Unveiling the Influence of a High-Fat Meal on the Pharmacokinetics of Oral Globalagliatin, A Glucokinase Activator, in Healthy Chinese Volunteers.

INTRODUCTION: Glucokinase (GK) plays a pivotal role in maintaining glucose homeostasis; globalagliatin, a newly developed drug, is a GK activator (GKA). This study constitutes a randomized, open-label, two-cycle, two-crossover, single-dose, phase I clinical trial conducted at a single center with healthy Chinese volunteers, aiming to examine the influence of a high-fat meal on the pharmacokinetics (PK) of orally administered globalagliatin. METHODS: Twenty-four healthy volunteers were randomly divided into two groups, with a washout period of 16 days between the two cycles. The first cycle involved Group 1 volunteers who were orally administered globalagliatin 80 mg with 240 mL of water while fasting on Day 1. In contrast, Group 2 volunteers began oral administration of globalagliatin 80 mg with 240 mL of water, 30 min after consuming a high-fat meal (where high-fat content contributed to 54% of the total calories; the high-calorie meal amounted to 988.4 kcal). After the washout period, both groups of volunteers entered the second cycle of drug administration, with meals and medication being swapped on Day 17. Each volunteer collected blood samples at the following time points: 0 h (within 1 h before administration), and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, and 168 h after administration on both trial Day 1 and Day 17. The primary and secondary PK parameters were collected. The validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to determine the concentration of globalagliatin in collected plasma samples, and the results were analyzed using Phoenix WinNonlin software. Safety evaluation was conducted by detecting or observing various adverse events (AEs) and serious AEs (SAEs). RESULTS: All 24 healthy Chinese volunteers enrolled completed the study and underwent PK analysis. The maximum concentration (Cmax; ng/mL), area under the plasma concentration-time curve (AUC) from time zero to time of the last quantifiable concentration (AUCt; h·ng/mL), and AUC from time zero extrapolated to infinity (AUC∞; h·ng/mL) of fasting administration were 22.35 ± 7.02, 725.74 ± 303.04, and 774.07 ± 343.89, respectively, while the Cmax, AUCt, and AUC∞ administered after a high-fat meal were 28.95 ± 12.60, 964.84 ± 333.99, and 1031.28 ± 392.80, respectively. The geometric mean ratios of Cmax, AUCt, and AUC∞ for high-fat meal/fasting administration of globalagliatin were 124.81%, 135.24%, and 135.42%, respectively, with 90% confidence intervals of 109.97-141.65, 124.24-147.20, and 124.42-147.39, respectively. Compared with the fasting state, healthy volunteers who consumed a high-fat meal showed a 24.8% increase in Cmax, a 35.2% increase in AUCt, and a 35.4% increase in AUC∞. The geometric mean of Tmax was 4.69 h under fasting conditions and 5.93 h in a high-fat state, with a median of 4.98 h. Among the 24 enrolled volunteers, 9 cases (37.5%) had 11 AEs, and 6 cases (25.0%) had 7 adverse drug reactions (ADRs) after medication, all of which were cured or improved without taking any treatment measures. There were no SAEs in this study, no volunteers withdrew from the study due to AEs or ADRs, and no hypoglycemic events occurred during the trial. CONCLUSION: A high-fat meal increased the Cmax, AUCt, and AUC∞ of globalagliatin compared with fasting conditions in healthy Chinese adult volunteers. Meanwhile, globalagliatin showed favorable safety and tolerability under fasting or high-fat meal conditions.

MicroRNA­29a is involved lipid metabolism dysfunction and insulin resistance in C2C12 myotubes by targeting PPARδ.

