The role of sirtuins in dermal fibroblast function.

The sirtuins are a family of seven proteins that perform a variety of dermatological functions and help maintain both the structure and function of the skin. More specifically, the sirtuins have been shown to be altered in multiple dermal cell types including dermal fibroblasts. The functions of dermal fibroblasts are extensive, and include playing a significant role in wound healing as well as helping to maintain the integrity of the skin. As dermal fibroblasts age, they can undergo a state of permanent cell cycle arrest, known as cellular senescence. This senescent process can occur as a result of various stressors, including oxidative stress, ultraviolet radiation -induced stress, and replicative stress. In recent years, there has been a growing interest in both enhancing the cutaneous fibroblast's ability to facilitate wound healing and altering fibroblast cellular senescence. Thus, in this review, we examine the relationship between sirtuin signaling and dermal fibroblasts to understand how this family of proteins may modulate skin conditions ranging from the wound healing process to photocarcinogenesis associated with fibroblast senescence. Additionally, we offer supporting data from experiments examining the relationship between fibroblast senescence and sirtuin levels in an oxidative stress model indicating that senescent dermal fibroblasts exhibit diminished sirtuin levels. Furthermore, we survey the research on the role of sirtuins in specific dermatological disease states that where dermal fibroblast function has been implicated. Finally, we conclude with outlining potential clinical applications of sirtuins in dermatology. In sum, we find that the literature on the involvement of sirtuins in dermal fibroblasts is limited, with research still in its early stages. Nevertheless, intriguing preliminary findings merit additional investigation into the clinical implications of sirtuins in dermatology.

Mice with gene alterations in the GH and IGF family.

Much of our understanding of GH's action stems from animal models and the generation and characterization of genetically altered or modified mice. Manipulation of genes in the GH/IGF1 family in animals started in 1982 when the first GH transgenic mice were produced. Since then, multiple laboratories have altered mouse DNA to globally disrupt Gh, Ghr, and other genes upstream or downstream of GH or its receptor. The ability to stay current with the various genetically manipulated mouse lines within the realm of GH/IGF1 research has been daunting. As such, this review attempts to consolidate and summarize the literature related to the initial characterization of many of the known gene-manipulated mice relating to the actions of GH, PRL and IGF1. We have organized the mouse lines by modifications made to constituents of the GH/IGF1 family either upstream or downstream of GHR or to the GHR itself. Available data on the effect of altered gene expression on growth, GH/IGF1 levels, body composition, reproduction, diabetes, metabolism, cancer, and aging are summarized. For the ease of finding this information, key words are highlighted in bold throughout the main text for each mouse line and this information is summarized in Tables 1, 2, 3 and 4. Most importantly, the collective data derived from and reported for these mice have enhanced our understanding of GH action.

Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo.

Growth hormone (GH) and the GH receptor (GHR) are expressed in a wide range of malignant tumors including melanoma. However, the effect of GH/insulin-like growth factor (IGF) on melanoma in vivo has not yet been elucidated. Here we assessed the physical and molecular effects of GH on mouse melanoma B16-F10 and human melanoma SK-MEL-30 cells in vitro. We then corroborated these observations with syngeneic B16-F10 tumors in two mouse lines with different levels of GH/IGF: bovine GH transgenic mice (bGH; high GH, high IGF-1) and GHR gene-disrupted or knockout mice (GHRKO; high GH, low IGF-1). In vitro, GH treatment enhanced mouse and human melanoma cell growth, drug retention and cell invasion. While the in vivo tumor size was unaffected in both bGH and GHRKO mouse lines, multiple drug-efflux pumps were up regulated. This intrinsic capacity of therapy resistance appears to be GH dependent. Additionally, epithelial-to-mesenchymal transition (EMT) gene transcription markers were significantly upregulated in vivo supporting our current and recent in vitro observations. These syngeneic mouse melanoma models of differential GH/IGF action can be valuable tools in screening for therapeutic options where lowering GH/IGF-1 action is important.

Crosstalk between the growth hormone/insulin-like growth factor-1 axis and the gut microbiome: A new frontier for microbial endocrinology.

Both the GH/IGF-1 axis and the gut microbiota independently play an important role in host growth, metabolism, and intestinal homeostasis. Inversely, abnormalities in GH action and microbial dysbiosis (or a lack of diversity) in the gut have been implicated in restricted growth, metabolic disorders (such as chronic undernutrition, anorexia nervosa, obesity, and diabetes), and intestinal dysfunction (such as pediatric Crohn's disease, colonic polyps, and colon cancer). Over the last decade, studies have demonstrated that the microbial impact on growth may be mediated through the GH/IGF-1 axis, pointing toward a potential relationship between GH and the gut microbiota. This review covers current research on the GH/IGF-1 axis and the gut microbiome and its influence on overall host growth, metabolism, and intestinal health, proposing a bidirectional relationship between GH and the gut microbiome.