Exosomes are extracellular vesicles derived from cell endocytosis which act as transmitters between cells. They are composed of proteins, lipids, and RNAs through which they participate in cellular crosstalk. Consequently, they play an important role in health and disease. Our view is that exosomes exert a bidirectional regulatory effect on pathogen infections by delivering their content. First, exosomes containing proteins and RNAs derived from pathogens can promote infections in three ways: (1) mediating further infection by transmitting pathogen-related molecules; (2) participating in the immune escape of pathogens; and (3) inhibiting immune responses by favoring immune cell apoptosis. Second, exosomes play anti-infection roles through: (1) inhibiting pathogen proliferation and infection directly; (2) inducing immune responses such as those related to the function of monocyte-macrophages, NK cells, T cells, and B cells. We believe that exosomes act as “bridges” during pathogen infections through the mechanisms mentioned above. The purpose of this review is to describe present findings regarding exosomes and pathogen infections, and highlight their enormous potential in clinical diagnosis and treatment. We discuss two opposite aspects: infection and anti-infection, and we hypothesize a balance between them. At the same time, we elaborate on the role of exosomes in immune regulation.

Aims/hypothesisObesity is associated with ageing and increased energy intake, while restriction of energy intake improves health and longevity in multiple organisms; the NAD+-dependent deacetylase sirtuin 1 (SIRT1) is implicated in this process. Pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons in the arcuate nucleus (ARC) of the hypothalamus are critical for energy balance regulation, and the level of SIRT1 protein decreases with age in the ARC. In the current study we tested whether conditional Sirt1 overexpression in mouse POMC or AgRP neurons prevents age-associated weight gain and diet-induced obesity.MethodsWe targeted Sirt1 cDNA sequence into the Rosa26 locus and generated conditional Sirt1 knock-in mice. These mice were crossed with mice harbouring either Pomc-Cre or Agrp-Cre and the metabolic variables, food intake, energy expenditure and sympathetic activity in adipose tissue of the resultant mice were analysed. We also used a hypothalamic cell line to investigate the molecular mechanism by which Sirt1 overexpression modulates leptin signalling.ResultsConditional Sirt1 overexpression in mouse POMC or AgRP neurons prevented age-associated weight gain; overexpression in POMC neurons stimulated energy expenditure via increased sympathetic activity in adipose tissue, whereas overexpression in AgRP neurons suppressed food intake. SIRT1 improved leptin sensitivity in hypothalamic neurons in vitro and in vivo by downregulating protein-tyrosine phosphatase 1B, T cell protein-tyrosine phosphatase and suppressor of cytokine signalling 3. However, these phenotypes were absent in mice consuming a high-fat, high-sucrose diet due to decreases in ARC SIRT1 protein and hypothalamic NAD+ levels.Conclusions/interpretationARC SIRT1 is a negative regulator of energy balance, and decline in ARC SIRT1 function contributes to disruption of energy homeostasis by ageing and diet-induced obesity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-013-3140-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

The kidney is an important target for the actions of the renin-angiotensin system (RAS) and this tissue contains a complete local RAS that expresses the bioactive peptides angiotensin II (ANG II) and Ang-(1-7). We find both angiotensin type 1 (AT(1)R) and type 2 (AT(2)R) receptors expressed on renal nuclei that stimulate reactive oxygen species and nitric oxide (NO), respectively. Since Ang-(1-7) also exhibits actions within the kidney and the Ang-(1-7)/Mas receptor protein contains a nuclear localization sequence, we determined the expression of Ang-(1-7) receptors in nuclei isolated from the kidneys of young adult sheep. Binding studies with (125)I-[Sar(1)Thr(8)]-ANG II revealed sites sensitive to the Ang-(1-7) antagonist [d-Ala(7)]-Ang-(1-7) (DALA, A779), as well as to AT(2) and AT(1) antagonists. Incubation of Ang-(1-7) [10(-15) to 10(-9) M] with isolated cortical nuclei elicited a dose-dependent increase in the fluorescence of the NO indicator [4-amino-5-methylamino-2',7']-difluorofluorescein diacetate. The NO response to Ang-(1-7) was abolished by the NO inhibitor N-nitro-l-arginine methyl ester and DALA, but not the AT(1) antagonist losartan or the AT(2) blocker PD123319. Immunofluorescent studies utilizing the Ang-(1-7)/Mas receptor antibody revealed immunolabeling of the proximal tubules but not staining within the glomerulus in cortical sections of the sheep kidney. In the nuclear fraction of isolated proximal tubules, immunoblots revealed the precursor angiotensinogen and renin, as well as functional activity for ACE, ACE2, and neprilysin. We conclude that renal nuclei express Ang-(1-7)/Mas receptors that are functionally linked to NO formation. The marked sensitivity of the intracellular NO response to Ang-(1-7) implicates a functional role of the Ang-(1-7) axis within the nucleus. Moreover, evidence for the precursor and enzymatic components of the RAS within the nuclear compartment of the proximal tubules provides a potential pathway for the intracellular generation of Ang-(1-7).

