[Role of endoplasmic reticulum stress response in regulation of adipose tissue metabolism].

In eukaryotic cells, the endoplasmic reticulum (ER) is the key quality control organelle for cellular protein synthesis and processing. It also serves as an important site for Ca2+ storage and lipid biosynthesis. In response to a variety of external stimuli, a cellular unfolded protein response (UPR) is activated to handle ER stress caused by increased accumulation of unfolded or misfolded proteins at the ER. The UPR plays a crucial role in maintaining ER homeostasis and cell functions. Three ER-localized transmembrane proteins, inositol-requiring enzyme 1α (IRE1α), PKR-like ER kinase (PERK), and activating transcription factor 6 (ATF6), act to sense ER stress and mediate three canonical UPR signaling pathways. Besides restoring the protein folding capability to relieve ER stress, the UPR pathways have also been implicated in the regulation of cell metabolism and energy balance. In the state of overnutrition, ER stress has been documented to occur in adipose tissue that has a key role in energy storage and consumption. As an endocrine organ, adipose tissue regulates glucose and lipid metabolism through secreting adipocyte cytokines, and it undergoes metabolic inflammation during pathogenic development of obesity, insulin resistance and type 2 diabetes. In this review, we attempt to summarize the recent progress with regard to the UPR regulation of adipose tissue physiology. We wish to focus upon the mechanism by which ER stress response is linked to adipose tissue dysfunction, hoping to promote our current understanding of UPR signaling in the pathophysiology of obesity and related metabolic diseases.

Gene Therapy and Photothermal Therapy of Layer-by-Layer Assembled AuNCs /PEI/miRNA/ HA Nanocomplexes.

BACKGROUND: MicroRNA (miRNA) therapy, which was widely considered to treat a series of cancer, has been confronted with numerous obstacles to being delivered into target cells because of its easy biodegradation and instability. METHODS: In this research, we successfully constructed 11-mercaptoundecanoic acid modified gold nanocages (AuNCs)/polyethyleneimine (PEI)/miRNA/hyaluronic acid (HA) complexes (abbreviated as AuNCs/PEI/miRNA/HA) using a layer-by-layer method for target-specific intracellular delivery of miRNA by HA receptor mediated endocytosis. RESULTS: The results of UV spectra, hydrodynamic diameter and zeta potential analyses confirmed the formation of AuNCs/PEI/ miRNA/HA complex with its average particle size of ca. 153 nm and surface charge of ca. -9.43 mV. Next, we evaluated the antitumor effect of the nanocomplex mediated by the combination of gene therapy and photothermal therapy (PTT) against hepatocellular carcinoma (HCC) in vitro. CONCLUSION: Our experimental results indicated that the AuNCs/PEI/miRNA/HA complex effectively delivered miRNA to the target cells and its antitumor effect was significantly enhanced by the combination of gene therapy and photothermal therapy. In addition, anti-miR-181b could promote Bel-7402 cell arrest in S phase and improve TIMP-3 mRNA expression. All these results suggested that AuNCs/PEI/miRNA/HA gene delivery system with combination of gene therapy and photothermal therapy might be exploited for HCC treatment.

Pharmacokinetics of three proton pump inhibitors in Chinese subjects in relation to the CYP2C19 genotype.

OBJECTIVE: Omeprazole, lansoprazole and rabeprazole have been widely used as proton pump inhibitors (PPIs). They can be metabolized in the liver by CYP2C19, a polymorphic enzyme, and have a wide inter-individual variability with respect to drug response. In the investigation reported here, we examined the kinetic characteristics of the three PPIs in healthy Chinese subjects in relation to CYP2C19 genotype status. METHODS: Six homozygous extensive metabolizers (homEMs), six heterozygous extensive metabolizers (hetEMs) and six poor metabolizers (PMs) were recruited for the study from a total of 90 healthy Chinese volunteers whose CYP2C19 genotype status was determined by means of PCR-restriction fragment length polymorphism (RFLP). The study was had an open label, randomized, three-way crossover design. After a single oral dose of 40 mg omeprazole, 30 mg lansoprazole or 40 mg rabeprazole, plasma concentrations of the three PPIs were determined by HPLC. RESULTS: There were some differences for the area under the plasma concentration-time curve (AUC), the elimination half-life (t(1/2 ke)) and the maximum plasma concentration (c(max)) in the three groups. In the homEMs, hetEMs and PMs, the relative AUC(0-infinity) values were 1:2.8:7.5 for omeprazole, 1:1.7:4.0 for lansoprazole and 1:1.6:3.7 for rabeprazole, respectively; the relative t(1/2 ke) values were 1:1.02:1.65 for omeprazole, 1:1.08:2.39 for lansoprazole and 1:1.37:1.85 for rabeprazole, respectively; the relative c(max) values were 1:2.09:4.39 for omeprazole, 1:1.34:1.72 for lansoprazole, and 1:1.24:2.04 for rabeprazole, respectively. CONCLUSION: The pharmacokinetic characteristics of the three PPIs are significantly dependent on the CYP2C19 genotype status. These data indicate that individualized dose regimen of the three PPIs, based on identification of genotype, can be of great benefit for ensuring the reasonable use of these drugs.

Pharmacokinetics of lansoprazole in Chinese healthy subjects in relation to CYP2C19 genotypes.

AIM: To study the kinetic characteristics of lansoprazole in healthy Chinese subjects in relation to CYP2C19 genotype status for the individualized dose regimen of lansoprazole. METHODS: Nine homozygous extensive metabolizers (homo EMs) and 9 poor metabolizers (PMs) were recruited for the study from a total of 70 healthy Chinese volunteers, whose CYP2C19 genotype status was determined by the PCR-RFLP techniques. After a single oral dose of 30 mg lansoprazole capsule, plasma concentrations of lansoprazole were determined with HPLC method. RESULTS: In Chinese subjects, the allele frequencies of the CYP2C19m1 and CYP2C19m2 mutation were 0.35 and 0.07, respectively. The concentration-time curves in the two groups were best fitted to a one-compartment model. In the homo EMs and the PMs groups, the main kinetic parameters were as follows: Tmax (2.44+/-0.85) and (2.33+/-0.94) h, Cmax(1.10+/-0.34) and (1.73+/-0.56) mg/L, Cl/F (16.55+/-0.38) and (3.58+/-1) L/h, T1/2ke (1.96+/-0.51) and (4.21+/-0.53) h, AUC were (3.23+/-0.08) and (11.05+/-0.23) mg.L(-1). A significant difference in AUC, T1/2ke, Cl/F, Cmax values existed between the two groups (P<0.01). CONCLUSION: CYP2C19 genotype is the major factor to influence the interindividual kinetic variability of lansoprazole. Individualized dose regimen of lansoprazole, based on identification of genotype, can be of great benefit for the reasonable use of this drug.