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1.  What Lives On Our Skin: Ecology, Genomics and Therapeutic Opportunities Of the Skin Microbiome 
Our skin is home to a rich community of microorganisms. Recent advances in sequencing technology have allowed more accurate enumeration of these human-associated microbiota and investigation of their genomic content. Staphylococcus, Corynebacterium and Propionibacterium represent the dominant bacterial genera on skin and illustrate how bacteria adapt to life in this harsh environment and also provide us with unique benefits. In healthy states, our skin peacefully co-exists with commensal bacteria while fending off potentially dangerous invaders. Disruption of this equilibrium, termed “dysbiosis”, can result from changes in the composition of our skin bacteria, an altered immune response to them, or both and may be a driving factor in certain types of inflammatory skin disease. Engineering topical therapeutics to favourably influence the composition of our skin flora and optimize interactions with them represents a real therapeutic opportunity for the field of dermatology and warrants additional investigation into skin microbial ecology and disease mechanisms related to host-microbe dysbiosis.
doi:10.1016/j.ddmec.2012.12.003
PMCID: PMC3833721  PMID: 24273587
2.  Innate immunity and the role of the antimicrobial peptide cathelicidin in inflammatory skin disease 
Cathelicidin antimicrobial peptide is an important mediator of the innate immune response. In addition to its potent antimicrobial activity, cathelicidin has been shown to have chemoattractant and angiogenic properties. Recent research has demonstrated that, in addition to its aforementioned functions, cathelicidin plays an important role in the complex pathogenesis of several chronic inflammatory skin diseases. This review will present a concise overview of the role of cathelicidin in infection and in the development of atopic dermatitis, psoriasis, and rosacea. This understanding will direct future research efforts to identify therapeutic approaches that use cathelicidin as a novel drug itself, or aim to modify its expression and regulation.
doi:10.1016/j.ddmec.2013.01.001
PMCID: PMC3904447  PMID: 24489580
3.  Cilia and cilia-associated proteins in cancer 
The primary cilium is a well-established target in the pathogenesis of numerous developmental and chronic disorders, and more recently is attracting interest as a structure relevant to cancer. Here we discuss mechanisms by which changes in cilia can contribute to the formation and growth of tumors. We emphasize the cancer-relevance of cilia-dependent signaling pathways and proteins including mTOR, VHL, TSC, WNT, Aurora-A, NEDD9, and Hedgehog, and highlight the emerging role of ciliary dysfunction in renal cell carcinoma, medulloblastoma, and breast cancer.
doi:10.1016/j.ddmec.2013.03.004
PMCID: PMC4073101  PMID: 24982684
4.  Cell Cycle Regulation of the Centrosome and Cilium 
Centrosomes and cilia are conserved microtubule-based organelles whose structure and function depend on cell cycle stages. In dividing cells, centrosomes organize mitotic spindle poles, while in differentiating cells, centrosomes template ciliogenesis. Classically, this functional dichotomy has been attributed to regulation by cell cycle-dependent post-translational modifications, and recently PLK1, Nek2, Aurora A, and tubulin deacetylase were implicated in regulating the transition from cilia to centrosome. However, other recent studies suggest that tubulin dimers, the core structural components of centrosomes and cilia, also have a regulatory role. These regulatory mechanisms can be a target for chemotherapeutic intervention.
doi:10.1016/j.ddmec.2013.03.002
PMCID: PMC4073209  PMID: 24982683
5.  Murine Models of Polycystic Kidney Disease 
Polycystic diseases affect approximately 1/1000 and are important causes of kidney failure. No therapies presently are in clinical practice that can prevent disease progression. Multiple mouse models have been produced for the genetic forms of the disease that most commonly affect humans. In this report, we review recent progress in the field and describe some of the outstanding challenges.
doi:10.1016/j.ddmec.2013.10.002
PMCID: PMC4085131  PMID: 25013443
6.  Blood in a dish: In vitro synthesis of red blood cells 
Red blood cells, currently obtained from donors, represent the most common form of cell-based therapy. A better understanding of normal erythropoiesis is leading to improved multi-step protocols for the in vitro generation of fully mature red cells. The extensive in vitro expansion of embryonic erythroblasts and development of erythroid precursors as a potential transfusion product may help to deal with issues of scale and eventually find a place in the treatment of patients with acute and chronic anemias.
doi:10.1016/j.ddmec.2011.10.002
PMCID: PMC4220296  PMID: 25383080
7.  GPCRs in cardiovascular pathologies 
PMCID: PMC4071045  PMID: 24976849 CAMSID: cams3857
8.  Obesity, cancer, and acetyl-CoA metabolism 
As rates of obesity soar in the Unites States and around the world, cancer attributed to obesity has emerged as major threat to public health. The link between obesity and cancer can be attributed in part to the state of chronic inflammation that develops in obesity. Acetyl-CoA production and protein acetylation patterns are highly sensitive to metabolic state and are significantly altered in obesity. In this article, we explore the potential role of nutrient-sensitive lysine acetylation in regulating inflammatory processes in obesity-linked cancer.
