Type 2 diabetes mellitus (DM) is a common metabolic disorder predisposing to diabetic cardiomyopathy and atherosclerotic cardiovascular disease (CVD), which could lead to heart failure through a ...variety of mechanisms, including myocardial infarction and chronic pressure overload. Pathogenetic mechanisms, mainly linked to hyperglycemia and chronic sustained hyperinsulinemia, include changes in metabolic profiles, intracellular signaling pathways, energy production, redox status, increased susceptibility to ischemia, and extracellular matrix remodeling. The close relationship between type 2 DM and CVD has led to the common soil hypothesis, postulating that both conditions share common genetic and environmental factors influencing this association. However, although the common risk factors of both CVD and type 2 DM, such as obesity, insulin resistance, dyslipidemia, inflammation, and thrombophilia, can be identified in the majority of affected patients, less is known about how these factors influence both conditions, so that efforts are still needed for a more comprehensive understanding of this relationship. The genetic, epigenetic, and environmental backgrounds of both type 2 DM and CVD have been more recently studied and updated. However, the underlying pathogenetic mechanisms have seldom been investigated within the broader shared background, but rather studied in the specific context of type 2 DM or CVD, separately. As the precise pathophysiological links between type 2 DM and CVD are not entirely understood and many aspects still require elucidation, an integrated description of the genetic, epigenetic, and environmental influences involved in the concomitant development of both diseases is of paramount importance to shed new light on the interlinks between type 2 DM and CVD. This review addresses the current knowledge of overlapping genetic and epigenetic aspects in type 2 DM and CVD, including microRNAs and long non-coding RNAs, whose abnormal regulation has been implicated in both disease conditions, either etiologically or as cause for their progression. Understanding the links between these disorders may help to drive future research toward an integrated pathophysiological approach and to provide future directions in the field.
The term osteoimmunology was coined many years ago to describe the research field that deals with the cross-regulation between bone cells and the immune system. As a matter of fact, many factors that ...are classically considered immune-related, such as InterLeukins (i.e., IL-6, -11, -17, and -23), Tumor Necrosis Factor (TNF)-α, Receptor-Activator of Nuclear factor Kappa B (RANK), and its Ligand (RANKL), Nuclear Factor of Activated T-cell, cytoplasmatic-1 (NFATc1), and others have all been found to be crucial in osteoclast and osteoblast biology. Conversely, bone cells, which we used to think would only regulate each other and take care of remodeling bone, actually regulate immune cells, by creating the so-called "endosteal niche." Both osteoblasts and osteoclasts participate to this niche, either by favoring engraftment, or mobilization of Hematopoietic Stem Cells (HSCs). In this review, we will describe the main milestones at the base of the osteoimmunology and present the key cellular players of the bone-immune system cross-talk, including HSCs, osteoblasts, osteoclasts, bone marrow macrophages, osteomacs, T- and B-lymphocytes, dendritic cells, and neutrophils. We will also briefly describe some pathological conditions in which the bone-immune system cross-talk plays a crucial role, with the final aim to portray the state of the art in the mechanisms regulating the bone-immune system interplay, and some of the latest molecular players in the field. This is important to encourage investigation in this field, to identify new targets in the treatment of bone and immune diseases.
Germline development
is dependent on the environment formed by somatic cells and the differentiation cues they provide; hence, the impact of local factors is highly relevant to the production of ...sperm. Knowledge of how somatic and germline cells interact is central to achieving biomedical goals relating to restoring, preserving or restricting fertility in humans. This review discusses the growing understanding of how cytokines contribute to testicular function and maintenance of male reproductive health, and to the pathologies associated with their abnormal activity in this organ. Here we consider both cytokines that signal through JAKs and are regulated by SOCS, and those utilizing other pathways, such as the MAP kinases and SMADs. The importance of cytokines in the establishment and maintenance of the testis as an immune-privilege site are described. Current research relating to the involvement of immune cells in testis development and disease is highlighted. This includes new data relating to testicular cancer which reinforce the understanding that tumorigenic cells shape their microenvironment through cytokine actions. Clinical implications in pathologies relating to local inflammation and to immunotherapies are discussed.
Insulin and IGF signaling (IIS) is a complex system that controls diverse processes including growth, development, metabolism, stress responses, and aging.
