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OBJECTIVE: Sjögren's disease (SjD) has a strong sex bias, suggesting an association with sex hormones. Male SjD represents a distinct subset of the disease, but the pathogenic mechanisms of male SjD is poorly characterized. The aim of this study is to identify initiating events related to the development of gland hypofunction and autoimmunity in male SjD patients.MATERIALS AND METHODS: Human minor salivary glands were transcriptomically analyzed with microarrays to detect differentially expressed genes in male SjD patients. Identified genes were tested on their involvement in the disease using conditional transgenic mice and gene-overexpressing cells.RESULTS: GPR78, an orphan G protein-coupled receptor, was overexpressed in salivary glands of male SjD patients compared with male healthy controls and female SjD patients. Male GPR78 transgenic mice developed salivary gland hypofunction with increased epithelial apoptosis, which were not seen in control or female transgenic mice. In cell culture, GPR78 overexpression decreased lysosomal integrity, leading to caspase-dependent apoptotic cell death. GPR78-induced cell death in vitro was inhibited by treatment with estradiol.CONCLUSION: GPR78 overexpression can induce apoptosis and salivary gland hypofunction in male mice through lysosomal dysfunction and increased caspase-dependent apoptosis in salivary gland epithelium, which may drive disease in humans.

Wang D, Xu X, Zhang K, et al. Int J Nanomedicine. 2018;13:187–198. The authors have advised due to an error at the time of figure assembly, Figure 5 on page 195 is incorrect. The correct Figure 5 is shown in Download Article. The authors apologize for this error and advise it does not affect the results of the paper. Read the original article

Dandan Wang, 1,* Xiaowei Xu, 2,* Kai Zhang, 3 Bin Sun, 4 Lu Wang, 1 Lin Meng, 1 Qilin Liu, 4 Changyu Zheng, 5 Bai Yang, 3 Hongchen Sun 1,3,6 1Department of Pathology, School and Hospital of Stomatology, Jilin University, Changchun, People’s Republic of China; 2Department of Periodontology, School and Hospital of Stomatology, Jilin University, Changchun, People’s Republic of China; 3State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, People’s Republic of China; 4Department of Oral and Maxilloficial Syrgery, School and Hospital of Stomatology, Jilin University, Changchun, People’s Republic of China; 5Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA; 6Key Laboratory of Science and Technology for Stomatology Nanoengineering, The Education Department of Jilin Province, Changchun, People’s Republic of China *These authors contributed equally to this work Abstract: Oral cancer is a type of head and neck cancer that is the seventh most frequent cancer and the ninth most frequent cause of death globally. About 90% of oral cancer is of squamous cell carcinoma type. Surgery and radiation with and without chemotherapy are the major treatments for oral cancer. Better advanced treatment is still needed. Multidrug resistance plays an important role in failure of oral cancer chemotherapy. In this study, we tried to fabricate a novel nanoparticle that could carry both MDR1-siRNA to block MDR1 expression and doxorubicin (DOX), a chemotherapy drug, into cancer cells in order to directly kill the cells with little or no effect of multidrug resistance. Results showed that mesoporous silica nanoparticles (MSNP) can be modified by cationic polymerpolyethylenimine (PEI) to obtain positive charges on the surface, which could enable the MSNP to carry MDR1-siRNA and DOX. The transf