doi:10.1016/j.ddmec.2013.03.005
PMCID: PMC3713850  PMID: 23878588
9.  Sirtuin 3: A major control point for obesity-related metabolic diseases? 
Obesity and obesity-related complications are epidemic issues currently plaguing much of the developed world with increasing associated morbidity, mortality, and economic burden. In this brief review, we discuss emerging evidence and remaining questions regarding the possible role for mitochondrial sirtuin 3 as a therapeutic target for the treatment of obesity-related metabolic diseases.
doi:10.1016/j.ddmec.2013.04.001
PMCID: PMC3756827  PMID: 23997790
10.  Obesity and metabolic inflammation 
Obesity epidemics affect 35.7% of adults and approximately 17% of children in the United States. Obesity has been associated with several health disorders, such as type 2 diabetes, cardiovascular diseases, fatty liver disease, and certain forms of cancer. Medical costs associated with obesity were estimated at $147 billion in 2008. Chronic tissue inflammation, particularly in adipose tissue, has been considered as a key underlying mechanism for the development of obesity-related metabolic syndrome. In this review, we discuss the recent progress in the field of metabolic inflammation and the potential implication of anti-inflammation approaches as therapeutic interventions for treating obesity-related metabolic disorders.
doi:10.1016/j.ddmec.2013.03.006
PMCID: PMC3758492  PMID: 24003334
WAT; obesity; inflammation
11.  Molecular Basis of Insulin Resistance: The Role of IRS and Foxo1 in the Control of Diabetes Mellitus and Its Complications 
Insulin/IGF-1 signaling plays a central role in control of cellular metabolism and survival, while insulin receptor substrate (IRS) protein -1 and -2 and downstream PI-3 kinase→Akt→Foxo1 signaling cascade play key roles in many functions of insulin/IGF-1. Dysregulation of this branch of signaling cascades may provide a mechanism for insulin resistance as we observed in cells, animals, and even humans. Targeting this branch of IRS→Foxo1 signaling may provide us with fundamental strategies for drug development in the future.
doi:10.1016/j.ddmec.2013.06.003
PMCID: PMC3763863  PMID: 24015152
12.  Obesity and Cardiac Function – The Role of Caloric Excess and its Reversal 
Obesity is recognized as an independent and increasingly prevalent risk factor for cardiovascular morbidity and mortality. This stems in part from the contribution of obesity towards insulin resistance and diabetes, which associate with premature atherosclerosis, enhanced thrombogenicity and activation of systemic inflammatory programs with resultant cardiovascular dysfunction. This review will focus on the more direct mechanisms underpinning obesity-associated cardiac pathophysiology including the metabolic consequences of lipid accumulation in the myocardium and the consequences of direct systemic effects of lipid toxicity. Furthermore, there is growing recognition that metabolic intermediates, which may be perturbed with caloric excess, may play an important role in intracellular signal transduction and on the post-translational control of metabolic functioning within the heart. As strategies to reverse obesity appear to have ameliorative cardiac effects, surgical and therapeutic approaches to facilitate weight reduction this will also be discussed.
doi:10.1016/j.ddmec.2013.05.004
PMCID: PMC3768162  PMID: 24039623
13.  A New Horizon: Oxytocin as a Novel Therapeutic Option for Obesity and Diabetes 
The story of oxytocin (OXT) began long ago in evolutionary terms with its recognition as a classical neurohypophyseal hormone important for lactation and uterine contraction. With the recent discovery of its local actions in the brain, its previously-unappreciated diverse functions in regulating social behaviors and metabolic physiology are emerging. In light of metabolic control, OXT has been shown to induce feeding restriction and body weight lowering through acting on brain regulatory regions, in particular the hypothalamus. Studies from pharmacologic interventions and genetic manipulations demonstrated that OXT can play significant roles in affecting glucose metabolism as well as insulin secretion and lipolysis, many of those functions being regulated both centrally and peripherally. Also excitingly, recent therapeutic success was obtained in clinical endeavor showing that OXT nasal spray effectively induced weight loss and metabolic improvement in human patients with obesity, thus further indicating OXT as a tangible drug target for treating obesity and metabolic complications. In addition to the native form, OXT-derived analogues have been found effective in inducing body weight control and glucose balance. Altogether, all recent advances in studying OXT and metabolic regulation has promoted a promising foundation for the therapeutic strategy of developing innovative OXT peptidyl drugs for the treatment of obesity and related metabolic diseases.
doi:10.1016/j.ddmec.2013.05.006
PMCID: PMC3804379  PMID: 24159336
14.  TSLP: A Key Regulator of Asthma Pathogenesis 
Drug discovery today. Disease mechanisms  2012;9(3-4):10.1016/j.ddmec.2012.09.003.
