Eucommia lignans alleviate the progression of diabetic nephropathy through mediating the AR/Nrf2/HO-1/AMPK axis in vivo and in vitro / 中国天然药物

Lignans derived from Eucommia ulmoides Oliver (Eucommia lignans) inhibit the progression of inflammatory diseases, while their effect on the progression of diabetic nephropathy (DN) remained unclear. This work was designed to assess the function of Eucommia lignans in DN. The major constituents of Eucommia lignans were analyzed by UPLC-Q-TOF-MS/MS. The binding between Eucommia lignans and aldose reductase (AR) was predicted by molecular docking. Eucommia lignans (200, 100, and 50 mg·kg-1) were used in model animals to evaluate their renal function changes. Rat glomerular mesangial cells (HBZY-1) were transfected with sh-AR, sh-AMPK, and oe-AR in the presence of high glucose (HG) or HG combined with Eucommia lignans to evaluate whether Eucommia lignans affected HG-induced cell injury and mitochondrial dysfunction through the AR/Nrf2/HO-1/AMPK axis. Eucommia lignans significantly attenuated the progression of DN in vivo. Eucommia lignans notably reversed HG-induced upregulation of inflammatory cytokines and mitochondrial injury, while downregulating the levels of Cyto c, caspase 9, AR, and NOX4 in HBZY-1 cells. In contrast, HG-induced downregulation of Nrf2, HO-1 and p-AMPKα levels were abolished by Eucommia lignans. Meanwhile, knockdown of AR exerted similar therapeutic effect of Eucommia lignans on DN progression, and AR overexpression reversed the effect of Eucommia lignans. Eucommia lignans alleviated renal injury through the AR/Nrf2/HO-1/AMPK axis. Thus, these findings might provide evidence for the use of Eucommia lignans in treating DN.

Development of quantitative analysis methods of Rituximab and it's biosimilar in biological samples / 中国临床药理学与治疗学

Rituximab is the main monoclonal antibody for targeted therapy currently. With more rituximab biosimilars appearing and clinical evaluation need increasing, it is crucial to develop rapid and effective quantitative methods to determine the rituximab blood concentration in biological matrices for drug metabolism and pharmacokinetics (DMPK) analysis. This article reviewed the application of ligand binding method (LBA), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and emerging quantitative technology to detect the blood concentration of Rituximab, which may provide valuable information for the analysts and testers when developing quantitative methods for rituximab and its biosimilars.

Bioequivalence of solifenacin succinate tablets in healthy Chinese volunteers / 中国临床药理学与治疗学

AIM: To evaluate the bioequivalence of the test and reference preparations of solifenacin succinate tablets administered once orally under fasting and fed conditions in Chinese healthy volunteers. METHODS: The study was designed as single-center, randomized, open, self-crossover and twenty four healthy volunteers were recruited respectively in fasting and fed conditions. Subjects were assigned to receive a single oral of the test or reference formulation per period at a dose of 10 mg. The plasma concentration of solifenacin was analyzed by LC-MS/MS. The major pharmacokinetic parameters were calculated by WinNonlin 7.0, then the bioequivalence was evaluated.RESULTS: The main pharmacokinetic parameters of a single oral solifenacin succinate under fasting condition for test and reference preparation were as follows: C

Effects of gut microbiota on pharmacokinetics and its consideration in the evaluation of the consistency of quality and efficacy of generic drugs / 中国临床药理学与治疗学

Generic drugs account for more than 95% of the chemicals market in China, and their quality is directly related to the efficacy and safety of the people. The bioequivalence evaluation with pharmacokinetic parameters as the end point is the main content of the consistency evaluation of the quality and efficacy of generic drugs. Gut microbiota is considered to have an important influence on pharmacokinetics. This article reviewed the influence of gut microbiota on pharmacokinetics and analyzed its potential significance in the evaluation of the consistency of quality and efficacy of generic drugs.