Han Jin,1 Kai Zhang,2 Chunyan Qiao,1 Anliang Yuan,1 Daowei Li,1 Liang Zhao,1 Ce Shi,1 Xiaowei Xu,1 Shilei Ni,1 Changyu Zheng,3 Xiaohua Liu,4 Bai Yang,2 Hongchen Sun11Department of Pathology, School of Stomatology, Jilin University, Changchun, People’s Republic of China; 2State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, People’s Republic of China; 3Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA; 4Department of Biomedical Sciences, Texas A&M University Baylor College of Dentistry, Dallas, TX, USAAbstract: Regeneration of large bone defects is a common clinical problem. Recently, stem cell sheet has been an emerging strategy in bone tissue engineering. To enhance the osteogenic potential of stem cell sheet, we fabricated bone morphogenetic protein 2 (BMP-2) gene-engineered cell sheet using a complex of polyethylenimine–alginate (PEI–al) nanocomposites plus human BMP-2 complementary(c)DNA plasmid, and studied its osteogenesis in vitro and in vivo. PEI–al nanocomposites carrying BMP-2 gene could efficiently transfect bone marrow mesenchymal stem cells. The cell sheet was made by culturing the cells in medium containing vitamin C for 10 days. Assays on the cell culture showed that the genetically engineered cells released the BMP-2 for at least 14 days. The expression of osteogenesis-related gene was increased, which demonstrated that released BMP-2 could effectively induce the cell sheet osteogenic differentiation in vitro. To further test the osteogenic potential of the cell sheet in vivo, enhanced green fluorescent protein or BMP-2-producing cell sheets were treated on the cranial bone defects. The results indicated that the BMP-2-producing cell sheet group was more efficient than other groups in promoting bone formation in the defect area. Our

Chunyan Qiao,1,* Kai Zhang,2,* Han Jin,1 Leiying Miao,3 Ce Shi,1 Xia Liu,1 Anliang Yuan,1 Jinzhong Liu,1 Daowei Li,1 Changyu Zheng,4 Guirong Zhang,5 Xiangwei Li,1 Bai Yang,2 Hongchen Sun11Department of Pathology, School of Stomatology, Jilin University, Changchun, 2State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, 3Institute and Hospital of Stomatology, Nanjing University Medical School, Nanjing, People's Republic of China; 4Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA; 5Department of Biochemistry, School of Basic Medicine, Jilin University, Changchun, People's Republic of China*These authors contributed equally to this workAbstract: Repair of large bone defects is a major challenge, requiring sustained stimulation to continually promote bone formation locally. Bone morphogenetic protein 2 (BMP-2) plays an important role in bone development. In an attempt to overcome this difficulty of bone repair, we created a delivery system to slowly release human BMP-2 cDNA plasmid locally, efficiently transfecting local target cells and secreting functional human BMP-2 protein. For transfection, we used polyethylenimine (PEI) to create pBMP-2/PEI nanoparticles, and to ensure slow release we used poly(lactic-co-glycolic acid) (PLGA) to create microsphere encapsulated pBMP-2/PEI nanoparticles, PLGA@pBMP-2/PEI. We demonstrated that pBMP-2/PEI nanoparticles could slowly release from the PLGA@pBMP-2/PEI microspheres for a long period of time. The 3–15 µm diameter of the PLGA@pBMP-2/PEI further supported this slow release ability of the PLGA@pBMP-2/PEI. In vitro transfection assays demonstrated that pBMP-2/PEI released from PLGA@pBMP-2/PEI could efficiently transfect MC3T3-E1 cells, causing MC3T3-E1 cells to secrete human BMP-2 protein, increase calcium deposition and gene express

Extreme salivary hypofunction is a result of tissue damage caused by irradiation therapy for cancer in the head and neck region. Unfortunately, there is no currently satisfactory treatment for this condition that affects up to 40,000 people in the United States every year. As a novel approach to managing this problem, we are attempting to develop an orally implantable, fluid-secreting device (an artificial salivary gland). We are using the well-studied HSG salivary cell line as a potential allogeneic graft cell for this device. One drawback of using a cell line is the potential for malignant transformation. If such an untoward response occurred, the device could be removed. However, in the event that any HSG cells escaped, we wished to provide additional patient protection. Accordingly, we have engineered HSG cells with a hybrid adeno-retroviral vector, AdLTR.CMV-tk, to express the herpes simplex virus thymidine kinase (HSV-tk) suicide gene as a novel safety factor. Cells were grown on plastic plates or on poly-L-lactic acid disks and then transduced with different multiplicities of infection (MOIs) of the hybrid vector. Thereafter, various concentrations of ganciclovir (GCV) were added, and cell viability was tested. Transduced HSG cells expressed HSV-tk and were sensitive to GCV treatment. Maximal effects were seen at a MOI of 10 with 50 μM of GCV, achieving 95% cell killing on the poly-L-lactic acid substrate. These results suggest that engineering the expression of a suicide gene in an allogeneic graft cell may provide additional safety for use in an artificial salivary gland device.