Platelet-rich plasma counteracts detrimental effect of high-glucose concentrations on mesenchymal stem cells from Bichat fat pad

Diabetic patients display increased risk of periodontitis and failure in bone augmentation procedures. Mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) represent a relevant advantage in tissue repair process and regenerative medicine. We isolated MSCs from Bichat's buccal fat pad (BFP) and measured the effects of glucose and PRP on cell number and osteogenic differentiation potential. Cells were cultured in the presence of 5.5-mM glucose (low glucose [LG]) or 25-mM glucose (high glucose [HG]). BFP–MSC number was significantly lower when cells were cultured in HG compared with those in LG. Following osteogenic differentiation procedures, calcium accumulation, alkaline phosphatase activity, and expression of osteogenic markers were significantly lower in HG compared with LG. Exposure of BFP–MSC to PRP significantly increased cell number and osteogenic differentiation potential, reaching comparable levels in LG and in HG. Thus, high-glucose concentrations impair BFP–MSC growth and osteogenic differentiation. However, these detrimental effects are largely counteracted by PRP

PED/PEA-15 Controls Fibroblast Motility and Wound Closure by ERK1/2-Dependent Mechanisms

Cell migration is dependent on the control of signaling events that play significant roles in creating contractile force and in contributing to wound closure. We evaluated wound closure in fibroblasts from mice overexpressing (TgPED) or lacking ped/pea-15 (KO), a gene overexpressed in patients with type 2 diabetes. Cultured skin fibroblasts isolated from TgPED mice showed a significant reduction in the ability to recolonize wounded area during scratch assay, compared to control fibroblasts. This difference was observed both in the absence and in the presence of mytomicin C, an inhibitor of mitosis. In time-lapse experiments, TgPED fibroblasts displayed about twofold lower velocity and diffusion coefficient, as compared to controls. These changes were accompanied by reduced spreading and decreased formation of stress fibers and focal adhesion plaques. At the molecular level, TgPED fibroblasts displayed decreased RhoA activation and increased abundance of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). Inhibition of ERK1/2 activity by PD98059 restored RhoA activation, cytoskeleton organization and cell motility, and almost completely rescued wound closure of TgPED fibroblasts. Interestingly, skin fibroblasts isolated from KO mice displayed an increased wound closure ability. In vivo, healing of dorsal wounds was delayed in TgPED and accelerated in KO mice. Thus, PED/PEA-15 may affect fibroblast motility by a mechanism, at least in part, mediated by ERK1/2. J. Cell. Physiol. 227: 2106–2116, 2012. © 2011 Wiley Periodicals, Inc

Mammary Adipose Tissue Control of Breast Cancer Progression: Impact of Obesity and Diabetes

Mammary adipose tissue (AT) is necessary for breast epithelium. However, in breast cancer (BC), cell-cell interactions are deregulated as the tumor chronically modifies AT microenvironment. In turn, breast AT evolves to accommodate the tumor, and to participate to its dissemination. Among AT cells, adipocytes and their precursor mesenchymal stem cells (MSCs) play a major role in supporting tumor growth and dissemination. They provide energy supplies and release a plethora of factors involved in cancer aggressiveness. Here, we discuss the main molecular mechanisms underlining the interplay between adipose (adipocytes and MSCs) and BC cells. Following close interactions with BC cells, adipocytes lose lipids and change morphology and secretory patterns. MSCs also play a major role in cancer progression. While bone marrow MSCs are recruited by BC cells and participate in metastatic process, mammary AT-MSCs exert a local action by increasing the release of cytokines, growth factors and extracellular matrix components and become principal actors in cancer progression. Common systemic metabolic diseases, including obesity and diabetes, further modify the interplay between AT and BC. Indeed, metabolic perturbations are accompanied by well-known alterations of AT functions, which might contribute to worsen cancer phenotype. Here, we highlight how metabolic alterations locally affect mammary AT and interfere with the molecular mechanisms of bidirectional communication between adipose and cancer cells

The Relevance of Insulin Action in the Dopaminergic System

The advances in medicine, together with lifestyle modifications, led to a rising life expectancy. Unfortunately, however, aging is accompanied by an alarming boost of age-associated chronic pathologies, including neurodegenerative and metabolic diseases. Interestingly, a non-negligible interplay between alterations of glucose homeostasis and brain dysfunction has clearly emerged. In particular, epidemiological studies have pointed out a possible association between Type 2 Diabetes (T2D) and Parkinson's Disease (PD). Insulin resistance, one of the major hallmark for etiology of T2D, has a detrimental influence on PD, negatively affecting PD phenotype, accelerating its progression and worsening cognitive impairment. This review aims to provide an exhaustive analysis of the most recent evidences supporting the key role of insulin resistance in PD pathogenesis. It will focus on the relevance of insulin in the brain, working as pro-survival neurotrophic factor and as a master regulator of neuronal mitochondrial function and oxidative stress. Insulin action as a modulator of dopamine signaling and of alpha-synuclein degradation will be described in details, too. The intriguing idea that shared deregulated pathogenic pathways represent a link between PD and insulin resistance has clinical and therapeutic implications. Thus, ongoing studies about the promising healing potential of common antidiabetic drugs such as metformin, exenatide, DPP IV inhibitors, thiazolidinediones and bromocriptine, will be summarized and the rationale for their use to decelerate neurodegeneration will be critically assessed