Progress in study on the association between HLA genetic variation and adverse drug reactions / 中南大学学报(医学版)

The human leukocyte antigen (HLA) molecules encoded within the human major histocompatibility complex are a group of highly conserved cell surface proteins, which are related to antigen recognition. HLA genes display a high degree of genetic polymorphism, which is the basis of individual differences in immunity. Specific HLA genotypes have been highly associated with typical adverse drug reactions. HLA-A*31:01 and HLA-B*15:02 are associated with carbamazepine-induced severe cutaneous adverse reactions, HLA-B*57:01 is related to abacavir-induced drug-induced hypersensitivity syndrome and flucloxacillin/pazopanib-induced drug-induced liver injury, while HLA-B*35:01 is a potential biomarker for predicting polygonum multiflorum-induced liver injury. It is not clear how small drug molecules to interact with HLA molecules and T cell receptors (TCR). There are four mechanistic hypotheses, including the hapten/prohapten theory, the pharmacological interaction concept, the altered peptide repertoire model, and the altered TCR repertoire model.

Expression and spatial distribution of P2X7 receptor in pilocarpine-induced epileptic rat hippocampus / 中南大学学报(医学版)

Objective:To investigate the dynamic expression and spatial distribution of P2X7 receptor in pilocarpine-induced epileptic rat hippocampus.Methods:Status epilepticus (SE) model of rats was established by intraperitoneal injection with chloride lithium and pilocarpine.Rat brain tissue and hippocampus were collected at 1,3,7,14,28 days after SE.The protein expression of P2X7 receptor in rat hippocampus was detected by Western blot.The distribution of P2X7 receptor in hippocampal sub-region was analyzed by immunohistochemistry.Results:Bilateral forelimb clonus appeared at (33.9±12.3 min after intraperitoneal injection with pilocarpine.The protein expression of P2X7 receptor was increased at 1d after SE,while it was decreased gradually from 3 d to minimum at 7 d,then it was elevated continuously to 28 d.Among them,the expression of P2X7 receptor was increased significantly at 1,14 and 28 d post-SE (P＜0.05).Immunohistochemical staining showed that P2X7 receptor was detected in all areas.The expression pattern of P2X7 receptor in hippocampal DG and CA3 area was consistent with protein expression,but its expression in hippocampal CA1 area was not significantly changed after SE.Conclusion:The expression of P2X7 receptor in post-SE hippocampus is in a time-dependent manner and spatial specificity.P2X7 receptor might be involved in the development of chronic epilepsy.

Targets of anti-hyperlipidemia drugs / 中南大学学报(医学版)

Hyperlipidemia is one of the most important risk factors for atherosclerosis, coronary heart disease and other cardiovascular diseases. It is the main effect of lipid-lowering drugs to reduce the plasma low-density lipoprotein or to enhance high-density lipoprotein. Niemann-Pick C1 like 1 protein (NPC1L1), acyl-coenzyme A: cholesterol acyltransferases (ACAT), ATP binding cassette transporter G member 5 and member 8 (ABCG5/G8), microsomal triglyceride transfer protein (MTP), monoacylglycerol acyltransferase, diacylglycerol acyltransferases (MAGT), peroxisome proliferator-activated receptor (PPAR), farnesoid X receptor (FXR), and proprotein convertase subtilisin/kexin type 9 (PCSK9) play key roles in the metabolism of lipid, which are regarded as the targets of anti-hyperlipidemia drugs and evidence for clinic choice of lipid-lowering drugs. These proteins are considered as breakthrough points for new lipid-lowering drug development.

Racial difference in aldose reductase C-106T genetic polymorphism and association with essential hypertension / 中南大学学报(医学版)

Objective:To investigate the distribution of aldose reductase (AR) C-106T genetic polymorphism in Chinese Han population and its association with the risk for essential hypertension (EH).Methods:The AR C-106T polymorphism was genotyped in 148 Chinese EH patients and 137controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).The genotype distribution between groups was contrasted by x2- test and the degree of genetic association was evaluated by 95％ confidence interval (CI).Results:Frequency of the variant AR C-106T allele was 13.9％ (95％ CI:11.2％-16.6％) in the controls,which was significantly lower than that in the Japanese (18.4％ in 712 individuals,P=0.0063),the Australians (37.9％ in 240 individuals,P＜0.0001) and the Brazilians (34.7％ in 62individuals,P＜ 0.0001).The frequency ofAR C-106T allele was 11.7％ (95％ CI:7.9％-15.5％)in the EH patients.No significant difference in the allele frequency was observed between the EH patients and the controls (P=0.147).Conclusion:There is obvious racial difference in the distribution of AR C-106T polymorphism.The polymorphism is not associated with the risk for EH.

