San Diego Healthcare Center

San Diego, CA, United States

San Diego Healthcare Center

San Diego, CA, United States
Time filter
Source Type

Kato K.,University of California at San Diego | Kato K.,Fukushima Medical University | Liu H.,University of California at San Diego | Liu H.,San Diego Healthcare Center | And 4 more authors.
Journal of Neuroscience Research | Year: 2010

Peripheral nerve regeneration begins immediately after injury. Understanding the mechanisms by which early modulators of axonal degeneration regulate neurite outgrowth may affect the development of new strategies to promote nerve repair. Tumor necrosis factor-α (TNF-α) plays a crucial role in the initiation of degenerative cascades after peripheral nerve injury. Here we demonstrate using real-time Taqman quantitative RT-PCR that, during the time course (days 1-60) of sciatic nerve crush, TNF-α mRNA expression is induced at 1 day and returned to baseline at 5 days after injury in nerve and the corresponding dorsal root ganglia (DRG). Immediate therapy with the TNF-α antagonist etanercept (fusion protein of TNFRII and human IgG), administered systemically (i.p.) and locally (epineurially) after nerve crush injury, enhanced the rate of axonal regeneration, as determined by nerve pinch test and increased number of characteristic clusters of regenerating nerve fibers distal to nerve crush segments. These fibers were immunoreactive for growth associated protein-43 (GAP-43) and etanercept, detected by anti-human IgG immunofluorescence. Increased GAP-43 expression was found in the injured nerve and in the corresponding DRG and ventral spinal cord after systemic etanercept compared with vehicle treatments. This study established that immediate therapy with TNF-α antagonist supports axonal regeneration after peripheral nerve injury. © 2009 Wiley-Liss, Inc.

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.

Nakatsuji T.,University of California at San Diego | Nakatsuji T.,San Diego Healthcare Center | Gallo R.L.,University of California at San Diego | Gallo R.L.,San Diego Healthcare Center
Journal of Investigative Dermatology | Year: 2012

Almost 90 years have passed since Alexander Fleming discovered the antimicrobial activity of lysozyme, the first natural antibiotic isolated from our body. Since then, various types of molecules with antibiotic activity have been isolated from animals, insects, plants, and bacteria, and their use has revolutionized clinical medicine. So far, more than 1,200 types of peptides with antimicrobial activity have been isolated from various cells and tissues, and it appears that all living organisms use these antimicrobial peptides (AMPs) in their host defense. In the past decade, innate AMPs produced by mammals have been shown to be essential for the protection of skin and other organs. Their importance is because of their pleiotrophic functions to not only kill microbes but also control host physiological functions such as inflammation, angiogenesis, and wound healing. Recent advances in our understanding of the function of AMPs have associated their altered production with various human diseases such as psoriasis, atopic dermatitis, and rosacea. In this review, we summarize the history of AMP biology and provide an overview of recent research progress in this field. © 2012 The Society for Investigative Dermatology.

Lo C.-W.,University of California at San Diego | Lo C.-W.,San Diego Healthcare Center | Lo C.-W.,National Tsing Hua University | Lai Y.-K.,National Tsing Hua University | And 5 more authors.
Journal of Investigative Dermatology | Year: 2011

The need for a new anti-Staphylococcus aureus therapy that can effectively cripple bacterial infection, neutralize secretory virulence factors, and lower the risk of creating bacterial resistance is undisputed. Here, we propose what is, to our knowledge, a previously unreported infectious mechanism by which S. aureus may commandeer Propionibacterium acnes, a key member of the human skin microbiome, to spread its invasion and highlight two secretory virulence factors (S. aureus Β-hemolysin and P. acnes CAMP (Christie, Atkins, Munch-Peterson) factor) as potential molecular targets for immunotherapy against S. aureus infection. Our data demonstrate that the hemolysis and cytolysis by S. aureus were noticeably augmented when S. aureus was grown with P. acnes. The augmentation was significantly abrogated when the P. acnes CAMP factor was neutralized or Β-hemolysin of S. aureus was mutated. In addition, the hemolysis and cytolysis of recombinant Β-hemolysin were markedly enhanced by recombinant CAMP factor. Furthermore, P. acnes exacerbated S. aureus-induced skin lesions in vivo. The combination of CAMP factor neutralization and Β-hemolysin immunization cooperatively suppressed the skin lesions caused by coinfection of P. acnes and S. aureus. These observations suggest a previously unreported immunotherapy targeting the interaction of S. aureus with a skin commensal. © 2011 The Society for Investigative Dermatology.