Asthma is a complex disorder of the airways that is characterized by T helper type 2 (Th2) inflammation. The pleiotrophic cytokine TSLP has emerged as an important player involved in orchestrating the inflammation seen in asthma and other atopic diseases. Early research elucidated the role of TSLP on CD4+ T cells, and recent work has revealed the impact of TSLP on multiple cell types. Furthermore, TSLP plays an important role in the sequential progression of atopic dermatitis to asthma, clarifying the key role of TSLP in the pathogenesis of asthma, a finding with therapeutic implications.
doi:10.1016/j.ddmec.2012.09.003
PMCID: PMC3859144  PMID: 24348685
15.  Antiestrogen Resistance and the Application of Systems Biology 
Understanding the molecular changes that drive an acquired antiestrogen resistance phenotype is of major clinical relevance. Previous methodologies for addressing this question have taken a single gene/pathway approach and the resulting gains have been limited in terms of their clinical impact. Recent systems biology approaches allow for the integration of data from high throughput “-omics” technologies. We highlight recent advances in the field of antiestrogen resistance with a focus on transcriptomics, proteomics and methylomics.
doi:10.1016/j.ddmec.2012.10.003
PMCID: PMC3607389  PMID: 23539064
Systems biology; breast cancer; estrogens; antiestrogens
16.  Modulation of Asthma Pathogenesis by Nitric Oxide Pathways and Therapeutic Opportunities 
Asthma, a chronic airway inflammatory disease is typically associated with high levels of exhaled nitric oxide (NO). Over the past decades, extensive research has revealed that NO participates in a number of metabolic pathways that contribute to animal models of asthma and human asthma. In asthmatic airway, high levels of NO lead to greater formation of reactive nitrogen species (RNS), which modify proteins adversely affecting functional activities. In contrast, high levels of NO are associated with lower than normal levels of S-nitrosothiols, which serve a bronchodilator function in the airway. Detailed mechanistic studies have enabled the development of compounds that target NO metabolic pathways, and provide opportunities for novel asthma therapy. This review discusses the role of NO in asthma with the primary focus on therapeutic opportunities developed in recent years.
doi:10.1016/j.ddmec.2012.10.004
PMCID: PMC3749883  PMID: 23976894
17.  Modulation of Estrogen Chemical Carcinogenesis by Botanical Supplements used for Postmenopausal Women’s Health 
Breast cancer risk has been associated with long-term estrogen exposure including traditional hormone therapy (HT, formally hormone replacement therapy). To avoid traditional HT and associated risks, women have been turning to botanical supplements such as black cohosh, red clover, licorice, hops, dong gui, and ginger to relieve menopausal symptoms despite a lack of efficacy evidence. The mechanisms of estrogen carcinogenesis involve both hormonal and chemical pathways. Botanical supplements could protect women from estrogen carcinogenesis by modulating key enzymatic steps [aromatase, P4501B1, P4501A1, catechol-O-methyltransferase (COMT), NAD(P)H quinone oxidoreductase 1 (NQO1), and reactive oxygen species (ROS) scavenging] in estradiol metabolism leading to estrogen carcinogenesis as outlined in Figure 1. This review summarizes the influence of popular botanical supplements used for women’s health on these key steps in the estrogen chemical carcinogenesis pathway, and suggests that botanical supplements may have added chemopreventive benefits by modulating estrogen metabolism.
doi:10.1016/j.ddmec.2012.11.001
PMCID: PMC3818722  PMID: 24223609
18.  TARGETING THE GENOTOXIC EFFECTS OF ESTROGENS 
Our studies indicate that expression of antioxidative stress enzymes is upregulated by Selective Estrogen Receptor Modulators (SERMs) in breast epithelial cell lines, providing protection against the genotoxic effects of estrogens and against estrogen-induced mammary tumorigenesis. This upregulation of antioxidative stress enzymes requires Estrogen Receptor beta (ERβ) and human homolog of Xenopus gene which Prevents Mitotic Catastrophe (hPMC2). Further studies indicate that hPMC2 has a functional exonuclease domain that is required for upregulation of antioxidative stress enzymes by SERMs and repair of estrogen-induced abasic sites.
doi:10.1016/j.ddmec.2012.11.005
PMCID: PMC3685422  PMID: 23795205
19.  An in vitro–in vivo model of epithelial mesenchymal transition in triple negative breast cancer 
The loss of epithelial expression markers by neoplastic breast cancer cells in the primary tumor is believed to play a pivotal role during breast cancer metastasis. This phenomenon is the hallmark of the epithelial mesenchymal transition (EMT) process. Gene expression microarrays were performed to investigate key functional elements on an in vitro metastasis model derived from human breast epithelial cells (MCF10F) treated with 17 beta estradiol. We identified groups of SLUG associated genes modulated during EMT.