Research progress in aldose reductase / 中南大学学报(医学版)

Aldose reductase is a member of aldehyde-keto reductase superfamily widely existing in the kidney, adrenal gland, lens, retina, nerve, heart, placenta, brain, skeletal muscle, testis, blood vessels, lung, liver, et al. It is a reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-dependent enzyme catalyzing the reduction of various aldehydes and ketones to the corresponding alcohol. It is involved in many oxidative stress diseases, cell signal transduction and cell proliferation process as well as diabetes complications. In recent years, some progress has been made in research of the activity and gene regulation of aldose reductase and the relation with many common diseases.

Effect of docetaxel on expression of eIF3a in human lung cancer A549 cell line / 中南大学学报(医学版)

Objective To explore the dose-dependent and time-dependent effect of docetaxel on the expression of mammalian eukaryotic initiation factor 3 subunit A (eIF3a) in lung cancer cell line. Methods The human lung cancer cell line A549 was treated with gradient concentrations of docetaxel for different time. Real-time PCR and Western blot were used to detect mRNA and protein expression levels of eIF3a and α-tubulin, respectively. Results Docetaxel did not affect α-tubulin expression at either mRNA level or protein level. When A549 cells were treated with high concentration of docetaxel (30 μg/L), the expression level of eIF3a mRNA tended to increase in a time-dependent manner. Protein expression level of α-tubulin was not associated with eIF3a expression significantly in cells treated by docetaxel.Conclusion Docetaxel could slightly increase the expression of eIF3a mRNA, and eIF3a does not regulate the expression of α-tubulin in A549 cells treated by docetaxel.

Differential effects of PPARγ ligand rosiglitazone and selective antagonist GW9662 on adipocytokine gene expression in 3T3-L1 adipocytes / 中国临床药理学与治疗学

BACKGROUND: There is a growing recognition that the adipose tissue is an endocrine organ that secretes signaling molecules such as adiponectin and resistin. The peroxisome proliferator activated receptor γ (PPARγ) is expressed in high levels in the adipose tissue. Thiazolidinediones are selective PPARγ agonists with insulin-sensitizing properties. It has been postulated that thiazolidinediones such as rosiglitazone exert their pharmacodynamic effects in part through modulation of resistin (implicated in insulin resistance) and adiponectin (an insulin-sensitizing molecule) expression subsequent to activation of PPARγ. There are conflicting data, however, on the biological direction in which resistin expression is modulated by PPARγ agonists and whether an increase in adiponectin expression can occur in the face of an upregulation of resistin. METHODS: Using the murine 3T3-L1 adipocytes as a model, we evaluated the changes in resistin and adiponectin gene expression after vehicle, rosiglitazone (10 μmol/L, a PPARγ agonist), GW9662 (5 μmol/L, a selective PPARγ antagonist) or GW662 and rosiglitazone co-treatment.RESULTS: In comparison to vehicle treatment, rosiglitazone increased the average adiponectin and resistin mRNA expression by 1.66- and 1.55-fold, respectively (P＜0.05). Importantly, GW9662 also upregulated adiponectin expression (by 1.57-fold, P＜0.05) but did not influence resistin expression (P＞0.05). Co-treatment with rosiglitazone and GW9662 maintained the adiponectin upregulation (1.87-fold increase from vehicle, P＜0.05) while attenuating resistin upregulation (1.31-fold increase from vehicle, P＜0.05) induced by rosiglitazone alone (1.55-fold increase from vehicle, P＜0.05). CONCLUSION: This study presents new evidence that adiponectin transcript is upregulated with both a PPARγ agonist (rosiglitazone) and antagonist (GW9662), while GW9662 co-treatment does not block rosiglitazone-induced adiponectin upregulation. These data collectively suggest that biological mechanisms independent from PPARγ may underlie thiazolidinedione pharmacodynamics on adiponectin expression. Moreover, increased adiponectin expression by GW9662, in the absence of an upregulation of resistin expression, lends further support on the emerging clinical potential of PPARγ antagonists in treatment of insulin resistance. Decreased resistin expression may not be crucial for the insulin-sensitizing effect of rosiglitazone. These findings may serve as a foundation for future dose-ranging and time-course studies of thiazolidinedione pharmacodynamics on adipocytokine expression in human adipocytes.