IIS is propagated by eight
insulin-like ...peptides (DILPs), homologs of both mammalian insulin and IGFs, with various spatiotemporal expression patterns and functions. DILPs 1-7 are thought to act through a single
insulin/IGF receptor, InR, but it is unclear how the DILPs thereby mediate a range of physiological phenotypes. We determined the distinct cell signaling effects of DILP2 and DILP5 stimulation upon
S2 cells. DILP2 and DILP5 induced similar transcriptional patterns but differed in signal transduction kinetics. DILP5 induced sustained phosphorylation of Akt, while DILP2 produced acute, transient Akt phosphorylation. Accordingly, we used phosphoproteomic analysis to identify distinct patterns of non-genomic signaling induced by DILP2 and DILP5. Across all treatments and replicates, 5,250 unique phosphopeptides were identified, representing 1,575 proteins. Among these peptides, DILP2, but not DILP5, dephosphorylated Ser15 on glycogen phosphorylase (GlyP), and DILP2, but not DILP5, was subsequently shown to repress enzymatic GlyP activity in S2 cells. The functional consequences of this difference were evaluated in adult
mutants:
null adults have elevated GlyP enzymatic activity relative to wild type, while
mutants have reduced GlyP activity. In flies with intact insulin genes,
overexpression extended lifespan in a Ser15 phosphorylation-dependent manner. In
mutants, that are otherwise long-lived, longevity was repressed by expression of phosphonull
that is enzymatically inactive. Overall, DILP2, unlike DILP5, signals to affect longevity in part through its control of phosphorylation to deactivate glycogen phosphorylase, a central modulator of glycogen storage and gluconeogenesis.
fertilization (IVF) is an effective means to treat infertility, but the pregnancy rate is still unsatisfactory and reliable markers to predict pregnancy outcome are ill-defined. Myeloid-derived ...suppressor cell (MDSC) are critically involved in decisions related to the acceptance or rejection of foreign fetal antigens by the maternal immune system. However, factors that regulate peripheral blood MDSC during pre-pregnancy are poorly defined. Thus, the goal of this study was to assess the relationships among serum estradiol (E
) and endothelial growth factor (VEGF) levels, MDSC ratios, and pregnancy outcome associated with IVF. Patients undergoing IVF treatment (
= 54) were recruited from January to June 2018. Levels of E
and VEGF were measured by ELISA, MDSC ratios among peripheral blood mononuclear cells (PBMC) were detected by flow cytometry, and the crosstalk among these parameters was analyzed. A receiver operating characteristic curve (ROC) of MDSC levels was plotted to assess this measure as an independent predictive factor for pregnancy. In addition, we analyzed the possible involvement of molecular pathways by bioinformatics. When E
levels were <4,000 pg/ml, MDSC proportion was positively correlated with serum E
and VEGF levels. However, when E
levels were >4,000 pg/ml, MDSC ratio and VEGF levels were negatively correlated with E
. A ROC curve revealed that the percentage of MDSC had better sensitivity and specificity at a concentration of 8.22% (0.875 and 0.75, respectively; area under the curve (AUC) = 0.859) to predict pregnancy success, based on multiple logistic regression analysis. Furthermore, we found 12 target genes of E
and VEGF, and also functional genes related to MDSC, indicating potential protein-protein interactions underlying these associations. In summary, we showed that E
, depending on its concentration, might play a dichotomous role in influencing the MDSC proportion by regulating VEGF. In IVF patients, an increased MDSC ratio among PBMC was highly correlated with elevated pregnancy rates, independent of the effects of E
, which might provide new insight into immune-related miscarriage and IVF failure.
Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN) is a dual phosphatase with both protein and lipid phosphatase activities. PTEN was first discovered as a tumor suppressor with growth ...and survival regulatory functions. In recent years, the function of PTEN as a metabolic regulator has attracted significant attention. As the lipid phosphatase that dephosphorylates phosphatidylinositol-3, 4, 5-phosphate (PIP
), PTEN reduces the level of PIP
, a critical 2nd messenger mediating the signal of not only growth factors but also insulin. In this review, we introduced the discovery of PTEN, the PTEN-regulated canonical and nuclear signals, and PTEN regulation. We then focused on the role of PTEN and PTEN-regulated signals in metabolic regulation. This included the role of PTEN in glycolysis, gluconeogenesis, glycogen synthesis, lipid metabolism as well as mitochondrial metabolism. We also included how PTEN and PTEN regulated metabolic functions may act paradoxically toward insulin sensitivity and tumor metabolism and growth. Further understanding of how PTEN regulates metabolism and how such regulations lead to different biological outcomes is necessary for interventions targeting at the PTEN-regulated signals in either cancer or diabetes treatment.
Type 2 diabetes mellitus (T2DM) is associated with skeletal complications, including an increased risk of fractures. Reduced blood supply and bone strength may contribute to this skeletal fragility. ...We hypothesized that long-term administration of Exenatide, a glucagon-like peptide-1 receptor agonist, would improve bone architecture and strength of T2DM mice by increasing blood flow to bone, thereby stimulating bone formation. In this study, we used a model of obesity and severe T2DM, the leptin receptor-deficient db/db mouse to assess alterations in bone quality and hindlimb blood flow and to examine the beneficial effects of 4 weeks administration of Exenatide. As expected, diabetic mice showed marked alterations in bone structure, remodeling and strength, and basal vascular tone compared with lean mice. Exenatide treatment improved trabecular bone mass and architecture by increasing bone formation rate, but only in diabetic mice. Although there was no effect on hindlimb perfusion at the end of this treatment, Exenatide administration acutely increased tibial blood flow. While Exenatide treatment did not restore the impaired bone strength, intrinsic properties of the matrix, such as collagen maturity, were improved. The effects of Exenatide on
bone formation were further investigated in primary osteoblasts cultured under high-glucose conditions, showing that Exenatide reversed the impairment in bone formation induced by glucose. In conclusion, Exenatide improves trabecular bone mass by increasing bone formation and could protect against the development of skeletal complications associated with T2DM.
The gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are key regulators of the reproductive axis in vertebrates. Despite the high popularity of zebrafish as a model ...organism for studying reproductive functions, to date no transgenic zebrafish with labeled gonadotropes have been introduced. Using gonadotropin regulatory elements from tilapia, we generated two transgenic zebrafish lines with labeled gonadotropes. The tilapia and zebrafish regulatory sequences were highly divergent but several conserved elements allowed the tilapia promoters to correctly drive the transgenes in zebrafish pituitaries. FSH cells reacted to stimulation with gonadotropin releasing hormone by proliferating and showing increased transgene fluorescence, whereas estrogen exposure caused a decrease in cell number and transgene fluorescence. Transgene fluorescence reflected the expression pattern of the endogenous fshb gene. Ontogenetic expression of the transgenes followed typical patterns, with FSH cells appearing early in development, and LH cells appearing later and increasing dramatically in number with the onset of puberty. Our transgenic lines provide a powerful tool for investigating the development, anatomy, and function of the reproductive axis in lower vertebrates.
Reproduction is associated with the circadian system, primarily as a result of the connectivity between the biological clock in the suprachiasmatic nucleus (SCN) and reproduction-regulating brain ...regions, such as preoptic area (POA), anteroventral periventricular nucleus (AVPV), and arcuate nucleus (ARC). Networking of the central pacemaker to these hypothalamic brain regions is partly represented by close fiber appositions to specialized neurons, such as kisspeptin and gonadotropin-releasing hormone (GnRH) neurons; accounting for rhythmic release of gonadotropins and sex steroids. Numerous studies have attempted to dissect the neurochemical properties of GnRH neurons, which possess intrinsic oscillatory features through the presence of clock genes to regulate the pulsatile and circadian secretion. However, less attention has been given to kisspeptin, the upstream regulator of GnRH and a potent mediator of reproductive functions including puberty. Kisspeptin exerts its stimulatory effects on GnRH secretion via its cognate Kiss-1R receptor that is co-expressed on GnRH neurons. Emerging studies have found that kisspeptin neurons oscillate on a circadian basis and that these neurons also express clock genes that are thought to regulate its rhythmic activities. Based on the fiber networks between the SCN and reproductive nuclei such as the POA, AVPV, and ARC, it is suggested that interactions among the central biological clock and reproductive neurons ensure optimal reproductive functionality. Within this neuronal circuitry, kisspeptin neuronal system is likely to "time" reproduction in a long term during development and aging, in a medium term to regulate circadian or estrus cycle, and in a short term to regulate pulsatile GnRH secretion.
Mitochondrial dysfunction is implicated in the pathogenesis of Type 2 diabetes (T2D) and the development of diabetes related complications such as cardiovascular disease and stroke. Mitochondria ...produce several small polypeptides that may influence mitochondrial function and may impact on insulin sensitivity, such as humanin (HN) and the mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) that are mitochondrial derived proteins (MDP). The aim of this study was to determine MDP in normal, prediabetes and diabetes subjects.
In this cross-sectional study, we analyzed the serum concentrations of MDP and adiponectin (ADP) in 225 subjects: normal (
= 68), pre-diabetes (
= 33), T2D less than (good control;
= 31), and greater than HbA1c 7% (poor control;
= 93) subjects. The relationship of serum MDP and ADP concentrations with biochemical and anthropometric measurements were performed and assessed by multilinear regression.
Serum HN concentrations were lower in T2D (
< 0.0001) and negatively correlated with age (
< 0.0001), HbA1c (
< 0.0001), glucose (
< 0.0001), triglycerides (
< 0.003), ALT (
< 0.004), and TG/HDL ratio (
< 0.001). Circulating HN levels were positively correlated to cholesterol (
< 0.017), LDL (
< 0.001), and HDL (
< 0.001). Linear regression analysis showed that HbA1c and ALT were two independent predictors of circulating HN. Similarly, serum MOTS-c was significantly lower in T2D subjects compared to controls (
< 0.007). Circulating MOTS-c positively correlated with BMI (
< 0.035), total cholesterol (
< 0.0001), and LDL (
< 0.001) and negatively correlated with age (
< 0.002), HbA1c (
< 0.001), and glucose (
< 0.002). Serum ADP concentrations were lower in T2D (
< 0.002) and negatively correlated with HbA1c (
< 0.001), weight (
< 0.032) TG (
< 0.0001), and ALT (
< 0.0001); and positively correlated with HDL (
< 0.0001) and HN (
< 0.003). Linear regression analysis showed that HbA1c and weight were two independent predictors of circulating ADP. Multilinear regression showed that HN and MOT-c correlated with each other, and only HN correlated with HbA1c.
The MDPs HN and MOT-c, similar to ADP, are decreased in T2D and correlate with HbA1c. The data provide an additional evidence that mitochondrial dysfunction contributes to glycemic dysregulation and metabolic defects in T2D.
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