MicroRNA­29a (miR­29a) expression has been reported to be closely associated with skeletal muscle insulin resistance and type 2 diabetes. The present study investigated the effect of miR­29a on palmitic acid (PA)­induced lipid metabolism dysfunction and insulin resistance in C2C12 myotubes via overexpressing or silencing of miR­29a expression. Mouse C2C12 myoblasts were cultured, differentiated and transfected with miR­29a or miR­29a inhibitor lentiviral with or without subsequent palmitic acid (PA) treatment. Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and western blot analysis were performed to assess the mRNA and protein levels of related genes, respectively. PA treatment increased the expression of miR­29a in a time­ and dose­ dependent manner. miR­29a silencing improved insulin­induced glucose uptake and increased glucose transporter­4 (GLUT4) transportation to the plasma membrane by upregulating its target peroxisome proliferator­activated receptor δ (PPARδ). Furthermore, it was observed that miR­29a regulated the expression of genes associated with lipid metabolism, including pyruvate dehydrogenase kinase isoform, mitochondrial uncoupling protein (UCP)2, UCP3, long chain specific acyl­CoA dehydrogenase, mitochondrial and fatty acid transport protein 2. The results confirmed that silencing miR­29a induced a decrease in glucose transport and affected lipid metabolism in PA­treated C2C12 cells, and therefore may be involved in insulin resistance by targeting PPARδ in skeletal muscle. Therefore, the inhibition of miR­29a may be a potential novel strategy for treating insulin resistance and type 2 diabetes.

[Molecular features of human bocavirus from infantile diarrhea in Suzhou area, Jiangsu province in 2010-2011].

OBJECTIVE: To investigate the status of human bocavirus and to identify its epidemiological characteristics as well as genotype distribution in patients with infantile viral diarrhea in Suzhou, Jiangsu province. METHODS: 832 fecal specimens from patients with infantile virus diarrhea cases were collected from Suzhou Children's Hospital in 2010-2011. Human bocavirus were detected by Real-Time RT-PCR, and genotype were determined by sequence analysis. RESULTS: Among all the fecal specimens, 51 (6.1%) cases were positive for human bocavirus. The peak season of rotavirus infection was between July and September. Of all the episodes on rotavirus diarrhea, 96% occurred before 2 years of age, with peaks in children with 7-12 months of age. Data from Nucleotide Sequence analysis showed that among 28 samples that carrying HBoV-1, 5 strains belonged to HBoV-2, HBoV type 3 but type 4 were absent. CONCLUSION: Human bocavirus were detected from fecal specimens of infantile virus diarrhea in Suzhou, with genotype HBoV-1 as the major strain. HBoV-2 genotype was also found.

Augmenting therapy of ovarian cancer efficacy by secreting IL-21 human umbilical cord blood stem cells in nude mice.

In the present study, CD34(+) human umbilical cord blood stem cells (UCBSCs) were engineered to express interleukin-21 (IL-21) and then were transplanted into A2780 ovarian cancer xenograft-bearing Balb/c nude mice. The therapeutic efficacy of this procedure on ovarian cancer was evaluated. The findings from the study indicated that UCBSCs did not form gross or histological teratomas until up to 70 days postinjection. The CD34(+) UCBSC-IL-21 therapy showed a consistent effect in the ovarian cancer of the treated mice, delaying the tumor appearance, reducing the tumor sizes, and extending life expectancy. The efficacy was attributable to keeping CD34(+) UCBSC-IL-21 in the neoplastic tissues for more than 21 days. The secreted IL-21 not only increased the quantity of CD11a(+) and CD56(+) NK cells but also increased NK cell cytotoxicities to YAC-1 cells and A2780 cells, respectively. The efficacy was also associated with enhancing the levels of IFN-γ, IL-4, and TNF-α in the mice as well as the high expressions of the NKG2D and MIC A/B molecules in the tumor tissues. This study suggested that transferring CD34(+) UCBSC-IL-21 into the nude mice was safe and feasible in ovarian cancer therapy, and that the method would be a promising new strategy for clinical treatment of ovarian cancer.

Using ABCG2-molecule-expressing side population cells to identify cancer stem-like cells in a human ovarian cell line.

CSCs (cancer stem cells) are a small subset of cells within a tumour that possesses the characteristics of stem cells and are considered to be responsible for resistance to chemoradiation. Identification of CSCs through stem cell characteristics might have relevant clinical implications. In this study, SP (side population ) cells were sorted from a human ovarian cancer cell line by FACS to determine whether cancer stem cell-like SP cells were present. A very small fraction of SP cells (2.6%) was detected in A2780 cells. SP cells possessed the following characteristics: highly proliferative activity, marked ability for self-renewal in soft agar and culture medium, high expression of ABCG2, drug resistance to vinblastine in vitro, and strong tumourigenic potential in Balb/c nude mice. It is concluded that there exists in the A2780 cell line a small number of SP cells with high expression of ABCG2. The cells have the characteristics of cancer stem-like cells, and identification and cloning of such human SP cells can help in improving therapeutic approaches to ovarian cancer in patients.