandem Mass Spectrometry ; Tryptophan Hydroxylase/metabolism*