doi:10.1016/j.ddmec.2012.11.002
PMCID: PMC3622948  PMID: 23585768
20.  Catechol-O-methyltransferase: characteristics, polymorphisms and role in breast cancer 
Catechol estrogens are carcinogenic, probably because of their estrogenicity and potential for further oxidative metabolism to reactive quinones. Estrogenic quinones cause oxidative DNA damage as well as form mutagenic depurinating adenine and guanine adducts. O-Methylation by catechol-O-methyltransferase (COMT) blocks their estrogenicity and prevents their oxidation to quinones. A single gene encodes both membrane bound (MB) and soluble (S) forms of COMT. The COMT gene contains 34 single nucleotide polymorphisms (SNPs). The valine108 (S-COMT)/158 (MB-COMT) SNP encodes a low activity form of COMT and has been widely studied as a putative risk factor for breast cancer, with inconsistent results. Investigations of two other SNPs in the promoter of MB-COMT that may affect its expression have also provided mixed results. Future studies on the role of COMT in breast cancer should incorporate measurement of biomarkers that reflect COMT activity and its protective effects.
doi:10.1016/j.ddmec.2012.10.002
PMCID: PMC3665426  PMID: 23734165
21.  SIGIRR, a negative regulator of colon tumorigenesis 
Inappropriate activation of the Toll-IL-1R (TL-IL-1) signaling by commensal bacteria contributes to the pathogenesis of inflammatory bowel diseases and colitis-associated cancer. Recent studies have identified SIGIRR as a negative regulator of TL-IL-1 signaling. It dampens intestinal inflammation and tumorigenesis in the colon. In this review, we will discuss the role of SIGIRR in different cell types and the mechanisms underlying its tumor suppressor function.
doi:10.1016/j.ddmec.2012.02.003
PMCID: PMC3331713  PMID: 22529873
22.  MicroRNAs and Gastroenterological Cancers 
MicroRNAs are small noncoding RNAs that control gene expression. In doing so, they functionally contribute to the maintenance of cellular processes as well as several important features related to cancer development and progression such as cell growth control, differentiation and apoptosis. In fact, recent studies have shown that microRNAs are suitable and effective cancer-related biomarkers since they display altered expression profiles in cancers versus normal tissue. In addition, microRNAs have been associated with cancer progression and outcome. In this review, the current state of knowledge microRNA expression and function in relation to gastroenterological cancers will be addressed. Moreover, the mechanisms to alter their expression and the potential application of microRNAs in clinical settings will also be highlighted. Finally, the challenges involved in translating microRNA research to the clinic will be discussed.
doi:10.1016/j.ddmec.2011.11.005
PMCID: PMC3349158  PMID: 22582080
23.  Modulation of gastrointestinal inflammation and colorectal tumorigenesis by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) 
Critical physiological roles of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) include the regulation glucose and lipid homeostasis, cellular differentiation, and modulation of inflammation. The potential for targeting PPARβ/δ for the prevention and treatment of metabolic diseases or cancer, is compromised because of major inconsistencies in the literature. This is due primarily to uncertainty regarding the effect of PPARβ/δ and its activation on cell proliferation, apoptosis and cell survival. This review summarizes both the confirmed and conflicting mechanisms that have been described for PPARβ/δ and the potential for targeting this nuclear receptor for the prevention and treatment of colon cancer.
doi:10.1016/j.ddmec.2011.11.002
PMCID: PMC3352671  PMID: 22611424
24.  HIV and SIV Associated Thrombocytopenia: An Expanding Role for Platelets in the Pathogenesis of HIV 
Thrombocytopenia is common in HIV and SIV infection, and is often associated with disease progression. HIV and SIV-associated thrombocytopenia arise through multiple mechanisms, including decreased platelet production, increased platelet destruction due to HIV-mimetic anti-platelet antibodies, and increased use of activated platelets. Activated platelets have the potential to contribute to the pathogenesis of HIV and SIV by interacting directly with inflammatory cells and endothelium and by releasing soluble immunomodulatory cytokines.
doi:10.1016/j.ddmec.2011.10.001
PMCID: PMC3346281  PMID: 22577463
25.  Platelet storage and transfusions: new concerns associated with an old therapy 
Platelet transfusion has long been practiced with rudimentary knowledge about optimal storage conditions and their implications for efficacy and, particularly, safety. Recent concerns about complications such as inflammation, thrombosis and altered recipient immunity have been raised about platelet transfusion. This review will discuss recent important findings that have raised these issues about platelet transfusion associated morbidity, mortality and the possible role of platelet storage in these associations.
doi:10.1016/j.ddmec.2011.06.001
PMCID: PMC3361759  PMID: 22662018

Results 1-25 (66)