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Shu C.-W.,Kaohsiung Veterans General Hospital | Liu P.-F.,Kaohsiung Medical University | Huang C.-M.,University of California at San Diego | Huang C.-M.,San Diego Healthcare Center
Combinatorial Chemistry and High Throughput Screening | Year: 2012

Autophagy is an evolutionally conserved process in cells for cleaning abnormal proteins and organelles in a lysosome dependent manner. Growing studies have shown that defects or induced autophagy contributes to many diseases including aging, neurodegeneration, pathogen infection, and cancer. However, the precise involvement of autophagy in health and disease remains controversial because the theories are built on limited assays and chemical modulators, indicating that the role of autophagy in diseases may require further verification. Many food and drug administration (FDA) approved drugs modulate autophagy signaling, suggesting that modulation of autophagy with pharmacological agonists or antagonists provides a potential therapy for autophagy-related diseases. This suggestion raises an attractive issue on drug discovery for exploring chemical modulators of autophagy. High throughput screening (HTS) is becoming a powerful tool for drug discovery that may accelerate screening specific autophagy modulators to clarify the role of autophagy in diseases. Herein, this review lays out current autophagy assays to specifically measure autophagy components such as LC3 (mammalian homologue of yeast Atg8) and Atg4. These assays are feasible or successful for HTS with certain chemical libraries, which might be informative for this intensively growing field as research tools and hopefully developing new drugs for autophagy-related diseases. © 2012 Bentham Science Publishers. Source

Edelman S.,San Diego Healthcare Center | Pettus J.,University of California at San Diego
American Journal of Medicine | Year: 2014

Despite advances in treatment for type 2 diabetes in recent decades, many patients are failing to achieve adequate glycemic control. Poor glycemic control has been shown to have a detrimental effect on patients' health and well-being, and to have significant negative financial implications for both patients and healthcare systems. Insulin therapy has been proven to significantly reduce glycated hemoglobin levels; however, both patients and physicians can be reluctant to initiate insulin therapy. Research shows that both patient and provider factors contribute to a delay in initiation of insulin therapy. This review discusses the most common barriers contributing to this delay with potential solutions to overcome them. Source

Liu P.-F.,Kaohsiung Veterans General Hospital | Liu P.-F.,Fooyin University | Huang I.-F.,Kaohsiung Veterans General Hospital | Shu C.-W.,Kaohsiung Veterans General Hospital | And 2 more authors.
Current Molecular Medicine | Year: 2013

Halitosis (bad breath) is estimated to influence more than half of the world's population with varying degree of intensity. More than 85% of halitosis originates from oral bacterial infections. Foul-smelling breath mainly results from bacterial production of volatile sulfur compounds (VSCs) such as hydrogen sulfide and methyl mercaptan. To date, major treatments for elimination of oral malodor include periodontal therapy combined with antibiotics or antimicrobial agents, and mechanical approaches including tooth and tongue cleaning. These treatments may transiently reduce VSCs but carry risks of generating toxicity, increasing resistant strains and misbalancing the resident human flora. Therefore, there is a need to develop alternative therapeutic modalities for halitosis. Plaque biofilms are the principal source for generating VSCs which are originally metabolized from amino acids during co-aggregation of oral bacteria. Blocking the bacterial co-aggregation, therefore, may prevent various biofilm-associated oral diseases such as periodontitis and halitosis. Fusobacterium nucleatum (F. nucleatum), a Gram-negative anaerobe oral bacterium, is a main bacterial strain related to halitosis. Aggregation of F. nucleatum with other bacteria to form plaque biofilms in oral cavity causes bad breath. FomA, the major outer membrane protein of F. nucleatum, recruits other oral pathogenic bacteria such as Porphyromonas gingivalis (P. gingivalis) in the periodontal pockets. A halitosis vaccine targeting F. bacterium FomA significantly abrogates the enhancement of bacterial co-aggregation, biofilms, production of VSCs, and gum inflammation mediated by an inter-species interaction of F. nucleatum with P. gingivalis, which suggests FomA of F. nucleatum to be a potential target for development of vaccines or drugs against bacterial biofilm formation and its associated pathogenicities. © 2013 Bentham Science Publishers. Source

Nakatsuji T.,University of California at San Diego | Nakatsuji T.,San Diego Healthcare Center | Chiang H.-I.,University of California at San Diego | Chiang H.-I.,National Chung Hsing University | And 5 more authors.
Nature Communications | Year: 2013

Commensal microbes on the skin surface influence the behaviour of cells below the epidermis. We hypothesized that bacteria or their products exist below the surface epithelium and thus permit physical interaction between microbes and dermal cells. Here to test this hypothesis, we employed multiple independent detection techniques for bacteria including quantitative PCR, Gram staining, immunofluorescence and in situ hybridization. Bacteria were consistently detectable within the dermis and dermal adipose of normal human skin. Sequencing of DNA from dermis and dermal adipose tissue identified bacterial 16S ribosomal RNA reflective of a diverse and partially distinct microbial community in each skin compartment. These results show the microbiota extends within the dermis, therefore, enabling physical contact between bacteria and various cells below the basement membrane. These observations show that normal commensal bacterial communities directly communicate with the host in a tissue previously thought to be sterile. © 2013 Macmillan Publishers Limited. Source

Nakatsuji T.,University of San Diego | Nakatsuji T.,San Diego Healthcare Center | Kao M.C.,University of San Diego | Kao M.C.,San Diego Healthcare Center | And 7 more authors.
Journal of Investigative Dermatology | Year: 2010

Various sebum free fatty acids (FFAs) have shown antibacterial activity against a broad range of Gram-positive bacteria, resulting in the suggestion that they are accountable, at least partially, for the direct antimicrobial activity of the skin surface. In this study, we examined the effects of sebum FFAs on the antimicrobial peptide (AMP)-mediated innate immune defense of human sebocytes. Incubation of lauric acid, palmitic acid, or oleic acid (OA) with human sebocytes dramatically enhanced their expression of human Β-defensin (hBD)-2, one of the predominant AMPs found in the skin, whereas remarkable increases in hBD-1, hBD-3, and human cathelicidin LL-37 were not observed. Secreted hBD-2 was detectable by western blotting in the supernatant of sebocyte culture incubated with each FFA, but not with a vehicle control. The supernatant of FFA-incubated sebocyte culture showed antimicrobial activity against Propionibacterium acnes, whereas the enhanced antimicrobial activity of human sebocytes was neutralized by anti-hBD-2 IgG. In addition, the FFA-induced hBD-2 expression was suppressed by blocking the cluster of differentiation (CD)36 fatty acid translocase on the surface of sebocytes with anti-human CD36 IgG or blocking the NF-κB signaling pathway with BMS-345541, a highly selective inhibitor of inhibitory B kinase. These data suggest that sebum FFAs upregulate the expression of hBD-2 in human sebocytes, which may enhance the disinfecting activity of the human sebaceous gland. The FFA-induced upregulation of hBD-2 is facilitated by CD36-mediated FFA uptake and NF-B-mediated transactivation. The upregulation of mouse Β-defensin 4, a mouse ortholog for hBD-2, was also observed in the hair follicle sebaceous glands of mouse ear skin after an epicutaneous application of OA, the most hBD-2-inducible FFA tested. This report highlights the potential of using FFAs as a multifunctional antimicrobial therapy agent for acne vulgaris treatment; FFAs may provide direct antibacterial activities against P. acnes and enhance the skin's innate antibacterial defense by inducing the expression of hBD-2 in sebocytes as well. © 2010 The Society for Investigative Dermatology. Source

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