Bisphenol-A Impairs Insulin Action and Up-Regulates Inflammatory Pathways in Human Subcutaneous Adipocytes and 3T3-L1 Cells.

Current evidence indicates that chemical pollutants may interfere with the homeostatic control of nutrient metabolism, thereby contributing to the increased prevalence of metabolic disorders. Bisphenol-A (BPA) is a lipophilic compound contained in plastic which is considered a candidate for impairing energy and glucose metabolism. We have investigated the impact of low doses of BPA on adipocyte metabolic functions. Human adipocytes derived from subcutaneous adipose tissue and differentiated 3T3-L1 cells were incubated with BPA, in order to evaluate the effect on glucose utilization, insulin sensitivity and cytokine secretion. Treatment with 1nM BPA significantly inhibited insulin-stimulated glucose utilization, without grossly interfering with adipocyte differentiation. Accordingly, mRNA levels of the adipogenic markers PPARγ and GLUT4 were unchanged upon BPA exposure. BPA treatment also impaired insulin-activated receptor phosphorylation and signaling. Moreover, adipocyte incubation with BPA was accompanied by increased release of IL-6 and IFN-γ, as assessed by multiplex ELISA assays, and by activation of JNK, STAT3 and NFkB pathways. Treatment of the cells with the JNK inhibitor SP600125 almost fully reverted BPA effect on insulin signaling and glucose utilization. In conclusion, low doses of BPA interfere with inflammatory/insulin signaling pathways, leading to impairment of adipose cell function

Caulerpin mitigates helicobacter pylori-induced inflammation via formyl peptide receptors

The identification of novel strategies to control Helicobacter pylori (Hp)-associated chronic inflammation is, at present, a considerable challenge. Here, we attempt to combat this issue by modulating the innate immune response, targeting formyl peptide receptors (FPRs), G-protein coupled receptors that play key roles in both the regulation and the resolution of the innate inflammatory response. Specifically, we investigated, in vitro, whether Caulerpin—a bis-indole alkaloid isolated from algae of the genus Caulerpa—could act as a molecular antagonist scaffold of FPRs. We showed that Caulerpin significantly reduces the immune response against Hp culture filtrate, by reverting the FPR2-related signaling cascade and thus counteracting the inflammatory reaction triggered by Hp peptide Hp(2–20). Our study suggests Caulerpin to be a promising therapeutic or adjuvant agent for the attenuation of inflammation triggered by Hp infection, as well as its related adverse clinical outcomes

Prep1 deficiency improves metabolic response in white adipose tissue

Prep1 is a gene encoding for a homeodomain transcription factor which induces hepatic and muscular insulin resistance. In this study, we show that Prep1 hypomorphic heterozygous (Prep1i/+) mice, expressing low levels of protein, featured a 23% and a 25% reduction of total body lipid content and epididymal fat, respectively. The percentage of the small adipocytes (25-75 μm) was 30% higher in Prep1i/+ animals than in the WT, with a reciprocal difference in the large adipose cells (100-150 and >150 μm). Insulin-stimulated insulin receptor tyrosine and Akt serine phosphorylation markedly increased in Prep1i/+ mice, paralleled by 3-fold higher glucose uptake and a significant increase of proadipogenic genes such as C/EBPα, GLUT4, and FABP4. Moreover, T cells infiltration and TNF-α, IFNγ and leptin expression were reduced in adipose tissue from Prep1i/+ mice, while adiponectin levels were 2-fold higher. Furthermore, Prep1i/+ mature adipocytes released lower amounts of pro-inflammatory cytokines and higher amount of adiponectin compared to WT cells. Incubation of murine liver cell line (NMuLi) with conditioned media (CM) from mature adipocytes of Prep1i/+ mice improved glucose metabolism, while those from WT mice had no effect. Consistent with these data, Prep1 overexpression in 3T3-L1 adipocytes impaired adipogenesis and insulin signaling, and increased proinflammatory cytokine secretion. All these findings suggest that Prep1 silencing reduces inflammatory response and increases insulin sensitivity in adipose tissue. In addition, CM from mature adipocytes of Prep1i/+ mice improve metabolism in hepatic cells