Nakatsuji T.,University of California at San Diego | Nakatsuji T.,San Diego Healthcare Center | Tang D.-c.C.,Vaxin Inc | Zhang L.,University of California at San Diego | And 4 more authors.
PLoS ONE | Year: 2011

Background:In the progression of acne vulgaris, the disruption of follicular epithelia by an over-growth of Propionibacterium acnes (P. acnes) permits the bacteria to spread and become in contact with various skin and immune cells.Methodology/Principal Findings:We have demonstrated in the present study that the Christie, Atkins, Munch-Peterson (CAMP) factor of P. acnes is a secretory protein with co-hemolytic activity with sphingomyelinase that can confer cytotoxicity to HaCaT keratinocytes and RAW264.7 macrophages. The CAMP factor from bacteria and acid sphingomyelinase (ASMase) from the host cells were simultaneously present in the culture supernatant only when the cells were co-cultured with P. acnes. Either anti-CAMP factor serum or desipramine, a selective ASMase inhibitor, significantly abrogated the P. acnes-induced cell death of HaCaT and RAW264.7 cells. Intradermal injection of ICR mouse ears with live P. acnes induced considerable ear inflammation, macrophage infiltration, and an increase in cellular soluble ASMase. Suppression of ASMase by systemic treatment with desipramine significantly reduced inflammatory reaction induced by intradermal injection with P. acnes, suggesting the contribution of host ASMase in P. acnes-induced inflammatory reaction in vivo. Vaccination of mice with CAMP factor elicited a protective immunity against P. acnes-induced ear inflammation, indicating the involvement of CAMP factor in P. acnes-induced inflammation. Most notably, suppression of both bacterial CAMP factor and host ASMase using vaccination and specific antibody injection, respectively, cooperatively alleviated P. acnes-induced inflammation. Conclusions/Significance:These findings envision a novel infectious mechanism by which P. acnes CAMP factor may hijack host ASMase to amplify bacterial virulence to degrade and invade host cells. This work has identified both CAMP factor and ASMase as potential molecular targets for the development of drugs and vaccines against acne vulgaris. © 2011 Nakatsuji et al.

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.

Gallo R.L.,University of California at San Diego | Gallo R.L.,San Diego Healthcare Center | Nakatsuji T.,University of California at San Diego | Nakatsuji T.,San Diego Healthcare Center
Journal of Investigative Dermatology | Year: 2011

Skin protects itself against infection through a variety of mechanisms. Antimicrobial peptides (AMPs) are major contributors to cutaneous innate immunity, and this system, combined with the unique ionic, lipid, and physical barrier of the epidermis, is the first-line defense against invading pathogens. However, recent studies have revealed that our skin's innate immune system is not solely of human origin. Staphylococcus epidermidis, a major constituent of the normal microflora on healthy human skin, acts as a barrier against colonization of potentially pathogenic microbes and against overgrowth of already present opportunistic pathogens. Our resident commensal microbes produce their own AMPs, act to enhance the normal production of AMPs by keratinocytes, and are beneficial to maintaining inflammatory homeostasis by suppressing excess cytokine release after minor epidermal injury. These observations indicate that the normal human skin microflora protects skin by various modes of action, a conclusion supported by many lines of evidence associating diseases such as acne, atopic dermatitis, psoriasis, and rosacea with an imbalance of the microflora even in the absence of classical infection. This review highlights recent observations on the importance of innate immune systems and the relationship with the normal skin microflora to maintain healthy skin. © 2011 The Society for Investigative Dermatology.

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.

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.

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.

Loading San Diego Healthcare Center collaborators
Loading San Diego Healthcare Center collaborators