Estrogen Therapy Delays Autoimmune Diabetes and Promotes the Protective Efficiency of Natural Killer T-Cell Activation in Female Nonobese Diabetic Mice.

Therapeutic strategies focused on restoring immune tolerance remain the main avenue to prevent type 1 diabetes (T1D). Because estrogens potentiate FoxP3+ regulatory T cells (Treg) and invariant natural killer T (iNKT) cells, two regulatory lymphocyte populations that are functionally deficient in nonobese diabetic (NOD) mice, we investigated whether estradiol (E2) therapy influences the course of T1D in this model. To this end, female NOD mice were sc implanted with E2- or placebo-delivering pellets to explore the course of spontaneous and cyclophosphamide-induced diabetes. Treg-depleted and iNKT-cell-deficient (Jα18(-/-)) NOD mice were used to assess the respective involvement of these lymphocyte populations in E2 effects. Early E2 administration (from 4 wk of age) was found to preserve NOD mice from both spontaneous and cyclophosphamide-induced diabetes, and a complete protection was also observed throughout treatment when E2 treatment was initiated after the onset of insulitis (from 12 wk of age). This delayed E2 treatment remained fully effective in Treg-depleted mice but failed to entirely protect Jα18(-/-) mice. Accordingly, E2 administration was shown to restore the cytokine production of iNKT cells in response to in vivo challenge with the cognate ligand α-galactosylceramide. Finally, transient E2 administration potentiated the previously described protective action of α-galactosylceramide treatment in NOD females. This study provides original evidence that E2 therapy strongly protects NOD mice from T1D and reveals the estrogen/iNKT cell axis as a new effective target to counteract diabetes onset at the stage of insulitis. Estrogen-based therapy should thus be considered for T1D prevention.

Myostimulating effect of sesamum radiatum aqueous leaf extract in isolated Guinea-pig Taenia caeci contractile activity.

This study was carried to examine the effects of the aqueous leaf extract of Sesamum radiatum, a laxative plant on the contractile activity of Taenia caeci, an intestinal smooth muscle. Strips of Taenia caeci were rapidly removed from guinea-pig and were suspended between two L-shaped stainless steel hooks in a 10 ml organ bath with Mac Ewen solution. The isometric contractile force of the Taenia caeci strips were recorded by using a strain gauge. S. radiatum aqueous leaf extract (ESera) is a spasmogenic substance. This myostimulant effect is characterized by the increase of the rhythm and the amplitude of isolated guinea-pig Taenia caeci smooth muscle in normal solution and by the development of contracture in modified solution and in solution without calcium. A similar effect was observed with ACh which caused a graded increase of the contractile activity of Taenia caeci. The effects induced by ESera and ACh were reversed in the presence of atropine. The spasmogenic effect induced by ESera could justify partially the use of S. radiatum as laxative in traditional medicine.

Ginger prevents Th2-mediated immune responses in a mouse model of airway inflammation.

It is well documented that compounds from rhizomes of Zingiber officinale, commonly called ginger, have anti-inflammatory properties. Here, we show that ginger can exert such functions in vivo, namely in a mouse model of Th2-mediated pulmonary inflammation. The preparation of ginger aqueous extract (Zo.Aq) was characterized by mass spectrometry as an enriched fraction of n-gingerols. Intraperitoneal injections of this extract before airway challenge of ovalbumin (OVA)-sensitized mice resulted in a marked decrease in the recruitment of eosinophils to the lungs as attested by cell counts in bronchoalveolar lavage (BAL) fluids and histological examination. Resolution of airway inflammation induced by Zo.Aq was accompanied by a suppression of the Th2 cell-driven response to allergen in vivo. Thus, IL-4, IL-5 and eotaxin levels in the lungs as well as specific IgE titres in serum were clearly diminished in ginger-treated mice relative to their controls after allergen sensitization and challenge. Finally, we found that [6]-gingerol, a major constituent of ginger, was sufficient to suppress eosinophilia in our model of inflammation. This is the first evidence that ginger can suppress Th2-mediated immune responses and might thus provide a possible therapeutic application in allergic asthma.

Human bone marrow adipocytes block granulopoiesis through neuropilin-1-induced granulocyte colony-stimulating factor inhibition.

Adipocytes are part of hematopoietic microenvironment, even though up to now in humans, their role in hematopoiesis is still questioned. We have previously shown that accumulation of fat cells in femoral bone marrow (BM) coincides with increased expression of neuropilin-1 (NP-1), while it is weakly expressed in hematopoietic iliac crest BM. Starting from this observation, we postulated that adipocytes might exert a negative effect on hematopoiesis mediated through NP-1. To test this hypothesis, we set up BM adipocytes differentiated into fibroblast-like fat cells (FLFC), which share the major characteristics of primitive unilocular fat cells, as an experimental model. As expected, FLFCs constitutively produced macrophage colony stimulating factor and induced CD34(+) differentiation into macrophages independently of cell-to-cell contact. By contrast, granulopoiesis was hampered by cell-to-cell contact but could be restored in transwell culture conditions, together with granulocyte colony stimulating factor production. Both functions were also recovered when FLFCs cultured in contact with CD34(+) cells were treated with an antibody neutralizing NP-1, which proved its critical implication in contact inhibition. An inflammatory cytokine such as interleukin-1 beta or dexamethasone modulates FLFC properties to restore granulopoiesis. Our data provide the first evidence that primary adipocytes exert regulatory functions during hematopoiesis that might be implicated in some pathological processes. Disclosure of potential conflicts of interest is found at the end of this article.