Mesenchymal stem cells (MSCs) are a group of stem cells derived from the mesodermal mesenchyme. MSCs can be obtained from a variety of tissues, including bone marrow, umbilical cord tissue, umbilical cord blood, peripheral blood and adipose tissue. Under certain conditions, MSCs can differentiate into many cell types both in vitro and in vivo, including hepatocytes. To date, four main strategies have been developed to induce the transdifferentiation of MSCs into hepatocytes: addition of chemical compounds and cytokines, genetic modification, adjustment of the micro-environment and alteration of the physical parameters used for culturing MSCs. Although the phenomenon of transdifferentiation of MSCs into hepatocytes has been described, the detailed mechanism is far from clear. Generally, the mechanism is a cascade reaction whereby stimulating factors activate cellular signalling pathways, which in turn promote the production of transcription factors, leading to hepatic gene expression. Because MSCs can give rise to hepatocytes, they are promising to be used as a new treatment for liver dysfunction or as a bridge to liver transplantation. Numerous studies have confirmed the therapeutic effects of MSCs on hepatic fibrosis, cirrhosis and other liver diseases, which may be related to the differentiation of MSCs into functional hepatocytes. In addition to transdifferentiation into hepatocytes, when MSCs are used to treat liver disease, they may also inhibit hepatocellular apoptosis and secrete various bioactive molecules to promote liver regeneration. In this review, the capacity and molecular mechanism of MSC transdifferentiation, and the therapeutic effects of MSCs on liver diseases are thoroughly discussed.

posure to clinically relevant doses of glucocorticoids during fetal life increases blood pressure in adult male and female sheep. The purpose of this study was to evaluate the effects of prenatal exposure to betamethasone at 80 -81 days of gestation on renal function in ewes and rams at 1.5 yr of age. In prenatal betamethasone-exposed males, compared with the vehicle-exposed animals, basal glomerular filtration rate (GFR) (1.93 Ϯ 0.08 vs. 2.27 Ϯ 0.10 ml ⅐ min Ϫ1 ⅐ kg body wt Ϫ1 ) and the ability to excrete an acute Na ϩ load (37.1 Ϯ 4.4 vs. 53.7 Ϯ 9.7%) were reduced. (P Ͻ 0.03 and P ϭ 0.03, respectively). In contrast, prenatal betamethasone exposure had no effect on basal GFR, Na ϩ excretion, or the percentage of the Na ϩ load excreted during the experiment in females. Systemic infusions of ANG-(1-7) at 9 ng⅐ min Ϫ1 ⅐ kg Ϫ1 for 2 h had minimal effects on basal GFR, renal plasma flow, and Na ϩ excretion in males but increased Na ϩ excretion in females. However, the percentage of Na ϩ load excreted during ANG-(1-7) infusion did not change in prenatal betamethasone-exposed females (113.1 Ϯ 14.2 vs. 98.1 Ϯ 12.2%) compared with the significant increase in vehicle females (139.2 Ϯ 22.3 vs. 92.2 Ϯ 7.5%) (P ϭ 0.01). The data indicate that antenatal betamethasone exposure produces gender-specific alternations in renal function and thus suggest that different mechanisms underlie the antenatal steroid-induced elevations in blood pressure in male and female offspring. prenatal steroid exposure; sodium load; glomerular filtration rate; sodium excretion; angiotensin-(1-7) SINCE ANTENATAL STEROID TREATMENT became the standard of care for enhancing fetal lung maturation in pregnancies threatened by premature labor between 24 and 34 wk of gestation, the use of corticosteroid therapy in the United States has increased from Ͻ15% of eligible pregnancies in 1990 to Ͼ75% in 1995 (1, 3). However, clinical epidemiological studies show an association between antenatal glucocorticoid administration and altered vascular function (7,46), suggesting that exposure to excess glucocorticoids in the prenatal period may have untoward consequences in adult offspring.We and others have shown using sheep and rat experimental models that prenatal steroid exposure results in elevated blood pressure in adulthood (8,10,14,36). Although there are likely multiple targets influencing the effect of steroids on blood pressure, several recent studies have suggested that altered kidney development induced by antenatal glucocorticoids may contribute to the elevations in arterial blood pressure (35,36,53). It is well known that the kidneys play a major role in the long-term regulation of arterial pressure and that change in renal function may lead to alterations in Na ϩ and water balance and blood pressure (19). In a rat model, Ortiz et al. (35,36) observed that prenatal exposure to dexamethasone on days 15 and 16 of gestation induced 30 and 20% reductions in glomerular number in offspring compared with controls when assessed at 60 -70 days and 6 -9 mo of age, ...