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Glycogen storage disease type Ia (GSD-Ia) is an inherited metabolic disease caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC) which plays a critical role in blood glucose homeostasis by catalyzing the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate in the terminal step of glycogenolysis and gluconeogenesis. Patients with GSD-Ia manifest life-threatening fasting hypoglycemia along with the excessive accumulation of hepatic glycogen and triglycerides which results in hepatomegaly and a risk of long-term complications such as hepatocellular adenoma and carcinoma (HCA/HCC). The etiology of HCA/HCC development in GSD-Ia, however, is unknown. Recent studies have shown that the livers in model animals of GSD-Ia display impairment of autophagy, a cellular recycling process which is critical for energy metabolism and cellular homeostasis. However, molecular mechanisms of autophagy impairment and its involvement in pathogenesis in GSD-Ia are still under investigation. Here, we summarize the latest advances for signaling pathways implicated in hepatic autophagy impairment and the roles of autophagy in hepatic tumorigenesis in GSD-Ia. In addition, recent evidence has illustrated that autophagy plays an important role in hepatic metabolism and liver-directed gene therapy mediated by recombinant adeno-associated virus (rAAV). Therefore, we highlight the possible role of hepatic autophagy in metabolic control and rAAV-mediated gene therapy for GSD-Ia. In this review, we also provide potential therapeutic strategies for GSD-Ia on the basis of molecular mechanisms underlying hepatic autophagy impairment in GSD-Ia.

Viral mediated gene therapy has progressed after overcoming early failures, and gene therapy has now been approved for several conditions in Europe and the USA. Glycogen storage disease (GSD) type Ia, caused by a deficiency of glucose-6-phosphatase-α, has been viewed as an outstanding candidate for gene therapy. This follow-up report describes the long-term outcome for the naturally occurring GSD-Ia dogs treated with rAAV-GPE-hG6PC-mediated gene therapy. A total of seven dogs were treated with rAAV-GPE-hG6PC-mediated gene therapy. The first four dogs were treated at birth, and three dogs were treated between 2 and 6 months of age to assess the efficacy and safety in animals with mature livers. Blood and urine samples, radiographic studies, histological evaluation, and biodistribution were assessed. Gene therapy improved survival in the GSD-Ia dogs. With treatment, the biochemical studies normalized for the duration of the study (up to 7 years). None of the rAAV-GPE-hG6PC-treated dogs had focal hepatic lesions or renal abnormalities. Dogs treated at birth required a second dose of rAAV after 2–4 months; gene therapy after hepatic maturation resulted in improved efficacy after a single dose. rAAV-GPE-hG6PC treatment in GSD-Ia dogs was found to be safe and efficacious. GSD-Ia is an attractive target for human gene therapy since it is a monogenic disorder with limited tissue involvement. Blood glucose and lactate monitoring can be used to assess effectiveness and as a biomarker of success. GSD-Ia can also serve as a model for other hepatic monogenic disorders.

Background and objective: The neurotransmitter, 5-hydroxytryptamine, acts as an immunomodulator by stimulating the release of inflammatory cytokines and regulating the function of dendritic cells and monocytes. The 5-hydroxytryptamine receptor 4 (HTR4) gene is located in a region previously linked to an increased risk of asthma and atopy. The aim of this study was to investigate the association between HTR4 and asthma. Methods: Thirty-two single nucleotide polymorphisms (SNP) in HTR4 were investigated by direct sequencing of 24 DNA samples from unrelated Korean subjects. Results: The 32 genetic variants comprised 22 intronic SNP, two SNP in the 3′-untranslated region (exon 7) and eight SNP in the 3′-downstream region. Logistic regression analysis showed that two intronic polymorphisms were significantly associated with the risk of asthma. Two minor HTR4 alleles, +142828G > A and +122769G > A, occurred at significantly higher frequencies in the asthmatic group than in the healthy control group (49.59% vs 42.29%, P = 0.003, and 47.99% vs 40.35%, P = 0.008, respectively), and these differences remained significant after correction for multiple testing (P = 0.05, dominant mode of inheritance; and P = 0.03, dominant mode, respectively). Haplotype analysis revealed three haplotype blocks. The frequency of haplotype 1 in block 2 was significantly higher in asthmatics (P = 0.003, dominant mode), whereas the frequency of haplotype 4 in block 3 was significantly lower in asthmatics (P = 0.0009, dominant mode). Conclusions: SNP and haplotypes of the HTR4 gene were associated with the asthma phenotype and genetic variation of HTR4 may affect susceptibility to the development of asthma.

Background: Chitinase may play a role in regulating allergic diseases. Objective: We studied the role of chitinase in a mouse model exposed to diesel exhaust particles (DEP). Mice were exposed to intranasal DEP (0.6 mg/mL) for 5 days and challenged with aerosolized DEP (6 mg/m3) on days 6–8. Enhanced pause (Penh), as an airway obstruction marker, was measured on day 9, and bronchoalveolar lavage (BAL) fluid and lung tissues were collected on day 10. The expression of Ym1 and Ym2 mRNA was assessed in lung tissue extracts by reverse transcription-polymerase chain reaction. Results: DEP induced significant increases in methacholine-induced Penh and IL-4 levels in BAL fluid relative to the control group. Peribronchial and perivascular inflammatory cell infiltrates were prominent in the DEP group. DEP induced Ym1 and Ym2 mRNA expression in lung tissue extracts relative to the control group. Conclusion: These results demonstrate that DEP induced airway hyperresponsiveness and Ym mRNA expression via a Th2 cell-biased response, suggesting that chitinase may play an important role in airway inflammation and responsiveness upon exposure to DEP in a mouse model, and may therefore be involved in regulating allergic diseases. © 2008 Wiley Periodicals, Inc. Environ Toxicol, 2008.

Low-density polyethylene (LDPE) composites containing untreated cellulose, cellulose treated with cellulase, and cellulose treated with cellulase after pretreating with NaOH were prepared. The purpose of the cellulase treatment of cellulose is to enhance the interfacial adhesion between the cellulose and the matrix. The effect of this treatment was studied by viscometry and X-ray diffraction. Maleic anhydrideg-polyethylene (MAH-PE) was also added to the composite to enhance interfacial interactions between the cellulose and the matrix and to increase the dispersibility and the wettability of cellulose. The increased adhesion in composites containing the treated cellulose and MAH-PE was studied by FTIR. In addition, the thermal, dynamic mechanical, and tensile properties of the composites were investigated. When MAH-PE was added to the composite, it was found that the reaction between MAH-PE and treated cellulose occurred more easily.